Does the anaerobic formation of hydroxyl radicals by paraquat monocation radicals and hydrogen peroxide require the presence of transition metals?

This in vitro study investigated the formation of hydroxyl radicals (*OH) under anaerobic conditions through the direct reaction between paraquat radicals (PQ(+)*) and hydrogen peroxide (H(2)O(2)) by quantitative UV-VIS and electron spin resonance (ESR) spectroscopy. PQ(+)* was formed by paraquat reduction using either sodium dithionite or the xanthine/xanthine oxidase reaction as electron donors. The anaerobic formation of PQ(+)* was quantified both by measuring light absorption at 605 nm or by ESR techniques respectively, using either the absorption coefficient or ultramarine as a stable spin standard. Detection of *OH took place with aid of the spin trap 5-diethoxyphosphoryl-5-methyl-1-pyrroline- N-oxide (DEPMPO). Generation or addition of H(2)O(2) to PQ(+)* eliminates the 35-line ESR signal of PQ(+)* and subsequently generates the 8-line ESR signal of the DEPMPO-OH adduct. The elimination of PQ(+)* as well as the formation of OH-DEPMPO adduct was not influenced by 1.0 mM deferoxamine, indicating that iron or other transition metals are, at least under anoxic conditions, not necessarily involved in the generation of the most aggressive reactive oxygen species *OH.     

Does brain slices from pentylenetetrazole-kindled mice provide a more predictive screening model for antiepileptic drugs?

The cortical wedge is a commonly applied model for in vitro screening of new antiepileptic drugs (AEDs) and has been extensively used in characterization of well-known AEDs. However, the predictive validity of this model as a screening model has been questioned as, e.g., carbamazepine has been reported to lack effect in this model. The neuroplastic changes induced in acute and chronic animal models of epilepsy are known to affect the pharmacological profile of AEDs in vivo. Hence, we investigated whether brain slices from pentylenetetrazole (PTZ)-kindled animals could provide a more predictive screening model for AEDs. To this end, we compared the in vitro and in vivo pharmacological profile of several selected AEDs (phenobarbital, phenytoin, tiagabine, fosphenytoin, valproate, and carbamazepine) along with citalopram using the PTZ-kindled model and brain slices from na?ve, saline-injected and PTZ-kindled mice. Our data suggest that the use of slices from PTZ-kindled mice in the cortical wedge does not increase the predictive validity of the model as an in vitro screening model for AEDs. Traditionally, the incidence of certain seizure types is widely used as a measure to characterize drug action in animal models of epilepsy. In our study, the anticonvulsant effect of the AEDs was investigated in vivo using several observational parameters (i.e., incidence and duration of convulsions, latency to clonic convulsions, and severity of convulsions). We found that including the observational parameter "severity" offered important additional information about the drug profile that would otherwise be lost if only a single parameter as "incidence" was used.     

Ghrelin inhibits interleukin-8 production induced by hydrogen peroxide in A549 cells via NF-κB pathway

Ghrelin, a novel growth hormone-releasing peptide, can influence appetite and induce positive energy balances. Previous studies have reported that ghrelin ameliorated inflammatory responses of the heart, liver and pancreas. We examined whether ghrelin inhibits the proinflammatory cytokine interleukin-8 production induced by hydrogen peroxide (H₂O₂) in human lung epithelia cell line A549 and which mechanism is related with this effect of ghrelin. A549 cells were preincubated with vehicle or ghrelin (0.1 to 1000 ng/mL) in a concentration-dependent manner and then H₂O₂ (0 to 50 μM) was added. The interleukin-8 released by A549 in the medium was determined by ELISA, the mRNA expressions of interleukin-8 and ghrelin receptor were detected by RT-PCR. We also examined the phosphorylation of NF-κB/p65 protein and the degradation of inhibitory protein-κB (I-κB) in A549 by western blot analysis, the NF-κB DNA-binding activity by electrophoretic mobility shift assay, and then detected the generation of reactive oxygen species (ROS) in A549 by nitroblue tetrazolium reduction assay. Cells treated with H₂O₂ (50 μM) exhibited significantly higher interleukin-8 production and ghrelin receptor mRNA expression compared with cells treated with vehicle alone (P < 0.05). Ghrelin inhibited H₂O₂-induced interleukin-8 production by A549 at both mRNA and protein levels in a concentration-dependent manner (P < 0.05). Moreover, ghrelin attenuated H₂O₂-triggered NF-κB activation dependent on I-κB degradation dose-dependently in A549, but the intracellular ROS level after application of H₂O₂ was not affected by ghrelin (1000 ng/mL). Together, these results suggest that ghrelin inhibits H₂O₂-induced interleukin-8 production in A549 cells by targeting on NF-κB pathway, but not by directly scavenging intracellular ROS.     

Gas–plasma sterilization: relative efficacy of the hydrogen peroxide phase compared with that of the plasma phase

Recent modifications specified in the European Pharmacopoeia IIIrd Edition (1 January 1997) have led us to investigate the sensitivity of Bacillus stearothermophilus ATCC 7953, a sporulated bacterial species now used instead of Bacillus subtilis var niger ATCC 9372 as a reference in peroxide sterilization. Inactivation kinetic studies have shown that this choice is well founded and also indicate that inherent efficacy of the STERRAD^® 100 gas–plasma process is above all due to hydrogen peroxide. The ionization obtained during the plasma phase is validated in its role of a residue detoxifying process, without any sporicidal effect.     

What does Brexit mean for UK tobacco control?

In January 2020 the UK left the European Union (EU), although a transition period extends EU rules/regulations until the end of 2020 while a longer-term relationship agreement is negotiated. After almost 50 years of membership the UK economy is tightly integrated into that of the EU single market, and many UK laws and regulations have their origins in the EU, including those concerning tobacco. This paper provides an overview of potential implications of Brexit for UK tobacco control. We examine the key areas of the supply, cost, taxation, and regulation of tobacco products, and the impact of commitments in regards to the border between Ireland and Northern Ireland (NI). We find that Brexit provides an opportunity for improved tobacco control with potential for particular enhancements in the areas of taxation and product regulation. However, commitments in regards to NI mean these benefits either won't extend to NI (which will continue to follow EU rules), or could lead to the whole UK having to follow most EU rules/regulations despite no longer being involved in the decision making process. The details of any future deal will be important, especially since virtually all UK tobacco products come from the EU, and hence would be subject to disruption/considerable new tariffs (i.e. taxation on imports) without a trade deal. We conclude that political will by the UK government to secure conditions which protect the UK's world leading tobacco control measures will be key to whether Brexit helps or hinders tobacco control in the UK. In this regards the signs are mixed.     

What does it mean to want to quit?

INTRODUCTION AND AIMS: To report on the prevalence of attitudes and beliefs about the importance of wanting to quit and need for use of cessation assistance, that may act as barriers to quitting smoking and adopting cessation assistance. DESIGN AND METHODS: National telephone survey of 802 randomly selected adults (685 smokers, 117 recent quitters). RESULTS: Seventy per cent of smokers believed that 'wanting to quit' was both a necessary and sufficient condition for being able to quit. While only one-third of smokers believed that they were too addicted to be able to quit, only a quarter believed they could quit any time they want to. Belief that use of cessation assistance is a sign of weakness was endorsed by 35% of participants, and related to stage of change. DISCUSSION AND CONCLUSIONS: Beliefs about the importance of wanting to quit are commonly held. Many smokers appear to believe that a rational, unambivalent desire to quit is needed before it is worthwhile trying. Short-term impulses to act are not perceived as sufficient. The role of cessation assistance in helping smokers form a rational desire to quit appears to be poorly understood by the majority of smokers. There is a need to engender greater understanding of the potential value of cessation aids to smokers experiencing ambivalence about wanting to quit.     

Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury： involvement of PI3 kinase signal pathway

Aim： Oxidative stress plays a critical role in the pathogenic cascade leading to neuronal degeneration in AD. Consequently, the induction of endogenous antioxidative proteins by antioxidants seems to be a very reasonable strategy for delaying the disease＇s progression. In previous work, we identified the neurotrophic and neuroprotective effects of geniposide, which result from the activation of glucagon-like peptide I receptor （GLP-1R）. In this study, we explore the role of PI3 kinase signaling pathway in the neuroprotection of geniposide in PC12 cells. Methods： Cell viability was determined by MTT assay. Apoptosis was detected by Hoechst and PI double staining. The protein expression of Bcl-2 and phosphorylation of Akt308, Akt473, GSK-313, and PDK1 was measured by Western blot. Results： Geniposide induced the expression of the antiapoptotic protein Bcl-2, which inhibited apoptosis in PC12 cells induced by H202, and this effect could be inhibited by preincubation with LY294002, a selective inhibitor of PI3K. Further-more, geniposide enhanced the phosphorylation of Akt308, Akt473, GSK-313 and PDK1 under conditions of oxidative stress. Conclusion： These results demonstrate that the PI3K signaling pathway is involved in the neuroprotection of geniposide in PC12 cells against the oxidative damage induced by H202 in PC12 cells.     

Alternating bowel pattern: what do people mean?

Summary

Background

With the introduction of new therapies, the subgrouping of patients based on bowel pattern has become important. However, the appropriate definition of an alternating bowel pattern remains unclear.

Aim

To determine if specific symptoms are reported by people with an alternating bowel pattern.

Methods

Using the Rochester Epidemiology Project, a series of population‐based surveys were undertaken in which valid self‐report gastrointestinal symptom questionnaires were mailed to 4029 randomly selected members of the community. One question asked was ‘How would you describe your usual bowel pattern in the last year'?

Results

3022 subjects (74%) provided questionnaire data and 2718 were eligible for this analysis, the mean age was 57 years, with a range of 20–98 years (median = 61). Of these, 9.2%, 2.5% and 7.6% reported their usual bowel pattern as being constipated, diarrhoea, or alternating respectively. At least 50% of those reporting alternating bowel pattern reported incomplete evacuation (63%), urgency (57%), straining (55%) and loose stool (50%). The proportion of alternators reporting each individual symptom was between that of diarrhoea and constipation except for mucus and incomplete evacuation; however, no symptom was unique to alternators.

Conclusion

People who self‐report an alternating bowel pattern appear to represent a blend of constipation and diarrhoea symptoms, rather than a distinct subgroup.

     

What does systems biology mean for drug development?

The complexity and flexibility of cellular architectures is increasingly recognized by impressive progress on the side of molecular analytics, i.e. proteomics, genomics and metabolomics. One of the messages from systems biology is that the number of molecular species in cellular networks is orders of magnitude bigger than anticipated by genomic analysis, in particular by fast posttranslational modifications of proteins. The requirements to manage external signals, integrate spatiotemporal signal transduction inside an organism and at the same time optimizing networks of biochemical and chemical reactions result in chemically extremely fine tuned molecular entities. Chemical side reactions of enzymatic activity, like e.g. random oxidative damage of proteins by free radicals during aging constantly introduce epigenetic alterations of protein targets. These events gradually and on an individual stochastic scale, keep modifying activities of these targets, and their affinities and selectivities towards biological and pharmacological ligands. One further message is that many of the key reactions in living systems are essentially based on interactions of low affinities and even low selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. So, in complex disorders like cancer or neurodegenerative diseases, which are rooted in relatively subtle and multimodal dysfunction of important physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds ("one-target, one-disease"), which still dominate the pharmaceutical industry increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade and the treatment of "complex diseases" remains a most pressing medical need. Currently a change of paradigm can be observed with regard to a new focus on agents that modulate multiple targets simultaneously. Targeting cellular function as a system rather than on the level of the single protein molecule significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data and extraction of "screenable" information from biological systems essentially ruled by deterministic chaotic processes on a background of individual stochasticity.     

Does acupuncture relieve tinnitus?

Wang K, Bugge J, Bugge S. A randomised, placebo‐controlled trial of manual and electrical acupuncture for the treatment of tinnitus. Complement Ther Med 2010; 18: 249–55.