Medicinal Chemistry approach, pharmacology and neuroprotective benefits of CB2R modulators in neurodegenerative diseases

In the last decades, cannabinoid receptor 2 (CB2R) has continued to receive attention as a key therapeutic target in neuroprotection. Indeed, several findings highlight the neuroprotective effects of CB2R through suppression of both neuronal excitability and reactive microglia. Additionally, CB2R seems to be a more promising target than cannabinoid receptor 1 (CB1R) thanks to the lack of central side effects, its lower expression levels in the central nervous system (CNS), and its inducibility, since its expression enhances quickly in the brain following pathological conditions. This review aims to provide a thorough overview of the main natural and synthetic selective CB2R modulators, their chemical classification and their potential therapeutic usefulness in neuroprotection, a crucial aspect for the treatment of neurodegenerative diseases

Transformasi Mite “Misteri Gang Keramat” Menjadi Naskah Drama sebagai Bahan Ajar Bahasa Indonesia Siswa Kelas VIII SMP Muhammadiyah 05 Medan Tahun Ajaran 2019/2020

Penelitian ini berjudul “Transformasi Mite “Misteri Gang Keramat” Menjadi Naskah Drama Sebagai Bahan Ajar Bahasa Indonesia Siswa Kelas VIII SMP Muhammadiyah 05 Medan Tahun Ajaran 2019/2020”. Penelitian ini diangkat untuk mentransformasikan mite “Misteri Gang Keramat” menjadi naskah drama dan dijadikan sebagai bahan ajar Bahasa Indonesia pada siswa SMP kelas VIII SMP Muhammdiyah 05 Medan. Penelitian ini menggunakan metode penelitian deskriptif kualitatif bertujuan untuk mendeskripsikan secara sistematis, faktual, dan akurat dengan menggunakan kata-kata atau kalimat. Penelitian ini dilaksanakan mulai bulan November 2018 sampai dengan Oktober 2019. Teknik pengumpulan data menggunakan teknik simak bebas libat cakap. Data dalam penelitian ini adalah data lisan berupa mite “Misteri Gang Keramat”. Sumber data dalam penelitian ini adalah informan dari masyarakat Gang Keramat, Mabar, Medan Deli. Teknik analisis data menggunakan analisis interaktif, yaitu reduksi, penyajian data, dan penarikan simpulan. Teknik validitas data menggunakan triangulasi metode dan sumber. Prosedur penelitian meliputi perencanaan, pelaksanaan, dan peyusunan laporan. Hasil penelitian diketahui mite “Misteri Gang Keramat” ini terbentuk karena adanya unsur mistis di daerah tersebut, terdapat sebuah pohon yang dianggap keramat dan sering didatangi oleh masyarakat sekitar untuk meminta sesuatu. Tujuan masyarakat bermacam-macam, ada yang meminta kesembuhan, keberuntungan dan sebagainya. Jika permintaan atau permohonannya terkabul, maka para penduduk sekitar akan meletakkan sesajen di bawah pohon sebagai wujud syukur. Sehingga dahulu para orang tua mengingatkan anaknya untuk tidak keluar malam karena daerah tersebut merupakan keramat, dari situlah mite ini muncul. Mite yang telah disusun kemudian ditransformasikan oleh peneliti menjadi naskah drama untuk dijadikan sebagai bahan ajar Bahasa Indonesia

The echo index and multistability in input-driven recurrent neural networks

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.A recurrent neural network (RNN) possesses the echo state property (ESP) if, for a given input sequence, it “forgets” any internal states of the driven (nonautonomous) system and asymptotically follows a unique, possibly complex trajectory. The lack of ESP is conventionally understood as a lack of reliable behaviour in RNNs. Here, we show that RNNs can reliably perform computations under a more general principle that accounts only for their local behaviour in phase space. To this end, we formulate a generalisation of the ESP and introduce an echo index to characterise the number of simultaneously stable responses of a driven RNN. We show that it is possible for the echo index to change with inputs, highlighting a potential source of computational errors in RNNs due to characteristics of the inputs driving the dynamics.Engineering and Physical Sciences Research Council (EPSRC)Canada Research Chairs programNZ Marsden fun

Antineoplastic effects of rosiglitazone and PPARγ transactivation in neuroblastoma cells

Neuroblastoma (NB) is the most common extracranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. In the present study, we evaluated the role of the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (RGZ) in two NB cell lines (SK-N-AS and SH-SY5Y), which express PPARγ. Rosiglitazone decreased cell proliferation and viability to a greater extent in SK-N-AS than in SH-SY5Y. Furthermore, 20 μM RGZ significantly inhibited cell adhesion, invasiveness and apoptosis in SK-N-AS, but not in SH-SY5Y. Because of the different response of SK-N-AS and SH-SY5Y cells to RGZ, the function of PPARγ as a transcriptional activator was assessed. Noticeably, transient transcription experiments with a PPARγ responsive element showed that RGZ induced a three-fold increase of the reporter activity in SK-N-AS, whereas no effect was observed in SH-SY5Y. The different PPARγ activity may be likely due to the markedly lower amount of phopshorylated (i.e. inactive) protein observed in SK-N-AS. To our knowledge, this is the first demonstration that the differential response of NB cells to RGZ may be related to differences in PPARγ transactivation. This finding indicates that PPARγ activity may be useful to select those patients, for whom PPARγ agonists may have a beneficial therapeutic effect

Selective inhibitors of cardiac ADPR cyclase as novel anti-arrhythmic compounds

ADP-ribosyl cyclases (ADPRCs) catalyse the conversion of nicotinamide adenine dinucleotide to cyclic adenosine diphosphoribose (cADPR) which is a second messenger involved in Ca2+ mobilisation from intracellular stores. Via its interaction with the ryanodine receptor Ca2+ channel in the heart, cADPR may exert arrhythmogenic activity. To test this hypothesis, we have studied the effect of novel cardiac ADPRC inhibitors in vitro and in vivo in models of ventricular arrhythmias. Using a high-throughput screening approach on cardiac sarcoplasmic reticulum membranes isolated from pig and rat and nicotinamide hypoxanthine dinuleotide as a surrogate substrate, we have identified potent and selective inhibitors of an intracellular, membrane-bound cardiac ADPRC that are different from the two known mammalian ADPRCs, CD38 and CD157/Bst1. We show that two structurally distinct cardiac ADPRC inhibitors, SAN2589 and SAN4825, prevent the formation of spontaneous action potentials in guinea pig papillary muscle in vitro and that compound SAN4825 is active in vivo in delaying ventricular fibrillation and cardiac arrest in a guinea pig model of Ca2+ overload-induced arrhythmia. Inhibition of cardiac ADPRC prevents Ca2+ overload-induced spontaneous depolarizations and ventricular fibrillation and may thus provide a novel therapeutic principle for the treatment of cardiac arrhythmias

Molecular Characterization of a Novel Intracellular ADP-Ribosyl Cyclase

Background. ADP-ribosyl cyclases are remarkable enzymes capable of catalyzing multiple reactions including the synthesis of the novel and potent intracellular calcium mobilizing messengers, cyclic ADP-ribose and NAADP. Not all ADP-ribosyl cyclases however have been characterized at the molecular level. Moreover, those that have are located predominately at the outer cell surface and thus away from their cytosolic substrates. Methodology/Principal Findings. Here we report the molecular cloning of a novel expanded family of ADP-ribosyl cyclases from the sea urchin, an extensively used model organism for the study of inositol trisphosphate-independent calcium mobilization. We provide evidence that one of the isoforms (SpARC1) is a soluble protein that is targeted exclusively to the endoplasmic reticulum lumen when heterologously expressed. Catalytic activity of the recombinant protein was readily demonstrable in crude cell homogenates, even under conditions where luminal continuity was maintained. Conclusions/Significance. Our data reveal a new intracellular location for ADP-ribosyl cyclases and suggest that production of calcium mobilizing messengers may be compartmentalized