Structure-activity relationship study of 16 a-thiocamptothecins: an integrated in vitro and in silico approach

The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I‐mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a‐thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I–DNA cleavable complex. These effects were prominent for thio‐SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.     

Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis

The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line.     

Observations on organic components of thermal mud: morphohistochemical and biochemical studies on lipid components of mud of the Terme dei Papi (Laghetto del Bagnaccio, Viterbo). Chemical bases of the interpretation of biological and therapeutic actions of thermal mud]

In previous findings the lipidic fractions extracted acc. to Folch from the mature muds of the majority of the Italian thermal springs hot baths was studied, with the aim to identify the organic substrates of their therapeutical activity. The organic components of the "mature" peloids are produced by the metabolism of the microphytozooplankton growing spontaneously in the clay-substrate, in contact with the hot water. The Popes thermal springs (Bagnaccio's Lake) are characterised by an unique environmental situation, because the muds are naturally matured in the hot thermal water, but not in artificial baths. The morphohistochemical aspects of thermal algae growing in the Bagnaccio's lake have been studied by means of Computerised Optic Probe Video-Microscopy, using a not contact zoom objective 70-400x. Peloid types, both the "white" and the "black" contains yellow pigments, fragments of hyphae, monocellular algae, Diatomeae, Cyanophyceae and few other species. The biochemical aspects of the muds extracts are characterised by the presence of Phospholipids (PC, PE, PS, SP), a series of Hydrocarbons ranging from C30 to C38, Phytosterols (beta-sitosterol, Campesterol, Stigmasterol and traces of Cholesterol), Free Fatty Acids (Palmitic, Palmitoleic, Myristic, Stearic, Oleic and Linoleic, heptadecenoic and heptadecanoic) and Terpenes (beta-amirrhyne, 24-methylene-cyclo-arthanole). In our opinion, the therapeutic effects of the mature muds are related to its organic components, with special regards to Phospholipids, Phytosterols and Terpenes. The richness of these components in the Popes Thermal springs seems to be great interest in the dermatological and cosmetic applications, other then the traditional use.     

The protection of polyunsaturated fatty acids in micellar systems against UVB-induced photo-oxidation by procyanidins from Vitis vinifera L., and the protective synergy with vitamin E

The protective effect of procyanidins (catechin oligomers) from Vitis vinifera seeds on the UVB-promoted photo-oxygenation of polyunsaturated fatty acids (PUFAs) (linoleic, linolenic and arachidonic acids, 35 mM) has been studied in 0.5 mM sodium dodecylsulfate micelles exposed to UVB radiation (1-8 J cm-2) and determined qualitatively by Fourier transform infrared spectroscopy (FT-IR) and quantitatively by UV spectroscopy (conjugated dienes and total lipid hydroperoxides). Procyanidins (1-10 muM) strongly and dose-dependently inhibit the formation of PUFA hydroperoxides (IC50 = 4-6 muM), with a potency comparable to that of vitamin E. In these micellar systems, a strong co-operative interaction (synergistic effect) between procyanidins and vitamin E (1:1 molar ratio) in PUFA protection was demonstrated; this, as shown by electron spin resonance (ESR) studies, is a result of the ability of procyanidins to regenerate alpha-tocopherol from the alpha-tocopheroxyl radical (generated by a UV Solar Simulator), through a hydrogen transfer mechanism. HPLC monitoring of vitamin E in PUFAs micelles oxidatively stressed by UVB, confirms that procyanidins save vitamin E from consumption. All these findings, if properly extrapolated to an in vivo situation, indicate that this class of radical scavengers can be used as adjuvants of physical/chemical sunscreens in skin protection from photodamage.     

Effects of treatment of periparturient dairy cows with recombinant bovine somatotropin on health and productive and reproductive parameters

The objectives of the current experiment were to evaluate the effects of treating periparturient dairy cows with recombinant bovine somatotropin (rbST) on incidence of postpartum diseases and performance. Holstein (HO) and Jersey (JS) cows from 2 herds were enrolled in the experiment at 253 ± 3 d of gestation and assigned to the control (n = 432) and rbST125 (n = 437) treatments. Cows in the rbST125 treatment received 125 mg of rbST, weekly, from ?21 to 21 d relative to calving. Blood sampled weekly, from ?21 to 21 d relative to calving, from a subsample of cows was used to determine the concentrations of growth hormone (GH, HO = 106) and insulin-like growth factor 1 (IGF-1, HO = 147 and JS = 49). Cows were scored for body condition (BCS) at enrollment and at 1 ± 3, 30 ± 3, and 60 ± 3 d in milk (DIM). Cows were milked thrice daily and energy-corrected milk (ECM) yield was recorded for the first 30 DIM. Treatment of cows with rbST resulted in greater concentrations of GH during the prepartum (log₁₀ back-transformed concentrations of GH: HO-control = 7.83 and HO-rbST125 = 10.36 ng/mL) and postpartum (log₁₀ back-transformed concentrations of GH: HO-control = 10.45 and HO-rbST125 = 18.47 ng/mL) periods. Similarly, IGF-1 concentrations were higher during the prepartum (HO-control = 115.1 ± 4.9, HO-rbST125 = 137.7 ± 4.7, JS-control = 120.2 ± 8.3, JS-rbST125 = 167.1 ± 8.1 ng/mL) and postpartum (HO-control = 61.3 ± 4.0, HO-rbST125 = 75.2 ± 3.8, JS-control = 35.5 ± 6.9, JS-rbST125 = 54.6 ± 6.9 ng/mL) periods for rbST-treated cows. During the prepartum period, BCS was not affected by treatment, but during the postpartum period, BCS was reduced for rbST-treated cows (HO-control = 3.00 ± 0.03, HO-rbST125 = 2.90 ± 0.03, JS-control = 2.64 ± 0.02, JS-rbST125 = 2.61 ± 0.02). Cows from the rbST125 treatment tended to have lower incidence of retained fetal membranes (HO-control = 14.3, HO-rbST125 = 6.1, JS-control = 1.5, JS-rbST125 = 1.2%) and had reduced incidence of metritis (HO-control = 26.2, HO-rbST125 = 16.6, JS-control = 19.9, JS-rbST125 = 13.3%) compared with control cows. Ketosis incidence tended to be higher for rbST125 cows (HO-control = 9.4, HO-rbST125 = 11.3, JS-control = 8.5, JS-rbST125 = 13.4%) compared with control cows. The interaction between treatment and herd tended to affect yield of ECM during the first 30 DIM because HO cows treated with rbST during the periparturient period had greater yield than control HO cows (HO-control = 35.5 ± 1.0 vs. HO-rbST125 = 39.4 ± 1.0 kg/d), but treatment with rbST did not affect yield of ECM of JS cows (JS-control = 26.7 ± 0.6 vs. JS-rbST125 = 27.8 ± 0.6 kg/d). Treatment of periparturient dairy cows with 125 mg of rbST decreased the incidence of uterine disorders in HO and JS cows and increased yield of ECM during the first 30 DIM among HO cows, despite slightly increasing the incidence of ketosis.     

Hydraulic Design of Large-Diameter Pipes

The Hazen–Williams formula is frequently used for the design of large-diameter pipes, without regard for its limited range of applicability. This practice can have very detrimental effects on pipe design, and could potentially lead to litigation. Available evidence shows that the application of the formula is accurate only if the operation of the pipe is located within the transition or smooth, turbulent-flow regimes. Most working ranges for water-supply pipes usually fall outside such conditions. This paper presents an analysis which highlights the potential implications of current use of the Hazen–Williams formula for the design of large-diameter pipe systems.     

Tracking aromaticity changes in heavy hydrocarbon processing by monitoring changes in electrical resistivity

In this work, the changes in electrical resistivities of a vacuum residuum are analyzed to determine pyrolysis reaction rates at different temperatures during high temperature processing. Fractions of the residual oil from vacuum distillation were treated at a constant and uniform temperature, and electrical resistance was related to aromaticity. The results show that resistivity behaves like a first order decay-like thermal cracking reaction. This method could replace chemical methods used to determine the temperature necessary for thermal cracking reactions and the kinetic parameters of heavy petroleum fractions.     

Relationship between rate and extent of catechin absorption and plasma antioxidant status

Three triplex DNAs containing 5-bromocytosine[BrC] were studied by vibrational spectroscopy and molecular modelling. Firstly, three oligodeoxypyrimidines of 5'-(TC)3-T4-(BrCT)3 [CBrC], 5'-(TBrC)3-T4-(CT)3 [BrCC] and 5'-(TBrC)3-T4-(BrCT)3 [BrCBrC] were synthesized and then reacted with an oligodeoxypurine of 5'-(AG)3 at pH=4.5 in phosphate buffer respectively to form three comparative hairpin triplex named CY,YC and YY. The results of FT-Raman and IR revealed that YY is almost in A-like form, CY and YC are combinations of A-like form and B-like form, but A-form dominates in CY while B-form is equivalent as A-form in YC. The result is consistent with the theoretical analysis.