Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondrial‐derived reactive oxygen species (ROS) play a causal role in aging‐related intervertebral disc degeneration

Oxidative damage is a well‐established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O2) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O2). Human disc cells grown at 20% O2 showed increased levels of mitochondrial‐derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria‐targeted reactive oxygen species (ROS) scavenger XJB‐5‐131 blunted the adverse effects caused by 20% O2. Importantly, we demonstrated that treatment of accelerated aging Ercc1−/Δ mice, previously established to be a useful in vivo model to study age‐related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial‐derived ROS contributes to age‐associated IDD in Ercc1−/Δ mice. Collectively, these data provide strong experimental evidence that mitochondrial‐derived ROS play a causal role in driving changes linked to aging‐related IDD and a potentially important role for radical scavengers in preventing IDD. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1150–1157, 2013
Calcium‐signaling components in rat insulinoma β‐cells (INS‐1) and pancreatic islets are differentially influenced by melatonin

The pineal secretory product melatonin exerts its influence on the insulin secretion of pancreatic islets by different signaling pathways. The purpose of this study was to analyze the impact of melatonin on calcium‐signaling components under different conditions. In a transfected INS‐1 cell line overexpressing the human MT2 receptor (hMT2‐INS‐1), melatonin treatment induced even stronger depressive effects on calcium/calmodulin‐dependent kinase 2d and IV (Camk2d, CamkIV) transcripts during 3‐isobutyl‐1‐methylxanthine (IBMX) treatment than in normal INS‐1 cells, indicating a crucial influence of melatonin receptor density on transcript‐level regulation. In addition, melatonin induced a significant downregulation of calmodulin (Calm1) in IBMX‐treated hMT2‐INS‐1 cells. Long‐term administration of melatonin alone reduced CamkIV transcript levels in INS‐1 cells; however, transcript levels of Camk2d remained unchanged. The release of insulin was diminished under long‐term melatonin treatment. The impact of melatonin also involved reductions in CAMK2D protein during IBMX or forskolin treatments in INS‐1 cells, as measured by an enzyme‐linked immunosorbent assay, indicating a functional significance of transcriptional changes in pancreatic islets. Furthermore, analysis of melatonin receptor knockout mice showed that the transcript levels of Camk2d, CamkIV, and Calm1 were differentially influenced according to the melatonin receptor subtype deleted. In conclusion, this study provides evidence that melatonin has different impacts on the regulation of Calm1 and Camk. These calcium‐signaling components are known as participants in the calcium/calmodulin pathway, which plays an important functional role in the modulation of the β‐cell signaling pathways leading to insulin secretion.
Effects of cartilage impact with and without fracture on chondrocyte viability and the release of inflammatory markers

Post‐traumatic arthritis (PTA) frequently develops after intra‐articular fracture of weight bearing joints. Loss of cartilage viability and post‐injury inflammation have both been implicated as possible contributing factors to PTA progression. To further investigate chondrocyte response to impact and fracture, we developed a blunt impact model applying 70%, 80%, or 90% surface‐to‐surface compressive strain with or without induction of an articular fracture in a cartilage explant model. Following mechanical loading, chondrocyte viability, and apoptosis were assessed. Culture media were evaluated for the release of double‐stranded DNA (dsDNA) and immunostimulatory activity via nuclear factor kappa B (NF‐κB) activity in Toll‐like receptor (TLR) ‐expressing Ramos‐Blue reporter cells. High compressive strains, with or without articular fracture, resulted in significantly reduced chondrocyte viability. Blunt impact at 70% strain induced a loss in viability over time through a combination of apoptosis and necrosis, whereas blunt impact above 80% strain caused predominantly necrosis. In the fracture model, a high level of primarily necrotic chondrocyte death occurred along the fracture edges. At sites away from the fracture, viability was not significantly different than controls. Interestingly, both dsDNA release and NF‐κB activity in Ramos‐Blue cells increased with blunt impact, but was only significantly increased in the media from fractured cores. This study indicates that the mechanism of trauma determines the type of chondrocyte death and the potential for post‐injury inflammation. (c) 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1283–1292, 2013
Systemic combined melatonin–mitochondria treatment improves acute respiratory distress syndrome in the rat

Despite high in‐hospital mortality associated with acute respiratory distress syndrome (ARDS), there is no effective therapeutic strategy. We tested the hypothesis that combined melatonin–mitochondria treatment ameliorates 100% oxygen‐induced ARDS in rats. Adult male Sprague‐Dawley rats (n = 40) were equally categorized into normal controls, ARDS, ARDS‐melatonin, ARDS with intravenous liver‐derived mitochondria (1500 μg per rat 6 hr after ARDS induction), and ARDS receiving combined melatonin–mitochondria. The results showed that 22 hr after ARDS induction, oxygen saturation (saO2) was lowest in the ARDS group and highest in normal controls, significantly lower in ARDS‐melatonin and ARDS‐mitochondria than in combined melatonin–mitochondria group, and significantly lower in ARDS‐mitochondria than in ARDS‐melatonin group. Conversely, right ventricular systolic blood pressure and lung weight showed an opposite pattern compared with saO2 among all groups (all P < 0.001). Histological integrity of alveolar sacs showed a pattern identical to saO2, whereas lung crowding score exhibited an opposite pattern (all P < 0.001). Albumin level and inflammatory cells (MPO+, CD40+, CD11b/c+) from bronchoalveolar lavage fluid showed a pattern opposite to saO2 (all P < 0.001). Protein expression of indices of inflammation (MMP‐9, TNF‐α, NF‐κB), oxidative stress (oxidized protein, NO‐1, NOX‐2, NOX‐4), apoptosis (mitochondrial Bax, cleaved caspase‐3, and PARP), fibrosis (Smad3, TGF‐β), mitochondrial damage (cytochrome C), and DNA damage (γ‐H2AX+) exhibited an opposite pattern compared to saO2 in all groups, whereas protein (HO‐1, NQO‐1, GR, GPx) and cellular (HO‐1+) expressions of antioxidants exhibited a progressively increased pattern from normal controls to ARDS combined melatonin–mitochondria group (all P < 0.001). In conclusion, combined melatonin–mitochondrial was superior to either treatment alone in attenuating ARDS in this rat model.
Drug‐associated blood dyscrasias

Drugs have been associated with the development of thrombocytopenia, thrombotic thrombocytopenia purpura–haemolytic–uraemic syndrome, haemolytic anaemia, and agranulocytosis caused by direct dose-related toxicity and by immune-mediated mechanisms. This article will review the drugs associated with these blood dyscrasias, describe the presumptive mechanisms, and discuss treatment options.
Daily differential expression of melatonin‐related genes and clock genes in rat cumulus–oocyte complex: changes after pinealectomy

This study investigated the maturational stage (immature and mature ovaries) differences of mRNA expression of melatonin‐forming enzymes (Aanat and Asmt), melatonin membrane receptors (Mt1 and Mt2) and putative nuclear (Rorα) receptors, and clock genes (Clock, Bmal1, Per1, Per2, Cry1, Cry2) in cumulus–oocyte complexes (COC) from weaning Wistar rats. We also examined the effects of pinealectomy and of melatonin pharmacological replacement on the daily expression of these genes in COC. qRT‐PCR analysis revealed that in oocytes, the mRNA expression of Asmt, Mt2, Clock, Bmal1, Per2, and Cry1 were higher (P < 0.05) in immature ovaries than in the mature ones. In cumulus cells, the same pattern of mRNA expression for Asmt, Aanat, Rorα, Clock, Per1, Cry1, and Cry2 genes was observed. In oocytes, pinealectomy altered the daily mRNA expression profiles of Asmt, Mt1, Mt2, Clock, Per1, Cry1, and Cry2 genes. In cumulus cells, removal of the pineal altered the mRNA expression profiles of Mt1, Mt2, Rorα, Aanat, Asmt, Clock, Bmal1, Per2, Cry1, and Cry2 genes. Melatonin treatment partially or completely re‐established the daily mRNA expression profiles of most genes studied. The mRNA expression of melatonin‐related genes and clock genes in rat COC varies with the maturational stage of the meiotic cellular cycle in addition to the hour of the day. This suggests that melatonin might act differentially in accordance with the maturational stage of cumulus/oocyte complex. In addition, it seems that circulating pineal melatonin is very important in the design of the daily profile of mRNA expression of COC clock genes and genes related to melatonin synthesis and action.
Melatonin protects porcine oocyte in vitro maturation from heat stress

Melatonin is a pleiotropic molecule which plays an important role in animal reproductive activities. Because of the increased global warming, the impact of heat stress (HS) on stockbreeding has become an inevitable issue to be solved. To investigate the potential effects of melatonin on the in vitro maturation of porcine oocyte under the HS, a HS model for porcine oocyte maturation has been used in this study and the different concentrations of melatonin (10−6–10−9 m) were also tested for their protective effects on oocytes. The polar body rate, the index of the nuclear maturation of the oocytes, and the cleavage rate as well as the blastocyst rate were measured to evaluate the developmental competence of the oocytes after parthenogenetic activation (PA). The results showed that HS [in vitro maturation (IVM) 20–24 hr, 42°C] significantly reduced the polar body rate of oocytes and the blastocyte rate of porcine PA embryos, while melatonin (10−7 m) application not only improved polar body rate and blastocyte rate, but also preserved the normal levels of steroid hormone which is disrupted by HS. The presence of melatonin (10−7 m) during the oocyte maturation under the HS reduced reactive oxygen species (ROS) formation, enhanced glutathione (GSH) production, inhibited cell apoptosis, and increased the gene expressions of SIRT1, AKT2, and Polg2. Importantly, the endogenously occurring melatonin of cumulus–oocyte complexes was significantly induced by HS. The results indicated that melatonin application effectively protected the oocytes from HS. These observations warranted the further studies in vivo regarding to improve the reproductive activities of animals under the global warming environment.
Glutathione‐dependent induction of local and systemic defense against oxidative stress by exogenous melatonin in cucumber (Cucumis sativus L.)

Melatonin is involved in defending against oxidative stress caused by various environmental stresses in plants. In this study, the roles of exogenous melatonin in regulating local and systemic defense against photooxidative stress in cucumber (Cucumis sativus) and the involvement of redox signaling were examined. Foliar or rhizospheric treatment with melatonin enhanced tolerance to photooxidative stress in both melatonin‐treated leaves and untreated systemic leaves. Increased melatonin levels are capable of increasing glutathione (reduced glutathione [GSH]) redox status. Application of H2O2 and GSH also induced tolerance to photooxidative stress, while inhibition of H2O2 accumulation and GSH synthesis compromised melatonin‐induced local and systemic tolerance to photooxidative stress. H2O2 treatment increased the GSH/oxidized glutathione (GSSG) ratio, while inhibition of H2O2 accumulation prevented a melatonin‐induced increase in the GSH/GSSG ratio. Additionally, inhibition of GSH synthesis blocked H2O2‐induced photooxidative stress tolerance, whereas scavenging or inhibition of H2O2 production attenuated but did not abolish GSH‐induced tolerance to photooxidative stress. These results strongly suggest that exogenous melatonin is capable of inducing both local and systemic defense against photooxidative stress and melatonin‐enhanced GSH/GSSG ratio in a H2O2‐dependent manner is critical in the induction of tolerance.
Factors predicting adherence to antidepressant treatment

Purpose of review Poor adherence and discontinuation of treatment are the major challenges of pharmacotherapy among patients with depression. This article reviews the factors predicting adherence to and persistence of antidepressant treatment identified in recent years. Recent findings Study populations have been extended to subgroups of patients with depression or depressive patients with comorbid medical conditions. Some studies have investigated the issues by analysing medical claims databases. Socio-demographic variables, clinical features of depression, comorbidities, pharmacological factors, attitudes towards antidepressants, previous experiences of antidepressant treatment, patient–professional relationship and genes were found to be common factors. An older age, positive attitudes to antidepressants and previous experiences and vicarious experiences of depression or treatment were found to be factors predicting better adherence or persistence. Conversely, patients in minority groups, those with a low family income, pregnancy, experience of side effects, dissatisfaction with treatment and a poor patient–professional relationship were found to be associated with poorer adherence or persistence. Summary The factors predicting adherence and persistence are complex and interactive. Different methods of studies have limitations in terms of exploring all these factors. Future studies should integrate these factors simultaneously and explore specific factors predicting adherence and persistence among subgroups of patients with depression.
Molecular Basis for Arrhythmias: Role of Two Nonsarcolemmal Ion Channels

Molecular Mechanisms for Arrhythmias. Ventricular tachycardia/fibrillation and sudden cardiac death occur frequently following myocardial ischemia or infarction. The recent Cardiac Arrhythmia Suppression Trial (CAST Study) found that patients treated with the Na‐channel antagonists encainide and flecainide suffered increased mortality over placebo. This unexpected result has dampened enthusiasm for treatment of asymptomatic ventricular arrhythmias and more subtly suggests a need for review of current strategies for analysis and treatment of cardiac arrhythmias. This article focuses on two nonsarcolemmal ion channels that may be involved in certain types of ventricular arrhythmias: the gap junction channel and the Ca2+‐release channel of sarcoplasmic reticulum (SR). Gap junctions enable conduction of the cardiac impulse from cell‐to‐cell and may be involved in reentrant arrhythmias. SR Ca2+‐release channels regulate the level of cytosolic Ca2+ during initiation of contraction and seem to be the basis for triggered activity. Gap junction and SR Ca2+‐release channels, though structurally dissimilar molecules, share certain functional and gating characteristics. In different ways, both channels couple the electrical response to the mechanical response. Furthermore, dysfunction of gap junction channels and/or SR Ca2+‐release channels may underlie the development of arrhythmias in postischemic cells. Classification of arrhythmias on the basis of which channel(s) is principally involved might expedite the development of new drugs targeted at functional regions of the chan‐nel(s). Ultimately, pharmacotherapy of arrhythmias directed at the molecules responsible for the electrical dysfunction may replace the empirical approach that dominates current cardiology practice. (J Cardiovasc Electrophysiol, Vol. 1, pp. 464–480, October 1990)
Melatonin rescues zebrafish embryos from the parkinsonian phenotype restoring the parkin/PINK1/DJ‐1/MUL1 network

Multiple studies reporting mitochondrial impairment in Parkinson's disease (PD) involve knockout or knockdown models to inhibit the expression of mitochondrial‐related genes, including parkin, PINK1, and DJ‐1 ones. Melatonin has significant neuroprotective properties, which have been related to its ability to boost mitochondrial bioenergetics. The meaning and molecular targets of melatonin in PD are yet unclear. Zebrafish are an outstanding model of PD because they are vertebrates, their dopaminergic system is comparable to the nigrostriatal system of humans, and their brains express the same genes as mammals. The exposure of 24 hpf zebrafish embryos to MPTP leads to a significant inhibition of the mitochondrial complex I and the induction of sncga gene, responsible for enhancing γ‐synuclein accumulation, which is related to mitochondrial dysfunction. Moreover, MPTP inhibited the parkin/PINK1/DJ‐1 expression, impeding the normal function of the parkin/PINK1/DJ‐1/MUL1 network to remove the damaged mitochondria. This situation remains over time, and removing MPTP from the treatment did not stop the neurodegenerative process. On the contrary, mitochondria become worse during the next 2 days without MPTP, and the embryos developed a severe motor impairment that cannot be rescued because the mitochondrial‐related gene expression remained inhibited. Melatonin, added together with MPTP or added once MPTP was removed, prevented and recovered, respectively, the parkinsonian phenotype once it was established, restoring gene expression and normal function of the parkin/PINK1/DJ‐1/MUL1 loop and also the normal motor activity of the embryos. The results show, for the first time, that melatonin restores brain function in zebrafish suffering with Parkinson‐like disease.
Efficacy of Different Fungicides against Mango Anthracnose in Senegalese Soudanian Agroclimate

Anthracnose is the one of the most devastating diseases of mango produced in the southern part of Senegal. The field trials against post harvest rot due to anthracnose took place in three orchards over two production seasons, in 2009 and 2010. Three systemic fungicides (thiophanate methyl, azoxystrobin and myclobutanyl) and one contact fungicide (mancozeb) were tested for their efficacy. The first treatments in 2009 took place in the rainy season, while 20% of mangoes on trees exhibited anthracnose lesions. At ripening stage, 100% of fruits from non treated control mango trees were affected by anthracnose and got rotten, while between 73.2% and 80% of mangoes ripened free of disease when treated with thiophanate methyl. With the treatment with azoxystrobin, between 46.6% and 60% of fruits were not infected. Treatment with myclobutanyl was less effective. This level of effectiveness was clearly improved in 2010 by preventive spraying, days ahead of onset of the rainy season, before the appearance of anthracnose symptoms on fruits. The level of effectiveness was higher respectively for thiophanate methyl (between 96% and 100% of fruits not infected) and azoxystrobin (between 84% and 96% of fruits not infected).
Influence of legal status on the uptake of cannabis in young people

Purpose of review Policies that limit young people's access to cannabis may reduce early onset of use and minimize health-related harm. This review article provides an update of recent research examining the influence of the cannabis policy frameworks on the use of cannabis by young people. Recent findings There are significant concerns that ongoing policy changes in favour of legalization will increase the uptake of cannabis by young people. Evidence to support a causal effect of cannabis policy changes on increased uptake by young people is lacking; more time may be needed to assess the impact because the policies are still evolving. Policy changes in favour of legalization were associated with reduced risk perception although this may be a cause or consequence. The need to situate the impact of these policies in the context of specific policy features, social norms and perceptions about cannabis has been highlighted. Summary A more nuanced understanding of the impact of the legal status of cannabis on young people is needed to build evidence for future policy options. The impact of these policies may not be immediately apparent but limiting young people's access to cannabis must be prioritized during policy deliberations.
In vivo loss of cement–bone interlock reduces fixation strength in total knee arthroplasties

Prevention of aseptic loosening of total knee arthroplasties (TKAs) remains a clinical challenge. Understanding how changes in morphology at the implant–bone interface with in vivo service affect implant stability and strength could lead to new approaches to mitigate loosening. Enbloc TKA retrievals and freshly‐cemented TKA tibial components were used to determine if the mechanical strength of the interface depended on the amount of cement–bone interlock and the morphology of the supporting bone under the cement layer. Implants were sectioned into small specimens of the cement–interface–bone from under the tibial tray. Micro‐CT scans were used to document interlock morphology and architecture of the supporting trabecular bone. Axial compression tests were used to assess mechanical behavior. Postmortem retrievals had lower contact fraction (42 ± 55%) compared to freshly‐cemented constructs (121 ± 61%) (p = 0.0008). Supporting bone architecture parameters were not different for the two groups. Increased interface contact fraction and supporting bone volume fraction (BV/TV) were positive predictors of interface strength (r2 = 0.72, p = 0.0001). For the same supporting bone BV/TV, postmortem specimens had weaker interfaces; they were also more compliant. Cemented TKAs with in vivo service experience a loss of fixation strength and increased micro‐motion due to the loss of cement–bone interlock. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1052–1060, 2014.