Histochemical and histomorphological evidence of the modulating role of 1-isothiocyanate-4-methyl sulfonyl butane on cisplatin-induced testicular-pituitary axis degeneration and cholesterol homeostasis in male Sprague-Dawley rats.

BACKGROUND: This study examine the histochemical and histomorphological effect of 1-isothiocyanato-4-methyl sulfonyl butane (SFN) on cisplatin (CP) induced testicular alteration and cholesterol homeostasis. MATERIALS AND METHODS: Ninety adult-male Sprague-Dawley rats were randomized into nine groups of ten (n=10) rats each. Group A (control) received normal saline, group B received a single dose of 10mg/Kg body weight (bwt) CP (i.p.), group C received 50mg/Kg bwt of SFN, group D received 100mg/Kg bwt of SFN, group E received 10mg/Kg bwt CP and 50mg/Kg bwt of SFN, group F received 10mg/Kg bwt CP and 100mg/Kg bwt of SFN, group G received 10mg/Kg bwt CP and 50mg/Kg bwt vitamin C, group H received 50mg/Kg bwt of SFN and 10mg/Kg bwt CP, group I received 100mg/Kg bwt of SFN and 10mg/Kg bwt CP. The procedure lasted for 56 days. Testicular histomorphology and histochemistry, testicular testosterone, sperm parameters, total antioxidant status (TSA), total oxidant status (TOS), oxidative stress index (OSI), and serum lipid profile were examined. RESULTS: Cisplatin decrease intra-testicular testosterone, sperm quality, and expression of glycogen and increases testicular TOS and OSI, serum lipid profile, collagen, and disruption of germinal epithelium. However, the intervention of SFN reversed the effect of CP on testes' weight and volume, DSP, ESP, testosterone production, TAS, TOS, and OSI. Histoarchitectecture showing normal seminiferous tubules and even distribution of glycogen and collagen fibers. CONCLUSION: Treatment with SFN ameliorate CP-induced testicular toxicity by reversing the cytotoxic mechanisms of CP.

Targeted metabolomics combined with network pharmacology to reveal the protective role of luteolin in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease that significantly endangers human health, where metabolism may drive pathogenesis: a shift from mitochondrial oxidation to glycolysis occurs in diseased pulmonary vessels and the right ventricle. An increase in pulmonary vascular resistance in patients with heart failure with a preserved ejection fraction portends a poor prognosis. Luteolin exists in numerous foods and is marketed as a dietary supplement assisting in many disease treatments. However, little is known about the protective effect of luteolin on metabolism disorders in diseased pulmonary vessels. In this study, we found that luteolin apparently reversed the pulmonary vascular remodeling of PAH rats by inhibiting the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs). Moreover, network pharmacology and metabolomics results revealed that the arachidonic acid pathway, amino acid pathway and TCA cycle were dysregulated in PAH. A total of 14 differential metabolites were significantly changed during the PAH, including DHA, PGE2, PGD2, LTB4, 12-HETE, 15-HETE, PGF2α, and 8-iso-PGF2α metabolites in the arachidonic acid pathway, and L-asparagine, oxaloacetate, N-acetyl-L-ornithine, butane diacid, ornithine, glutamic acid metabolites in amino acid and TCA pathways. However, treatment with luteolin recovered the LTB4, PGE2, PGD2, 12-HETE, 15-HETE, PGF2α and 8-iso-PGF2α levels close to normal. Meanwhile, we showed that luteolin also downregulated the gene and protein levels of COX 1, 5-LOX, 12-LOX, and 15-LOX in the arachidonic acid pathway. Collectively, this work highlighted the metabolic mechanism of luteolin-protected PAH and showed that luteolin would hold great potential in PAH prevention.

Exploring nordihydroguaretic acid (NDGA) as a plausible neurotherapeutic in the experimental paradigm of autism spectrum disorders targeting nitric oxide pathway.

The present study investigates the neuro-protective ability of nordihydroguaretic acid (NDGA) in the experimental paradigm of autism spectrum disorders (ASD) and further decipher the nitric oxide pathway's role in its proposed action. An intracerebroventricular infusion of 4 µl of 1 M PPA was given in the lateral ventricle's anterior region to induce autism-like phenotype in male rats. Oral administration of NDGA (5, 10 & 15 mg/kg) was initiated from the 3rd day lasting till the 28th day. L-NAME (50 mg/kg) and L-Arginine (800 mg/kg) were also given individually and combined to explore NDGA's ability to act via the nitric oxide pathway. Behavior tests for sociability, stereotypy, anxiety, depression, novelty, repetitive and perseverative behavior were carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To assess the involvement of the nitric oxide pathway, levels of iNOS and homocysteine were estimated. Treatment with NDGA significantly restored behavioral, biochemical, neurological, and molecular deficits. Hence, NDGA can be used as a neurotherapeutic agent in ASD. Targeting nitric oxide pathway mediated oxidative & nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway. The evaluation of iNOS and homocysteine levels conclusively establishes the nitric oxide pathway's role in causing behavioral, biochemical & molecular deficits and NDGA's beneficial effect in restoring these alterations.

Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1ß pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.

DBPR108, a novel dipeptidyl peptidase-4 inhibitor with antihyperglycemic activity.

AIMS: Dipeptidyl peptidase 4 (DPP-4) is a valid molecular drug target from which its inhibitors have been developed as medicines for treating diabetes. The present study evaluated a new synthetic DPP-4-specific inhibitor of small molecule DBPR108 for pharmacology and pharmacokinetic profiles. MAIN METHODS: DBPR108 of various doses was orally administered to rats, diabetic mice, and dogs and the systemic circulating DPP-4 activities in the animals were measured to demonstrate the pharmacological mechanisms of action via DPP-4 inhibition. Upon an oral administration of DBPR108, the serum active GLP-1 and insulin levels of the rats challenged with an oral glucose ingestion were measured. Oral glucose tolerance test in diet-induced obese mice was performed to examine if DBPR108 increases the glucose tolerability in animals. KEY FINDINGS: Orally administered DBPR108 inhibited the systemic plasma DPP-4 activities in rats, dogs and diabetic mice in a dose-dependent manner. DBPR108 caused elevated serum levels of active GLP-1 and insulin in the rats. DBPR108 dose-dependently increased the glucose tolerability in diet-induced obese (DIO) mice and, furthermore, DIO mice treated with DBPR108 (0.1 mg/kg) in combination with metformin (50 or 100 mg/kg) showed a prominently strong increase in the glucose tolerability. SIGNIFICANCE: DBPR108 is a novel DPP-4-selective inhibitor of small molecule that demonstrated potent in vivo pharmacological effects and good safety profiles in animals. DBPR108 is now a drug candidate being further developed in the clinical studies as therapeutics for treating diabetes.

CPI-1189 protects neuronal cells from oxygen glucose deprivation/re-oxygenation-induced oxidative injury and cell death.

Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) induces profound oxidative injury and neuronal cell death. It mimics ischemia-reperfusion neuronal injury. CPI-1189 is a novel tumor necrosis factor alpha-inhibiting compound with potential neuroprotective function. Here in SH-SY5Y neuronal cells and primary murine cortical neurons, CPI-1189 pretreatment potently inhibited OGDR-induced viability reduction and cell death. In OGDR-stimulated neuronal cells, p38 phosphorylation was blocked by CPI-1189. In addition, CPI-1189 alleviated OGDR-induced reactive oxygen species production, lipid peroxidation, and glutathione consumption. OGDR-induced neuronal cell apoptosis was also inhibited by CPI-1189 pretreatment. Furthermore, in SH-SY5Y cells and cortical neurons, CPI-1189 alleviated OGDR-induced programmed necrosis by inhibiting mitochondrial p53-cyclophilin D-adenine nucleotide translocase 1 association, mitochondrial depolarization, and lactate dehydrogenase release to the medium. In summary, CPI-1189 potently inhibited OGDR-induced oxidative injury and neuronal cell death.

Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains.

Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 (SST4) without endocrine actions. SST4 is suggested to be a unique novel drug target for chronic neuropathic pain, and depression, as a common comorbidity. However, its neuronal expression and cellular mechanism are poorly understood. Therefore, our goals were (i) to elucidate the expression pattern of Sstr4/SSTR4 mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the Sstr4/SSTR4-expressing neuronal populations in the mouse and human brains. Here, we describe SST4 expression pattern in the nuclei of the mouse nociceptive and anti-nociceptive pathways as well as in human brain regions, and provide neurochemical and electrophysiological characterization of the SST4-expressing neurons. Intense or moderate SST4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST4 agonist J-2156 significantly decreased the firing rate of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K+ current (M-current) leading to remarkable inhibition. These are the first translational results explaining the mechanisms of action of SST4 agonists as novel analgesic and antidepressant candidates.

Identification and validation of novel and more effective choline kinase inhibitors against Streptococcus pneumoniae.

Streptococcus pneumoniae choline kinase (sChoK) has previously been proposed as a drug target, yet the effectiveness of the first and only known inhibitor of sChoK, HC-3, is in the millimolar range. The aim of this study was thus to further validate sChoK as a potential therapeutic target by discovering more powerful sChoK inhibitors. LDH/PK and colorimetric enzymatic assays revealed two promising sChoK inhibitor leads RSM-932A and MN58b that were discovered with IC50 of 0.5 and 150 µM, respectively, and were shown to be 2-4 magnitudes more potent than the previously discovered inhibitor HC-3. Culture assays showed that the minimum inhibitory concentration (MIC) of RSM-932A and MN58b for S. pneumoniae was 0.4 µM and 10 µM, respectively, and the minimum lethal concentration (MLC) was 1.6 µM and 20 µM, respectively. Western blot monitoring of teichoic acid production revealed differential patterns in response to each inhibitor. In addition, both inhibitors possessed a bacteriostatic mechanism of action, and neither interfered with the autolytic effects of vancomycin. Cells treated with MN58b but not RSM-932A were more sensitive to a phosphate induced autolysis with respect to the untreated cells. SEM studies revealed that MN58b distorted the cell wall, a result consistent with the apparent teichoic acid changes. Two novel and more highly potent putative inhibitors of sChoK, MN58b and RSM-932A, were characterized in this study. However, the effects of sChoK inhibitors can vary at the cellular level. sChoK inhibition is a promising avenue to follow in the development of therapeutics for treatment of S. pneumoniae.

Cyhalofop-butyl and Glyphosate Multiple-Herbicide Resistance Evolved in an Eleusine indica Population Collected in Chinese Direct-Seeding Rice.

Eleusine indica is a typical xerophytic weed species with a cosmopolitan distribution. It is invasive and highly adaptable to diverse habitats and crops. Due to rice cropping-pattern changes, E indica has become one of the main dominant grass weeds infecting direct-seeding paddy fields. A Chinese E. indica population has evolved multiple-herbicide resistance to cyhalofop-butyl and glyphosate. In this study, the multiple-resistance profile of E. indica to these two different types of herbicides and their resistance mechanisms were investigated. Whole-plant dose-response assays indicated that the multiple-herbicide-resistant (MHR) population exhibited 10.8-fold resistance to cyhalofop-butyl and 3.1-fold resistance to glyphosate compared with the susceptible (S) population. ACCase sequencing revealed that the Asp-2078-Gly mutation was strongly associated with E. indica resistance to cyhalofop-butyl. The MHR plants accumulated less shikimic acid than S plants at 4, 6, and 8 days after glyphosate treatment. In addition, no amino acid substitution in the EPSPS gene was found in MHR plants. Further analysis revealed that the relative expression level of EPSPS in MHR plants was 6-10-fold higher than that in S plants following glyphosate treatment, indicating that EPSPS overexpression may contribute to the glyphosate resistance. Furthermore, the effectiveness of nine post-emergence herbicides against E. indica were evaluated, and one PPO inhibitor pyraclonil was identified as highly effective in controlling the S and MHR E. indica populations.

Structural optimization of natural product nordihydroguaretic acid to discover novel analogues as AcrB inhibitors.

Drug efflux pumps confer multidrug resistance to dangerous bacterial pathogens which makes these proteins promising drug targets. Herein, we present initial chemical optimization and structure-activity relationship (SAR) data around a previously described efflux pump inhibitor, nordihydroguaretic acid (NDGA). Four series of novel NDGA analogues that target Escherichia coli AcrB were designed, synthesized and evaluated for their ability to potentiate the activity of antibiotics, to inhibit AcrB-mediated substrate efflux and reduce off-target activity. Nine novel structures were identified that increased the efficacy of a panel of antibiotics, inhibited drug efflux and reduced permeabilization of the bacterial outer and inner membranes. Among them, WA7, WB11 and WD6 possessing broad-spectrum antimicrobial sensitization activity were identified as NDGA analogues with favorable properties as potential AcrB inhibitors, demonstrating moderate improvement in potency as compared to NDGA. In particular, WD6 was the most broadly active analogue improving the activity of all four classes of antibacterials tested.

Molecular basis of resistance to ACCase-inhibiting herbicide cyhalofop-butyl in Chinese sprangletop (Leptochloa chinensis (L.) Nees) from China.

Chinese sprangletop (Leptochloa chinensis (L.) Nees) is one of the most troublesome grass weeds in rice in China. Seven suspected cyhalofop-butyl-resistant L. chinensis populations were collected from different rice fields with a history of cyhalofop-butyl use. The level of resistance and resistance mechanisms in seven populations were studied. Dose-response tests indicated that five populations (JS3, JS4, JS6, JS7 and JS8) had evolved high-level resistance (26.9 to 123.0-fold) to cyhalofop-butyl compared with the susceptible (S) population, and other two populations (JS2 and JS5) were still sensitive to the herbicide. Two acetyl-coenzyme A carboxylase (ACCase) genes were cloned from each population, and three different ACCase mutations (Ile-1781-Leu, Trp-1999-Cys, and Trp-2027-Cys) in ACCase2 gene were determined in different resistant (R) populations. In addition, no resistance-conferring mutations was detected in the R population (JS7), and ACCase gene expression was similar between the S and R populations. Thus, non-target-site resistance mechanisms may be involved in the JS7 population. Moreover, the patterns of cross-resistance of JS6 (Ile-1781-Leu), JS4 (Trp-1999-Cys), JS8 (Trp-2027-Cys), and JS7 (unknown resistance mechanisms) populations to other ACCase-inhibiting herbicides were determined. The JS6 and JS8 populations showed resistance to fenoxaprop-P-ethyl, metamifop, clethodim and pinoxaden, the JS4 population was resistant to fenoxaprop-P-ethyl, metamifop and pinoxaden, and the JS7 population had resistance only to fenoxaprop-P-ethyl and metamifop. These results indicated the diversity of the target-site mutations in ACCase gene of L. chinensis, and provide a better understanding of cross-resistance in L. chinensis, which would be helpful for the management of cyhalofop-butyl-resistant L. chinensis.

J-2156, a somatostatin receptor type 4 agonist, alleviates mechanical hyperalgesia in a rat model of chronic low back pain.

Chronic low back pain (LBP) ranks among the most common reasons for patient visits to healthcare providers. Drug treatments often provide only partial pain relief and are associated with considerable side-effects. J-2156 [(1'S,2S)-4amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4"-methyl-1"-naphthalenesulfonylamino)butanamide] is an agonist that binds with nanomolar affinity to the rat and human somatostatin receptor type 4 (SST4 receptor). Hence, our aim was to assess the efficacy of J-2156 for relief of chronic mechanical LBP in a rat model. Male Sprague Dawley rats were anaesthetised and their lumbar L4/L5 and L5/L6 intervertebral discs (IVDs) were punctured (0.5 mm outer diameter, 2 mm-deep) 10 times per disc. Sham-rats underwent similar surgery, but without disc puncture. For LBP-rats, noxious pressure hyperalgesia developed in the lumbar axial deep tissues from day 7 to day 21 post-surgery, which was maintained until study completion. Importantly, mechanical hyperalgesia did not develop in the lumbar axial deep tissues of sham-rats. In LBP-rats, single intraperitoneal (i.p.) injection of J-2156 (3, 10, 30 mg kg-1) alleviated primary and secondary hyperalgesia in the lumbar axial deep tissues at L4/L5 and L1, respectively. This was accompanied by a reduction in the otherwise augmented lumbar (L4-L6) dorsal root ganglia expression levels of the pro-nociceptive mediators: phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) and phosphorylated p44/p42 MAPK and a reduction in pp38 MAPK in the lumbar enlargement of the spinal cord. The SST4 receptor is worthy of further investigation as a target for discovery of novel analgesics for the relief of chronic LBP.

Choline Uptake and Metabolism Modulate Macrophage IL-1ß and IL-18 Production.

Choline is a vitamin-like nutrient that is taken up via specific transporters and metabolized by choline kinase, which converts it to phosphocholine needed for de novo synthesis of phosphatidylcholine (PC), the main phospholipid of cellular membranes. We found that Toll-like receptor (TLR) activation enhances choline uptake by macrophages and microglia through induction of the choline transporter CTL1. Inhibition of CTL1 expression or choline phosphorylation attenuated NLRP3 inflammasome activation and IL-1ß and IL-18 production in stimulated macrophages. Mechanistically, reduced choline uptake altered mitochondrial lipid profile, attenuated mitochondrial ATP synthesis, and activated the energy sensor AMP-activated protein kinase (AMPK). By potentiating mitochondrial recruitment of DRP1, AMPK stimulates mitophagy, which contributes to termination of NLRP3 inflammasome activation. Correspondingly, choline kinase inhibitors ameliorated acute and chronic models of IL-1ß-dependent inflammation.

Changes in spatio-temporal localization of tripeptidyl peptidase II (TPPII) in murine colon adenocarcinoma cells during aggresome formation: a microscopy study based on a novel fluorescent proteasome inhibitor.

Extralysosomal proteolysis is a multistep process involving the Ubiquitin- Proteasome System (UPS) and supplementary peptidases. Tripeptidyl peptidase II (TPPII) is the most extensively characterized enzyme, supplementing and sometimes substituting for proteasomal functions. In response to proteasome inhibition, polyubiquitinated proteins acting as proteasome substrates aggregate with proteasomes and form aggresomes. Several proteasome inhibitors are used as anti-cancer drugs. Thus, in our study, we used a novel fluorescent-tagged proteasome inhibitor BSc2118 to induce aggresome formation in C26 murine colon adenocarcinoma cells. It allowed us to obtain effective, inhibitor-based, proteasome staining in vivo. This method has been validated by standard post-fixed indirect immunostaining and also allowed co-immunodetection of TPPII and polyubiquitinated proteins under laser scanning confocal microscopy. We found that in the absence of the inhibitor, TPPII is diffusely dispersed within the cytoplasm of C26 cells. The proteasome and ubiquitin-rich perinuclear region failed to display enhanced TPPII staining. However, when proteasome function was impaired by the inhibitor, TPPII associated more closely with both the proteasome and polyubiquitinated proteins via TPPII recruitment to the perinuclear region and subsequently into emerging aggresomal structures. Furthermore, we have demonstrated the dynamic recruitment of TPPII into the developing aggresome: TPPII in the early aggresome was dispersed within the central part but subsequently aggregated on the surface of this structure. In the mature aggresome of C26 cells TPPII formed a spherical mantle, which surrounded the round core containing proteasomes and polyubiquitinated proteins. Our morphological data indicate that TPPII displays spatial localization with proteasomes especially upon proteasome inhibition in aggresomes of C26 cells.

Pd(II) and Pt(II) saccharinate complexes of bis(diphenylphosphino)propane/butane: Synthesis, structure, antiproliferative activity and mechanism of action.

[M(sac)2(dppp)] (1 and 2), [M(dppp)2](sac)2 (3 and 4) and [M(sac)2(dppb)] (5 and 6) complexes, where M = PdII (1, 3 and 5) and PtII (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/HSA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondrial depolarization and DNA damage.

Isobutylhydroxyamides from Sichuan Pepper and Their Protective Activity on PC12 Cells Damaged by Corticosterone.

The pericarp of Zanthoxylum bungeanum Maxim., commonly known as Sichuan pepper, is a widely used spice to remove fishy odor and add palatable taste. A phytochemical investigation of the 95% ethanol extract of Sichuan pepper resulted in the isolation of 21 isobutylhydroxyamides, including 8 new ones named ZP-amides G-N, among which the chiral resolution of racemic ZP-amide A and ZP-amide B was successfully accomplished. The protective activity on corticosterone-treated PC12 cells of the isolated isobutylhydroxyamides was also evaluated. The new compounds 3-5 and the known compounds 1, 1a, 2, 2a, 11, and 15 improved the survival rate of PC12 cells. The bioactivity studies disclosed the potential of Sichuan pepper to be developed as new neuroprotective functional food.

Novel butanehydrazide derivatives of purine-2,6-dione as dual PDE4/7 inhibitors with potential anti-inflammatory activity: Design, synthesis and biological evaluation.

A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties. The inhibition of both the cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect. Compounds 31, 34, and 37 in the in vivo study in rats with LPS-induced endotoxemia decreased the maximum concentration of this proinflammatory cytokine by 53, 84 and 88%, respectively.

Modification of cellulose foam paper for use as a high-quality biocide disinfectant filter for drinking water.

Development of a foam-formed cellulose filter paper with high wet strength was carried out for application as a drinking water filter. The wet strength and antimicrobial activity of cellulose foam paper against several bacteria species (Bacillus subtilis MTCC 441 (Gram +ve), B. cereus NCDC 240 (Gram +ve), Pseudomonas aeruginosa NCDC 105 (Gram -ve), Klebsiella pneumonia NCDC 138 (Gram -ve), and Escherichia coli MTCC 40 (Gram -ve)) were investigated. The morphology and structure of the cellulose foam paper were characterized using scanning electron microscopy (SEM). The results of our study confirmed that glutaraldehyde solution or 1,2,3,4-butanetetracarboxylic acid (BTCA) added to cellulose foam paper pretreated with cationic polyacrylamide (C-PAM) provided very high and stable wet strength performance together with excellent antimicrobial properties.

NO donors exhibit anti-inflammatory properties by modulating inflammatory signatures and by regulating the life cycle of dendritic cells.

NO mediates a variety of physiologic processes and is considered an important intracellular messenger in different cellular systems. Because of its complex regulation and multiple molecular and cellular targets, NO provides both stimulatory and suppressive properties in the immune system. Dendritic cells (DCs) are considered the most potent APCs, whose regulation has important implications in the induction of an effective immune response. In this study, we analyzed the effect of the compound NCX 2057, a new class of NO-releasing derivatives of ferulic acid, on activation and functional properties of DCs. NCX 2057 was able to modulate the inflammatory program, the cytokines production, and the cellular life cycle but not the maturation markers and the T cells stimulatory capacity of DCs in the presence or absence of LPS. The results indicate that NCX 2057 may modulate different aspects of the activation of DCs and suggest novel applications of NO donors in the contest of inflammatory response modulation through the life cycle regulation of DCs.

Anesthetic synergy between two n-alkanes.

OBJECTIVE: N-butane and n-pentane can both produce general anesthesia. Both compounds potentiate γ-aminobutyric acid type A (GABAA) receptor function, but only butane inhibits N-methyl-d-aspartate (NMDA) receptors. It was hypothesized that butane and pentane would exhibit anesthetic synergy due to their different actions on ligand-gated ion channels. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of four Xenopus laevis frogs and 43 Sprague-Dawley rats. METHODS: Alkane concentrations for all studies were determined via gas chromatography. Using a Xenopus oocyte expression model, standard two-electrode voltage clamp techniques were used to measure NMDA and GABAA receptor responses in vitro as a function of butane and pentane concentrations relevant to anesthesia. The minimum alveolar concentrations (MAC) of butane and pentane were measured separately in rats, and then pentane MAC was measured during coadministration of 0.25, 0.50 or 0.75 times MAC of butane. An isobole with 95% confidence intervals was constructed using regression analysis. A sum of butane and pentane that was statistically less than the lower-end confidence bound isobole indicated a synergistic interaction. RESULTS: Both butane and pentane dose-dependently potentiated GABAA receptor currents over the study concentration range. Butane dose-dependently inhibited NMDA receptor currents, but pentane did not modulate NMDA receptors. Butane and pentane MAC in rats was 39.4±0.7 and 13.7±0.4 %, respectively. A small but significant (p<0.03) synergistic anesthetic effect with pentane was observed during administration of either 0.50 or 0.75×MAC butane. CONCLUSIONS: Butane and pentane show synergistic anesthetic effects in vivo consistent with their different in vitro receptor effects. CLINICAL RELEVANCE: Findings support the relevance of NMDA receptors in mediating anesthetic actions for some, but not all, inhaled agents.