SPOP promotes CREB5 ubiquitination to inhibit MET signaling in liver cancer.

Liver cancer is ranked as the sixth most prevalent from of malignancy globally and stands as the third primary contributor to cancer-related mortality. Metastasis is the main reason for liver cancer treatment failure and patient deaths. Speckle-type POZ protein (SPOP) serves as a crucial substrate junction protein within the cullin-RING E3 ligase complex, acting as a significant tumor suppressor in liver cancer. Nevertheless, the precise molecular mechanism underlying the role of SPOP in liver cancer metastasis remain elusive. In the current study, we identified cAMP response element binding 5 (CREB5) as a novel SPOP substrate in liver cancer. SPOP facilitates non-degradative K63-polyubiquitination of CREB5 on K432 site, consequently hindering its capacity to activate receptor tyrosine kinase MET. Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver cancer metastasis.

High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate.

Emerging studies have addressed the tumor-promoting role of fructose in different cancers. The effects and pathological mechanisms of high dietary fructose on hepatocellular carcinoma (HCC) remain unclear. Here, we examined the effects of fructose supplementation on HCC progression in wild-type C57BL/6 mice using a spontaneous and chemically induced HCC mouse model. We show that elevated uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and O-GlcNAcylation levels induced by high dietary fructose contribute to HCC progression. Non-targeted metabolomics and stable isotope tracing revealed that under fructose treatment, microbiota-derived acetate upregulates glutamine and UDP-GlcNAc levels and enhances protein O-GlcNAcylation in HCC. Global profiling of O-GlcNAcylation revealed that hyper-O-GlcNAcylation of eukaryotic elongation factor 1A1 promotes cell proliferation and tumor growth. Targeting glutamate-ammonia ligase or O-linked N-acetylglucosamine transferase (OGT) remarkably impeded HCC progression in mice with high fructose intake. We propose that high dietary fructose promotes HCC progression through microbial acetate-induced hyper-O-GlcNAcylation.

Comparison of the Detection Performance Between FAP and FDG PET/CT in Various Cancers: A Systemic Review and Meta-analysis.

PURPOSE: 18F-FDG is the dominant radiotracer in oncology; however, it has limitations. Novel labeled fibroblast activation protein (FAP) radiotracers have been developed and published in several studies. Thus, this meta-analysis aimed to compare the detection rates (DRs) of FDG and FAP, based on previous studies from a systematic review. METHODS: PubMed/MEDLINE and Cochrane library databases were used to perform a comprehensive and systematic search and are updated to April 30, 2022. The DR, relative risk, and the SUVmax were calculated between the FAP and FDG tracers. Finally, the sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve of FAP and FDG were analyzed using gold and reference standards. RESULTS: Thirty studies (1170 patients) were included in the meta-analysis. The relative risks of FAP DR for the primary tumor, recurrent tumor, lymph node metastasis, and distant metastasis were FDG 1.06- to 3.00-fold per patient and per lesion. For the primary tumor, FAP uptake was most intense in pancreatic cancer, followed by head and neck, cervical, colorectal, lung, gastric, and hepatocellular carcinoma, and was higher than FDG except for urological system cancer. The sensitivity (0.84-0.98), diagnostic odds ratio (19.36-358.47), and summary receiver operating characteristic curve (0.94-0.99) of FAP based on patient and lesion were better for primary tumors, LN metastasis, and distant metastasis than FDG. CONCLUSIONS: Fibroblast activation protein is an extremely potential radiotracer to replace most of the use of FDG in oncology. It is noteworthy that the FAP tracers for primary tumors had low specificity despite excellent sensitivity and had lower uptake than FDG in urological system cancer. In addition, the difference in detection between FAP and FDG for LN metastasis could not be certain in sarcoma.

O-GlcNAcylation of SPOP promotes carcinogenesis in hepatocellular carcinoma.

Aberrantly elevated O-GlcNAcylation level is commonly observed in human cancer patients, and has been proposed as a potential therapeutic target. Speckle-type POZ protein (SPOP), an important substrate adaptor of cullin3-RING ubiquitin ligase, plays a key role in the initiation and development of various cancers. However, the regulatory mechanisms governing SPOP and its function during hepatocellular carcinoma (HCC) progression remain unclear. Here, we show that, in HCC, SPOP is highly O-GlcNAcylated by O-GlcNAc transferase (OGT) at Ser96. In normal liver cells, the SPOP protein mainly localizes in the cytoplasm and mediates the ubiquitination of the oncoprotein neurite outgrowth inhibitor-B (Nogo-B) (also known as reticulon 4 B) by recognizing its N-terminal SPOP-binding consensus (SBC) motifs. However, O-GlcNAcylation of SPOP at Ser96 increases the nuclear positioning of SPOP in hepatoma cells, alleviating the ubiquitination of the Nogo-B protein, thereby promoting HCC progression in vitro and in vivo. In addition, ablation of O-GlcNAcylation by an S96A mutation increased the cytoplasmic localization of SPOP, thereby inhibiting the Nogo-B/c-FLIP cascade and HCC progression. Our findings reveal a novel post-translational modification of SPOP and identify a novel SPOP substrate, Nogo-B, in HCC. Intervention with the hyper O-GlcNAcylation of SPOP may provide a novel strategy for HCC treatment.

Comparison of the synthesis and biological properties of no-carrier-added and carrier-added 4-borono-2-[18F]fluorophenylalanine ([18F]FBPA).

PURPOSE: Boron neutron capture therapy (BNCT), an attractive strategy for cancer treatment, can kill tumor cells and avoid injury to surrounding healthy cells. 4-Borono-2-[18F]fluorophenylalanine ([18F]FBPA) positron emission tomography (PET) is a reliable tool for patient screening. Due to the relatively low radiochemical yield when employing the electrophilic route, this study was able to develop a new method to produce no-carrier-added (NCA) [18F]FBPA and compare the biological characteristics with carrier-added (CA) characteristics. PROCEDURES: By starting from 4-bromo-2-nitrobenzaldehyde, NCA [18F]FBPA was prepared using radiofluorination, alkylation, borylation, and hydrolysis. Cellular uptake analyses, microPET imaging, and biodistribution analyses were conducted to characterize the biological properties of NCA and CA [18F]FBPA. RESULTS: The radiochemical yield of NCA [18F]FBPA was 20 % ± 6 % (decay corrected) with a radiochemical purity of >98 % and molar activity of 56 ± 15 GBq/µmol in a 100-min synthesis. The in vitro accumulation was significantly higher for NCA [18F]FBPA than for CA [18F]FBPA in both SAS and CT-26 cells. However, no apparent differences in tumor uptake were observed between NCA and CA [18F]FBPA-injected tumor-bearing mice. CONCLUSIONS: We successfully prepared NCA [18F]FBPA through nucleophilic substitution and achieved improved radiochemical yield and purity. We also demonstrated the effects of the amount of nonradioactive FBPA on in vitro cellular uptake and in vivo imaging studies.

Radiometal-Labeled Chitosan Microspheres as Transarterial Radioembolization Agents against Hepatocellular Carcinoma.

Transarterial radioembolization (TARE) is an emerging treatment for patients with unresectable hepatocellular carcinoma (HCC). This study successfully developed radiometal-labeled chitosan microspheres (111In/177Lu-DTPA-CMS) with a diameter of 36.5 ± 5.3 µm for TARE. The radiochemical yields of 111In/177Lu-DTPA-CMS were greater than 90% with high radiochemical purities (>98%). Most of the 111In/177Lu-DTPA-CMS were retained in the hepatoma and liver at 1 h after intraarterial (i.a.) administration. Except for liver accumulation, radioactivity in each normal organ was less than 1% of the injected radioactivity (%IA) at 72 h after injection. At 10 days after injection of 177Lu-DTPA-CMS (18.6 ± 1.3 MBq), the size of the hepatoma was significantly reduced by around 81%, while that of the rats in the control group continued to grow. This study demonstrated the effectiveness of 177Lu-DTPA-CMS in the treatment of N1-S1 hepatoma. 111In/177Lu-DTPA-CMS have the potential to be a superior theranostic pair for the treatment of clinical hepatoma.

Detection of cancer stem cells by EMT-specific biomarker-based peptide ligands.

The occurrence of epithelial-mesenchymal transition (EMT) within tumors, which enables invasion and metastasis, is linked to cancer stem cells (CSCs) with drug and radiation resistance. We used two specific peptides, F7 and SP peptides, to detect EMT derived cells or CSCs. Human tongue squamous carcinoma cell line-SAS transfected with reporter genes was generated and followed by spheroid culture. A small molecule inhibitor-Unc0642 and low-dose ionizing radiation (IR) were used for induction of EMT. Confocal microscopic imaging and fluorescence-activated cell sorting analysis were performed to evaluate the binding ability and specificity of peptides. A SAS xenograft mouse model with EMT induction was established for assessing the binding affinity of peptides. The results showed that F7 and SP peptides not only specifically penetrated into cytoplasm of SAS cells but also bound to EMT derived cells and CSCs with high nucleolin and vimentin expression. In addition, the expression of CSC marker and the binding of peptides were increased in tumors isolated from Unc0642/IR-treated groups. Our study demonstrates the potential of these peptides for detecting EMT derived cells or CSCs and might provide an alternative isolation method for these subpopulations within the tumor in the future.

Fractionated deep-inspiration breath-hold ZTE Compared with Free-breathing four-dimensional ZTE for detecting pulmonary nodules in oncological patients underwent PET/MRI.

The zero echo time (ZTE) technique has improved the detection of lung nodules in PET/MRI but respiratory motion remains a challenge in lung scan. We investigated the feasibility and performance of fractionated deep-inspiration breath-hold (FDIBH) three-dimensional (3D) ZTE FDG PET/MRI for assessing lung nodules in patients with proved malignancy. Sixty patients who had undergone ZTE FDG PET/MRI and chest CT within a three-day interval were retrospectively included. Lung nodules less than 2 mm were excluded for analysis. Two physicians checked the adequacy of FDIBH ZTE and compared the lung nodule detection rates of FDIBH 3D ZTE and free-breathing (FB) four-dimensional (4D) ZTE, with chest CT as the reference standard. FDIBH resolved the effect of respiratory motion in 49 patients. The mean number and size of the pulmonary nodules identified in CT were 15 ± 31.3 per patient and 5.9 ± 4.6 mm in diameter. The overall nodule detection rate was 71% for FDIBH 3D ZTE and 70% for FB 4D ZTE (p = 0.73). FDIBH 3D ZTE significantly outperformed FB 4DZTE in detecting lung base nodules (72% and 68%; p = 0.03), especially for detecting those less than 6 mm (61% and 55%; p = 0.03). High inter-rater reliability for FDIBH 3D ZTE and FB 4D ZTE (k = 0.9 and 0.92) was noted. In conclusion, the capability of FDIBH 3D ZTE in respiratory motion resolution was limited with a technical failure rate of 18%. However, it could provide full expansion of the lung in a shorter scan time which enabled better detection of nodules (< 6 mm) in basal lungs, compared to FB 4D ZTE.

Keratoconus Screening Based on Deep Learning Approach of Corneal Topography.

Purpose: To develop and compare deep learning (DL) algorithms to detect keratoconus on the basis of corneal topography and validate with visualization methods. Methods: We retrospectively collected corneal topographies of the study group with clinically manifested keratoconus and the control group with regular astigmatism. All images were divided into training and test datasets. We adopted three convolutional neural network (CNN) models for learning. The test dataset was applied to analyze the performance of the three models. In addition, for better discrimination and understanding, we displayed the pixel-wise discriminative features and class-discriminative heat map of diopter images for visualization. Results: Overall, 170 keratoconus, 28 subclinical keratoconus and 156 normal topographic pictures were collected. The convergence of accuracy and loss for the training and test datasets after training revealed no overfitting in all three CNN models. The sensitivity and specificity of all CNN models were over 0.90, and the area under the receiver operating characteristic curve reached 0.995 in the ResNet152 model. The pixel-wise discriminative features and the heat map of the prediction layer in the VGG16 model both revealed it focused on the largest gradient difference of topographic maps, which was corresponding to the diagnostic clues of ophthalmologists. The subclinical keratoconus was positively predicted with our model and also correlated with topographic indexes. Conclusions: The DL models had fair accuracy for keratoconus screening based on corneal topographic images. The visualization mentioned in the current study revealed that the model focused on the appropriate region for diagnosis and rendered clinical explainability of deep learning more acceptable. Translational Relevance: These high accuracy CNN models can aid ophthalmologists in keratoconus screening with color-coded corneal topography maps.

Resveratrol suppresses neutrophil activation via inhibition of Src family kinases to attenuate lung injury.

The natural stilbenoid, Resveratrol (RSV; 3,5,4'-trihydroxystilbene) has been shown to have beneficial effects on inflammatory diseases as well as cancer, neurodegenerative diseases, and cardiovascular disorders. The underlying mechanism by which RSV affects neutrophil activation has yet to be fully elucidated. In this study, we tested the hypothesis that RSV modulates the inflammatory activities of formyl-Met-Leu-Phe-stimulated human neutrophils. We employed a well-established isolated-neutrophil model to investigate the effects of RSV on neutrophil functions and the underlying mechanism of signaling transduction. The lipopolysaccharide-induced ALI murine model was employed to evaluate the therapeutic effects of RSV. Experiment results demonstrate that RSV reduces respiratory burst, degranulation, integrin expression, and cell adhesion in activated neutrophils in dose-dependent manners. RSV inhibited phosphorylation of Src family kinases (SFKs) and reduced their enzymatic activities. Moreover, RSV and a selective inhibitor of SFKs (PP2) reduced the phosphorylation of Bruton's tyrosine kinase and Vav. There results indicated that the inhibitory effects of RSV are mediated through the inhibition of the SFKs-Btk-Vav pathway. This study also revealed that RSV attenuates endotoxin-induced lung injury. We surmise that the therapeutic effects of RSV on ALI may derive from its anti-neutrophilic inflammation function and free radical-scavenging effects.

Development of theranostic active-targeting boron-containing gold nanoparticles for boron neutron capture therapy (BNCT).

Successful boron neutron capture therapy (BNCT) requires sufficient and specific delivery of boron atoms to malignant cells. Gold nanoparticles (AuNPs) have been used as a useful delivery system for selectively releasing cytotoxic payloads in the tumor. However, studies demonstrating the in vivo distribution or pharmacokinetics of boron-containing AuNPs via noninvasive imaging are lacking. This study aims to develop theranostic AuNP-boron cage assemblies (B-AuNPs) and evaluate its feasibility for BNCT. The commercial citrate-coated AuNPs were subjected to PEGylation, azide addition, and carborane modification on the surface. To further arm the AuNPs, we conjugated anti-HER2 antibody (61 IgG) with boron-containing PEGylated AuNPs to form 61-B-AuNPs. The diameter and radiolabeling efficiency of boron-containing AuNPs were determined by dynamic light scattering (DLS) and radio thin-layer chromatography (radio TLC), respectively. Noninvasive single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging was performed to determine the pharmacokinetics of radioiodinated AuNPs in N87 gastric cancer xenografts, and the content of boron in tumor and muscle was assessed by inductively coupled plasma mass spectrometry (ICP-MS). After the 3-step modification, the diameter of B-AuNPs increased by ˜25 nm, and antibody conjugation did not affect the diameter of AuNPs. Radioactive iodine (I-123) was introduced in AuNPs by Click chemistry under copper catalysis. The radiolabeling efficiency of 123I-B-AuNPs and 123I-61-B-AuNPs was approximately 60 ± 5%. After purification, the radiochemical purity (RCP) of these NPs was greater than 90%. MicroSPECT/CT imaging showed that the tumor-to-muscle (T/M) ratio of 123I-B-AuNP-injected mice reached 1.91 ± 0.17 at 12 h post-injection, while that of 123I-61-B-AuNP-injected mice was 12.02 ± 0.94. However, the increased uptake of AuNPs by the thyroid was observed at 36 h after the administration of 123I-61-B-AuNPs, indicating antibody-mediated phagocytosis. The T/M ratio, assessed by ICP-MS, of B-AuNP- and 61-B-AuNP-injected mice was 4.91 ± 2.75 and 41.05 ± 11.15, respectively. We successfully developed detectable HER2-targeting boron-containing AuNPs with high RCP and an acceptable yield. Noninvasive imaging could be a valuable tool for the noninvasive determination of the pharmacokinetics of AuNPs and measurement of boron concentration in the tumor.

Cancer-coping profile predicts long-term psychological functions and quality of life in cancer survivors.

PURPOSE: Cancer survivors experience significant psychosocial distress even after completion of cancer treatment. The association between cancer coping and cancer recovery is not well established. The present study investigated the cancer-coping profile and cancer outcomes in breast cancer survivors. METHODS: A three-wave longitudinal study was conducted. In 2009 (wave 1), 248 breast cancer survivors completed a package of psychological inventories to evaluate cancer copying style, psychological distress, anxiety and depression, and quality of life. They received follow-up survey in 2012 (wave 2) and 2016 (wave 3). A latent profile analysis (LPA) was conducted among participants in wave 1 to identify cancer-coping class. Identified cancer-coping class was used to predict psychological and survival outcomes in waves 2 and 3. RESULTS: Two cancer-coping classes were identified through LPA, namely adaptive cancer coping (class I; 52%) and maladaptive cancer coping (class II; 47.8%). Demographic and clinical factors did not differ significantly between the two classes. Subsequent analyses demonstrated that the cancer-coping style in wave 1 predicted the psychological symptoms and quality of life outcomes at the two follow-ups (waves 2 and 3). Survivors in the adaptive group (class I) exhibited lower cancer distress, anxiety and depression scores, and higher quality of life scores than those in the maladaptive group did. Cancer coping were not found to be significantly associated with cancer survival or recurrence. CONCLUSIONS: The identified cancer-coping styles were predictive of the survivors' psychological symptoms, psychological well-being, and health-related quality of life but not cancer survival or recurrence.

Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury.

BACKGROUND/AIMS: Formyl peptide receptors (FPRs) recognize different endogenous and exogenous molecular stimuli and mediate neutrophil activation. Dysregulation of excessive neutrophil activation and the resulting immune responses can induce acute lung injury (ALI) in the host. Accordingly, one promising approach to the treatment of neutrophil-dominated inflammatory diseases involves therapeutic FPR1 inhibition. METHODS: We extracted a potent FPR1 antagonist from Garcinia multiflora Champ. (GMC). The inhibitory effects of GMC on superoxide anion release and elastase degranulation from activated human neutrophils were determined with spectrophotometric analysis. Reactive oxygen species (ROS) production and the FPR1 binding ability of neutrophils were assayed by flow cytometry. Signaling transduction mediated by GMC in response to chemoattractants was assessed with a calcium influx assay and western blotting. A lipopolysaccharide (LPS)-induced ALI mouse model was used to determine the therapeutic effects of GMC in vivo. RESULTS: GMC significantly reduced superoxide anion release, the reactive oxidants derived therefrom, and elastase degranulation mediated through selective, competitive FPR1 blocking in N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. In cell-free systems, GMC was unable to scavenge superoxide anions or suppress elastase activity. GMC produced a right shift in fMLF-activated concentration-response curves and was confirmed to be a competitive FPR1 antagonist. GMC binds to FPR1 not only in neutrophils, but also FPR1 in neutrophil-like THP-1 and hFPR1-transfected HEK293 cells. Furthermore, the mobilization of calcium and phosphorylation of mitogen-activated protein kinases and Akt, which are involved in FPR1-mediated downstream signaling, was competitively blocked by GMC. In an in vivo study, GMC significantly reduced pulmonary edema, neutrophil infiltration, and alveolar damage in LPS-induced ALI mice. CONCLUSION: Our findings demonstrate that GMC is a natural competitive FPR1 inhibitor, which makes it a possible anti-inflammatory treatment option for patients critically inflicted with FPR1-mediated neutrophilic lung damage.

Determining the optimal number and location of cutoff points with application to data of cervical cancer.

It is often helpful to classify biomarker values into groups of different risk levels to facilitate evaluation of a biological, physiological, or pathological state. Stratification of patients into two risk groups is commonly seen, but there is always need for more than two groups for fine assessment. So far, there are no standard methods or tools to help decide how many cutoff points are optimal. In this study, we developed a comprehensive package that included methods to determine both the optimal number and locations of cutoff points for both survival data and dichotomized outcome. We illustrated workflow of this package with data from 797 patients with cervical cancer. By analyzing several risk factors of cervical cancer such as tumor size, body mass index (BMI), number of lymph nodes involved and depth of stromal invasion, in relation to survival and clinical outcome such as lymph nodal metastasis and lymphovascular invasion, we demonstrated that the best choice for BMI and stromal invasion was two cutoff points and one for the others. This study provided a useful tool to facilitate medical decisions and the analyses on cervical cancer may also be of interest to gynecologists. The package can be freely downloaded.

6-Hydroxy-5,7-dimethoxy-flavone suppresses the neutrophil respiratory burst via selective PDE4 inhibition to ameliorate acute lung injury.

Over-activated neutrophils produce enormous oxidative stress and play a key role in the development of acute and chronic inflammatory diseases. 6-Hydroxy-5,7-dimethoxy-flavone (UFM24), a flavone isolated from the Annonaceae Uvaria flexuosa, showed inhibitory effects on human neutrophil activation and salutary effects on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. UFM24 potently inhibited superoxide anion (O2•-) generation, reactive oxidants, and CD11b expression, but not elastase release, in N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils. However, UFM24 failed to scavenge O2•- and inhibit the activity of subcellular NADPH oxidase. fMLF-induced phosphorylation of protein kinase B (Akt) was inhibited by UFM24. Noticeably, UFM24 increased cyclic adenosine monophosphate (cAMP) concentration and protein kinase (PK) A activity in activated human neutrophils. PKA inhibitors significantly reversed the inhibitory effects of UFM24, suggesting that the effects of UFM24 were through cAMP/PKA-dependent inhibition of Akt activation. Additionally, activity of cAMP-related phosphodiesterase (PDE)4, but not PDE3 or PDE7, was significantly reduced by UFM24. Furthermore, UFM24 attenuated neutrophil infiltration, myeloperoxidase activity, and pulmonary edema in LPS-induced ALI in mice. In conclusion, our data demonstrated that UFM24 inhibits oxidative burst in human neutrophils through inhibition of PDE4 activity. UFM24 also exhibited significant protection against endotoxin-induced ALI in mice. UFM24 has potential as an anti-inflammatory agent for treating neutrophilic lung damage.

Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance.

The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1ß processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1ß and caspase-1 activation. UgU induced Ca2+ mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IP3R). Blocking Ca2+ mobilization, PLC, or IP3R diminished UgU-induced IL-1ß release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca2+ mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases.

Ilex kaushue and Its Bioactive Component 3,5-Dicaffeoylquinic Acid Protected Mice from Lipopolysaccharide-Induced Acute Lung Injury.

Acute lung injury (ALI) is a severe respiratory disease with high mortality rates worldwide. Recent reports suggest that human neutrophil elastase (HNE) plays a key role in the inflammatory response that is characteristic of ALI, which indicates that the development of HNE inhibitors could be an efficient treatment strategy. In the current study, an enzyme-based screening assay was used to identify effective HNE inhibitors from a number of traditional Chinese medicines (TCMs). Among them, a water extract of Ilex kaushue (IKWE) effectively inhibited HNE activity (IC50, 11.37 ± 1.59 µg/mL). Using bioactivity-guided fractionation, one new compound and 23 known compounds were identified. Compound 6 (identified as 3,5-dicaffeoylquinic acid; 3,5-DCQA) exerted the most potent and selective inhibitory effect on HNE activity (IC50, 1.86 ± 0.06 µM). In a cell-based assay, 3,5-DCQA not only directly reduced superoxide generation and elastase activity but also attenuated the Src family kinase (SRKs)/Vav signaling pathway in N-formyl-L-Met-L-Leu-L-Phe (fMLF)-stimulated human neutrophils. In an animal disease model, both 3,5-DCQA and standardized IKWE protected against lipopolysaccharide-induced ALI in mice, which provides support for their potential as candidates in the development of new therapeutic agents for neutrophilic inflammatory diseases.

Tumor Size Has a Time-Varying Effect on Recurrence in Cervical Cancer.

OBJECTIVE: This study analyzed the risk factors for their possible association with overall survival and progression-free survival in cervical cancer, with a flexible model that allowed time-varying effects. METHODS: Information about patients with cervical cancer from 2002 to 2012 was collected in the Kaohsiung Veterans General Hospital. All available biological and clinicopathologic factors were tested for the assumption of the Cox proportional hazard model, that is, whether they had time-varying effect on survival. The factors were also analyzed in univariate and multivariate statistics to identify independent risk factors. The multivariate analysis was performed with an extended Cox model so that those factors that failed the assumption test were allowed to vary with time. RESULTS: Approximately 797 patients were included in the final analysis. Most factors tested passed the Cox assumption test, except tumor size and body mass index in the event of recurrence and preoperative CA125 values in the event of death (P < 0.05). Univariate and multivariate analysis identified tumor size, stage, and lymph nodal metastasis as independent significant risk factors for both recurrence and death (P < 0.05), with tumor size being a time-varying factor for recurrence. CONCLUSIONS: Patients with larger tumor size, higher FIGO stage, and lymph nodal metastasis are faced with higher risk of recurrence and death. A larger tumor size poses increasingly higher risk for recurrence initially, and its importance declines as the patient survives longer without disease progression. These findings may be helpful to gynecologists when assessing tumor risk of patients with cervical cancer and in patient consultation.

Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation.

Neutrophils are widely recognized to play an important role in acute inflammatory responses, and recent evidence has expanded their role to modulating chronic inflammatory and autoimmune diseases. Reactive oxygen species (ROS) and microbicidal compounds released from neutrophils that are recruited to the site of inflammation contribute to the pathogenesis of multiple inflammation-associated diseases such as chronic obstructive pulmonary disease, atherosclerosis, and hepatitis. Marine organisms are a valuable source of bioactive compounds with potential for industrial and pharmaceutical application. Marine natural products that inhibit neutrophil activation could be used as drugs for the treatment of inflammatory diseases. Numerous studies investigating marine natural products have reported novel anti-inflammatory agents. Nevertheless, the detailed mechanisms underlying their actions, which could facilitate our understanding of the molecular events occurring in neutrophils, have not been reported in most of the associated research studies. Therefore, in this review, we will present marine products that inhibit neutrophil-associated inflammation. Furthermore, we will be limiting the detailed discussion to agents with well-investigated molecular targets.

Anti-inflammatory and cytotoxic compounds from Solanum macaonense.

One new cerebroside, macaocerebroside A (1), and 15 known compounds (2-16) were isolated from Solanum macaonense for the first time. In an antineutrophilic inflammatory assay, four caffeic acid derivatives (2-5) were active against superoxide anion generation with IC50 values of 3.3-4.8 µM; especially, 3 inhibited elastase release with an IC50 value of 4.0 µM. Additionally, kaempferol (8) also showed inhibition against elastase release with an IC50 value of 4.0 µM. In a cytotoxic assay, rutin (14) had selective moderate cytotoxicity toward human lung (A549), bladder (NTUB1), and prostate (DU145) cancer cell lines with IC50 values of 34.6, 41.3, and 31.8 µM, respectively.