Physical activity may a probably protective factor for postoperative delirium: the PNDABLE study.

Objective: This study aims to explore the relationship between physical activity (PA) and postoperative delirium (POD). Methods: We selected 400 patients from the Perioperative Neurocognitive Disorder and Biomarkers Lifestyle (PNDABLE) database, and the patients in the PNDABLE database were sampled and tested Alzheimer's biomarkers. The diagnosis of POD was made using the Confusion Assessment Scale (CAM) and the severity was assessed using Memorial Delirium Assessment Scale (MDAS). Mini-Mental State Examination (MMSE) scale was used to detect the mental state of the patients. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of preoperative cerebrospinal fluid (CSF) biomarkers, such as amyloid ß plaque 42 (Aß42), total tau protein (T-tau), and phosphorylated tau protein (P-tau). Logistic regression, sensitivity analysis, and post hoc analysis were used to explore the relationship between risk and protective factors on POD. We used the mediating effect to explore whether PA mediates the occurrence of POD through CSF biomarkers. Results: The incidence of POD was 17.5%. According to our research, the consequence prompted that PA might be the protective factor for POD [odds ratio (OR): 0.336, 95% confidence interval (95 CI) 0.206-0.548, P < 0.001]. The result of logistic regression revealed that CSF biomarker Aß42 (OR: 0.997, 95 CI 0.996-0.999, P < 0.001) might be a protective factor against POD, and the T-tau (OR: 1.006, 95 CI 1.003-1.009, P = 0.001) and P-tau (OR: 1.039, 95 CI 1.018-1.059, P < 0.001) might risk factors for POD. Sensitivity analysis confirmed the correlation between PA and CSF biomarkers in the patients with POD. Mediation effect analysis showed that PA may reduce the occurrence of POD partly through CSF biomarkers, such as Aß42 (proportion: 11%, P < 0.05), T-tau (proportion: 13%, P < 0.05), and P-tau (proportion: 12%, P < 0.05). Conclusion: Physical activity is probably a protective factor for POD and may exert a mediating effect through CSF biomarkers.

Refining postoperative monitoring of recurrent laryngeal nerve injury in esophagectomy patients through transcutaneous laryngeal ultrasonography.

BACKGROUND: Recurrent laryngeal nerve injury (RLNI) leading to vocal cord paralysis (VCP) is a significant complication following minimally invasive esophagectomy (MIE) with upper mediastinal lymphadenectomy. Transcutaneous laryngeal ultrasonography (TLUSG) has emerged as a non-invasive alternative to endoscopic examination for evaluating vocal cord function. Our study aimed to assess the diagnostic value of TLUSG in detecting RLNI by evaluating vocal cord movement after MIE. METHODS: This retrospective study examined 96 patients with esophageal cancer who underwent MIE between January 2021 and December 2022, using both TLUSG and endoscopy. RESULTS: VCP was observed in 36 out of 96 patients (37.5%). The incidence of RLNI was significantly higher on the left side than the right (29.2% vs. 5.2%, P < 0.001). Postoperative TLUSG showed a sensitivity and specificity of 88.5% (31/35) and 86.5% (45/52), respectively, with an AUC of 0.869 (P < 0.001, 95% CI 0.787-0.952). The percentage agreement between TLUSG and endoscopy in assessing VCP was 87.4% (κ = 0.743). CONCLUSIONS: TLUSG is a highly effective screening tool for VCP, given its high sensitivity and specificity. This can potentially eliminate the need for unnecessary endoscopies in about 80% of patients who have undergone MIE.

Prognostic and risk factor analysis of cancer patients after unplanned ICU admission: a real-world multicenter study.

To investigate the occurrence and 90-day mortality of cancer patients following unplanned admission to the intensive care unit (ICU), as well as to develop a risk prediction model for their 90-day prognosis. We prospectively analyzed data from cancer patients who were admitted to the ICU without prior planning within the past 7 days, specifically between May 12, 2021, and July 12, 2021. The patients were grouped based on their 90-day survival status, and the aim was to identify the risk factors influencing their survival status. A total of 1488 cases were included in the study, with an average age of 63.2 ± 12.4 years. The most common reason for ICU admission was sepsis (n = 940, 63.2%). During their ICU stay, 29.7% of patients required vasoactive drug support (n = 442), 39.8% needed invasive mechanical ventilation support (n = 592), and 82 patients (5.5%) received renal replacement therapy. We conducted a multivariate COX proportional hazards model analysis, which revealed that BMI and a history of hypertension were protective factors. On the other hand, antitumor treatment within the 3 months prior to admission, transfer from the emergency department, general ward, or external hospital, high APACHE score, diagnosis of shock and respiratory failure, receiving invasive ventilation, and experiencing acute kidney injury (AKI) were identified as risk factors for poor prognosis within 90 days after ICU admission. The average length of stay in the ICU was 4 days, while the hospital stay duration was 18 days. A total of 415 patients died within 90 days after ICU admission, resulting in a mortality rate of 27.9%. We selected 8 indicators to construct the predictive model, which demonstrated good discrimination and calibration. The prognosis of cancer patients who are unplanned transferred to the ICU is generally poor. Assessing the risk factors and developing a risk prediction model for these patients can play a significant role in evaluating their prognosis.

Advances in the use of ECMO in oncology patient.

BACKGROUND: Over the past decade, ECMO has provided temporary cardiopulmonary support to an increasing number of patients, but the use of extracorporeal membrane oxygenation (ECMO) to provide temporary respiratory and circulatory support to adult patients with malignancy remains controversial. OBJECTIVES: This paper reviews the specific use of extracorporeal membrane oxygenation (ECMO) in oncology patients. METHODS: We searched PubMed, CINAHL, Cochrane Library, and Embase databases for studies on the use of ECMO in cancer patients between 1998 and 2022. Twenty-four retrospective, prospective, and case reports were included. The primary outcome was survival during extracorporeal membrane oxygenation. RESULTS: Most studies suggest that ECMO can be used in oncology patients requiring life support during surgery, solid tumor patients with respiratory failure, and hematological tumor patients requiring ECOM as a supportive means of chemotherapy; however, in patients with hematologic oncology undergoing hematopoietic stem cell transplantation, there was no clear benefit after the use of ECMO. CONCLUSION: Current research suggests that ECMO may be considered as a salvage support in specific cancer patients. Future studies should include larger sample sizes than those already conducted, including studies on efficacy, adverse events, and health.

Analysis of the role and mechanism of EGCG in septic cardiomyopathy based on network pharmacology.

Background: Septic cardiomyopathy (SC) is a common complication of sepsis that leads to an increase in mortality. The pathogenesis of septic cardiomyopathy is unclear, and there is currently no effective treatment. EGCG (epigallocatechin gallate) is a polyphenol that has anti-inflammatory, antiapoptotic, and antioxidative stress effects. However, the role of EGCG in septic cardiomyopathy is unknown. Methods: Network pharmacology was used to predict the potential targets and molecular mechanisms of EGCG in the treatment of septic cardiomyopathy, including the construction and analysis of protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and molecular docking. The mouse model of septic cardiomyopathy was established after intraperitoneal injection of LPS (lipopolysaccharide). The myocardial protective effect of EGCG on septic mice is observed by cardiac ultrasound and HE staining. RT-PCR is used to verify the expression level of the EGCG target in the septic cardiomyopathy mouse model. Results: A total of 128 anti-SC potential targets of EGCGareselected for analysis. The GO enrichment analysis and KEGG pathway analysis results indicated that the anti-SC targets of EGCG mainly participate in inflammatory and apoptosis processes. Molecular docking results suggest that EGCG has a high affinity for the crystal structure of six targets (IL-6 (interleukin-6), TNF (tumor necrosis factor), Caspase3, MAPK3 (Mitogen-activated protein kinase 3), AKT1, and VEGFA (vascular endothelial growth factor)), and the experimental verification result showed levated expression of these 6 hub targets in the LPS group, but there is an obvious decrease in expression in the LPS + EGCG group. The functional and morphological changes found by echocardiography and HE staining show that EGCG can effectively improve the cardiac function that is reduced by LPS. Conclusion: Our results reveal that EGCG may be a potentially effective drug to improve septic cardiomyopathy. The potential mechanism by which EGCG improves myocardial injury in septic cardiomyopathy is through anti-inflammatory and anti-apoptotic effects. The anti-inflammatory and anti-apoptotic effects of EGCG occur not only through direct binding to six target proteins (IL-6,TNF-α, Caspase3, MAPK3, AKT1, and VEGFA) but also by reducing their expression.

Whole transcriptome analysis of the differential RNA profiles and associated competing endogenous RNA networks in LPS-induced acute lung injury (ALI).

Acute lung injury (ALI) is a serious inflammation disease usually arises alveolar epithelial membrane dysfunction and even causes death. Therefore, the aims of this study are to screen the differentially expressed lncRNAs, circRNAs, miRNAs, and mRNAs in ALI based on the high-throughput sequencing. The lipopolysaccharide (LPS)-induced ALI mouse model was established, the injury of ALI mouse model was evaluated through histological analysis with hemotoxylin and eosin (H & E) staining assay, dry/wet ratio, infiltrated-immune cells, ET-1 mRNA expression and released-proinflammation factors. Then, expression data of lncRNAs, circRNAs, miRNAs and mRNAs in ALI were acquired using whole-transcriptome sequencing. The differential expression of lncRNAs (DE lncRNAs), circRNAs (DE circRNAs), miRNAs (DE miRNAs) and mRNAs (DE mRNAs) were identified, and the lncRNA-miRNA-mRNA network and circRNA-miRNA-mRNA network were constructed, and the biological function of target genes were annotated based on bioinformatics analysis. In the present study, the LPS-induced ALI mouse model was successfully established. The biological analysis results showed that total 201 DE lncRNAs, 172 DE circRNAs, 62 DE miRNAs, and 3081 DE mRNAs were identified in ALI. The 182 lncRNA-miRNA-mRNA networks and 32 circRNA-miRNA-mRNA networks were constructed were constructed based on the correlation between lncRNAs/circRNAs, miRNAs, mRNAs. The biological function analysis indicated that TNF signaling pathway, chemokine signaling pathway and so on involved in ALI. In the present study, the differential expression coding and non-coding RNAs (ncRNAs) in ALI were identified, and their regulatory networks were constructed. There might provide the potential biomarkers and underlying mechanism for ALI diagnosis and treatment.

Efficacy of early prone or lateral positioning in patients with severe COVID-19: a single-center prospective cohort.

Background: Position intervention has been shown to improve oxygenation, but its role in non-invasively ventilated patients with severe COVID-19 has not been assessed. The objective of this study was to investigate the efficacy of early position intervention on non-invasively ventilated patients with severe COVID-19. Methods: This was a single-center, prospective observational study in consecutive patients with severe COVID-19 managed in a provisional ICU at Renmin Hospital of Wuhan University from 31 January to 15 February 2020. Patients with chest CT showing exudation or consolidation in bilateral peripheral and posterior parts of the lungs were included. Early position intervention (prone or lateral) was commenced for > 4 hours daily for 10 days in these patients, while others received standard care. Results: The baseline parameters were comparable between the position intervention group (n = 17) and the standard care group (n = 35). Position intervention was well-tolerated and increased cumulative adjusted mean difference of SpO2/FiO2 (409, 95% CI 86 to 733) and ROX index (26, 95% CI 9 to 43) with decreased Borg scale (-9, 95% CI -15 to -3) during the first 7 days. It also facilitated absorption of lung lesions and reduced the proportion of patients with high National Early Warning Score 2 (≥ 7) on days 7 and 14, with a trend toward faster clinical improvement. Virus shedding and length of hospital stay were comparable between the two groups. Conclusions: This study provides the first evidence for improved oxygenation and lung lesion absorption using early position intervention in non-invasively ventilated patients with severe COVID-19, and warrants further randomized trials.

Tumor suppressor miR-128-3p inhibits metastasis and epithelial-mesenchymal transition by targeting ZEB1 in esophageal squamous-cell cancer.

MicroRNAs (miRNAs) are some short RNAs that regulate multiple biological functions at post-transcriptional levels, such as tumorigenic processes, inflammatory lesions and cell apoptosis. Zinc finger E-box binding homeobox factor 1 (ZEB1) is a crucial mediator of epithelial-mesenchymal transition (EMT). It induces malignant progression of various cancers including human esophageal squamous-cell carcinoma (ESCC). In this study, we found that miR-128-3p was downregulated in ESCC tissues and cells by using PCR. Moreover, down-regulated expression of miR-128-3p was testified to be associated with poor prognosis of ESCC patients and might be regarded as an independent prognostic factor. Then, we examined the role of miR-128-3p in ESCC cells, and found that miR-128-3p could suppress the cell migration and invasion in vitro. Furthermore, ZEB1 was confirmed to be a direct target of miR-128-3p by luciferase reporter assay. Rescue experiments proved that EMT was regulated by miR-128-3p via suppression of ZEB1. Taken all together, we conclude that miR-128-3p suppresses EMT and metastasis via ZEB1, and miR-128-3p may be a critical mediator in ESCC.

[Progresses of immunomodulatory therapy in sever acute pancreatitis].

Severe acute pancreatitis (SAP) is accompanied with complex pathogenic course and high mortality. The imbalance of immune response is an important cause which leads the SAP patients to the severe situation and even death. The immunomodulatory therapy can regulate the imbalance of inflammation, alleviate SAP-associated organ injury, and improve the prognosis of patients. Previous immunomodulatory therapy had some problems, such as single-object and simple-method. In recent years, some new methods of immunomodulatory therapy, such as regulating the apoptosis and mature of immune cells, applying of mesenchymal stem cells (MSCs) and multi-regulation methods, provide some new ideas and hopes for SAP therapy. This paper reviewed the history and recent research progresses of SAP immunomodulatory therapy.

Efficacy of sorafenib in patients with hepatocellular carcinoma after resection: a meta-analysis.

BACKGROUND: The prognosis of hepatocellular carcinoma remains poor even after curative resection and it has no effective adjuvant therapy. AIM: This meta-analysis aimed to assess efficacy of sorafenib as adjuvant therapy for patients with hepatocellular carcinoma after resection. MATERIALS AND METHODS: A systematic search was conducted of Medline, Embase, Web of Science, Cochrane Library, Chinese Wanfang database, Chinese biological and medical database, China National Knowledgeand the Internet, data from 5 studies that included 296 participants were analyzed. The primary outcome was overall survival. Secondary outcomes included recurrence rate and mortality rate. RESULTS: In the comparison of sorafenib versus control, no significant difference in overall survival (hazard ratio 1.39, 95% confidence interval [CI] 0.71-2.74, P = 0.34) or recurrence rate [risk ratio (RR) 0.81, 95% CI; 0.65-1.01, P = 0.06) was found. For mortality rate, subgroup analysis was conducted according to study type, only in subgroup 2, the RR was significantly reduced (0.66, 95% CI; 0.51-0.87, P = 0.003) in studies. CONCLUSIONS: In this meta-analysis, sorafenib achieves no significant benefit in any of the endpoints except a lower mortality rate in subgroup analysis, indicating that there is no convincing evidence of sorafenib as an effective adjuvant therapy in patients with hepatocellular carcinoma after resection.

A simple and rapid electrochemical strategy for non-invasive, sensitive and specific detection of cancerous cell.

Developing non-invasive, sensitive and specific sensing strategies for cancerous cell detection with simple and low cost instrumentations provide great advantages in cancer research and early diagnosis of diseases. In the present work, gold nanoparticles (Au NPs) functionalized with recognition components (folic acid) and signal indicator (ferrocene) was designed to fabricate electrochemical cytosensor. The Au NPs can not only accelerate electron transfer between signal indicator and the underlying electrode but also accumulate more ferrocene on the cytosensor surface to magnify signal for improving detection sensitivity. The surface-tethered folic acid plays a key role in specific binding folate receptor-riched HeLa cells on the cytosensor surface, resulting in corresponding current signal change measured by differential pulse voltammetry method. A wide detection range from 10 to 10(6) cells/mL with a detection limit as low as 10 cells/mL for cancerous cells was reached in the presence of a large amount of normal ones with fast differential pulse voltammetry measurement. Detection of the captured cells can be finished within 1 min. The developed strategy provides a new way for operationally simple, rapid, sensitive and specific detection of cancerous cells.

G-quadruplex-based ultrasensitive and selective detection of histidine and cysteine.

Histidine and cysteine detection is critically important since an abnormal level of histidine or cysteine is an indicator for many diseases. In this paper, we demonstrated a novel label-free, G-quadruplex-based approach for simultaneous detection of histidine and cysteine. The present assay is based on the highly specific interaction among amino acids (histidine or cysteine), Cu(2+) and NMM/G-4 (NMM: N-methylmesoporphyrin IX; G-4: G-quadruplex). The fluorescence intensity of NMM was dramatically enhanced in the presence of G-quadruplex formed from 24GT, which can be effectively quenched by cupric ion (Cu(2+)) due to the chelation of Cu(2+) by NMM as well as the unfolding of G-quadruplex by Cu(2+). The presence of histidine or cysteine will disturb the interaction between Cu(2+) and NMM/G-4 because of the strong binding affinity of Cu(2+) to the imidazole group of histidine or the interaction of Cu(2+) with thiol group in cysteine, leading to distinct fluorescence emission intensity. High selectivity is conferred by the use of cysteine-masking agent N-ethylmaleimide (NEM), which helps to discriminate histidine from cysteine. At last, a novel and simple approach was developed to determine each precise concentration of histidine and cysteine according to the different response of the system with and without NEM. Importantly, histidine can be also detected even in the presence of a large amount of other amino acids. A detection limit as low as 3 nM for histidine and 5 nM for cysteine was obtained by practical measurement rather than conventional calculation (S/N=3), confirming the high sensitivity of the present approach. Meanwhile, this sensing protocol can determine histidine and cysteine in diluted biological samples such as urine, exhibiting great potential to meet the need of practical application.

Interface synthesis, assembly and characterization of close-packed monolayer of prussian blue/polypyrrole nanocomposites.

The self-assembly of nanomaterials into ordered two- or three-dimensional structures has been extensively explored over the past years due to the great application potential. This paper reports a simple one-step methodology for the synthesis and assembly of Prussian blue/polypyrrole (PBPPy) nanocomposites into close-packed monolayer at a toluene-water interface where the formation of PBPPy and evaporation of organic phase happen simultaneously. The formed films could be easily transferred onto the glass carbon surface by layer-by-layer technique. The obtained PBPPy nanocomposites and their assembled film were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, UV-vis spectroscopy and cyclic voltammetry. The PBPPy nanocomposite film on the electrode surface exhibits excellent electron transfer and high electrocatalysis toward the reduction of H2O2. Herein, PPy component in PBPPy nanocomposites plays a great role in this great electrochemical performance. On the one hand, the presence of PPy is helpful of the formation of close-packed monolayer of PBPPy nanocomposites, and the adhesion of the ordered monolayer or multilayer onto the electrode surface due to the molecular interaction of PPy or the surface group of electrode. On the other hand, the conductive PPy facilitates the electron transfer between PB and PB or PB and electrode. The suggested method can be extended to a wide range of nanomaterials assembly and devise development.

Electrochemical current rectifier as a highly sensitive and selective cytosensor for cancer cell detection.

Signal amplification originating from electrochemical current rectifier (ECR) was firstly applied to construct a cytosensor for rapid and non-invasive detection of folate receptor-rich cancer cells with high sensitivity. It exhibits a broad linear range with a detection limit as low as 10 cells mL(-1) even in the presence of a large number of normal cells.

A superoxide-mediated mitogen-activated protein kinase phosphatase-1 degradation and c-Jun NH(2)-terminal kinase activation pathway for luteolin-induced lung cancer cytotoxicity.

Although luteolin is identified as a potential cancer therapeutic and preventive agent because of its potent cancer cell-killing activity, the molecular mechanisms by which its cancer cell cytotoxicity is achieved have not been well elucidated. In this report, luteolin-induced cellular signaling was systematically investigated, and a novel pathway for luteolin's lung cancer killing was identified. The results show that induction of superoxide is an early and crucial step for luteolin-induced apoptotic and nonapoptotic death in lung cancer cells. The c-Jun N-terminal kinase (JNK) was potently activated after superoxide accumulation. Suppression of superoxide completely blocked luteolin-induced JNK activation, which was well correlated to alleviation of luteolin's cytotoxicity. Although luteolin slightly stimulated the JNK-activating kinase mitogen-activated protein kinase kinase 7, the latter was not dependent on superoxide. We further found that luteolin triggers a superoxide-dependent rapid degradation of the JNK-inactivating phosphatase mitogen-activated protein kinase phosphatase-1 (MKP-1). Introduction of a degradation-resistant MKP-1 mutant effectively attenuated luteolin-induced JNK activation and cytotoxicity, suggesting that inhibition of the JNK suppressor MKP-1 plays a major role in luteolin-induced lung cancer cell death. Taken together, our results unveil a novel pathway consisting of superoxide, MKP-1, and JNK for luteolin's cytotoxicity in lung cancer cells, and manipulation of this pathway could be a useful approach for applying luteolin for lung cancer prevention and therapy.

Blocking NF-κB and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death.

NF-κB and Akt are two main cell survival pathways that attenuate the anticancer efficacy of therapeutics. Our previous studies demonstrated that the Smac mimetic compound 3 (SMC3) specifically suppresses c-IAP1 and induces TNF-α autocrine to kill cancer cells. However, SMC3 also induces a cell survival signal through NF-κB activation. In this report, we further found that SMC3 potently activates Akt, which inhibits SMC3-induced cancer cell death. Strikingly, concurrent blocking NF-κB and Akt resulted in a significantly potentiated cytotoxicity. Because heat shock protein 90 (Hsp90) plays an important role in maintaining the integrity of both the NF-κB and Akt pathways in cancer cells, we examined if suppression of Hsp90 is able to potentiate SMC3-induced cancer cell death. The results show that targeting Hsp90 does not interfere with SMC3-induced c-IAP1 degradation and TNF-α autocrine, the key processes for SMC3-induced cancer cell apoptosis. However, Hsp90 inhibitors effectively blocked SMC3-induced NF-κB activation through degradation of RIP1 and IKKß, two key components of the NF-κB activation pathway, and reduced both the constitutive and SMC3-induced Akt activity through degradation of the Akt protein. Consistently, with the co-treatment of SMC3 and Hsp90 inhibitors, apoptosis was markedly sensitized and a synergistic cytotoxicity was observed. The results suggest that concurrent targeting c-IAP1 and Hsp90 by combination of SMC3 and Hsp90 inhibitors is an effective approach for improving the anticancer value of SMC3.

The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy.

IMPORTANCE OF THE FIELD: Nuclear factor kappa B (NF-kappaB) is activated by a variety of cancer-promoting agents. The reciprocal activation between NF-kappaB and inflammatory cytokines makes NF-kappaB important for inflammation-associated cancer development. Both the constitutive and anticancer therapeutic-induced NF-kappaB activation blunts the anticancer activities of the therapy. Elucidating the roles of NF-kappaB in cancer facilitates developing approaches for cancer prevention and therapy. AREAS COVERED IN THIS REVIEW: By searching PubMed, we summarize the progress of studies on NF-kappaB in carcinogenesis and cancer cells' drug resistance in recent 10 years. WHAT THE READER WILL GAIN: The mechanisms by which NF-kappaB activation pathways are activated; the roles and mechanisms of NF-kappaB in cell survival and proliferation, and in carcinogenesis and cancer cells' response to therapy; recent development of NF-kappaB-modulating means and their application in cancer prevention and therapy. TAKE HOME MESSAGE: NF-kappaB is involved in cancer development, modulating NF-kappaB activation pathways has important implications in cancer prevention and therapy. Due to the complexity of NF-kappaB roles in different cancers, careful evaluation of NF-kappaB's in each cancer type is crucial in this regard. More cancer cell-specific NF-kappaB inhibiting means are desired for improving anticancer efficacy and reducing systemic toxicity.

Acquired activation of the Akt/cyclooxygenase-2/Mcl-1 pathway renders lung cancer cells resistant to apoptosis.

Acquired apoptosis resistance plays an important role in acquired chemoresistance in cancer cells during chemotherapy. Our previous observations demonstrated that acquired tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells was associated with Akt-mediated stabilization of cellular FLICE-like inhibitory protein (c-FLIP) and Mcl-1. In this report, we determined that these cells also have acquired resistance to apoptosis induced by chemotherapeutics such as cisplatin and doxorubicin (Adriamycin), which was detected in vitro in cell cultures and in vivo in xenografted tumors. We further found that cyclooxygenase-2 (COX-2) is dramatically overexpressed in cells with acquired apoptosis resistance. COX-2 seems to be a crucial mediator in acquired apoptosis resistance because suppressing COX-2 activity with a chemical inhibitor or reducing COX-2 protein expression level with COX-2 small interfering RNA dramatically alleviated resistance to therapeutic-induced apoptosis. Inhibiting Akt markedly suppressed COX-2 expression, suggesting COX-2 is a downstream effector of this cell survival kinase-mediated apoptosis resistance. Furthermore, the expression of Mcl-1 but not c-FLIP was significantly reduced when COX-2 was suppressed, and knockdown of Mcl-1 substantially sensitized the cells to apoptosis. Our results establish a novel pathway that consists of Akt, COX-2, and Mcl-1 for acquired apoptosis resistance, which could be a molecular target for circumventing acquired chemoresistance in lung cancer.

Attenuating Smac mimetic compound 3-induced NF-kappaB activation by luteolin leads to synergistic cytotoxicity in cancer cells.

Smac mimetics are potential anticancer therapeutics selectively killing cancer cells through autocrine tumor necrosis factor (TNF)-mediated apoptosis pathway. Our recent study reveal that the Smac mimetic compound 3 (SMC3)-activated NF-kappaB protects cancer cells against apoptosis, thus blunting SMC3's anticancer activity. Based on our previous observations that the nutrient flavonoid luteolin potently blocks TNF-induced NF-kappaB activation in cancer cells, we investigated if the combination of SMC3 and luteolin would achieve a synergistic anticancer activity. The results show that luteolin had no effect on autocrine TNF but it effectively blocked SMC3-induced nuclear factor kappa B (NF-kappaB) activation and expression of anti-apoptotic NF-kappaB targets. When SMC3 and luteolin were combined in treating cancer cells derived from lung and liver tumors, the activation of TNF-dependent apoptosis was markedly sensitized and a synergistic cytotoxic effect was achieved. In addition, the SMC3 and luteolin co-treatment had marginal effect on immortalized normal human bronchial epithelial cells. The results suggest that combination of SMC3 and luteolin is an effective approach for improving the anticancer value of SMC3, which has implications in cancer prevention and therapy.