scholarly journals In silico analysis of antihypertensive and hepatotoxicity potential of the n-butanol fraction of the methanol extract of of cantaloupe (Cucumis melo var. cantalupensis)

2020 ◽  
Vol 11 (2) ◽  
pp. 106-114
Author(s):  
Dian Laila ◽  
Dianita Rifqia Putri ◽  
Galuh Wening Permatasari
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Calcium Channels ◽  
In Silico ◽  
Cucumis Melo ◽  
Methanol Extract ◽  
Action Mechanism ◽  
Inactive Conformation ◽  
Voltage Gated ◽  
Butanol Fraction

Latar belakang: Hipertensi merupakan faktor risiko utama penyakit kardiovaskular. Penduduk Indonesia cenderung mengkonsumsi herbal dalam terapi hipertensi dalam mempertahankan kadar tekanan darah seperti buah blewah (Cucumis melo var. cantalupensis). Namun mekanisme kerja buah blewah dalam menurunkan tekanan darah, dan potensi toksisitasnya jika dikonsumsi dalam jangka panjang masih belum jelas. Tujuan studi ini adalah untuk menganalisis mekanisme antihipertensi dari buah blewah dan potensi toksiknya melalui pendekatan in silico. Metode: Bubuk blewah kering dimaserasi menggunakan metanol absolut, difraksinasi menggunakan n-butanol. Uji fitokimia dilakukan dengan metode LC-MS, kemudian senyawa bioaktif ditelusuri hingga SMILESnya di PubChem. Analisis QSAR untuk analisis potensi antihipertensi dilakukan dengan PASS server. Kelas toksisitas dan potensi hepatotoksisitas dianalisis menggunakan ProTox-II, dilanjutkan dengan analisis networking menggunakan STITCH dan STRINGdb. Hasil: Setidaknya terdapat 434 jenis senyawa yang terdapat pada fraksi n-butanol dari ekstrak metanol buah blewah (FBEMB). Berdasarkan analisis STITCH dan STRINGdb, FBEMB dapat bekerja dalam menurunkan tekanan darah melalui mekanisme aksi seperti senyawa amlodipine, yang menstabilkan saluran kalsium tipe-L yang terisi tegangan dalam konformasi tidak aktifnya. Dengan demikian, mencegah kontraksi myocyte yang bergantung pada kalsium dan vasokonstriksi. FBEMB mungkin berpotensi hepatotoksik melalui mekanisme kerja senyawa seperti itrakonazol yang menghambat enzim sitokrom P450 yang mempengaruhi gangguan pada sintesis ergosterol, dan efavirenz yang memiliki efek neurotoksik. Penghambatan sitokrom P450 dapat menyebabkan toksisitas obat dan kerusakan hati. Kesimpulan: FBEMB dapat bekerja dalam menurunkan tekanan darah melalui mekanisme penstabilan saluran kalsium tipe-L yang terisi tegangan dalam konformasi tidak aktifnya. Kata kunci: in silico, antihipertensi, hepatotoksisitas, blewah   Abstract Background: Hypertension is a major cardiovascular disease risk factor. Indonesian people tend to consume herbal medicine to maintain hypertension therapy, i.e cantaloupe (Cucumis melo var. cantalupensis). However, the mechanism of action of cantaloupe in lowering blood pressure and toxicity potential for long term consumption is unclear. The study aimed to analyze the antihypertensive mechanism of cantaloupe and its toxic potential through the in silico. Methods: The dried cantaloupe powder was macerated using absolute methanol, then fractionated using n-butanol. The phytochemical test was done by LC-MS method, then the bioactive compounds were traced to their SMILES in the PubChem. The QSAR analysis of the antihypertensive potential was done using the PASS server. The toxicity class and hepatotoxicity potential were analyzed using ProTox-II, followed by networking analysis using STITCH and STRINGdb. Results: At least 434 types of compounds were shown in the n-butanol fraction of the methanol extract of cantaloupe (BFMEC). Based on the networking analysis, BFMEC may work in lowering blood pressure through the action mechanism of the amlodipine compound-like, which stabilizes voltage-gated L-type calcium channels in an inactive conformation, thus, prevents calcium-dependent myocyte contraction and vasoconstriction. BFMEC presumably has hepatotoxic through the action mechanism of itraconazole compound-like inhibited cytochrome P450-dependent enzymes, affecting the impairment of ergosterol synthesis, and efavirenz which has neurotoxic effects. The inhibition of cytochrome P450 may cause drug toxicity and liver damage. Conclusion: BFMEC may work in lowering blood pressure through the action mechanism which stabilizes voltage-gated L-type calcium channels in an inactive conformation. Keywords: in silico, antihypertensive, hepatotoxicity, cantaloupe  

Synthetic Lapachol Derivatives Relax Guinea-Pig Ileum by Blockade of the Voltage-Gated Calcium Channels

2010 ◽  
Vol 65 (9-10) ◽  
pp. 627-636
Author(s):  
Fabiana de A. Cavalcante ◽  
Fabio De S. Monteiro ◽  
Italo Rossi R. Martins ◽  
Ticiano P. Barbosa ◽  
Celso de A Camara ◽  
...  
Keyword(s):  
Free Radicals ◽  
Guinea Pig ◽  
Calcium Channels ◽  
Action Mechanism ◽  
Guinea Pig Ileum ◽  
Spasmolytic Activity ◽  
Tonic Component ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Antioxidant Agent

The present study was designed to further evaluate a possible spasmolytic activity of synthetic lapachol derivatives, norlapachol, α-norlapachone, β-norlapachone and hydro-hydroxy- norlapachol (HH-norlapachol), on guinea-pig ileum. In guinea-pig ileum, except for norlapachol, all naphthoquinones inhibited the phasic contractions induced by carbachol or histamine. Even when the ileum was pre-contracted with KCl, carbachol or histamine, all naphthoquinones induced relaxation, suggesting that these naphthoquinones could be acting on the voltage-gated calcium channels (CaV). As the tonic component this contraction is maintained mainly by the opening of the CaV, we hypothesized that these naphthoquinones might be acting on these channels. This hypothesis was confirmed by the observation that norlapachol (pD’2 = 4.99), α-norlapachone (pD’2 = 4.49), β-norlapachone (pD’2 = 6.33), and HH-norlapachol (pD’2 = 4.53) antagonized the contractions induced by CaCl2 in depolarizing medium nominally without Ca2+. As β-norlapachone was the most potent we decided to continue the study of its action mechanism. The fact that this naphthoquinone has inhibited the tonic contractions induced by S-(-)-Bay K8644 [EC50 = (1.6 ± 0.30) · 10-5 M] suggests that the Ca2+ channel involved belongs to the type L (CaV1.2). In addition, in the functional level, the spasmolytic effect of β-norlapachone does not involve participation of free radicals, since its curve of relaxation was unchanged in the presence of glutathione, an antioxidant agent.

scholarly journals Caenorhabditis elegans Junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin

Genetics ◽  
2021 ◽  
Author(s):  
Christopher A Piggott ◽  
Zilu Wu ◽  
Stephen Nurrish ◽  
Suhong Xu ◽  
Joshua M Kaplan ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Tissue Specific ◽  
Voltage Gated ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Pharyngeal Muscles ◽  
Membrane Contact ◽  
Null Mutants

Abstract The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole C. elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 co-localizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68/RyR calcium channel, and is required for animal movement. In neurons, JPH-1 co-localizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell non-autonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and unc-68/RyR for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68/RyR is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

scholarly journals In Silico Structural Modeling and Analysis of Interactions of Tremellomycetes Cytochrome P450 Monooxygenases CYP51s with Substrates and Azoles

2021 ◽  
Vol 22 (15) ◽  
pp. 7811
Author(s):  
Olufunmilayo Olukemi Akapo ◽  
Joanna M. Macnar ◽  
Justyna D. Kryś ◽  
Puleng Rosinah Syed ◽  
Khajamohiddin Syed ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Structural Analysis ◽  
In Silico ◽  
Web Application ◽  
Cytochrome P450 Monooxygenases ◽  
Agglomerative Clustering ◽  
Ligand Complex ◽  
P450 Monooxygenase ◽  
Study Results

Cytochrome P450 monooxygenase CYP51 (sterol 14α-demethylase) is a well-known target of the azole drug fluconazole for treating cryptococcosis, a life-threatening fungal infection in immune-compromised patients in poor countries. Studies indicate that mutations in CYP51 confer fluconazole resistance on cryptococcal species. Despite the importance of CYP51 in these species, few studies on the structural analysis of CYP51 and its interactions with different azole drugs have been reported. We therefore performed in silico structural analysis of 11 CYP51s from cryptococcal species and other Tremellomycetes. Interactions of 11 CYP51s with nine ligands (three substrates and six azoles) performed by Rosetta docking using 10,000 combinations for each of the CYP51-ligand complex (11 CYP51s × 9 ligands = 99 complexes) and hierarchical agglomerative clustering were used for selecting the complexes. A web application for visualization of CYP51s’ interactions with ligands was developed (http://bioshell.pl/azoledocking/). The study results indicated that Tremellomycetes CYP51s have a high preference for itraconazole, corroborating the in vitro effectiveness of itraconazole compared to fluconazole. Amino acids interacting with different ligands were found to be conserved across CYP51s, indicating that the procedure employed in this study is accurate and can be automated for studying P450-ligand interactions to cater for the growing number of P450s.

scholarly journals Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update

2021 ◽  
Vol 11 (8) ◽  
pp. 1035
Author(s):  
Maria Pia Giannoccaro ◽  
Patrizia Avoni ◽  
Rocco Liguori
Keyword(s):  
Potassium Channels ◽  
Neuromuscular Junction ◽  
Calcium Channels ◽  
Myasthenia Gravis ◽  
Neuromuscular Transmission ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Immune Mediated ◽  
Recent Developments ◽  
Myasthenic Syndrome

The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ.

scholarly journals Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal

2019 ◽  
Vol 216 (5) ◽  
pp. 250-253 ◽  
Author(s):  
Paul J. Harrison ◽  
Elizabeth M. Tunbridge ◽  
Annette C. Dolphin ◽  
Jeremy Hall
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Psychiatric Disorders ◽  
Calcium Channel Blockers ◽  
Channel Blockers ◽  
Risk Genes ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Second Use

SummaryWe reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.

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