Notes

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Larger multicenter studies are needed to confirm these results.Three experiments were conducted with pigeons to assess discriminated periods of nonreinforcement as precipitators of resurgence. Each experiment occurred in three phases. In the Training phase, key-pecking was reinforced according to variable-interval schedules that alternated between two response keys (Experiment 1) or were concurrently available on two response keys (Experiments 2a & 2b). In the Alternative-Reinforcement phase, responding to one key was extinguished, while that to the other was reinforced according to tandem schedules. These then were replaced by chained schedules with the same programmed reinforcement rate in the Resurgence-Test phase. Resurgence occurred both when the signaled period of nonreinforcement was a darkened keylight in the terminal link of the chain schedule (Experiment 1) and a darkened keylight (Experiment 2a) or keylight color change (Experiment 2b) in the initial link of the chain schedule. Thus, signaled periods of extinction, without accompanying reductions in reinforcement rate, precipitated resurgence, suggesting that resurgence is not the result of worsening of overall reinforcement conditions, but also occurs when local conditions of reinforcement are worsened.Cancer cells exhibit extreme sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) over normal cells, highlighting TRAIL's potential as a novel and effective cancer drug. However, the therapeutic effect of TRAIL is limited due to drug resistance. In the present study, we sought to investigate the potential effects of luteolin as a TRAIL sensitizer in non-small cell lung cancer (NSCLC) cells. A549 and H1975 cells had low sensitivity or were resistant to TRAIL. Luteolin alone or in combination with TRAIL decreased cell viability and increased apoptosis. Furthermore, luteolin alone or in combination with TRAIL enhanced death receptor 5 (DR5) expression and dynamin-related protein 1 (Drp1)-dependent mitochondrial fission. However, the synergistic effect of luteolin on cell viability and apoptosis was reversed by DR5 and Drp1 inhibition, suggesting that DR5 upregulation and mitochondrial dynamics may be essential for luteolin as a sensitizer of TRAIL-based therapy in NSCLC. Moreover, luteolin treatment alone or in combination with TRAIL increased the phosphorylation of c-Jun N-terminal kinase (JNK), while SP600125 (the JNK inhibitor) significantly abolished the synergistic effect on DR5 expression and Drp1 translocation, indicating that JNK signaling activation was greatly associated with the synergistic effect exerted by luteolin in NSCLC cells. Therefore, TRAIL combined with luteolin could be as an effective chemotherapeutic strategy for NSCLC.Direct compression remains one of the most favourable methods available to produce tablet compacts due to its simplicity, efficiency and cost effectiveness however, the technique still remains unsuitable for the majority of formulations due to materials exhibiting poor physical properties such as inadequate compressibility and deformation mechanisms. Whereas crystallo-co-spray drying of various blends has shown to improve the tabletting properties of poorly processable materials, the role of the solvent feed composition in altering the soluble fraction ratio of the excipient to the drug in a crystallo-co-spray dried agglomerate is not well understood. The aim of this work was to investigate the role of the soluble fraction of a drug (paracetamol) and an excipient (α-lactose monohydrate) on the tabletting properties of their crystallo-co-spray dried agglomerates produced via co-spray drying using various inlet feed solvent compositions in order to vary the soluble fraction of the excipient in the feed. It was found that an increase in excipient soluble fraction in the inlet feed resulted in a greater degree of intimate mixing in the final spray dried powder blend, which in turn led to an improvement in tabletting properties of the poorly processable drug.Octreotide is approved as a one-month injectable for treatment of acromegaly and neuroendocrine tumours. Oral delivery of the octapeptide is a challenge due mainly to low intestinal epithelial permeability. The intestinal permeation enhancer (PE) salcaprozate sodium (SNAC) has Generally Regarded As Safe (GRAS) status and is a component of an approved oral peptide formulation. The purpose of the study was to examine the capacity of salcaprozate sodium (SNAC), to increase its permeability across isolated rat intestinal mucosae from five regions and across human colonic mucosae mounted in Ussing chambers. Apical-side buffers were Kreb's-Henseleit (KH), fasted simulated intestinal fluid (FaSSIF-V2), rat simulated intestinal fluid (rSIF), and colonic simulated intestinal fluid (FaSSCoF). The basal apparent permeability coefficient (Papp) of [3H]-octreotide was equally low across rat intestinal regional mucosae in KH, rSIF, and FaSSIF-V2. Apical addition of 20 mM SNAC increased the Papp across rat tissue in KH colon (by 3.2-fold) > ileum (3.4-fold) > upper jejunum (2.3-fold) > duodenum (1.4-fold) > stomach (1.4-fold). 20 mM and 40 mM SNAC also increased the Papp by 1.5-fold and 2.1-fold respectively across human colonic mucosae in KH. Transepithelial electrical resistance (TEER) values were reduced in the presence in SNAC especially in colonic regions. LC-MS/MS analysis of permeated unlabelled octreotide across human colonic mucosae in the presence of SNAC indicated that [3H]-octreotide remained intact. No gross damage was caused to rat or human mucosae by SNAC. Attenuation of the effects of SNAC was seen in rat jejunal mucosae incubated with FaSSIF-V2 and rSIF, and also to some extent in human colonic mucosae using FaSSCoF, suggesting interaction between SNAC with buffer components. In conclusion, SNAC showed potential as an intestinal permeation enhancer for octreotide, but in vivo efficacy may be attenuated by interactions with GI luminal fluid contents.
Repeated methamphetamine (METH) administration in mice readily produces behavioural sensitization, but the underlying mechanisms remain elusive. The present research aimed to identify new targets affecting METH-induced behavioural sensitization.

We first established a mouse model of METH-induced behavioural sensitization. To characterize the animal model, we performed behavioural tests at different stages of behavioural sensitization and simultaneously detected changes in several neurotransmitters in the prefrontal cortex (PFC). Next, we perfromed RNA sequencing (RNA-seq) to screen new targets, which were subsequently and verified by RT-PCR and western blot. Finally, we confirmed the roles of the new targets in METH-induced behavioural sensitization by injection of overexpressed lentiviruses and further detected related protein levels by western blot and histological changes by haematoxylin and eosin (HE) staining.

We successfully established a mouse model of METH-induced behavioural sensitization. The on to METH may be mediated by Fas and GIT1 through the MEK1-Erk1/2-CREB pathway.
The findings indicated that the development of behavioural sensitization to METH may be mediated by Fas and GIT1 through the MEK1-Erk1/2-CREB pathway.At present, there are still no official or semi-official recommendations for the treatment of muscle fatigue. We previously reported that acute phase protein orosomucoid (ORM) can enhance muscle endurance and exert anti-fatigue effect. In attempting to seek anti-fatigue drugs that target ORM, we found macrolide antibiotics, particularly erythromycin, were effective. Erythromycin can significantly prolong the time of mice forced-swimming and treadmill running, increase muscle fatigue index, alleviate fatigue-induced tissue damage, and elevate glycogen content, mitochondria function and ATP level in the muscle. Also, erythromycin increases ORM protein expression in a dose- and time- dependent manner both in vitro and in vivo. Further studies found that erythromycin could increase the activity of ORM promoter and the stability of ORM mRNA, which might both be responsible for the ORM up-regulation. ORM knockdown or knockout could abolish the promoting effect of erythromycin in mice forced-swimming time, muscle fatigue index and glycogen level. Furthermore, those effects were also abolished in mice with C-C motif chemokine receptor 5 (CCR5) antagonist administration or AMPKα2 deficiency. Therefore, erythromycin could enhance muscle glycogen and endurance via up-regulating the level of ORM and activating CCR5-AMPK pathway, indicating it might act as a potential drug to treat muscle fatigue.Diclofenac is a non-steroidal anti-inflammatory drug widely used by the general population and, although generally contraindicated during pregnancy, it is also used by some pregnant women. This study investigated endocrine, reproductive and behavioral effects of diclofenac in male and female offspring rats exposed in utero from gestational days 10-20. Pregnant rats were treated with diclofenac at doses of 0.2, 1 and 5 mg/kg/day via oral gavage. CW069 Anogenital distance (AGD), number of nipples, and developmental landmarks of puberty onset - vaginal opening (VO), first estrus (FE) and preputial separation (PPS) - were evaluated in the offspring. At adulthood, behavioral and reproductive parameters were assessed. Male and female rats were tested in the elevated plus maze test to assess locomotor activity and anxiety-like behaviors, while male rats were also evaluated in the partner preference test. No significant effects were observed on AGD and number of nipples in both males and females. Diclofenac treatment induced an overall delay in developmental landmarks of puberty onset in male and female offspring, which reached statistical significance for PPS at the lowest diclofenac dose. Prenatal exposure to all tested doses abolished the preference of male rats for an estrous female, suggesting an impairment of brain masculinization. No changes were observed on male or female reproductive parameters at adulthood. Overall, our results indicate that prenatal exposure to therapeutically relevant doses of diclofenac may have an impact in the pubertal development of rats and negatively affect male partner preference behavior.Echo intensity (EI) is being increasingly utilized by investigators as an index of skeletal muscle quality. Previous studies have reported independent associations between EI versus both age and muscle strength.
We sought to determine whether EI is more strongly associated with age or strength.

Twenty-eight younger adults (13 men, 15 women; mean age=22years) and 25 older adults (10 men, 15 women; age=71years) participated. B-mode ultrasonography was utilized to acquire images of the vastus lateralis and rectus femoris. ImageJ software was used to quantify corrected EI and muscle cross-sectional area (CSA). Each participant performed 40 maximal concentric isokinetic muscle actions of the knee extensors (velocity=180°·s
). The mean peak torque of the best three attempts was used to quantify muscle strength. Specific torque was calculated as strength relative to CSA. Fatigability was also quantified. Statistical analyses included independent samples t-tests and stepwise regression.

There were large differences between age groups for strength (p<.
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