Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid.

OBJECTIVE: This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA. METHODS: We retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co-administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co-administerd VPA and other broad-spectrum antibiotics were allocated to the control group. RESULTS: The exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co-administration (24.6 ± 4.3 µg/mL) compared with that before co-administration (88.8 ± 13.6 µg/mL, p < 0.0001), and it was partly recovered with the termination of co-administration (39.8 ± 13.2 µg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before-during and before-after (p = 0.074 and 0.153, respectively). Seizure duration during VPA-MEPM co-administration was not significantly different from that before co-administration (p = 0.291). CONCLUSIONS: In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020.

Safety of Tigecycline in Patients on Antithrombotic Therapy: A Single-Center Retrospective Study.

INTRODUCTION: The aims of the study were to investigate the risk factors of tigecycline-induced hypofibrinogenemia and to evaluate the safety of tigecycline with concomitant antithrombotic drugs. METHODS: We performed a retrospective analysis of patients who received tigecycline for more than 3 days between January 2015 and June 2019. Clinical and laboratory data were collected including fibrinogen concertation, tigecycline dose, duration of treatment, disease severity, complete blood count, indicators of infection, liver and renal function. Risk factors of hypofibrinogenemia were analyzed by univariate and multivariate analysis. To evaluate the safety of tigecycline and concomitant antithrombotic drugs, bleeding events were assessed by comparing the decline in hemoglobin and the amount of red blood cell transfusion in patients with antithrombotic drugs and those without. RESULTS: This study included a total of 68 cases, 20 of which experienced hypofibrinogenemia while receiving tigecycline treatment. Duration of treatment, cefoperazone/sulbactam combination therapy, and fibrinogen levels prior to initiation of tigecycline were risk factors associated with tigecycline-induced hypofibrinogenemia. There were 26 recorded bleeding incidents, 25 of which happened before the start of tigecycline. Antithrombotic and non-antithrombotic patients did not differ in their hemoglobin decline or need for red blood cell transfusions while taking tigecycline. CONCLUSION: A longer treatment duration, cefoperazone/sulbactam combination therapy, and a lower level of fibrinogen before tigecycline were associated with an increased risk of tigecycline-induced hypofibrinogenemia. A combination of antithrombotic drugs and tigecycline did not aggravate the bleeding events during tigecycline treatment.

Tracing carbonation in cementitious slurry using anthocyanin extracted from fresh or stale petals.

Tracing carbonation in cementitious slurries is very necessary, as it helps to accurately design the durability of infrastructure and achieve carbon neutrality. In this study, anthocyanins extracted from fresh or stale Orychophragmus violaceus (O. violaceus) flowers on campus were prepared, and their capability as substitute of phenolphthalein, to trace carbonation in cementitious materials was studied. Anthocyanin extracted from stale petal had undergone significant deterioration, while that extracted from fresh petal could be cryo-preserved effectively for at least one year. Combining pH, chemical and porosity analysis, the reliability of the novel anthocyanin indicator in tracing carbonation was verified. With the increase of discoloration pH, the carbonation depth read from anthocyanin contained partial carbonated zone, thus was larger than those read from phenolphthalein. Moreover, the varied evolving pattern on the spatial distribution of local saturation degree in cementitious slurries during carbonation was studied, based on which factors affecting the broadness of partial carbonated zone were offered, and circumstances under which anthocyanin would be more accurate than phenolphthalein were offered. For conditions where a broad partial carbonated zone is presented or a condition where higher standard on human safety is required, the new-developed O. violaceus indicator is more competitive over phenolphthalein.

Tigecycline-Associated Coagulopathy: A Single-Center Retrospective Analysis.

INTRODUCTION: The purpose of this study was to assess clinical characteristics and risk factors for tigecycline-associated prothrombin time (PT) and activated partial thromboplastin time (aPTT) prolongation. METHODS: We performed a retrospective analysis on coagulation parameters before and during tigecycline treatment in 55 patients in our hospital with severe infections, mainly pneumonia caused by Acinetobacter baumannii. Patients were divided into different groups according to prolongation of PT and aPTT, and clinical features involved were explored. Univariate and multivariable binary logistic regression analyses were used to identify risk factors for tigecycline-associated PT and aPTT increase. RESULTS: We found that PT values increased from 12.73 ± 1.87 to 13.86 ± 2.06 during the treatment compared with premedication (p < 0.001), and the aPTT level prolonged significantly from 33.63 ± 11.24 to 38.15 ± 11.81 (p < 0.001). The multivariate analyses identified 2 variables that were associated with tigecycline-induced PT prolongation: albumin level (p = 0.018) and weight-adjusted tigecycline dosage (p = 0.005). In addition, treatment duration was the only risk factor for tigecycline-induced aPTT prolongation (p = 0.043). CONCLUSION: Albumin level, weight-adjusted tigecycline dosage, treatment duration may serve as risk indicators for tigecycline-associated coagulation dysfunction. Physicians should be careful with coagulation disorder when prescribing tigecycline in clinical practice, especially in patients with risk factors.

Impact of early protein provision on the mortality of acute critically ill stroke patients.

BACKGROUND: Stroke is the leading cause of death in China, and dysphagia is a common symptom of stroke. For acute critically ill stroke patients, whether the protein provision overwhelming calorie provision impacts the outcome still requires investigation. MATERIALS AND METHODS: We conducted a retrospectively observational study. Acute stroke patients admitted to our neurocritical care unit between January 2013 and January 2017 were enrolled. Primary end points were short-term (30-day) and long-term (6-month) mortality, as well as long-term poor outcome with a modified Rankin scale score ≥4. RESULTS: Of 208 eligible patients, 127 (61.1%) patients were diagnosed with acute ischemic stroke and 81 (38.9%) with intracranial hemorrhage. In multivariate logistic regression analysis, the increased protein provision was significantly associated with reduced 30-day and 6-month mortality (P = .041 and P = .020, respectively) but not 6-month functional outcome (P = .365), whereas calorie provision had no independent association with either mortality or functional outcome. When the protein provision ≤1.74 g/kg/day, there was a 9.37% decrease in short-term mortality and a 9.21% decrease in long-term mortality with each 0.1 g/kg/day increase in protein delivery. The patients were further divided into five subgroups based on the amount of protein provision, and Linear-by-Linear Association tests showed there was a negative linear relationship between the protein provision and 30-day and 6-month mortality (P = .048 and P = .017, respectively). CONCLUSIONS: Early protein provision during the first week is an independent predictor of short-term and long-term mortality in acute critically ill stroke patients.

The Relationship of Compressive Strength and Chemically Bound Water Content of High-Volume Fly Ash-Cement Mortar.

Fly ash (FA) has been widely used in cement-based materials, but limited work has been conducted to establish the relationship between the compressive strength and hydration process of high-volume FA (HVFA)-cement-based material. In this study, the compressive strength and chemically bound water contents of FA-cement-based materials with different water-to-binder ratios (0.4, 0.5, and 0.6) and FA contents (0%, 30%, 40%, 50%, 60%, and 70%) were tested. Replacing more cement with FA reduced the compressive strength and of HVFA-cement-based materials. The compressive strength and chemically bound water content reduced by about 60-70% when 70% cement was replaced by FA. Water-to-binder ratio showed more significant influence on the chemically bonded water at later ages than that at early ages. Based on test results, the prediction equation of chemically bound water content was established, and its accuracy was verified. The error was less than 10%. The relationship between the compressive strength and chemically bound water content was also fitted. The compressive strength and chemically bound water content showed linear relationships for different water-to-binder ratios, hence the compressive strength of HVFA-cement mortar could be predicted with the chemically bound water content and water-to-binder ratios. The results of this study could be used for the prediction of the compressive strength development of HVFA-cement mortars, and is helpful to develop the mix design method of HVFA-cement-based materials.

Evaluation of the Thermal and Shrinkage Stresses in Restrained High-Performance Concrete.

The early age volume deformation is the main course for the cracking of high-performance concrete (HPC). Hence, the shrinkage behavior and the restrained stress development of HPC under different restraints and curing conditions were experimentally studied in this paper. The method to separate the stress components in the total restraint stress was proposed. The total restrained stress was separated into autogenous shrinkage stress, drying shrinkage stress and thermal stress. The results showed that the developments of the free shrinkage (autogenous shrinkage and drying shrinkage) and the restrained stress were accelerated when the drying began; but the age when the drying began did not significantly influence the long-term shrinkage and restrained stress of HPC; the autogenous shrinkage stress continuously contributed to the development of the total restrained stress in HPC; the drying shrinkage stress developed very rapidly soon after the drying began; and the thermal stress was generated when the temperature dropped. The thermal stress was predominant at the early age, but the contributions of the three stresses to the total restrained stress were almost the same at the age of 56 d in this study.

The effectiveness of phenobarbital in patients with refractory status epilepticus undergoing therapeutic plasma exchange.

This study aimed to elucidate the therapeutic concentration range of phenobarbital (PB) for adults, as well as the influence of therapeutic plasma exchange (TPE) on plasma concentration of PB. We retrospectively reviewed consecutive patients diagnosed with refractory status epileptic (RSE) and treated with a bolus injection of PB as well as TPE, admitted to our neurocritical care unit from November 2015 to October 2016. Continuous electroencephalographic monitoring was performed routinely for these patients. TPE was performed using a continuous-flow cell separator. PB concentrations in the plasma and cerebrospinal fluid were measured by gas chromatography-mass spectrometer analysis before and after TPE. A total of seven patients were included; among these, one patient had RSE related to anti-N-methyl-D-aspartate receptor encephalitis, another patient had Hashimoto encephalopathy, and five patients had undetermined etiology. For patients with clinical and electrographic control (n=6), the plasma concentration of PB ranged from 138 to 243.7 µg/ml. In addition, of six paired plasma samples (before and after TPE) obtained from three patients, no significant differences between the concentrations of PB were detected (P=0.6), suggesting that TPE may not significantly affect the plasma concentration of PB. This study confirmed that PB more than 100 µg/ml was effective for adults with RSE. Moreover, TPE may not have an influence on the plasma concentration of PB.Video abstract: http://links.lww.com/WNR/A489.

Investigation of the Pharmaceutical Care in One Elderly Parkinson's Disease Patient with Psychotic Symptoms.

A 66-year-old male patient with a 10-year course of Parkinson's disease (PD) was admitted for hallucination lasting a half a month. After treatment with levodopa/carbidopa, selegiline, and piribedil, the patient's motor symptoms were improved while no significant effects were observed on psychotic symptoms. A clinical pharmacist analyzed the pharmacologic and pharmacokinetic characteristics of selegiline and piribedil, summarized the scheme of PD with psychotic symptoms in the literature, and discovered that selegiline might potentiate psychotic side effects of piribedil, while the use of levodopa/carbidopa cannot be ruled out either. Finally, the clinical pharmacist proposed to reduce the dosage of levodopa/carbidopa, increase the dosage of selegiline and quetiapine, and discontinue piribedil. The clinician accepted this suggestion. After the adjustment of medication, the patient's motor symptoms were absolutely improved and the psychotic symptoms were notably improved. This case study suggests that long-term treatment with levodopa/carbidopa and piribedil, along with the progression of the disease itself, could contribute to the emergence of psychotic symptoms in PD. Additionally, selegiline could potentiate psychotic side effects of piribedil. Neurology clinical pharmacists should work alongside neurology clinicians at the bedside to optimize pharmacotherapy, improve patient safety, and contribute to scholarly efforts.

TMC120 displayed potent cytotoxic effect on human cervical carcinoma through enhancing the polymerization of microtubules.

OBJECTIVE: In the post-HAART era, the incidence of some AIDS-defining cancers declined markedly likely reflecting HAART-related improvements in immunity, whereas incidence of some cancers such as cervical cancer has not been affected. Therefore, it is valuable to find whether antiretroviral drugs or prophylactic microbicides could treat or prevent these cancers, especially the cervical cancer. DESIGN: We screened the anti-HIV drugs, approved or in phase III clinical trials, to identify a potential anticancer drug candidate. METHODS: We chose cervical HeLa and SiHa cancer cells and focused on studying the antitumor effects in vitro and in vivo. Cell proliferation was measured by MTT assay, the cytotoxic effect was obtained through apoptosis as evidenced by Annexin V flow cytometry assay because of the arresting of cancer cells in G2/M phase of cell cycle. Nude mice xenograft model was performed to detect the antitumor effect in vivo. RESULTS: TMC120 was identified as a potential anticancer drug candidate. TMC120 displayed potent cytotoxic effect on various human cancer cells, including cervical carcinoma cell line HeLa and SiHa. Further mechanism study showed that TMC120 enhanced the polymerization of microtubules, which was followed by mitotic arrest, as well as abnormal mitotic spindles. TMC120 also substantially retarded the growth rate of the tumor in vivo. CONCLUSION: TMC120 is a potential chemoprophylactic and therapeutic agent for cervical cancers in a manner similar to paclitaxel, and could be suitable for helping healthy women to prevent HIV infection and cervical cancer.

ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro.

Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC50 values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 µmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5-20 µmol/L) dose-dependently induced G1/G0-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21Waf1/Cip1 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G1/G0-phase arrest. Knockdown of p21Waf1/Cip1 attenuated ABT-263-induced G1/G0-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity.

[Synergistic anti-tumor effect of obatoclax and MG-132 in esophageal cancer cell line CaES-17].

OBJECTIVE: To explore whether MG-132 could enhance the anti-tumor activity of obatoclax against esophageal cancer cell line CaES-17. METHODS: MTT assay was used to determine the cytotoxicity of obatoclax and MG-132 in CaES-17 cells. The IC(50) of obatoclax and MG-132 were used to determine the molar ratio (1:2.4) of the two drugs for combined treatment of the cells. The concentrations of obatoclax and MG-132 ranged from 1/8 IC(50) to 4 IC(50) after serial dilution, and their combination index (CI) was calculated using CompuSyn software. The expression of ubiquitin and the cleavage of PARP, caspase-9, phospho-histone H3 and phospho-aurora A/B/C in the exposed cells were examined with Western blotting; the cell apoptosis was measured by flow cytometry with Annexin V staining, and the percentage of cells in each cell cycle phase was also determined by flow cytometry. RESULTS: The CI of obatoclax and MG-132 was 0.296 for a 50% inhibition of Caes-17 cells and was 0.104 for a 95% inhibition. The cells treated with obatoclax or MG-132 alone showed increased expression of ubiquitin and cleavage of PARP and caspase-9. Compared with the cells treated with obatoclax or MG-132 alone, the cells with a combined treatment exhibited significantly increased expression of ubiquitin, cleavage of PARP and caspase-9, and expression of phospho-Histone H3 (P<0.05). The combined treatment of the cells also resulted in significantly increased expression of phospho-Aurora A/B/C compared with obatoclax treatment alone. The cells with the combined treatment showed significantly higher percentages of apoptotic cells and cells in sub-G(1) and G(2)/M phases compared with the cells treated with either of the drugs (P<0.05). CONCLUSION: Obatoclax combined with MG-132 shows a significant synergistic anti-tumor effect against esophageal cancer CaES-17 cells by inducing apoptosis and cell cycle arrest.

Obatoclax impairs lysosomal function to block autophagy in cisplatin-sensitive and -resistant esophageal cancer cells.

Obatoclax, a pan-inhibitor of anti-apoptotic Bcl-2 proteins, exhibits cytotoxic effect on cancer cells through both apoptosis-dependent and -independent pathways. Here we show that obatoclax caused cytotoxicity in both cisplatin-sensitive and -resistant esophageal cancer cells. Although obatoclax showed differential apoptogenic effects in these cells, it consistently blocked autophagic flux, which was evidenced by concomitant accumulation of LC3-II and p62. Obatoclax was trapped in lysosomes and induced lysosome clustering. Obatoclax also substantially reduced the expression of lysosomal cathepsins B, D and L. Moreover, cathepsin knockdown was sufficient to induce cytotoxicity, connecting lysosomal function to cell viability. Consistent with the known function of autophagy, obatoclax caused the accumulation of polyubiquitinated proteins and showed synergy with proteasome inhibition. Taken together, our studies unveiled impaired lysosomal function as a novel mechanism whereby obatoclax mediates its cytotoxic effect in esophageal cancer cells.

Celecoxib antagonizes the cytotoxicity of oxaliplatin in human esophageal cancer cells by impairing the drug influx.

It has been demonstrated that COX-2-selective inhibitor celecoxib shows synergy with oxaliplatin for suppressing tumor growth. However, the benefit of adding celecoxib to oxaliplatin-based regimen in human esophageal cancer is largely unknown. In the present study, we demonstrated that celecoxib antagonized oxaliplatin-induced cytotoxicity and apoptosis independent of COX-2 inhibition in human esophageal cancer cells. Celecoxib decreased cellular oxaliplatin accumulation and Pt-DNA adduction formation due to reduced drug influx. Celecoxib alone or combined with oxaliplatin substantially reduced the expression of organic cation transporter 2 (OCT2). To this end, OCT2 knockdown was sufficient to reduce oxaliplatin uptake, connecting OCT2 expression to oxaliplatin accumulation. Moreover, oxaliplatin combined with celecoxib also showed no beneficial effect when compared with monotherapy in esophageal cancer cell-xenografted nude mice. To conclude, our data provide evidence that the addition of celecoxib to oxaliplatin-containing regimens for patients with OCT2-expressing cancers should be cautious.

[Cellular response to altered autophagy activity in human fibroblast cells overexpressing Ha-RasV12].

OBJECTIVE: To study the effect of oncogenic Ras overexpression on autophagic activity in human fibroblast cells in vitro. METHODS: BJ cells were transfected with H-RasV12 or control vector and treated with chloroquine, small interfering RNA (siRNA) for ATG7, or rapamycin. The cellular responses were analyzed by monitoring the parameters and biomarkers for cell growth, senescence and cell death. RESULTS: In BJ cells overexpressing H-RasV12, chloroquine treatment resulted in more prominent cell senescence and a significantly increased cell death rate. Suppression of ATG7 mediated by siRNA also promoted cell senescence. Rapamycin treatment also caused an increased cell death rate but attenuated senescence in surviving cells. In control BJ cells, the cellular response to chloroquine included senescence and cell death, which occurred slowly. Rapamycin treatment and siRNA suppression of ATG7 had no obvious effect on control BJ cells. CONCLUSION: Stable cellular overexpression of oncogenic Ras causes tightly controlled suppression of the autophagic activity of human fibroblast cells, and such changes produce significant effect on cell senescence and survival.

Induction of autophagy counteracts the anticancer effect of cisplatin in human esophageal cancer cells with acquired drug resistance.

Cisplatin-based chemotherapy frequently resulted in acquired resistance. The underpinning mechanism of such resistance remains obscure especially in relation to autophagic response. This study thus investigated the role of autophagy in the anticancer activity of cisplatin in human esophageal cancer cells with acquired cisplatin resistance. In response to cisplatin treatment, EC109 cells exhibited substantial apoptosis and senescence whereas cisplatin-resistant EC109/CDDP cells exhibited resistance. In this respect, cisplatin increased ERK phosphorylation whose inhibition by MEK inhibitor significantly attenuated the cytotoxic and cytostatic effect of cisplatin. Notably, cisplatin preferentially induces autophagy in EC109/CDDP cells but not in EC109 cells. Moreover, the induction of autophagy was accompanied by the suppression of mTORC1 activity. Abolition of autophagy by pharmacological inhibitors or knockdown of ATG5/7 re-sensitized EC109/CDDP cells. Co-administration of an autophagy inhibitor chloroquine and cisplatin significantly suppressed tumor growth whereas cisplatin monotherapy failed to elicit anticancer activity in nude mice xenografted with EC109/CDDP cells. To conclude, our data implicate autophagic response as a key mechanism of acquired resistance to cisplatin, suggesting that autophagy is a novel target to improve therapy efficiency of cisplatin toward human esophageal cancers with acquired resistance.

[Celecoxib antagonizes the cytotoxic effect of carboplatin in human esophageal cancer cells].

OBJECTIVE: To explore the antagonizing effect of celecoxib against the cytotoxicity of carboplatin in human esophageal cancer cells. METHODS: The cell viability of cisplatin-resistant cell line EC109/CDDP and its parental cell line EC109 exposed to carboplatin alone or carboplatin plus celecoxib was determined by MTT assay. The expression of CTR1, caspase-3 activation and PARP cleavage in the exposed cells were examined by Western blotting. Caspase-3 activity and cell apoptosis after the exposure were detected with Caspase-3/7 assay and flow cytometry, respectively. The effect of celecoxib on carboplatin accumulation in the cells was measured using inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Celecoxib treatment significantly increased the IC50 of carboplatin, suppressed carboplatin-induced caspase-3 and PARP cleavage and caspase-3 activity in EC109 and EC109/CDDP cells. Celecoxib also inhibited carboplatin-induced apoptosis and suppressed intracellular carboplatin accumulation in both cell lines. A combined exposure to celecoxib and carboplatin did not cause significant changes in the protein expression of CTR1. CONCLUSION: Celecoxib antagonizes the cytotoxic effect of carboplatin and inhibits carboplatin-induced apoptosis in human esophageal cancer cells by reducing intracellular carboplatin accumulation.

Obatoclax induces G1/G0-phase arrest via p38/p21(waf1/Cip1) signaling pathway in human esophageal cancer cells.

Pan-Bcl-2 family inhibitor obatoclax has been demonstrated to be effective against various cancers, of which the mechanism of action is not fully understood. In this study, we demonstrate that obatoclax suppressed esophageal cancer cell viability with concomitant G1/G0-phase cell cycle arrest. At the tested concentrations (1/2 IC50 and IC50), obatoclax neither induced PARP cleavage nor increased the Annexin V-positive population, suggesting G1/G0-phase arrest rather than apoptosis accounts for most of the reduction of cell viability produced by obatoclax. Double knockdown of Bak and Bax by small interference RNA failed to block obatoclax-induced G1/G0-phase arrest, implying its role in cell cycle progression is Bak/Bax-independent. The cell cycle arresting effect of obatoclax was associated with up-regulation of p21(waf1/Cip1). Knockdown of p21(waf1/Cip1) significantly attenuated obatoclax-induced G1/G0-phase arrest. Although obatoclax stimulated phosphorylation of Erk, p38, and JNK, pharmacological inhibition of p38 but not Erk or JNK blocked obatoclax-induced G1/G0-phase arrest. Moreover, knockdown of p38 abolished the cell cycle arresting effect of obatoclax. In consistent with this finding, inhibition of p38 blocked obatoclax-induced p21(waf1/Cip1) expression while inhibition of Erk or JNK failed to exert similar effect. To conclude, these findings suggest that obatoclax induced cell cycle arrest via p38/p21(waf1/Cip1) signaling pathway. This study may shed a new light on the anti-cancer activity of obatoclax in relation to cell cycle arrest.

Synthesis, selective cytotoxicities and probable mechanism of action of 7-methoxy-3-arylflavone-8-acetic acids.

Thirteen new analogues of flavone-8-acetic acid, that is, compounds 10a-m bearing a methoxy group at the 7-position and diverse subsitiuents on the benzene ring at the 2- and 3-positions of flavone nucleus, were synthesized and evaluated for their direct antiproliferative effects on two human tumor cell lines and for their indirect antiproliferative activities in the transwell co-culture system. The results indicated that most of compounds 10a-m showed moderate direct cytotoxicities. Among them, compound 10i exhibited higher direct cytotoxicity and selectivity for both cell lines over BJ human foreskin fibroblast cells than 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Interestingly, compared with DMXAA, compound 10e showed comparable indirect cytotoxicity and higher selectivity. In addition, compound 10e was found to be able to induce tumor necrosis factor α (TNF-α) production in human peripheral blood mononuclear cells.

A novel synthetic dibenzocyclooctadiene lignan analog XLYF-104-6 attenuates lipopolysaccharide-induced inflammatory response in RAW264.7 macrophage cells and protects BALB/c mice from sepsis.

The wide range of inflammation mechanisms under control by NF-κB makes this pathway as an attractive target for new anti-inflammatory drugs. Herein, we showed that a new dibenzocyclooctadiene lignan analog XLYF-104-6, with a chemical name of 1,2,3,10,11-pentamethoxydibenzocycloocta-6,7-[c] pyrrole-1,3-dione, inhibited lipopolysaccharide (LPS)-induced NF-κB activation in RAW264.7 cells through preventing IκBα degradation and p65 nuclear translocation. The inhibitory activity of this compound on NF-κB activation contributes to the reduction of LPS-induced TNF-α and IL-6 productions. Notably, XLYF-104-6 suppressed LPS-induced iNOS expression and NO production in a NF-κB independent manner, since IKK inhibitor BAY 11-7082 has failed to exert similar inhibitory effect on iNOS expression and NO production. In addition, XLFY-104-6 also exerted anti-inflammatory action in endotoxemic mice by decreasing plasma LPS-induced TNF-α and IL-1ß levels as well as increasing plasma LPS-induced IL-10 concentrations. These findings suggest XLYF-104-6 could act as a leading compound for developing a potential anti-inflammatory drug.