Cancer screening in hospitalized ischemic stroke patients: a multicenter study focused on multiparametric analysis to improve management of occult cancers.

Background/aims: The reciprocal promotion of cancer and stroke occurs due to changes in shared risk factors, such as metabolic pathways and molecular targets, creating a "vicious cycle." Cancer plays a direct or indirect role in the pathogenesis of ischemic stroke (IS), along with the reactive medical approach used in the treatment and clinical management of IS patients, resulting in clinical challenges associated with occult cancer in these patients. The lack of reliable and simple tools hinders the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) approach. Therefore, we conducted a multicenter study that focused on multiparametric analysis to facilitate early diagnosis of occult cancer and personalized treatment for stroke associated with cancer. Methods: Admission routine clinical examination indicators of IS patients were retrospectively collated from the electronic medical records. The training dataset comprised 136 IS patients with concurrent cancer, matched at a 1:1 ratio with a control group. The risk of occult cancer in IS patients was assessed through logistic regression and five alternative machine-learning models. Subsequently, select the model with the highest predictive efficacy to create a nomogram, which is a quantitative tool for predicting diagnosis in clinical practice. Internal validation employed a ten-fold cross-validation, while external validation involved 239 IS patients from six centers. Validation encompassed receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and comparison with models from prior research. Results: The ultimate prediction model was based on logistic regression and incorporated the following variables: regions of ischemic lesions, multiple vascular territories, hypertension, D-dimer, fibrinogen (FIB), and hemoglobin (Hb). The area under the ROC curve (AUC) for the nomogram was 0.871 in the training dataset and 0.834 in the external test dataset. Both calibration curves and DCA underscored the nomogram's strong performance. Conclusions: The nomogram enables early occult cancer diagnosis in hospitalized IS patients and helps to accurately identify the cause of IS, while the promotion of IS stratification makes personalized treatment feasible. The online nomogram based on routine clinical examination indicators of IS patients offered a cost-effective platform for secondary care in the framework of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00354-8.

Integrated Network Pharmacology Analysis and Serum Metabolomics to Reveal the Anti-malaria Mechanism of Artesunate.

Artesunate is a widely used drug in clinical treatment of malaria. The aim of this study was to investigate the therapeutic mechanism of artesunate on malaria using an integrated strategy of network pharmacology and serum metabolomics. The mice models of malaria were established using 2 × 107 red blood cells infected with Plasmodium berghei ANKA injection. Giemsa and hematoxylin-eosin (HE) staining were used to evaluate the efficacy of artesunate on malaria. Next, network pharmacology analysis was applied to identify target genes. Then, a metabolomics strategy has been developed to find the possible significant serum metabolites and metabolic pathways induced by artesunate. Additionally, two parts of the results were integrated to confirm each other. Giemsa and HE staining results showed that artesunate significantly inhibited the proliferation of Plasmodium and reduced liver and spleen inflammation. Based on metabolomics, 18 differential endogenous metabolites were identified as potential biomarkers related to the artesunate for treating malaria. These metabolites were mainly involved in the relevant pathways of biosynthesis of unsaturated fatty acids; aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; and phenylalanine, tyrosine, and tryptophan biosynthesis. The results of the network pharmacology analysis showed 125 potential target genes related to the treatment of malaria with artesunate. The functional enrichment was mainly associated with lipid and atherosclerosis; pathways of prostate cancer and proteoglycans in cancer; and PI3K-Akt, apoptosis, NF-κB, Th17 cell, and AGE-RAGE signaling pathways. These findings were partly consistent with the findings of the metabolism. Our results further suggested that artesunate could correct the inflammatory response caused by malaria through Th17 cell and NF-κB pathways. Meanwhile, our work revealed that cholesterol needed by Plasmodium berghei came directly from serum. Cholesterol and palmitic acid may be essential in the growth and reproduction of Plasmodium berghei. In summary, artesunate may have an effect on anti-malarial properties through multiple targets.

The Intracellular Interaction of Porcine ß-Defensin 2 with VASH1 Alleviates Inflammation via Akt Signaling Pathway.

Defensins are a major class of antimicrobial peptides that facilitate the immune system to resist pathogen infection. To date, only ß-defensins have been identified in pigs. In our previous studies, porcine ß-defensin 2 (PBD-2) was shown to have both bactericidal activity and modulatory roles on inflammation. PBD-2 can interact with the cell surface TLR4 and interfere with the NF-κB signaling pathway to suppress the inflammatory response. In this study, the intracellular functions of PBD-2 were investigated. The fluorescently labeled PBD-2 could actively enter mouse macrophage cells. Proteomic analysis indicated that 37 proteins potentially interacted with PBD-2, among which vasohibin-1 (VASH1) was further tested. LPS, an inflammation inducer, suppressed the expression of VASH1, whereas PBD-2 inhibited this effect. PBD-2 inhibited LPS-induced activation of Akt, expression and release of the inflammatory mediators vascular endothelial growth factor and NO, and cell damage. A follow-up VASH1 knockdown assay validated the specificity of the above observations. In addition, PBD-2 inhibited LPS-induced NF-κB activation via Akt. The inhibition effects of PBD-2 on LPS triggered suppression of VASH1 and activation of Akt, and NF-κB and inflammatory cytokines were also confirmed using pig alveolar macrophage 3D4/21 cells. Therefore, the data indicate that PBD-2 interacts with intracellular VASH1, which inhibits the LPS-induced Akt/NF-κB signaling pathway, resulting in suppression of inflammatory responses. Together with our previous findings, we conclude that PBD-2 interacts with both the cell surface receptor (TLR4) and also with the intracellular receptor (VASH1) to control inflammation, thereby providing insights into the immunomodulatory roles of defensins.

Primary Esophageal Small Cell Carcinoma Masquerading as Non-Hodgkin Lymphoma in a Young Patient.

BACKGROUND/AIM: Small cell cancer of the esophagus (SCCE) is an extremely rare entity with an aggressive clinical course, thus early diagnosis and treatment are important for improved survival. CASE REPORT: A 35-year-old male presented with dysphagia, loss of appetite and weight loss. Diagnostic workup revealed an esophageal mass, which was diagnosed as primary non-Hodgkin lymphoma (NHL) on initial biopsy. Despite receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy for 3 months, there was an interval increase in the size of the esophagus mass, which unveiled underlying SCCE. A re-review of the previous biopsy specimen with immunohistochemical staining confirmed the initial diagnosis as SCCE as well. Despite 4 cycles of platinum-based chemotherapy and radiotherapy, the malignancy progressed and proved fatal. CONCLUSION: SCCE and non-Hodgkin lymphomas are rare entities, whose morphologies can be diagnostically challenging, hence they require special immunostaining for accurate diagnosis. Prompt diagnosis and initiation of treatment can confer better quality of life and survival.

MiR-22-3p suppresses cell growth via MET/STAT3 signaling in lung cancer.

MiR-22-3p has been reported to be down-regulated in several cancers, but its expression pattern and roles in lung cancer is unclear. Given the crucial role of microRNAs in cancer progression, we examined the expression and function of miR-22-3p in lung adenocarcinoma. MiR-22-3p expression in lung cancer tissues and cell lines was measured by qRT-PCR. Cell proliferation was measured by WST-1 and colony formation assays were used to reveal the role of miR-22-3p in lung cancer in vitro. MiR-22-3p was notably down-regulated in lung cancer tissues as compared to normal lung tissues, but it was not associated with the clinical characteristics of tumor stage, differentiation and patient's smoking status. Colony formation ability and cell proliferation were suppressed by miR-22-3p mimics in lung cancer cell lines. Mechanistically, miR-22-3p mimics could reduce MET and STAT3 protein expression and induce apoptosis as measured by PARP protein. We conclude that miR-22-3p may play a tumor suppressor role via inhibiting MET-STAT3 signaling and have potential to be a therapeutic target and biomarker in lung adenocarcinoma.

Protein-Based Nanomedicine for Therapeutic Benefits of Cancer.

Proteins, a type of natural biopolymer that possess many prominent merits, have been widely utilized to engineer nanomedicine for fighting against cancer. Motivated by their ever-increasing attention in the scientific community, this review aims to provide a comprehensive showcase on the current landscape of protein-based nanomedicine for cancer therapy. On the basis of role differences of proteins in nanomedicine, protein-based nanomedicine engineered with protein therapeutics, protein carriers, enzymes, and composite proteins is introduced. The cancer therapeutic benefits of the protein-based nanomedicine are also discussed, including small-molecular therapeutics-mediated therapy, macromolecular therapeutics-mediated therapy, radiation-mediated therapy, reactive oxygen species-mediated therapy, and thermal effect-mediated therapy. Lastly, future developments and potential challenges of protein-based nanomedicine are elucidated toward clinical translation. It is believed that protein-based nanomedicine will play a vital role in the battle against cancer. We hope that this review will inspire extensive research interests from diverse disciplines to further push the developments of protein-based nanomedicine in the biomedical frontier, contributing to ever-greater medical advances.

NUPR1 is a critical repressor of ferroptosis.

Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in ferroptosis, although the key regulator for ferroptosis in iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, a stress-inducible transcription factor, as a driver of ferroptosis resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic cell death through diminishing iron accumulation and subsequent oxidative damage. Consequently, LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, whereas transfection-enforced re-expression of LCN2 restores resistance to ferroptosis in NUPR1-deficient cells. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn2 conditional knockout mice, or the small molecule ZZW-115) increases the activity of the ferroptosis inducer erastin and worsens pancreatitis, in suitable mouse models. These findings suggest a link between NUPR1-regulated iron metabolism and ferroptosis susceptibility.

Highly Efficient 2D NIR-II Photothermal Agent with Fenton Catalytic Activity for Cancer Synergistic Photothermal-Chemodynamic Therapy.

Photothermal therapy (PTT) has emerged as a promising cancer therapeutic modality with high therapeutic specificity, however, its therapeutic effectiveness is limited by available high-efficiency photothermal agents (PTAs), especially in the second near-infrared (NIR-II) biowindow. Here, based on facile liquid-exfoliated FePS3 nanosheets, a highly efficient NIR-II PTA with its photothermal conversion efficiency of up to 43.3% is demonstrated, which is among the highest reported levels in typical PTAs. More importantly, such Fe-based 2D nanosheets also show superior Fenton catalytic activity facilitated by their ultrahigh specific surface area, simultaneously enabling cancer chemodynamic therapy (CDT). Impressively, the efficiency of CDT could be further remarkably enhanced by its photothermal effect, leading to cancer synergistic PTT/CDT. Both in vitro and in vivo studies reveal a highly efficient tumor ablation under NIR-II light irradiation. This work provides a paradigm for cancer CDT and PTT in the NIR-II biowindow via a single 2D nanoplatform with desired therapeutic effect. Furthermore, with additional possibilities for magnetic resonance imaging, photoacoustic tomography, as well as drug loading, this Fe-based 2D material could potentially serve as a 2D "all-in-one" theranostic nanoplatform.

Intelligent Nanocomposites with Intrinsic Blood-Brain-Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma.

The blood-brain barrier (BBB) is the most important obstacle to improving the clinical outcomes of diagnosis and therapy of glioblastoma. Thus, the development of a novel nanoplatform that can efficiently traverse the BBB and achieve both precise diagnosis and therapy is of great importance. Herein, an intelligent nanoplatform based on holo-transferrin (holo-Tf) with in situ growth of MnO2 nanocrystals is constructed via a reformative mild biomineralization process. Furthermore, protoporphyrin (ppIX), acting as a sonosensitizer, is then conjugated into holo-Tf to obtain MnO2 @Tf-ppIX nanoparticles (TMP). Because of the functional inheritance of holo-Tf during fabrication, TMP can effectively traverse the BBB for highly specific magnetic resonance (MR) imaging of orthotopic glioblastoma. Clear suppression of tumor growth in a C6 tumor xenograft model is achieved via sonodynamic therapy. Importantly, the experiments also indicate that the TMP nanoplatform has satisfactory biocompatibility and biosafety, which favors potential clinical translation.

Serum microRNA Signature Is Capable of Early Diagnosis for Non-Small Cell Lung Cancer.

Despite decades of efforts, non-small-cell lung cancer (NSCLC) remains the leading cause of cancer mortality globally primarily due to the challenge in early detection of the cancer. Being an important player in cancer development, the dysregulated miRNAs have been shown promising values as non-invasive diagnostic and prognostic biomarkers for NSCLC. The aim of our study is to access the efficacy and reliability of a potential circulating miRNA panel in early diagnosis of NSCLC. We first selected eight candidate miRNAs, miR-146b, miR-205, miR-29c, miR-31, miR-30b, miR-337, miR-411, and miR-708, which have been shown frequently aberrant in primary NSCLC patients based on our previous studies and other reports. The serum level of each of these miRNAs was evaluated by quantitative real-time PCR (qRT-PCR) in training and testing sets. We found that 5 out of 8 miRNAs (miR-146b, miR-205, miR-29c, miR-30b, and miR-337) were significantly up-regulated in NSCLCs patients compared to healthy or cancer-free controls in both training and testing sets. Based on the logistic regression model, a 4-miRNAs set (miR-146b, miR-205, miR-29c and miR-30b) was picked out of the 5 miRNAs owing to its excellent diagnostic power for NSCLC patients in the training set (AUC=0.99, accuracy=95.00%), the testing set (AUC=0.93, accuracy=89.69%), and the training-testing combined set ( AUC=0.96, accuracy=92.00%). When pathological subtypes of NSCLC are compared, this 4-miRNA panel carried a relatively higher prediction power and higher sensitivity for adenocarcinoma (AC) (AUC=0.98, sensitivity=99.10%) than for squamous cell carcinoma (SCC) (AUC=0.93, sensitivity=90.32%). Additionally, this panel demonstrated a comparable diagnostic capacity for stage I (AUC=0.96) and stage II-III (AUC=0.95) of NSCLC, suggesting its role in reflecting the tumor load. Importantly, the high levels of miR-146b and miR-29c in serum were significantly associated with poor 5-year overall survival (OS) (both p=0.04). Further survival analysis showed that high level of miR-146b in serum is specifically correlated with poor survival rate in SCC patients (p=0.0035) but not in AC patients (p=0.83), consistent with our previous finding that the high tissue expression of miR-146b in lung cancer specimen is indicative of a poor prognosis for SCC patients. Altogether, our study demonstrated that the 4-miRNA panel is a novel, sensitive and non-invasive serum marker for the early diagnosis of NSCLC.

Inlaying Radiosensitizer onto the Polypeptide Shell of Drug-Loaded Ferritin for Imaging and Combinational Chemo-Radiotherapy.

Rationale: Ferritin with unique hollow cavity is an emerging protein-based nanoplatform for anticancer-drug delivery, but the in vivo chemotherapeutic effectiveness is still unsatisfactory with such a monotherapy modality, which is urgently in need of improvement. Methods: Here a novel ferritin nanotheranostic with anticancer-drug doxorubicin encapsulated into its hollow interior and nanoradiosensitizer bismuth sulfide nanocrystals inlayed onto its polypeptide shell was synthesized for combinational therapeutic benefits. The formation mechanism of bismuth sulfide nanocrystals based on ferritin has been analyzed. The in vitro and in vivo treatment effects were carried out on HeLa cancer cells and tumor-bearing mice, respectively. The biocompatibility and excretion of the ferritin nanotheranostic have also been evaluated to guarantee their biosafety. Results: The polypeptide shell of ferritin provides nucleation sites for the bismuth sulfide nanocrystals through coordination interaction, and simultaneously inhibits the further growth of bismuth sulfide nanocrystals, rendering the bismuth sulfide nanocrystals like rivets inlaying onto the polypeptide firmly, which can not only strengthen the architectural stability of ferritin to prevent drug burst leakage during systemic circulation, but also act as excellent computed tomography contrast agents and nanoradiosensitizers for in vivo imaging-guided cancer combinational treatments. Conclusions: The design concept of inlaying bismuth sulfide nanocrystals onto the polypeptide shell of doxorubicin-encapsulated ferritin significantly inhibits the tumor growth and simultaneously further broadens the application of ferritin in nanomedicine.

A network-centric approach to drugging TNF-induced NF-κB signaling.

Target-centric drug development strategies prioritize single-target potency in vitro and do not account for connectivity and multi-target effects within a signal transduction network. Here, we present a systems biology approach that combines transcriptomic and structural analyses with live-cell imaging to predict small molecule inhibitors of TNF-induced NF-κB signaling and elucidate the network response. We identify two first-in-class small molecules that inhibit the NF-κB signaling pathway by preventing the maturation of a rate-limiting multiprotein complex necessary for IKK activation. Our findings suggest that a network-centric drug discovery approach is a promising strategy to evaluate the impact of pharmacologic intervention in signaling.

Nix/BNIP3L-dependent mitophagy accounts for airway epithelial cell injury induced by cigarette smoke.

Cigarette smoke-induced airway epithelial cell mitophagy is an important mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). Mitochondrial protein Nix (also known as BNIP3L) is a selective autophagy receptor and participates in several human diseases. However, little is known about the role of Nix in airway epithelial cell injury during the development of COPD. The aim of the present study is to investigate the effects of Nix on mitophagy and mitochondrial function in airway epithelial cells exposed to cigarette smoke extract (CSE). Our present study has found that CSE could increase Nix protein expression and induce mitophagy in airway epithelial cells. And Nix siRNA significantly inhibited mitophagy and attenuated mitochondrial dysfunction and cell injury when airway epithelial cells were stimulated with 7.5% CSE. In contrast, Nix overexpression enhanced mitophagy and aggravated mitochondrial dysfunction and cell injury when airway epithelial cells were incubated with 7.5% CSE. These data suggest that Nix-dependent mitophagy promotes airway epithelial cell and mitochondria injury induced by cigarette smoke, and may be involved in the pathogenesis of COPD and other cigarette smoke-associated diseases.

[Inhibitory effect of polyphyllin â on the proliferation of prostate cancer PC3 cells via ERK1/2/P65/DNMT1 and its molecular mechanism].

OBJECTIVE: To explore the inhibitory effect of polyphyllin Ⅰ (PPⅠ) on the proliferation of castration-resistant prostate cancer PC3 cells and its molecular mechanism. METHODS: We cultured human prostate cancer PC3 cells in vitro and treated them with PPⅠ at the concentrations of 0 (blank group), 0.4, 0.8, 1.2, 1.6, 2.0, and 2.4 µmol/L for 24, 48, and 72 hours, respectively. Then we detected the proliferation of the cells by MTT assay, measured their apoptosis by flow cytometry, and determined the expressions of p-ERK1/2, ERK1/2, NF-κB/p65 and DNMT1 proteins as well as the level of NF-κB/p65 in the cells additionally treated with the ERK1/2 inhibitor SP600125 by Western blot. RESULTS: Compared with the blank control group, the PPⅠ-treated PC3 cells showed a concentration- and time-dependent reduction of the survival rate (1.00 ± 0.00 vs 0.85 ± 0.05, P < 0.01) at 0.4 µmol/L after 48 hours of intervention, concentration-dependent early apoptosis at 0.8 µmol/L (4.83 ± 0.95 vs 13.83 ± 2.97, P < 0.01), time-dependent increase of the expressions of p-ERK1/2 (1.00 ± 0.00 vs 1.73 ± 0.17, P < 0.01) and ERK1/2 (1.00 ± 0.00 vs 1.36 ± 0.12, P < 0.01) at 2 hours, and concentration-dependent decrease of the expressions of NF-κB/p65 and DNMT1 at 1.2 µmol/L (1.00 ± 0.00 vs 0.78 ± 0.10 and 0.63 ± 0.06, P < 0.01) and 1.6 µmol/L (1.00 ± 0.00 vs 0.67 ± 0.11 and 0.52 ± 0.09, P<0.01). Inhibition of ERK1/2 phosphorylation with PD98059 markedly reversed PPⅠ-induced decrease of the NF-κB/p65 expression as compared with that in the PPⅠ group (0.86 ± 0.18 vs 0.43 ± 0.09, P < 0.05). CONCLUSIONS: PPⅠ induces the early apoptosis and suppresses the proliferation of PC3 cells, probably by activating the ERK1/2 pathway and inhibiting the expressions of the NF-κB/p65 and DNMT1 proteins.

Influence of iron plaque on the uptake and accumulation of chromium by rice (Oryza sativa L.) seedlings: Insights from hydroponic and soil cultivation.

The effects of iron plaque formation on chromium (Cr) uptake and accumulation by rice seedlings (Oryza sativa L.) were assessed using hydroponic and soil experiments, where each 3 levels of Fe supplementation were added to Hoagland solution (0, 30, and 100 mg Fe2+ L-1) and a typical paddy soil (0, 1, and 2 g Fe2+ kg-1). For each treatment, rice seedlings were exposed to different levels of Cr as chromate at 0, 0.5, 2, 5, 10, and 20 mg L-1 in solution or 300 mg kg-1 in soil. Low levels of Cr supply (0.5, 2, and 5 mg L-1) promoted root biomass, while high levels (10 and 20 mg L-1) decreased root and shoot biomass and undermined the density and integrity of iron plaque. Iron supply significantly increased the proportion of Cr in iron plaque, but decreased that in rice plants. The results of hydroponic experiment showed that iron plaque formed with Fe supply at 100 mg L-1 markedly reduced Cr accumulation in shoots of rice seedlings when exposure to 10 and 20 mg L-1 Cr. The soil culture experiment also demonstrated that exogenous Fe addition significantly decreased Cr concentration in leaf and stem of rice seedlings. These results suggested that iron plaque with appropriate amount was effective to reduce the uptake and accumulation of Cr in rice plants, which have strong implication for taking measures to regulate Cr accumulation in rice grains.

p66Shc Mediates Mitochondrial Dysfunction Dependent on PKC Activation in Airway Epithelial Cells Induced by Cigarette Smoke.

Airway epithelial mitochondrial injury plays a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The p66Shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction. However, little is known about the effect of p66Shc on airway epithelial damage in the development of COPD. The aim of the present study is to investigate the roles of p66Shc and its upstream regulators in the mitochondrial injury of airway epithelial cells (Beas-2b) induced by cigarette smoke extract (CSE). Our present study revealed that CSE increased p66Shc expression and its mitochondrial translocation in concentration and time-dependent manners in airway epithelial cells. And p66Shc siRNA significantly attenuated mitochondrial dysfunction and cell injury when airway epithelial cells were stimulated with 7.5% CSE. The total and phosphorylated expression of PKCß and PKCδ was significantly increased associated with mitochondrial dysfunction and cell injury when airway epithelial cells were exposed to 7.5% CSE. The pretreatments with pharmacological inhibitors of PKCß and PKCδ could notably suppress p66Shc phosphorylation and its mitochondrial translocation and protect the mitochondria and cells against oxidative damage when airway epithelial cells were incubated with 7.5% CSE. These data suggest that a novel PKCß/δ-p66Shc signaling pathway may be involved in the pathogenesis of COPD and other oxidative stress-associated pulmonary diseases and provide a potential therapeutic target for these diseases.

The clinical implication of serum cyclophilin A in patients with chronic obstructive pulmonary disease.

Background: Cyclophilin A (CyPA) is a secreted molecule that is regulated by inflammatory stimuli. Although inflammation has an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), little is known regarding the relationship between serum CyPA and COPD. Methods: Ninety-three COPD patients with acute exacerbation were enrolled in the study and were reassessed during the convalescence phase. Eighty-eight controls were matched for age, gender, body mass index, smoking index and comorbidity. The basic clinical information and pulmonary function of all participants were collected. Serum levels of CyPA and other inflammation indexes were further measured. Results: Serum CyPA was significantly increased in convalescent COPD patients compared to healthy controls, and further elevated in COPD patients with acute exacerbation. Serum CyPA positively correlated with serum interleukin-6, matrix metalloproteinase-9 and high-sensitivity C-reactive protein in both the exacerbation and convalescence phases of COPD. Furthermore, it negatively correlated with percent value of forced expiratory volume in 1 second (FEV1%) predicted and FEV1/forced vital capacity in convalescent COPD patients. Conclusion: These results suggest that serum CyPA can be used as a potential inflammatory biomarker for COPD and assessment of serum CyPA may reflect the severity of inflammation in COPD.

NF-κB Dynamics Discriminate between TNF Doses in Single Cells.

Although cytokine-dependent dynamics of nuclear factor κB (NF-κB) are known to encode information that regulates cell fate decisions, it is unclear whether single-cell responses are switch-like or encode more information about cytokine dose. Here, we measure the dynamic subcellular localization of NF-κB in response to a range of tumor necrosis factor (TNF) stimulation conditions to determine the prevailing mechanism of single-cell dose discrimination. Using an information theory formalism that accounts for signaling dynamics and non-responsive cell subpopulations, we find that the information transmission capacity of single cells exceeds that predicted from a switch-like response. Instead, we observe that NF-κB dynamics within single cells contain sufficient information to encode multiple, TNF-dependent cellular states, and have an activation threshold that varies across the population. By comparing single-cell responses to an internal, experimentally observed reference, we demonstrate that cells can grade responses to TNF across several orders of magnitude in concentration. This suggests that cells contain additional control points to fine-tune their cytokine responses beyond the decision to activate.

Curcumin attenuates skeletal muscle mitochondrial impairment in COPD rats: PGC-1α/SIRT3 pathway involved.

Curcumin has been widely used to treat numerous diseases due to its antioxidant property. The aim of the present study is to investigate the effect of curcumin on skeletal muscle mitochondria in chronic obstructive pulmonary disease (COPD) and its underlying mechanism. The rat model of COPD was established by cigarette smoke exposure combined with intratracheal administration of lipopolysaccharide. Airway inflammation and emphysema were notably ameliorated by the treatment with curcumin. Oral administration of curcumin significantly improved muscle fiber atrophy, myofibril disorganization, interstitial fibrosis and mitochondrial structure damage in the skeletal muscle of COPD rats. Mitochondrial enzyme activities of cytochrome c oxidase, succinate dehydrogenase, Na+/K+-ATPase and Ca2+-ATPase in skeletal muscle mitochondria from COPD rats were significantly increased after treatment with curcumin. Moreover, curcumin significantly decreased oxidative stress and inflammation by determining the levels of malondialdehyde, manganese superoxide dismutase, glutathione peroxidase, catalase, IL-6 and TNF-α in skeletal muscle of COPD rats. Furthermore, curcumin significantly increased the mRNA and protein expression of PGC-1α and SIRT3 in the skeletal muscle tissues of COPD rats. These results suggested that curcumin can attenuate skeletal muscle mitochondrial impairment in COPD rats possibly by the up-regulation of PGC-1α/SIRT3 signaling pathway.

Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic K-Ras remains among the most lethal human cancers despite recent advances in modern medicine. The pathogenesis of PDAC is partly attributable to intrinsic chromosome instability and extrinsic inflammation activation. However, the molecular link between these two events in pancreatic tumorigenesis has not yet been fully established. Here, we show that intracellular high mobility group box 1 (HMGB1) remarkably suppresses oncogenic K-Ras-driven pancreatic tumorigenesis by inhibiting chromosome instability-mediated pro-inflammatory nucleosome release. Conditional genetic ablation of either single or both alleles of HMGB1 in the pancreas renders mice extremely sensitive to oncogenic K-Ras-driven initiation of precursor lesions at birth, including pancreatic intraepithelial neoplasms, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms. Loss of HMGB1 in the pancreas is associated with oxidative DNA damage and chromosomal instability characterized by chromosome rearrangements and telomere abnormalities. These lead to inflammatory nucleosome release and propagate K-Ras-driven pancreatic tumorigenesis. Extracellular nucleosomes promote interleukin 6 (IL-6) secretion by infiltrating macrophages/neutrophils and enhance oncogenic K-Ras signaling activation in pancreatic lesions. Neutralizing antibodies to IL-6 or histone H3 or knockout of the receptor for advanced glycation end products all limit K-Ras signaling activation, prevent cancer development and metastasis/invasion, and prolong animal survival in Pdx1-Cre;K-RasG12D/+;Hmgb1-/- mice. Pharmacological inhibition of HMGB1 loss by glycyrrhizin limits oncogenic K-Ras-driven tumorigenesis in mice under inflammatory conditions. Diminished nuclear and total cellular expression of HMGB1 in PDAC patients correlates with poor overall survival, supporting intracellular HMGB1 as a novel tumor suppressor with prognostic and therapeutic relevance in PDAC.