Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models

Liposomes, such as pegylated-liposomal CKD-602 (S-CKD602), undergo catabolism by macrophages and dendritic cells (DCs) of the reticuloendothelial system (RES). The relationship between plasma and tumor disposition of S-CKD602 and RES was evaluated in mice bearing A375 melanoma or SKOV-3 ovarian xenografts. Area under the concentration-time curves (AUCs) of liposomal encapsulated, released, and sum total (encapsulated + released) CKD-602 in plasma, tumor, and tumor extracellular fluid (ECF) were estimated. A375 and SKOV-3 tumors were stained with cd11b and cd11c antibodies as measures of macrophages and DC. The plasma disposition of S-CKD602 was similar in both xenograft models. The ratio of tumor sum total AUC to plasma sum total AUC was 1.7-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The ratio of tumor ECF AUC to tumor sum total AUC was 2-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The staining of cd11c was 4.5-fold higher in SKOV-3, compared with A375 (P?<?0.0001). The increased tumor delivery and release of CKD-602 from S-CKD602 in the ovarian xenografts, compared with the melanoma xenografts, was consistent with increased cd11c staining, suggesting that variability in the RES may affect the tumor disposition of liposomal agents.     

Hemodialysis Decreases Serum Brain-Derived Neurotrophic Factor Concentration in Humans

In the present study we have evaluated the effect of a single hemodialysis session on the brain-derived neurotrophic factor levels in plasma [BDNF]_pl and in serum [BDNF]_s as well as on the plasma isoprostanes concentration [F₂ isoprostanes]_pl, plasma total antioxidant capacity (TAC) and plasma cortisol levels in chronic kidney disease patients. Twenty male patients (age 69.8?±?2.9?years (mean?±?SE)) with end-stage renal disease undergoing maintenance hemodialysis on regular dialysis treatment for 15?C71?months participated in this study. A single hemodialysis session, lasting 4.2?±?0.1?h, resulted in a decrease (P?=?0.014) in [BDNF]_s by ~42?% (2,574?±?322 vs. 1,492?±?327?pg?ml^?1). This was accompanied by an increase (P?<?10^?4) of [F₂-Isoprostanes]_pl (38?±?3 vs. 116?±?16?pg?ml^?1), decrease (P?<?10^?4) in TAC (1,483?±?41 vs. 983?±?35 trolox equivalents, ??mol?l^?1) and a decrease (P?=?0.004) in plasma cortisol level (449.5?±?101.2 vs. 315.3?±?196.3?nmol?l^?1). No changes (P?>?0.05) in [BDNF]_pl and the platelets count were observed after a single dialysis session. Furthermore, basal [BDNF]_s in the chronic kidney disease patients was significantly lower (P?=?0.03) when compared to the age-matched control group (n?=?23). We have concluded that the observed decrease in serum BDNF level after hemodialysis accompanied by elevated [F₂-Isoprostanes]_pl and decreased plasma TAC might be caused by enhanced oxidative stress induced by hemodialysis.     

Increases in serum concentration of human heart-type fatty acid-binding protein following elective coronary intervention

Background: Heart-type fatty acid-binding protein (H-FABP) is considered a marker of myocardial necrosis but whether or not it is modified by myocardial ischemia is not clear. We sought to investigate if H-FABP serum levels increase following non-urgent coronary angioplasty.

Methods: We studied 31 patients undergoing coronary angioplasty. Peripheral venous samples were drawn immediately before angioplasty, 1?h after the first balloon inflation and 24?h after the procedure and assayed for H-FABP.

Results: Serum levels of H-FABP increased significantly at 1?h vs baseline from 2554?±?1268 to 3322?±?245?pg?ml^?1 (p?=?0.024). However, no differences were observed between 1?h and 24?h after angioplasty (3268?±?1861 vs 3322?±?2459?pg ml^?1, p?=?0.87). Moreover, no significant difference was observed when we compared 24?h after angioplasty with the baseline (3268?±?1861vs 2554?±?1268?pg ml^?1, p?=?0.112).

Conclusions: We conclude that H-FABP significantly increases after elective coronary angioplasty at 1?h compared with baseline values; whether or not this has any prognostic significance for future events, as it occurs with troponins, needs to be studied further.     

Serum procollagen type III is associated with elevated right-sided filling pressures in stable outpatients with congestive heart failure

Elevated filling pressures are associated with heart failure deterioration, but mechanisms underlying this association remain poorly understood. We sought to investigate whether or not elevated filling pressures are associated with increased collagen turnover, evaluated by procollagen type III aminoterminal peptide (PIIINP) levels, in stable systolic heart failure. Eighty patients with heart failure with severe systolic dysfunction (ejection fraction 26?±?7%) were included. Patients underwent simultaneous echocardiogram with evaluation of haemodynamic parameters and blood sampling for PIIINP measurement. Mean PIIINP level was 6.11?±?2.62 μg l^?1. PIIINP was positively associated with estimated right atrial pressure (RAP) (r?=?0.36; p?=?0.001). Mean PIIINP values were 5.04?±?2.42 μg l^?1 in patients with estimated RAP ≤?5?mmHg, and 7.59?±?2.54 μg l^?1 in those with RAP >?15?mmHg (p?相似文献   

Assessment of oxidative stress biomarkers – neuroprostanes and dihomo-isoprostanes – in the urine of elite triathletes after two weeks of moderate-altitude training

This randomized and controlled trial investigated whether the increase in elite training at different altitudes altered the oxidative stress biomarkers of the nervous system. This is the first study to investigate four F₄-neuroprostanes (F₄-NeuroPs) and four F₂-dihomo-isoprostanes (F₂-dihomo-IsoPs) quantified in 24-h urine. The quantification was carried out by ultra high pressure liquid chromatography-triple quadrupole-tandem mass spectrometry (UHPLC-QqQ-MS/MS). Sixteen elite triathletes agreed to participate in the project. They were randomized in two groups, a group submitted to altitude training (AT, n?=?8) and a group submitted to sea level training (SLT) (n?=?8), with a control group (Cg) of non-athletes (n?=?8). After the experimental period, the AT group triathletes gave significant data: 17-epi-17-F_2t-dihomo-IsoP (from 5.2?±?1.4?μg/mL 24?h^?1 to 6.6?±?0.6?μg/mL 24?h^?1), ent-7(RS)-7-F_2t-dihomo-IsoP (from 6.6?±?1.7?μg/mL 24?h^?1 to 8.6?±?0.9?μg/mL 24?h^?1), and ent-7-epi-7-F_2t-dihomo-IsoP (from 8.4?±?2.2?μg/mL 24?h^?1 to 11.3?±?1.8?μg/mL 24?h^?1) increased, while, of the neuronal degeneration-related compounds, only 10-epi-10-F_4t-NeuroP (8.4?±?1.7?μg/mL 24?h^?1) and 10-F_4t-NeuroP (5.2?±?2.9?μg/mL 24?h^?1) were detected in this group. For the Cg and SLT groups, no significant changes had occurred at the end of the two-week experimental period. Therefore, and as the main conclusion, the training at moderate altitude increased the F₄-NeuroPs- and F₂-dihomo-isoPs-related oxidative damage of the central nervous system compared to similar training at sea level.     

Evaluation of a granular formulation containing Metarhizium brunneum F52 (Hypocreales: Clavicipitaceae) microsclerotia in controlling eggs of Aedes aegypti (Diptera: Culicidae)

We evaluated the potential of a granular formulation of Metarhizium brunneum F52 containing microsclerotia (MbMSc granules) for control of Aedes aegypti by targeting eggs. MbMSc granules produced infective conidia within 14 days after application to 2.5?g moist potting soil, producing 5.9?×?10⁵, 2.08?×?10⁶ and 6.85?×?10⁶ conidia from 1, 5 and 25?mg MbMSc granules, respectively. Application of MbMSc triggered premature eclosion of eggs (EC_50?=?12?mg) with percentages as high as 31?±?2.9% and 67?±?4.3% of the eggs treated with 5 and 25?mg MbMSc granules, respectively, after 14 days on moist filter paper. Premature eclosion of eggs started at 3 days subsequent to MbMSc granule application and survival of larvae was significantly reduced for granule treated eggs (74?±?2.2%, 39?±?2.0% and 23?±?4.9% larvae survived for 1, 5 and 25?mg granule treatments, respectively, EC₅₀?=?4.9?mg). When MbMSc granules were applied in moist potting soil with mosquito eggs, rates of 1, 5 and 25?mg of MbMSc granules significantly reduced adult emergence with only 81?±?2.1%, 47?±?1.9%, and 34?±?2.1% emergence, respectively (EC₅₀?=?7?mg). Eggs treated with increasing concentrations of fungal conidia enhanced premature eclosion of eggs with an EC₅₀?=?1.6?×?10⁶ conidia/mL. Our results demonstrate that MbMSc granules are a promising candidate for control of A. aegypti and that fermentative production of Mb F52 microsclerotia as the active propagule has the potential for use for mosquito control.     

Myeloperoxidase expression in human colonic mucosa is related to systemic oxidative balance in healthy subjects

Objectives: To improve understanding of the preclinical stage of colonic inflammation by exploring the existence of a link between early inflammatory changes in the colonic mucosa and the systemic redox balance.

Methods: Clinical characteristics, a fasting blood draw, and mucosal biopsies from the right, left, and sigmoid-rectum colonic tracts collected from 28 healthy individuals (14/14 males/females) who underwent colonoscopy. Myeloperoxidase (MPO) positive cells infiltrating colonic mucosa specimens were assessed by immunohistochemistry, and patients divided into high or low MPO expressing cells/optical field groups (MPO^high or MPO^low, respectively).The systemic oxidative balance has been studied through derived-Reactive Oxygen Metabolites (d-ROMs), Biological Antioxidant Potential (BAP), and Lipoperoxide-cholesterol Oxidizing (LP-CHOLOX) tests on serum.

Results: MPO^high patients demonstrated an increased systemic oxidative stress compared to MPO^low individuals (P?=?0.035), especially when MPO is referred to the left-sided colonic mucosa (P?=?0.007). MPO^low subjects in the sigmoid-rectum showed a significant higher antioxidant capacity in the serum (P?P?=?0.044), and a decreasing gradient in MPO expression moving from the cecum to the rectum (ascendant, descendant, and sigmoid-rectum: 3.7?±?2.8, 3.1?±?1.7, and 1.4?±?0.5, respectively, P?=?0.012) were also found and discussed.

Discussion: The study is the first demonstrating a connection between systemic redox balance and MPO expression in the colonic mucosa, according to the colonic tract and patient gender. Further research evaluating the MPO expression in the human colon and its relationship with pathological conditions could benefit from these results.     

Ischaemia-modified albumin in pulmonary hypertension

Background: Pulmonary hypertension (PH) may be associated with subendocardial ischaemia. We investigated whether ischaemia-modified albumin (IMA), an established marker of ischaemia, is elevated in stable patients with PH.

Methods: We studied 32 patients with PH and an equal number of age-matched normal volunteers. We assessed serum IMA levels with the albumin cobalt-binding test.

Results: Patients’ mean ± SD (range) pulmonary arterial pressure was 56?±?12 (33–73) mmHg and their exercise capacity was 394?±?145 (121–688) m in the 6-min walk test. IMA was 92?±?14 (69–115) U ml^?1 in the patient group and 93?±?9.4 (76–122) U ml^?1 in the control group with no significant difference between the two (p?=?0.85), although almost one-third of the patients had detectable troponin-I.

Conclusions: We conclude that IMA, a marker of ischaemia, does not differ in patients with advanced clinically stable PH compared with normal subjects.     

Unraveling the binding mechanism of asiatic acid with human serum albumin and its biological implications

Asiatic acid (AsA), a naturally occurring pentacyclictriterpenoid found in Centella asiatica, plays a major role in neuroprotection, anticancer, antioxidant, and hepatoprotective activities. Human serum albumin (HSA), a blood plasma protein, participates in the regulation of plasma osmotic pressure and transports endogenous and exogenous substances. The study undertaken to analyze the drug-binding mechanisms of HSA is crucial in understanding the bioavailability of drugs. In this study, we analyzed the cytotoxic activity of AsA on HepG2 (human hepatocellular carcinoma) cell lines and its binding, conformational, docking, molecular simulation studies with HSA under physiological pH 7.2. These studies revealed a clear decrease in the viability of HepG2 cells upon exposure to AsA in a dose-dependent manner with an IC50 of 45?μM. Further studies showed the quenching of intrinsic fluorescence of HSA by AsA with a binding constant of K_AsA?=?3.86?±?0.01?×?10⁴?M^?1, which corresponds to the free energy of (ΔG) ?6.3?kcal?M^?1 at 25?°C. Circular dichroism (CD) studies revealed that there is a clear decrease in the α-helical content from 57.50?±?2.4 to 50%?±?2.3 and an increase in the β-turns from 25?±?0.65 to 29%?±?0.91 and random coils from 17.5%?±?0.95 to 21%?±?1.2, suggesting partial unfolding of HSA. Autodock studies revealed that the AsA is bound to the subdomain IIA with hydrophobic and hydrophilic interactions. From molecular dynamics, simulation data (RMSD, Rg and RMSF) emphasized the local conformational changes and rigidity of the residues of both HSA and HSA–AsA complexes.     

Estimation of total hemolymph volume in the horseshoe crab Limulus polyphemus

Biomedical companies extract blood from the horseshoe crab, Limulus polyphemus, for the production of Limulus Amebocyte Lysate, used worldwide for detecting endotoxins in injectable solutions and medical devices. Despite the extensive use of horseshoe crabs by the biomedical industry, total hemolymph volume for this species is not known. The hemolymph volume of 60 adult horseshoe crabs was estimated using an inulin dilution technique. Blood volume of the horseshoe crab represented as a percentage of wet body weight was 25?±?2.2% for males and 25?±?5.1% (mean?±?SD) for females. Relationships between hemolymph volume and weight (p?=?0.0026, r ²?=?0.8762), hemolymph volume and prosomal width (p?<?0.0001), and hemolymph volume and inter-ocular width (p?<?0.0001) were observed. No significant differences were observed between males and females. The relationship of animal size and hemolymph volume can be used to predict how much blood can be drawn from horseshoe crabs used by the biomedical industry, and can be of further use in future bleeding mortality studies.     

Analysis of myosmine,cotinine and nicotine in human toenail,plasma and saliva

Myosmine is a minor tobacco alkaloid with widespread occurrence in the human diet. Myosmine is genotoxic in human cells and is readily nitrosated and peroxidated yielding reactive intermediates with carcinogenic potential. For biomonitoring of short-term and long-term exposure, analytical methods were established for determination of myosmine together with nicotine and cotinine in plasma, saliva and toenail by gas chromatography–mass spectrometry (GC/MS). Validation of the method with samples of 14 smokers and 10 non-smokers showed smoking-dependent differences of myosmine in toenails (66?±?56 vs 21?±?15?ng?g^?1, p?<0.01) as well as saliva (2.54?±?2.68 vs 0.73?±?0.65?ng ml^?1, p <0.01). However, these differences were much smaller than those with nicotine (1971?±?818 vs 132?±?82?ng g^?1, p <0.0001) and cotinine (1237?±?818 vs <35?ng?g^?1) in toenail and those of cotinine (97.43?±?84.54 vs 1.85?±?4.50?ng ml^?1, p <0.0001) in saliva. These results were confirmed in plasma samples from 84 patients undergoing gastro-oesophageal endoscopy. Differences between 25 smokers and 59 non-smokers are again much lower for myosmine (0.30?±?0.35 vs 0.16?±?0.18?ng?ml^?1, p <0.05) than for cotinine (54.67?±?29.63 vs 0.61?±?1.82?ng ml^?1, p <0.0001). In conclusion, sources other than tobacco contribute considerably to the human body burden of myosmine.     

Effects of levobupivacaine and bupivacaine on intracellular calcium signaling in cultured rat dorsal root ganglion neurons

Bupivacaine and levobupivacaine have been shown to be effective in the treatment of pain as local anesthetics, although the mechanisms mediating their antinociceptive actions are still not well understood. The aim of this study was to investigate the effects of bupivacaine and levobupivacaine on intracellular calcium ([Ca²⁺]_i) signaling in cultured rat dorsal root ganglion (DRG) neurons. DRG neuronal cultures loaded with 5?μM Fura-2/AM and [Ca²⁺]_i transients for stimulation with 30?mM KCl (Hi K⁺) were assessed by using fluorescent ratiometry. DRGs were excited at 340 and 380?nm, emission was recorded at 510?nm, and responses were determined from the change in the 340/380 ratio (basal-peak) for individual DRG neurons. Data were analyzed by using Student’s t-test. Levobupivacaine and bupivacaine attenuated the KCl-evoked [Ca²⁺]_i transients in a reversible manner. [Ca²⁺]_i increase evoked by Hi K⁺ was significantly reduced to 99.9?±?5.1% (n?=?18) and 62.5?±?4.2% (n?=?15, P?<?0.05) after the application of 5 and 50?µM levobupivacaine, respectively. Bupivacaine also inhibited Hi K⁺-induced [Ca²⁺]_i responses, reduced to 98.7?±?4.8% (n?=?10) and 69.5?±?4.5% (n?=?9, P?<?0.05) inhibition of fluorescence ratio values of Hi K⁺-induced responses at 5 and 50?μM, respectively. Our results indicate that bupivacaine and levobupivacaine, with no significant differences between both agents, attenuated KCl-evoked calcium transients in a reversible manner. The inhibition of calcium signals in DRG neurons by levobupivacaine and bupivacaine might contribute to the antinociceptive effects of these local anesthetics.     

Potential CD34 signaling through phosphorylated-BAD in chemotherapy-resistant acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) constitutively express growth factors and cytokines for survival. Chemotherapy alters these signals to induce cell death. However, drug resistance in AML remains a major hindrance to successful treatment and early warning is unavailable. Modulation of signaling pathways during chemotherapy may provide a window to detect response and predict treatment outcome. Blood samples collected from AML patients before and at day-3 of induction therapy were compared for changes in expression of CD117, CD34, pro-inflammatory cytokines and mediators of Akt and MAPK pathways, using multi-color flow cytometry. Nine patients were diagnosed as drug-resistant and seven sensitive to chemotherapy. Twelve were paired. Average percentages of CD34 (66.8?±?11.7% vs. 26.2?±?5.8%, p?=?0.033) and pBAD (66.9?±?8.2% vs. 28.9?±?8.2%, p?=?0.016) were significantly increased in chemo-resistant (N?=?9) compared to chemo-sensitive (N?=?5) samples. Percentages of CD34 were strongly correlated with pBAD (R?=?0.785; p?=?0.001; N?=?14) and pFKHR (R?=?0.755; p?=?0.002; N?=?14) at day-3 induction. Chemo-sensitive cases expressed significantly higher percentages of IL-18Rα (71.9?±?9.6% vs. 29.8?±?5.8%, p?=?0.016). Though not significantly different in the outcome, IL-1β was strongly associated with activated Akt-S473, IL-6 with phosphorylated JNK and FKHR while TNF-α appeared to trigger Bim, in treated samples. These preliminary results suggested AML cells resistant to chemotherapy increased expression of CD34 and may signal through pBAD while cells sensitive to chemotherapy-induced IL18Rα expression. These were observed early during induction therapy. Identifying CD34 is interesting as it is a convenient marker to monitor drug-resistance in AML patients. Inhibition of CD34 and pBAD signaling may be important in treating drug-resistant AML.     

Relations of Bromine,Iron, Rubidium,Strontium, and Zinc Content to Morphometric Parameters in Pediatric and Nonhyperplastic Young Adult Prostate Glands

The variation with age of the Br, Fe, Rb, Sr, and Zn mass fractions and some histological characteristics of intact prostate glands of 50 subjects aged 0–30 years was investigated by an energy-dispersive X-ray fluorescence and a quantitative morphometric analysis. Mean values?±?standard error of the mean (M?±?SΕΜ) for the mass fractions (in milligrams per kilogram wet-mass basis) of these trace elements in pre-puberty were: Br—10.5?±?1.3, Fe—28.6?±?4.1, Rb—3.05?±?0.27, Sr—0.42?±?0.08, and Zn—32.9?±?3.2. During puberty and postpuberty, when there is a significant increase in circulating androgens, the mean values were: Br—5.60?±?0.57, Fe—19.3?±?1.6, Rb—3.50?±?0.28, Sr—0.24?±?0.03, and Zn—113?±?10. Mean values (M?±?SΕΜ) of percent volumes (%) of the stroma, epithelium, and lumen in the prostate before puberty were 73.4?±?2.6, 20.4?±?1.7, and 4.45?±?0.94, respectively, versus 46.5?±?2.5, 38.5?±?1.9, and 14.9?±?1.2 during puberty and postpuberty. A significant positive correlation between the prostatic Zn and percent volume of both glandular epithelium (r?=?0.573, p?≤?0.001) and glandular lumen (r?=?0.725, p?≤?0.001) was found. For the first time, it has been demonstrated that the glandular lumen is a main pool of Zn accumulation, and that the stroma is a main pool of Br and Fe accumulation in the normal human prostate, for the age range 14 to 30 years. It was concluded that the Zn binds tightly within the prostatic fluid because the volume of glandular lumen reflects the volume of prostatic fluid.     

Prostaglandin Endoperoxide H Synthase-2 (PGHS-2) Variants and Risk of Obesity and Microvascular Dysfunction Among Tunisians: Relevance of rs5277 (306G/C) and rs5275 (8473T/C) Genetic Markers

The purpose of this study was to determine the impact of six PGHS-2 genetic variants on obesity development and microvascular dysfunction. The study included 305 Tunisian subjects (186 normal weights, 35 overweights and 84 obeses). PCR analyses were used for allelic discrimination between polymorphisms. Prostaglandin (PGE2, PGI2), leptin, and matrix metalloproteinase (MMP1, 2, 3, 9) levels were evaluated by ELISA. Fatty acid composition was performed by gas chromatography–mass spectrometry. Our results revealed that subjects carrying the PGHS-2 306CC (rs5277) and 8473CC (rs5275) genotypes present higher anthropometric values compared to wild-type genotypes (306GG, BMI (Kg/m²): 27.11?±?0.58; WC (cm): 93.09?±?1.58; 306CC, BMI: 33.83?±?2.46; WC: 109.93?±?5.41; 8473TT, BMI: 27.75?±?0.68; WC: 93.96?±?1.75; 8473CC, BMI: 33.72?±?2.2; WC: 117.89?±?2.94). A reduced microvascular reactivity and a higher PGE2 level were also found in individuals with the 306CC and 8473CC genotypes in comparison to 306GG and 8473TT carriers (306GG, Peak Ach-CVC (PU/mmHg): 0.46?±?0.03; PGE2 (pg/ml): 7933.1?±?702; 306CC, Peak Ach-CVC: 0.24?±?0.01; PGE2: 13,380.3?±?966.2; 8473TT, Peak Ach-CVC: 0.48?±?0.05; PGE2: 7086.41?±?700.31; 8473CC, Peak Ach-CVC: 0.23?±?0.01; PGE2: 13,175.7?±?1165.8). Fatty acid analysis showed a significant increase of palmitic acid (PA) (34.2?±?2.09 vs. 16.82%?±?1.76, P?<?0.001), stearic acid (SA) (25.76?±?3.29 vs. 9.05%?±?2.53, P?<?0.001), and linoleic acid (LA) (5.25?±?1.18 vs. 0.5%?±?0.09, P?<?0.001) levels in individuals carrying the PGHS-2 306CC genotype when compared to GG genotype individuals. Subjects with the 8473CC genotype showed also a significant increase of PA, SA ,and LA levels when compared to TT genotype carriers (PA: 38.02?±?1.51 vs. 12.65%?±?1.54, P?<?0.001; SA: 32.96?±?1.87 vs. 1.38%?±?0.56, P?<?0.001; LA: 26.84?±?2.09 vs. 3.7%?±?1.54, P?<?0.001). Logistic regression analysis revealed that PGHS-2 306CC and 8473CC variants are significantly associated with obesity status (OR 6.25, CI (1.8–21.6), P?=?0.004; OR 3.01, CI (1.13–8.52), P?=?0.03, respectively). Haplotypes containing the C₃₀₆:T₈₄₇₃ (OR 2.91; P?=?0.01) and G_306:C₈₄₇₃ (OR 5.25; P?=?0.002) combinations were associated with an enhanced risk for obesity development in the studied population. In conclusion, our results highlight that PGHS-2 306G/C and 8473T/C variants could be useful indicators of obesity development, inflammation, and microvascular dysfunction among Tunisians.

     

Increased plasma concentration of 4-pyridone-3-carboxamide-1-ß-D-ribonucleoside (4PYR) in lung cancer. Preliminary studies

Abstract

4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) is a new nicotinamide derivative, which is potentially toxic to the endothelium. Dysfunction of the endothelium promotes cancer cell proliferation, invasiveness, and inflammatory signaling. The aim of this study was to analyze 4PYR concentration in the plasma of lung cancer patients and its relationship to other known biochemical parameters associated with the endothelium function.

The concentration of 4PYR, nicotinamide, 1-methylnicotinamide (MNA), amino acids, and their derivatives were measured in samples obtained from patients with primary squamous cell carcinoma (n?=?48) and control group (n?=?100).

The concentration of 4PYR and 4PYR/MNA ratio were significantly higher in lung cancer patients as compared to controls (0.099?±?0.009 vs. 0.066?±?0.006?µmol/L and 1.10?±?0.08 vs. 1.97?±?0.15, respectively). The plasma arginine/asymmetric dimethylarginine (Arg/ADMA) ratio was considerably lower in lung cancer patients (253?±?17 vs. 369?±?19) as well as plasma MNA (0.057?±?0.004 vs. 0.069?±?0.003?µmol/L). There was no difference in the plasma concentrations of nicotinamide and nicotinamide riboside in both groups (0.116?±?0.019 vs. 0.131?±?0.014 and 0.102?±?0.006 vs. 0.113?±?0.011, respectively).

In this study, a higher 4PYR concentration was observed for the first time in patients with squamous cell carcinoma. This change may be related to the endothelial dysfunction that promote cancer progression since 4PYR and its derivatives are known to disrupt glycolytic pathway.     

Pudendal and median nerve sensory perception threshold: A comparison between normative studies

Background: For the evaluation of sensory innervation, normative data are necessary as a comparison.

Aims: To compare our current perception thresholds (CPTs) with normative data from other research.

Methods: Healthy volunteers were assessed for 2000, 250, and 5?Hz CPTs of the median and pudendal nerve and data were compared with other studies.

Results: Normative data in the studied group n?=?41 (male: 21; female: 20) for the median nerve, 2?kHz, 250?Hz, and 5?Hz were respectively: 241.85?±?67.72 (140–444); 106.27?±?39.12 (45–229); 82.05?±?43.40 (13–271). Pudendal nerve CPTs 250?Hz were: 126.44?±?69.46 (6–333). For men 2?kHz: 349.95?±?125.76 (100–588); 5?Hz: 132.67?±?51.81 (59–249) and women 2?kHz: 226.20?±?119.65 (64–528); 5?Hz: 92.45?±?44.66 (35–215). For the median nerve no statistical differences for gender were shown. For the pudendal nerve, only 250?Hz showed no difference for gender (t-test: 0.516). Comparison of our data with CPTs of other normative data showed no agreement for the pudendal nerve. For the median nerve only 2?kHz showed agreement in three studies and for 5?Hz with one study.

Conclusion: Comparing normative data of multiple studies shows a variety of results and poor agreement. Therefore, referring to normative data of other studies should be handled with caution.     

Life table of Gaeolaelaps aculeifer (Acari: Laelapidae) feeding on larvae of Lycoriella auripila (Diptera: Sciaridae) with stage-specific estimates of consumption

Gaeolaelaps aculeifer (Canestrini, 1883) is a soil-dwelling predatory mite with potential for use as a biological control agent of fungus gnats (Diptera: Sciaridae) in mushroom production. The life table, predation rate and population growth rate of G. aculeifer on a diet of larvae of the sciarid fly, Lycoriella auripila, at 23?±?1°C, 60?±?5% RH and a photoperiod of 0:24 (L:D)?h was investigated. The results revealed that the duration of egg, larva, protonymph, deutonymph, females and males of G. aculeifer were 3.8?±?0.1, 1.4?±?0.1, 3.9?±?0.1, 4.1?±?0.1, 67.7?±?2.8 and 60.3?±?3.1 days, respectively. Net reproductive rate (R₀) was 54.8?±?7.1 offspring, intrinsic rate of increase (r) was 0.12?±?0.01 offspring day^?1, finite rate of increase (λ) was 1.13?±?0.01 day^?1and mean generation time (T) was 32.3?±?0.6 days. The predator consumed a mean of 0.08?±?0.05, 1.73?±?0.18, 3.16?±?0.28 and 75.9?±?7.1 third instar L. auripila larvae during the larval (1.3?±?0.1 days), protonymph (3.9?±?0.1 days), deutonymph (4.1?±?0.1 days) and adult (52.6?±?2.2 days) stages. Population parameters and consumption rates suggest that G. aculeifer has good potential as a biological control agent of L. auripila in mushroom production.     

Urinary cell cycle arrest biomarker [TIMP-2]·[IGFBP7] in patients with hepatorenal syndrome

Abstract

Background: Patients with hepatorenal syndrome carry a high short-term mortality. Early diagnosis and treatment are essential for patients’ outcome. Nevertheless diagnosis of HRS remains difficult. First-line therapy terlipressin is often associated with severe complications. Biomarkers become more on focus for an early diagnosis.

Objective: The aim of this study was to test the diagnostic accuracy of urinary [TIMP-2]·[IGFBP7] for HRS patients and prognostic value for therapy responding patients.

Material and methods: NephroCheck^® measures urinary concentrations of TIMP-2 and IGFBP-7, both indicating stress of renal cells and associated with induction of cell cycle arrest. 22 HRS patients and 30 patients with normal kidney function were included. [TIMP-2]·[IGFBP7] was measured using NephroCheck^®. HRS patients receiving terlipressin were also examined.

Results: [TIMP-2]·[IGFBP7] values did not differ significantly (1.3?±?2.09 vs. 1.03?±?1.03; p?=?0.55). Furthermore, there was no significant difference of [TIMP-2]·[IGFBP7] regarding response of terlipressin (1.32?±?2.39 vs. 0.81?±?1.05; p?=?0.56). Low [TIMP-2]·[IGFBP7] values were significantly associated with higher mortality (p?=?0.01).

Conclusions: The results of this study suggest that [TIMP-2]·[IGFBP7] is not suitable for diagnostic of HRS and prediction of therapy response, but there might be evidence for prognostic value of [TIMP-2]·[IGFBP7] in regard to mortality of liver cirrhosis patients.     

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

In the present study, some thiazole derivatives were synthesized via the ring closure reaction of 1-[2-(2-oxobenzo[d]thiazol-3(2H)-yl)acetyl]thiosemicarbazide with various phenacyl bromides. The chemical structures of the compounds were elucidated by ¹H NMR, ¹³C NMR and mass spectral data and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman’s spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. The most potent AChE inhibitor was found as compound 4e (IC₅₀?=?25.5?±?2.12 µg/mL) followed by compounds 4i (IC₅₀?=?38.50?±?2.12 µg/mL), 4c (IC₅₀?=?58.42?±?3.14 µg/mL) and 4g (IC₅₀?=?68?±?2.12 µg/mL) when compared with eserine (IC₅₀?=?0.025?±?0.01 µg/mL). Effective compounds on AChE exhibited weak inhibition on BuChE (IC₅₀ > 80 µg/mL). MTT assay indicated that the cytotoxic dose (IC₅₀?=?71.67?±?7.63 µg/mL) of compound 4e was higher than its effective dose.