Gap junction blockers: a potential approach to attenuate morphine withdrawal symptoms

Background

The exact mechanisms of morphine-induced dependence and withdrawal symptoms remain unclear. In order to identify an agent that can prevent withdrawal syndrome, many studies have been performed. This study was aimed to evaluate the effect of gap junction blockers; carbenoxolone (CBX) or mefloquine (MFQ); on morphine withdrawal symptoms in male rat.Adult male Wistar rats (225 – 275 g) were selected randomly and divided into 10 groups. All groups underwent stereotaxic surgery and in order to induce dependency, morphine was administered subcutaneously) Sc) at an interval of 12 hours for nine continuous days. On the ninth day of the experiment, animals received vehicle or CBX (100, 400, 600 μg/10 μl/rat, icv) or MFQ (50, 100 and 200 μg/10 μl/rat, icv) after the last saline or morphine (Sc) injection. Morphine withdrawal symptoms were precipitated by naloxone hydrochloride 10 min after the treatments. The withdrawal signs including: jumping, rearing, genital grooming, abdomen writhing, wet dog shake and stool weight, were recorded for 60 minutes.

Results

Results showed that CBX and MFQ decreased all withdrawal signs; and the analysis indicated that they could attenuate the total withdrawal scores significantly.

Conclusion

Taking together it is concluded that gap junction blockers prevented naloxone-precipitated withdrawal symptoms.     

The Prooxidant Action of Dietary Antioxidants Leading to Cellular DNA Breakage and Anticancer Effects: Implications for Chemotherapeutic Action Against Cancer

Plant-derived dietary antioxidants have attracted considerable interest in recent past for their ability to induce apoptosis and regression of tumors in animal models. While it is believed that the antioxidant properties of these agents may contribute to lowering the risk of cancer induction by impeding oxidative injury to DNA, it could not account for apoptosis induction and chemotherapeutic observations. In this article, we show that dietary antioxidants can alternatively switch to a prooxidant action in the presence of transition metals such as copper. Such a prooxidant action leads to strand breaks in cellular DNA and growth inhibition in cancer cells. Further, the cellular DNA breakage and anticancer effects were found to be significantly enhanced in the presence of copper ions. Moreover, inhibition of antioxidant-induced DNA strand breaks and oxidative stress by Cu(I)-specific chelators bathocuproine and neocuproine demonstrated the role of endogenous copper in the induction of the prooxidant mechanism. Since it is well established that tissue, cellular, and serum copper levels are considerably elevated in various malignancies, such a prooxidant cytotoxic mechanism better explains the anticancer activity of dietary antioxidants against cancer cells.     

Accounting for robustness in modeling signal transduction responses

Abstract

A classical question in systems biology is to find a Boolean model which is able to predict the observed responses of a signaling network. It has been previously shown that such models can be tailored based on experimental data. While fitting a minimum-size network to the experimentally observed data is a natural assumption, it can potentially result in a network which is not so robust against the noises in the training dataset. Indeed, it is widely accepted now that biological systems are generally evolved to be very robust. Therefore, in the present work, we extended the classical formulation of Boolean network construction in order to put weight on the robustness of the created network. We show that our method results generally in more relevant networks. Consequently, considering robustness as a design principle of biological networks can result in more realistic models.     

In vitro cytotoxic,antibacterial, antifungal and urease inhibitory activities of some N4- substituted isatin-3-thiosemicarbazones

A series of 15 previously reported N⁴-substituted isatin-3-thiosemicarbazones 3a-o has been screened for cytotoxic, antibacterial, antifungal and urease inhibitory activities. Compounds 3b, 3e and 3n proved to be active in cytotoxicity assay; 3e exhibited a high degree of cytotoxic activity (LD₅₀ = 1.10 × 10^{? 5} M). Compound 3h exhibited significant antibacterial activity against B. subtilis, whereas compounds 3a, 3k and 3l displayed significant antifungal activity against one or more fungal strains i.e. T. longifusus, A. flavus and M. canis. In human urease enzyme inhibition assay, compounds 3g, 3k and 3m proved to be the most potent inhibitors, exhibiting relatively pronounced inhibition of the enzyme. These compounds, being non-toxic, could be potential candidates for orally effective therapeutic agents to treat certain clinical conditions induced by bacterial ureases like H. pylori urease. This study presents the first example of inhibition of urease by isatin-thiosemicarbazones and as such provides a solid basis for further research on such compounds to develop more potent inhibitors.     

Dual Substrate Model for Novel Approach Towards a Kinetic Study of Acetylcholinesterase Inhibition by Diazinon

Limited reports as compared to other insecticides appear in the literature for acetylcholinester-ase (AChE) inhibition by diazinon. In the current study, new kinetic parameters of AChE inhibition by diazinon have been investigated. The assay was done with bovine retinal AChE using two different substrate (ASCh) concentrations in the absence and presence of diazinon (0.08-1.28 mM). The optical density was monitored up to 25min (reaction time) for the assay. New kinetic parameters (k¹_oms, k¹_sms, k¹_oms, k¹_sms, k¹_asms and k¹_asms) were calculated from these experimental data.     

When to estimate sex ratio in natural populations of insects? A study on sex ratio variations of gall midges within a generation

Precise estimation of arthropods' sex ratio is an important issue in a wide range of ecological studies and biological control programs. Although, in many cases changes in arthropods' sex ratio may be under the control of parents or some symbiotic microorganisms, biased sex ratios in some other species are caused by some extrinsic factors, neglect of which may lead to under/overestimation of true sex ratio. In this paper, we pursued those factors that cause false estimation of sex ratio in insects' species. We studied the predatory gall midge, Aphidoletes aphidimyza Rondani (Diptera: Cecidomyiidae), an important biological control agent of aphids, that shows protandry (i.e. early male emergence), differential lifespan of sexes, and differential distribution of sexes across habitat. Ten populations of A. aphidimyza were released separately in transparent cages and their sex ratio variations were recorded every 12 hours. The primary sex ratio in this species seems to be slightly male‐biased (52.41% males), however early emergence of males biases the sex ratio up to 72% males in a few hours after emergence. Shortly after the emergence of females, the sex ratio reaches its primary situation, but as a result of male‐biased mortality after mating, the proportion of females increases gradually to 97% by the fourth and fifth days after emergence. These results explicitly suggest that direct estimation of sex ratio in natural populations may be affected by some secondary factors such as differential mortality of sexes, protandry, and differential distribution of males and females over time and/or across habitat.     

Pitfalls in screening streptococci for retrieving superior streptokinase (SK) genes: no activity correlation for streptococcal culture supernatant and recombinant SK

Streptokinase (SK), the heterogeneous protein family secreted by some groups of β-hemolytic streptococci (βHS), is a plasminogen activator and well-known drug for thrombolytic therapy. Differences in plasminogen activation property of streptococcal culture supernatants (SCS) have been traditionally used to identify superior producer strains and SK genes (skc) for recombinant SK (rSK) production. However, the role of SK heterogeneity and whether SK activities in SCS correlate with that of their corresponding rSK is a matter of debate. To address these concerns, SCS of nine group C streptococci (GCS) screened among 252 βHS clinical isolates were compared for plasminogen activation using S-2251 chromogenic assay. The GCS (Streptococcus equisimilis) showing the highest (GCS-S87) and lowest (GCS-S131) activities were selected for PCR-based isolation of skc, cloning and rSK production in Escherichia coli. The 6×His-tagged rSK proteins were purified by NI–NTA chromatography, analyzed by SDS-PAGE and Western blotting and their activities were determined. While SCS of GCS-S87 and GCS-S131 showed different plasminogen activations (95 and 35 %, respectively) compared to that of the reference strain (GCS-9542), but interestingly rSK of all three strains showed close specific activities (1.33, 1.70, and 1.55 × 10⁴ IU mg^?1). Accordingly, SKS87 and SKS131 had more than 90 % sequence identity at the amino acids level compared to SK9542. Therefore, SK heterogeneity by itself may not contribute to the differences in plasminogen activation properties of SCS and evaluation of this activity in SCS might not be a proper assay for screening superior skc.