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Cytisine is a low-cost medication that is potentially beneficial in smoking cessation. In this placebo-controlled trial, 12-month abstinence rates were 8.4% among participants randomly assigned to 4 weeks of cytisine and 2.4% among participants assigned to placebo. Tobacco smoking contributes to some 5 million premature deaths each year worldwide. 1 It is highly addictive, with more than 95% of unaided attempts at cessation failing to last 6 months. 2 Every year that a smoker delays quitting beyond the mid-30s, the person loses 3 months of life expectancy. 3 The World Health Organization's Framework Convention on Tobacco Control identifies evidence-based approaches to promote smoking cessation, which include mass-media campaigns, tax increases on tobacco, and help for smokers wanting to stop. 4 Success in quitting is increased by behavioral support and a range of pharmacotherapies. 5 – 8 Some pharmacotherapies have been shown to be . . .

Background This study examined the efficacy and safety of N-acetylcysteine (NAC) augmentation for treating irritability in children and adolescents with autism spectrum disorders (ASD). Method Forty children and adolescents met diagnostic criteria for ASD according to DSM-IV. They were randomly allocated into one of the two groups of NAC (1200 mg/day)+risperidone or placebo+risperidone. NAC and placebo were administered in the form of effervescent and in two divided doses for 8 weeks. Irritability subscale score of Aberrant Behavior Checklist (ABC) was considered as the main outcome measure. Adverse effects were also checked. Results The mean score of irritability in the NAC+risperidone and placebo+risperidone groups at baseline was 13.2(5.3) and 16.7(7.8), respectively. The scores after 8 weeks were 9.7(4.1) and 15.1(7.8), respectively. Repeated measures of ANOVA showed that there was a significant difference between the two groups after 8 weeks. The most common adverse effects in the NAC+risperidone group were constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%). There was no fatal adverse effect. Conclusions Risperidone plus NAC more than risperidone plus placebo decreased irritability in children and adolescents with ASD. Meanwhile, it did not change the core symptoms of autism. Adverse effects were not common and NAC was generally tolerated well. Trial registration This trial was registered at http://www.irct.ir . The registration number of this trial was IRC T201106103930N6

Parkinson’s disease (PD) is an advanced neurodegenerative condition distinguished by the rapid decline of dopamine neurons in the midbrain, leading to an imbalance in dopamine and acetylcholine levels, precipitating associated symptoms. The main objective of this work was to fabricate solid lipid nanoparticles (SLNs) loaded with S-carboxymethyl-L-cystine (SC) for enhanced delivery to the brain. This study examines the impact of these SLNs on rotenone (RT) caused Parkinson’s disease (PD) in both rat and zebrafish models. The process of loading SC into SLNs was achieved through the solvent evaporation-emulsification method. The SC-encapsulated solid lipid nanoparticles (SCSLNs) were subjected to physicochemical evaluation, and their properties were verified. For 28 days, the rats received subcutaneous injections of RT at a dosage of 2 mg × kg −1 body weight. Additionally, the rats in the experimental group received SCSLNs from the 14th to the 28th days of the trial. Interestingly, the locomotor activity, grip strength, and exploratory behaviour of the rats with SCSLNs significantly improved. Furthermore, it was observed that the quantities of acetylcholinesterase (AchE) inside the brain tissue had increased, and oxidative biomarkers had decreased. In addition, there was a discernible decrease in Lewy body development and cellular damage compared to the positive control group. Zebrafish were dosed with SCSLNs simultaneously as they were subjected to a 5 µg × L −1 RT concentration for 28 days during the experiment. AchE levels in the fish brain increased, resulting in improved locomotor activity in the SCSLN group of zebrafish. The findings of this investigation imply that using SCSLNs may reduce Parkinson’s disease symptoms via enhanced delivery of SC into the brain.

The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutat hione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11 high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucoseand glutamine-dependency in SLC7A11 high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11 high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and-independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.

Cancer cells rewire their metabolism and rely on endogenous antioxidants to mitigate lethal oxidative damage to lipids. However, the metabolic processes that modulate the response to lipid peroxidation are poorly defined. Using genetic screens, we compared metabolic genes essential for proliferation upon inhibition of cystine uptake or glutathione peroxidase-4 (GPX4). Interestingly, very few genes were commonly required under both conditions, suggesting that cystine limitation and GPX4 inhibition may impair proliferation via distinct mechanisms. Our screens also identify tetrahydrobiopterin (BH4) biosynthesis as an essential metabolic pathway upon GPX4 inhibition. Mechanistically, BH4 is a potent radical-trapping antioxidant that protects lipid membranes from autoxidation, alone and in synergy with vitamin E. Dihydrofolate reductase catalyzes the regeneration of BH4, and its inhibition by methotrexate synergizes with GPX4 inhibition. Altogether, our work identifies the mechanism by which BH4 acts as an endogenous antioxidant and provides a compendium of metabolic modifiers of lipid peroxidation. Genetic screens reveal a compendium of metabolic modifiers of lipid peroxidation. Tetrahydrobiopterin is essential under GPX4 inhibition, acting as a radical-trapping antioxidant that inhibits lipid peroxidation and is regenerated by DHFR.

Crystallization of L-cystine is a critical step in the pathogenesis of cystine kidney stones. Treatments for this disease are somewhat effective but often lead to adverse side effects. Real-time in situ atomic force microscopy (AFM) reveals that L-cystine dimethylester (L-CDME) and L-cystine methylester (L-CME) dramatically reduce the growth velocity of the six symmetry-equivalent {100} steps because of specific binding at the crystal surface, which frustrates the attachment of L-cystine molecules. L-CDME and L-CME produce L-cystine crystals with different habits that reveal distinct binding modes at the crystal surfaces. The AFM observations are mirrored by reduced crystal yield and crystal size in the presence of L-CDME and L-CME, collectively suggesting a new pathway to the prevention of L-cystine stones by rational design of crystal growth inhibitors.

Appropriate dosing of cystine-binding thiol drugs in the management of cystinuria has been based on clinical stone activity. When new stones form, the dose is increased. Currently, there is no method of measuring urinary drug levels to guide the titration of therapy. Increasing cystine capacity, a measure of cystine solubility, has been promoted as a method of judging the effects of therapy. In this study, we gave increasing doses of tiopronin or d-penicillamine, depending on the patients’ own prescriptions, to ten patients with cystinuria and measured cystine excretion and cystine capacity. The doses were 0, 1, 2, 3 g per day, given in two divided doses, and administered in a random order. Going from 0 to 1 g/day led to an increase in cystine capacity from − 39.1 to 130.4 mg/L (P < 0.009) and decreased 24 h cystine excretion from 1003.9 to 834.8 mg/day (P = 0.039). Increasing the doses from 1 to 2 to 3 g/day had no consistent or significant effect to further increase cystine capacity or decrease cystine excretion. Whether doses higher than 1 g/day have additional clinical benefit is not clear from this study. Limiting doses might be associated with fewer adverse effects without sacrificing the benefit of higher doses if higher doses do not offer clinical importance. However, trials with stone activity as an outcome would be desirable.

By reducing the availability of extracellular L -cyst(e)ine, an engineered enzyme inhibits glutathione production and cripples antioxidant defenses of tumors in a variety of mouse models. Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation 1 , 2 , 3 . Under conditions of elevated ROS, endogenous L -cysteine ( L -Cys) production is insufficient for GSH synthesis. This necessitates uptake of L -Cys that is predominantly in its disulfide form, L -cystine (CSSC), via the xCT(−) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L -Cys and CSSC pool in mice and non-human primates. Treatment with this enzyme selectively causes cell cycle arrest and death in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS; yet this treatment results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in both prostate and breast cancer xenografts and doubled the median survival time of TCL1 -Tg: p53 −/− mice, which develop disease resembling human chronic lymphocytic leukemia. It was observed that enzyme-mediated depletion of the serum L -Cys and CSSC pool suppresses the growth of multiple tumors, yet is very well tolerated for prolonged periods, suggesting that cyst(e)inase represents a safe and effective therapeutic modality for inactivating antioxidant cellular responses in a wide range of malignancies 4 , 5 .

The extra domain B splice variant (EDB) of human fibronectin selectively expressed in the tumor vasculature is an attractive target for cancer imaging and therapy. Here, we describe the generation and characterization of EDB-specific optical imaging probes. By screening combinatorial cystine-knot miniprotein libraries with phage display technology we discover exquisitely EDB-specific ligands that share a distinctive motif. Probes with a binding constant in the picomolar range are generated by chemical oligomerization of selected ligands and fluorophore conjugation. We show by fluorescence imaging that the probes stain EDB in tissue sections derived from human U-87 MG glioblastoma xenografts in mice. Moreover, we demonstrate selective accumulation and retention of intravenously administered probes in the tumor tissue of mice with U-87 MG glioblastoma xenografts by in vivo and ex vivo fluorescence imaging. These data warrants further pursuit of the selected cystine-knot miniproteins for in vivo imaging applications. Cystine-knot miniprotein are small, highly stable, disulfide-rich peptides with increasing potential as drugs and tumor imaging agents. Here the authors develop cystine-knot miniproteins targeting the vascular tumor marker EDB, and use them as probes for in vivo tumor vasculature imaging.

A sensitive solid-state electrochemiluminescence (ECL) electrode for L-cysteine was developed based on depositing layers of a hybrid nanocomposite of polypyrrole-dodecyl benzene sulfate-sodium perchlorate-sodium carbonate-gadolinium (PPy-Gd.sub.2O.sub.3) on a platinum substrate. The presence of the Gd.sub.2O.sub.3 nanoparticle layer improved the ECL signal, and under optimum conditions, a linear relationship was observed between the signal and the logarithm of L-cysteine concentration from 1.0 x 10.sup.-13 to 1.0 x 10.sup.-6 M (R.sup.2 = 0.9937). At the emission wavelength around 425 nm, at which the analytical signal was measured, the electrode showed an RSD of less than 4% and a low detection limit of 4.2 x 10.sup.-14 M. The results proved to be reproducible and stable, and the electrode was applicable in the determination of L-cysteine in biological fluids with recoveries from 94.0-107%.