[Importance of full-cycle management for diabetic retinopathy].

Diabetic retinopathy (DR), one of the chronic complications of diabetes, is a serious and irreversible blinding disease. It is difficult to detect in the early stage, to control in the progressive stage, to operate in the advanced stage of DR. Recently, the "14th Five-year plan" for National Eye Health proposed to "improve the management mode of chronic eye disease, and build a chronic disease management system". The project team used artificial intelligence technology based on cloud platform, joint outpatient service, virtual ward to explore the comprehensive management of DR from the aspects of early screening, multidisciplinary collaborative diagnosis and treatment, and refined blood glucose management during perioperative period. In the future, it is urgent to integrate DR chronic disease management with other systemic chronic diseases to reduce the blindness caused by DR.

[Impact of neoadjuvant immunotherapy on pulmonary function and perioperative outcomes in patients with resectable non-small cell lung cancer].

Objective: To explore the effect of neoadjuvant immunotherapy on pulmonary function and the efficacy in patients with resectable non-small cell lung cancer. Methods: Data of 30 patients with non-small cell lung cancer (NSCLC) who received neoadjuvant immunotherapy before surgery in the Chest Hospital of Shanghai Jiaotong University from March 2018 to September 2021 were retrospectively collect. The efficacy and safety of neoadjuvant immunotherapy in the perioperative period and changes in pulmonary function of patients before and after neoadjuvant treatment were valuated. Results: The patients were all-male with age of (61±8)years old, The major pathological response (MPR) rate of patients receiving neoadjuvant immunotherapy was 43%(13 cases), the pathologic complete response (pCR) rate was 37% (11 cases), disease control rate (DCR) was 97% (29 cases), objective response rate (ORR) was 67% (20 cases). The forced expiratory volume in one second (FEV1) after treatment was (2.59±0.63) L, and the ratio of FEV1 to the predicted value (FEV1%pred) was 85.27%±15.86%, which were significantly higher than those before treatment [(2.48±0.59)L, 81.73%±15.94%, respectively] (P=0.013, 0.022, respectively). Forced vital capacity (FVC) after treatment was (3.59±0.77) L, which was also significantly higher than before [(3.47±0.76) L,P=0.036]; while there were no statistical difference in FEV1/FVC and FVC accounted for the proportion of predicted values (FVC%pred) between before and after treatment (P=0.084, 0.344, respectively). The ratio of carbon monoxide dispersion (DLCO) to the predicted value (DLCO%pred) decreased from 83.61%±13.10% to 78.69%±13.85% after treatment (P=0.023). There was no significant difference in the incidence of postoperative complications between the DLCO%pred decreased group and the non-decreased group (3/18 vs 0/6; P=0.546). Conclusions: Neoadjuvant immunotherapy can increase the rate of MPR and PCR, significantly increase FEV1 and FEV1%pred, but also lead to a decrease in DLCO%pred; neoadjuvant immunotherapy does not increase the incidence of postoperative complications.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in 2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treatment of HCC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with intermediate and advanced/relapsed HCC representing the oncology societies of Taiwan (TOS), China (CSCO), India (ISMPO) Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Singapore (SSO). The voting was based on scientific evidence, and was independent of the current treatment practices, the drug availability and reimbursement situations in the individual participating Asian countries.

[Bioinformatics analysis of severe emphysema genome microarray based on GEO database].

Objective: To investigate differential genes (DEGs) between no/mild and severe emphysema by bioinformatics analysis. Methods: The microarray dataset GSE1650, of lung tissue in no/mild and severe emphysema, was downloaded from the GEO database, and DEGs were obtained by t test. Analysis of DEGs based on DAVID database was used to obtain gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway. The protein-protein interaction network (PPI) was established using STRING database to identify hub genes. Results: A total of 76 DEGs were obtained, of which 62 genes were up-regulated and 14 genes were down-regulated in severe emphysema group. Gene ontology showed that the DEGs were mainly involved in neutrophil chemotaxis, cellular response to interleukin-1, extracellular matrix organization, immune response, and KEGG pathway involved cytokine-cytokine receptor interaction, ECM-receptor interaction, PI3K-Akt signaling pathway, platelet activation. Seventeen hub genes were recognized by PPI analysis, including CXCL8, RRAD, CLU, TIMP1, SEPP1, ISLR, BGN, COL1A1, COLIA2, ACTA2, ACTN1, FIGF, TPM1, TPM2, LUM, COL6A3 and TAGLN. Among them, fifteen genes (CLU, TIMP1, SEPP1, ISLR, BGN, COLIA2, COL1A1, ACTA2, ACTN1, FIGF, TPM1, TPM2, LUM, COL6A3, TAGLN) were up-regulated and two genes (CXCL8, RRAD) were down-regulated. Conclusion: Bioinformatics analysis based on GEO database showed that there were DEGs between non/mild and severe emphysema patients.

[Association of plasma roundabout 4 concentration with pulmonary ventilation function decline in COPD patients].

Objective: To investigate the association of plasma roundabout 4 concentration with pulmonary ventilation function decline in chronic obstructive pulmonary disease (COPD) patients. Methods: To get the effective data, the study was conducted in the outpatient department of West China Hospital from September 2017 to September 2018. The subjects meeting the inclusion and exclusion criteria were continuously included. Among them, the COPD group (75 cases) was from the respiratory outpatient department, and the healthy control group (57 cases) was from the health examination center at the same time. Data of basic demographic characteristics, clinical characteristics, pulmonary ventilation function parameters and blood samples were collected. The concentrations of roundabout 4, C reactive protein (CRP), interleukin (IL)-6, IL-8, IL-1b and tumor necrosis factor (TNF)-α in plasma were detected, and the differences among groups were compared, the correlation between plasma roundabout 4 and pulmonary ventilation function parameters and inflammatory factors was analyzed. The diagnostic efficiency of roundabout 4 to COPD was analyzed according to receiver operating characteristic (ROC) curve. Results: The plasma concentration of roundabout 4 in COPD group was significantly higher than that in healthy control group [(41.3±14.2) vs (27.7±13.3) ng/L; P<0.001], the sensitivity and specificity of roundabout 4 in the diagnosis of COPD were 0.827 and 0.702 respectively. Correlation analysis showed that the plasma concentration of roundabout 4 was negatively correlated with lung function parameters forced expiratory volume in one second/forced vital capacity (FEV(1)/FVC), the first second forced expiratory volume as a percentage of the estimated value (FEV(1)%pred), forced exhalation of 50% and 25% lung capacity (MEF50, MEF25) and maximal mid-expiratory flow (MMEF) (r=-0.399, -0.321, -0.439, -0.363, -0.458; all P<0.001), positively correlated with CRP (adjusted r=0.311, P<0.001). Conclusion: The increased concentration of roundabout 4 in plasma leads to the decline of pulmonary ventilation function in COPD patients.

Nucleic Acid Tests for BK Polyomavirus Is Critical in Renal Transplant Recipients.

This study evaluates the incidence of BK polyomavirus (BKV) and prognosis of BKV infection in kidney transplant recipients (KTRs) who received transplantation in our hospital before and after regular BKV nucleic acid test (NAT) was implemented. METHODS: The study included 74 KTRs who received a single kidney either from standard- or expanded-criteria deceased donor between March 2011 and March 2017. BKV NATs were regularly checked in 26 patients (group 1) in the first posttransplant year in accordance with current guidelines since NAT was implemented in our laboratory in 2014. We retrospectively compared 48 KTRs (group 2) who either received NAT when necessary in another laboratory or were not checked before 2014. RESULTS: There was no significant difference in patient characteristics between groups. BKV viruria were confirmed in 8 of 26 (30.8%) group 1 patients, whereas only 2 of 48 (4.2%) BKV infections were confirmed in group 2. None of the BKV(+) KTRs in group 1 developed BK polyomavirus-associated nephropathy (BKVAN), whereas 2 BKV(+) patients (100%) of group 2 developed BKVAN, which indicates renal function deterioration and biopsy-validated nephropathy. There was no significant difference in graft survival and renal function between the 2 groups. CONCLUSIONS: The risk of BKV infection is considerably higher in KTRs using NAT. Because there is no approval treatment, early diagnosis of BKV infection and early reduction of immunosuppression agents is critical for KTRs. Implementation of regular BKV NAT is mandatory before BKVAN and malignant neoplasms develop.

Serum angiopoietin-like 4 is over-expressed in COPD patients: association with pulmonary function and inflammation.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is both a pulmonary and systematic disease, which will cause abnormal expression of some circulating factors. Angiopoietin-like protein 4 (ANGPTL4) has been reported to play important role in inflammatory responses and several diseases. However, whether it contributes to COPD is an open question. The aim of this study is to explore the potential relationship between ANGPTL4 and COPD. PATIENTS AND METHODS: In this study, circulating levels of ANGPTL4, C-reactive protein (CRP), adiponectin, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-9 and monocyte chemotactic protein (MCP)-1 in 73 COPD patients and 40 healthy volunteers were investigated using multiplex enzyme-linked immunosorbent assay Kits. Then, we analyzed the correlations between ANGPTL4 with other inflammatory mediators and pulmonary function. RESULTS: Serum ANGPTL4 levels were significantly elevated in COPD patients compared with healthy controls (122.86 ± 38.59 ng/mL versus 99.03 ± 31.84 ng/mL, p = 0.001). Besides, serum ANGTPL4 levels were much higher in ever-smokers with COPD than in never-smokers with COPD (131.71 ± 32.92 ng/mL versus 113.25 ± 42.34 ng/mL, p = 0.03). More importantly, the concentrations of circulating ANGPLT4 correlated inversely with forced expiratory volume in 1 second (FEV1) % predicted, an index of lung function in COPD (r = -0.450, p < 0.001) and in all participants (r = -0.369, p < 0.001), while correlated positively with CRP (r = 0.312, p = 0.007 for COPD; r = 0.404, p < 0.001 for total subjects), adiponectin (r = 0.266, p = 0.004 for total subjects), and MMP-9 (r = 0.254, p = 0.03 for COPD). CONCLUSIONS: Our results suggest that circulating ANGPTL4 levels are up-regulated in COPD patients, and have correlations with pulmonary function and systematic inflammation in COPD, which provides a novel idea to further dig the pathogenic mechanisms of COPD, and justifies more studies to determine how ANGPTL4 contributes to COPD.

DNA damage regulates ARID1A stability via SCF ubiquitin ligase in gastric cancer cells.

OBJECTIVE: The gene product of the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) is a member of the SWI/SNF adenosine triphosphate-dependent chromatin-remodeling complexes, which plays an essential role in controlling gene expression and is also involved in cancer development. ARID1A is frequently mutated in a wild variety of cancers and function as a tumor suppressor in several kinds of cancers. ARID1A was down-regulated in gastric cancer, and associated poor patient prognosis. However, how ARID1A protein is regulated in gastric cancer remains largely unknown. MATERIALS AND METHODS: Here, we show that ARID1A protein is rapidly ubiquitinated and degradated in gastric cancer cells in response to DNA damage treatment. RESULTS: Using genetic and pharmacologic Cullin inactivation coupled with in vitro ubiquitination assay, we demonstrate that ARID1A is a substrate of the Cullin-SKP1-F-box protein (SCF) complexes. Moreover, gastric cancer cells with forced expression of ARID1A showed an increased sensitivity to DNA damage reagents. Thus, our data uncovered a previous unknown posttranscriptional regulation of ARID1A by SCF E3 ligase in gastric cancer cells in DNA damage response. CONCLUSIONS: These findings suggest ARID1A might be a promising drug target in gastric cancer treatment.

Intraarterial chemotherapy as the first-line therapy in penile cancer.

BACKGROUND: Limited literature on the role of intraarterial chemotherapy as first-line therapy for penile squamous cell carcinoma is available. METHODS: From 2005 to 2013, a total of 12 patients with various stages of penile squamous cell carcinoma received intraarterial chemotherapy. The chemotherapeutic agents used were methotrexate, mitomycin C, bleomycin, cisplatin, and 5-fluorouracil. Surgery was followed by the tumour responses. RESULTS: An objective tumour response was noted in 10 of 12 patients (83%, 4 complete responders and 6 partial responders). In node-negative patients (n=7), the response rate was 100% (4 complete responders and 3 partial responders). Even in advanced penile squamous cell carcinoma with nodal invasion, a response rate of 60% could be achieved. Grade 2 anorexia was the most frequent chemotherapy-related toxicity and no toxic death was noted. Recurrence-free survival was significantly better in patients without lymph node invasion (log-rank test, P=0.041). CONCLUSIONS: Neoadjuvant intraarterial chemotherapy displayed excellent responses for penile squamous cell carcinoma. This therapy could effectively shrink the tumour burden or even achieve complete response before surgery. It could be used as first-line strategy for penile cancer treatment because of low toxicity.

Different risk factors of recurrent pulmonary tuberculosis between Tibetan and Han populations in Southwest China.

OBJECTIVE: The geographical environment and living habits are different between Tibetan and Han populations. The present study aimed to investigate the risk factors of recurrent pulmonary tuberculosis (TB), and analyze the differences between the two populations. PATIENTS AND METHODS: A total of 480 TB patients, including 80 Tibetan and 80 Han patients with recurrent pulmonary TB, and 320 patients without recurrent pulmonary TB, were included in present study. All patients with pulmonary TB were diagnosed between 2000 and 2001 and followed until December 2012. Multivariate logistic regression was used for the statistical analysis. RESULTS: Among all patients, the independent risk factors associated with recurrent pulmonary TB were no use of directly observed therapy, short course (DOTS) (HR 5.867, 95% CI 2.557-13.461), diabetes (HR 3.288, 95% CI 1.301-8.312), smoking (HR 2.387, 95% CI 1.328-4.291) and malnutrition (HR 1.910, 95% CI 1.110-3.285). The independent risk factors of recurrent pulmonary TB for the Tibetan patients included no use of DOTS and malnutrition, while the independent risk factors for the Han patients were diabetes and smoking. CONCLUSIONS: The risk factors of pulmonary TB recurrence were different between Tibetan and Han patients. To reduce the recurrent rate of pulmonary TB, especially for Tibetan populations, pursuing high-quality DOTS is essential.

Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma.

BACKGROUND: Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC. METHODS: Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy. RESULTS: The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity (R(2)=0.9067, among sorafenib-naive cell lines; P=0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9%; Huh-7 R, 25.3± 5.7% vs 4.3±1.5%; each P<0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg(-1) per day) plus DCA (100 mg kg(-1) per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: -87% vs -36%, P<0.001). CONCLUSION: The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.

Diagnostic Value of p16 Methylation for Malignant Pleural Effusions: A Meta-analysis.

OBJECTIVE: To evaluate the overall diagnostic performance of the p16 methylation for diagnosing malignant pleural effusion (MPE). METHODS: All published literature in English and Chinese were reviewed. Sensitivity, specificity, likelihood ratio and diagnostic odds ratio (DOR) were pooled by using random-effects model or fixed-effects model. Summary receiver operating characteristic (SROC) curve was used to evaluate the overall diagnostic value. RESULTS: Six studies were included with a total of 378 cases. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and DOR of p16 methylation in the diagnosis of MPE were 0.41 [95% confidence interval (CI) 0.35, 0.48], 0.97 [95% CI 0.93, 0.99], 9.57 [95% CI 4.53, 20.20], 0.61 [95% CI 0.45, 0.82] and 19.82 [95% CI 8.35, 47.04], respectively. The area under the curve (AUC) was 0.864. CONCLUSION: Pleural p16 methylation test plays a useful role in the diagnosis of MPE.

Prognosis of advanced hepatocellular carcinoma patients enrolled in clinical trials can be classified by current staging systems.

BACKGROUND: Patients enrolled in clinical trials of advanced hepatocellular carcinoma (HCC) are usually required to have good liver reserve and organ function. However, their outcomes are still highly variable. We aimed to examine whether current staging systems can predict the survival of these highly selected patients. METHODS: Patients from clinical trials involving first-line anti-angiogenic therapy were assigned to different stage groups using the American Joint Committee on Cancer (AJCC), Barcelona Clinic Liver Cancer (BCLC), China integrated score, Cancer of the Liver Italian Program (CLIP) score, Chinese University Prognostic Index (CUPI), Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GETCH), Japan Integrated Staging (JIS) score, Okuda, Tokyo score, and a new staging system recently proposed. Survival prediction by the 10 systems was then compared by both univariate and multivariate analyses. RESULTS: A total of 157 patients were selected for this study. In univariate analysis, all staging systems can predict patient survival except AJCC, BCLC, and JIS score. Concordance indexes for CLIP score, CUPI, and GETCH (0.752, 0.775, and 0.791, respectively) were significantly higher than those obtained for other staging systems. In multivariate analysis, the CLIP score and CUPI (P<0.001 and 0.009, respectively) predicted survival more accurately than did the other tested staging systems. Hepatitis B infection and poor performance status were also associated with poor survival. CONCLUSION: Several HCC staging systems, especially the CLIP score and CUPI, can predict prognosis of patients who are enrolled in clinical trials of advanced HCC.

Effects of a Chinese medical herbs complex on cellular immunity and toxicity-related conditions of breast cancer patients.

Rose geranium (Pelargonium graveolens, Geraniaceae) has anti-cancer and anti-inflammatory properties, and promotes wound healing. Similarly, Ganoderma tsugae (Ganodermataceae), Codonopsis pilosula (Campanulaceae) and Angelica sinensis (Apiaceae) are traditional Chinese herbs associated with immunomodulatory functions. In the present study, a randomised, double-blind, placebo-controlled study was conducted to examine whether the Chinese medicinal herb complex, RG-CMH, which represents a mixture of rose geranium and extracts of G. tsugae, C. pilosula and A. sinensis, can improve the immune cell count of cancer patients receiving chemotherapy and/or radiotherapy to prevent leucopenia and immune impairment that usually occurs during cancer therapy. A total of fifty-eight breast cancer patients who received chemotherapy or radiotherapy were enrolled. Immune cell levels in patient serum were determined before, and following, 6 weeks of cancer treatment for patients receiving either an RG-CMH or a placebo. Administration of RG-CMH was associated with a significant reduction in levels of leucocytes from 31·5 % for the placebo group to 13·4 % for the RG-CMH group. Similarly, levels of neutrophils significantly decreased from 35·6 % for the placebo group to 11·0 % for the RG-CMH group. RG-CMH intervention was also associated with a decrease in levels of T cells, helper T cells, cytotoxic T cells and natural killer cells compared with the placebo group. However, these differences between the two groups were not statistically significant. In conclusion, administration of RG-CMH to patients receiving chemotherapy/radiotherapy may have the capacity to delay, or ease, the reduction in levels of leucocytes and neutrophils that are experienced by patients during cancer treatment.

Critical appraisal of ex vivo expansion of human limbal epithelial stem cells.

The stem cells (SCs) of the corneal epithelium located in the limbal basal layer are the ultimate source to maintain corneal epithelial homeostasis. Like other adult tissue-specific SCs, self renewal and fate decision of limbal SCs are regulated by a specialized in vivo microenvironment, termed "niche". Loss of limbal SCs or dysfunction of the limbal niche renders corneas with a unique clinical disease labeled limbal stem cell deficiency (LSCD). Besides transplantation of autologous or allogeneic limbal SCs or amniotic membrane, a new strategy of treating LSCD is to transplant a bio-engineered graft by expanding limbal SCs ex vivo. Herein, we conduct a critical appraisal of six protocols that have successfully been practiced in treating human patients with LSCD, and identify issues whether niche regulation has been disrupted or maintained during isolation and expansion. Consequently, we propose a future direction that may circumvent the potential pitfalls existing in these conventional protocols by preserving the interaction between limbal SCs and their native niche cells during isolation and expansion. Such an approach may one day help realize considerable promise held by adult SCs in treating a number of diseases.

Adrenomedullin enhances baroreceptor reflex response via cAMP/PKA signaling in nucleus tractus solitarii of rats.

Adrenomedullin (ADM), a 52-amino acid peptide, elicits differential cardiovascular responses when it is administered systemically or directly to the brain. We evaluated in the present study the hypothesis that ADM may modulate baroreceptor reflex (BRR) response through an ADM receptor-mediated cAMP/ protein kinase A (PKA)-dependent mechanism in the nucleus tractus solitarii (NTS), the terminal site for primary baroreceptor afferents, using Sprague-Dawley rats. Our immunoblot and immunohistochemical results showed that the two component proteins of the ADM(1) receptor complex, calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP)-2, were uniformly distributed and highly co-localized in the NTS. Site-specific microinjection of ADM (0.02-0.2pmol) unilaterally into the NTS significantly increased BRR response and sensitivity in a time- and dose-related manner, without affecting arterial pressure and heart rate. The BRR enhancing effect of ADM was also temporally correlated with an up-regulation of PKA(beta), the active form of PKA and an increase in PKA activity. In addition, the ADM-evoked BRR enhancement or PKA activation was abolished by co-microinjection with a selective ADM(1) receptor antagonist, ADM(22-52), an adenylyl cyclase inhibitor, SQ22536, or a PKA inhibitor, Rp-8-bromo-cAMP. These results suggest that ADM enhances BRR via activation of a cAMP/PKA-dependent mechanism by acting site-specifically on ADM(1) receptors in NTS.

Anti-inflammatory effects of dimemorfan on inflammatory cells and LPS-induced endotoxin shock in mice.

BACKGROUND AND PURPOSE: Dimemorfan (a sigma1 receptor agonist) showed neuroprotective properties in animal models of inflammation-mediated neurodegenerative conditions, but its effects on inflammatory cells and systemic inflammation remain unclear. EXPERIMENTAL APPROACH: The effects of dimemorfan on phorbol-12-myristate-13-acetate (PMA)- and N-formyl-methionyl-leucyl-phenylalanine (fMLP)- induced neutrophils and lipopolysaccharide (LPS)-activated microglial cells, as well as LPS-induced endotoxin shock in mice were elucidated. KEY RESULTS: Dimemorfan decreased PMA- and fMLP-induced production of reactive oxygen species (ROS) and CD11b expression in neutrophils, through mechanisms independent of sigma1 receptors, possibly by blocking ROS production and G-protein-mediated intracellular calcium increase. Dimemorfan also inhibited LPS-induced ROS and nitric oxide (NO) production, as well as that of monocyte chemoattractant protein-1 and tumour necrosis factor-alpha (TNF-alpha), by inhibition of NADPH oxidase (NOX) activity and suppression of iNOS up-regulation through interfering with nuclear factor kappa-B (NF-kappaB) signalling in microglial cells. Treatment in vivo with dimemorfan (1 and 5 mg kg(-1), i.p., at three successive times after LPS) decreased plasma TNF-alpha, and neutrophil infiltration and oxidative stress in the lung and liver. CONCLUSIONS AND IMPLICATIONS: Our results suggest that dimemorfan acts via sigma1 receptor-independent mechanisms to modulate intracellular calcium increase, NOX activity, and NF-kappaB signalling, resulting in inhibition of iNOS expression and NO production, and production of pro-inflammatory cytokines. These effects may contribute its anti-inflammatory action and protective effects against endotoxin shock in mice.

Contribution of tomato phenolics to suppression of COX-2 expression in KB cells.

Tomatoes, which are consumed worldwide, contain abundant phenolics. The objective of this study was to understand the suppression effect of phenolics in fresh and heated tomatoes on the expression of cyclooxygenase 2 (COX-2). Both small and big tomatoes of fresh or heated (in boiling water for 30 min) treatments were used. Sephadex LH-20 gel was used to separate the noncondensed tannin containing and the condensed tannin containing fractions from the crude phenolic extracts of tomatoes. The condensed tannin containing fraction was rich in condensed tannins and simple phenolics. The noncondensed tannin containing fraction contained abundant nontannin flavans. This study explored the effect of tomato phenolic extracts on the regulation of 12-o-teradecanoylphorbol-13-acetate (TPA)-induced inflammatory responses in KB cells. HPLC showed that tomato phenolic profiles were similar between small and big tomatoes either by fresh or heated treatment. Fresh tomato extracts had 70.8 +/- 4.8% (mean +/- SD) noncondensed tannin containing polyphenols (6.68 +/- 0.09 mg/g dry weight), 27.4 +/- 6.9% condensed tannin containing polyphenols (3.52 +/- 0.24 mg/g dry weight), and 1.7 +/- 0.6% other residues. Instead, heated tomato had 53.3 +/- 4.3% noncondensed tannin containing polyphenols (2.70 +/- 0.20 mg/g dry weight), 24.2 +/- 1.7% condensed tannin containing polyphenols (7.37 +/- 0.03 mg/g dry weight), and 22.5 +/- 4.8% other residues. Cell studies showed that phenolic extracts of heated tomatoes resulted in increased suppression of COX-2 expression compared with that of fresh tomato. Noncondensed tannin containing fraction of fresh tomato greatly suppressed COX-2 expression (P < 0.05) that compared to the negative control, but both noncondensed tannin containing and condensed tannin containing fractions of heated tomatoes showed suppression on COX-2 expression. These results suggest that tomato phenolics may play an important role in the chemoprevention of cancer.