Studi Docking Molekuler Senyawa Dalam Minyak Atsiri Pala (Myristica fragrans H.) Dan Senyawa Turunan Miristisin Terhadap Target Terapi Kanker Kulit

Kanker kulit adalah penyakit di mana kulit kehilangan kemampuannya untuk regenerasi dan tumbuh secara normal. Penyebab umum terjadinya kanker kulit adalah intesitas paparan sinar UVB. Penelitian terdahulu telah membuktikan kandungan senyawa di dalam minyak atsiri pala (Myristica fragrans H.) khususnya miri stsin memiliki khasiat sebagai antioksidan dan efek cytotoxic. Telah dilakukan skrining target molekuler dari kandungan kimia minyak atsiri pala beserta turunan miristisin-nya terhadap target molekuler antikanker kulit antara lain Heat Shock Protein 90 (HSP90A), Prostaglandin Synthase 2 (PTGS2) dan Dihydroorotate Dehidrogenase (DHODH), dan memprediksi interaksi senyawa dari ke 61 ligan uji dengan target molekuler tersebut, kemudian dilakukan docking molekuler menggunakan perangkat lunak PyRx 0.8. Hasil penelitian menunjukkan bahwa senyawa dalam minyak atsiri pala yaitu Guanicin memiliki nilai ΔGbind yang baik pada HSP90A dengan nilai -8,2 kkal/mol. Hasil docking antara protein PTGS2 dan DHODH dengan ligan baik dari senyawa dalam minyak atsiri pala maupun senyawa turunan miristisin menunjukkan bahwa hampir semua ligan dapat berinteraksi dengan kedua target dengan ligan yang nilai ΔGbind paling kecil dan memiliki model interaksi terbaik dari senyawa minyak atisi pala adalah asam dihidroguaiaretik, dengan nilai ΔGbind secara berurut-urut sebesar -8,1 kkal/mol dan -9,3 kkal/mol.

An Efficient Synthesis Towards the Core of Crinipellin and Alliacol-B Along With Their Docking Studies

In this present work, we are reporting a novel route for the synthesis of the tetracyclic ring systems, which is a common core of crinipellin via oxidative dearomatization, cycloaddition and oxa- di-pi-methane rearrangement. We considered to exploring a route to tetracyclic core (1e) of Crinipellin and tricyclic core (1g) of Allicaol B through intermolecular diels alder reaction and photochemically 1,2 acyl shift. Moreover, docking study of compound 13 and 16has been investigated against AcrB multidrug efflux pump of Escherichia coli (PDB ID: 1T9U), main protease of SARS COV-2 (PDB ID: 6W63), DNA gyrase of Streptococcus pneumonia (PDB ID: 4Z2C), human estrogen receptor alpha (PDB ID: 3ERT), human lanosterol 14-alpha-demethylase (CYP51)(PDB ID: 3JUS) and cyclooxygenase-2 (Prostaglandin Synthase-2) (PDB ID: 1CX2). The obtained results herein are important for the exploitation of the therapeutic potential of these derivatives as antimicrobial, antiviral, anticancer, antifungal or anti-inflammatory agents.

A Representative GIIA Phospholipase A2 Activates Preadipocytes to Produce Inflammatory Mediators Implicated in Obesity Development

Adipose tissue secretes proinflammatory mediators which promote systemic and adipose tissue inflammation seen in obesity. Group IIA (GIIA)-secreted phospholipase A2 (sPLA2) enzymes are found to be elevated in plasma and adipose tissue from obese patients and are active during inflammation, generating proinflammatory mediators, including prostaglandin E2 (PGE2). PGE2 exerts anti-lipolytic actions and increases triacylglycerol levels in adipose tissue. However, the inflammatory actions of GIIA sPLA2s in adipose tissue cells and mechanisms leading to increased PGE2 levels in these cells are unclear. This study investigates the ability of a representative GIIA sPLA2, MT-III, to activate proinflammatory responses in preadipocytes, focusing on the biosynthesis of prostaglandins, adipocytokines and mechanisms involved in these effects. Our results showed that MT-III induced biosynthesis of PGE2, PGI2, MCP-1, IL-6 and gene expression of leptin and adiponectin in preadipocytes. The MT-III-induced PGE2 biosynthesis was dependent on cytosolic PLA2 (cPLA2)-α, cyclooxygenases (COX)-1 and COX-2 pathways and regulated by a positive loop via the EP4 receptor. Moreover, MT-III upregulated COX-2 and microsomal prostaglandin synthase (mPGES)-1 protein expression. MCP-1 biosynthesis induced by MT-III was dependent on the EP4 receptor, while IL-6 biosynthesis was dependent on EP3 receptor engagement by PGE2. These data highlight preadipocytes as targets for GIIA sPLA2s and provide insight into the roles played by this group of sPLA2s in obesity.

Computational and pharmacological evaluation of stevioside derivatives for antinociceptive and antiinflammatory potential

Purpose: To carry out computational and pharmacological evaluation of two stevioside derivatives in order to develop more effective candidates for analgesia and inflammation.Methods: Primarily, compounds were docked against targets of nociception and inflammation such as cyclooxygenase-1, cyclooxygenase-2, 5-lypooxygenase 12-lypooxygenase, 15-lypooxygenase, prostaglandin synthase, leukotrienes C4 synthase, mu, kappa, and delta receptors to obtain their possible binding modes. Test compounds were then screened in animal model of nociception and inflammation.Results: The results of docking show that IO possesses good affinity when compared to ID. IO showed two hydrogen bonds against COX-1 and COX-2. IO also demonstrated good binding against 5-LOX, 12- LOX and 15-LOX, exhibited four, one and two hydrogen bonds respectively. Against PG synthase and LTC4, both IO and ID produced moderate binding. IO also showed significant binding against opoid receptors (p < 0.05). IO and ID significantly decrease the number of writhes to 21.20 ± 2.1 and 27.0 ± 2.12 at 10 mg/kg in acetic acid mediated pain test respectively. In hot plate method, IO and ID increase the latency period of mice to 14.14 ± 0.40 and 10.50 ± 0.34 s, respectively. IO and ID significantly reduced the paw edema to 1.69 ± 0.14 and 1.94 ± 0.14 mL, respectively, in acute inflammation (p < 0.05). In chronic inflammatory model, IO and ID decreased paw volume to 3.26 ± 0.38 and 4.20 ± 0.38 mL, respectively.Conclusion: The results show that IO is a promising candidate for further development as analgesic and anti-inflammatory agents. However, their pharmacokinetic and pharmacodynamic profiles need to be investigated. Keywords: Computational, Stevioside, Docking, Analgesic, Anti-inflammatory

Changes in expression of prostaglandin synthase in ovine liver during early pregnancy

Liver can function as part of the innate and adaptive immune systems. We hypothesize that prostaglandins participate in the regulation of hepatic immune function during early pregnancy in sheep. The objective of this study was to elucidate expression of prostaglandin synthase in ovine liver during early pregnancy. Ovine livers were sampled on day 16 of the estrous cycle, and days 13, 16, and 25 of pregnancy, and the expression of prostaglandin synthases, including prostaglandin-endoperoxide synthase 1 (PTGS1), PTGS2, prostaglandin E synthase (PTGES), and aldo-keto reductase family 1, member B1, a prostaglandin F synthase (PGFS), were detected by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry analysis. There were increases in the expression of mRNA and the proteins of PTGS2, PTGES, and PGFS in the livers during early pregnancy, but PTGS1 was decreased in the pregnant ewes. The PGFS protein was limited to the hepatocytes and the endothelial cells of the proper hepatic arteries and hepatic portal veins. In summary, the upregulation of PTGS2, PTGES, and PGFS and downregulation of PTGS1 may be involved in the maternal hepatic immune adjustment during early pregnancy in sheep.

Impact of Epigenetic alterations in the development of oral diseases

Background: Epigenetic mechanisms alter gene expression and regulate vital cellular processes that contribute to the onset and the progression of major dental diseases. Their reversible character may prove beneficial for therapeutic targeting. This review aims to provide an update on the main epigenetic changes that contribute to the pathogenesis of Oral Squamous Cell Carcinoma (OSCC), pulpitis and periodontitis as well as in dental caries and congenital orofacial malformations, in an effort to identify potential therapeutic targets. Methods: We undertook a structured search of bibliographic databases (PubMed and MEDLINE) for peer-reviewed epigenetic research studies focused in oral diseases the last ten years. A qualitative content analysis was performed in screened papers and a critical discussion of main findings is provided. Results: Several epigenetic modifications have been associated with OSCC pathogenesis including promoter methylation of genes involved in DNA repair, cell cycle regulation and proliferation leading to malignant transformation. Additionally, epigenetic inactivation of tumor suppressor genes, overexpression of histone chaperones and several microRNAs are implicated in OSCC aggressiveness. Changes in the methylation patterns of IFN-γ and trimethylation of histone Η3Κ27 have been detected in pulpitis, along with aberrant expression of several microRNAs, mainly affecting cytokine production. Chronic periodontal disease has been associated with modifications in the methylation patterns of Toll-Like Receptor 2, Prostaglandin synthase 2, E-cadherin and some inflammatory cytokines, along with overexpression of miR-146a and miR155. Furthermore, DNA methylation was found to regulate amelogenesis and has been implicated in the pathogenesis of dental caries as well as in several congenital orofacial malformations. Conclusion: Strong evidence indicates that epigenetic changes participate in the pathogenesis of oral diseases and epigenetic targeting may be considered as a complementary therapeutic scheme to current management of oral health.

Increased inflammatory lipid metabolism and anaplerotic mitochondrial activation follow acquired resistance to vemurafenib in BRAF-mutant melanoma cells

Background BRAF inhibitors, such as vemurafenib, have shown efficacy in BRAF-mutant melanoma treatment but acquired-resistance invariably develops. Unveiling the potential vulnerabilities associated with vemurafenib resistance could provide rational strategies for combinatorial treatment. Methods This work investigates the metabolic characteristics and vulnerabilities of acquired resistance to vemurafenib in three generated BRAF-mutant human melanoma cell clones, analysing metabolic profiles, gene and protein expression in baseline and nutrient withdrawal conditions. Preclinical findings are correlated with gene expression analysis from publicly available clinical datasets. Results Two vemurafenib-resistant clones showed dependency on lipid metabolism and increased prostaglandin E2 synthesis and were more responsive to vemurafenib under EGFR inhibition, potentially implicating inflammatory lipid and EGFR signalling in ERK reactivation and vemurafenib resistance. The third resistant clone showed higher pyruvate-carboxylase (PC) activity indicating increased anaplerotic mitochondrial metabolism, concomitant with reduced GLUT-1, increased PC protein expression and survival advantage under nutrient-depleted conditions. Prostaglandin synthase (PTGES) expression was inversely correlated with melanoma patient survival. Increases in PC and PTGES gene expression were observed in some patients following progression on BRAF inhibitors. Conclusions Altogether, our data highlight heterogeneity in metabolic adaptations during acquired resistance to vemurafenib in BRAF-mutant melanoma, potentially uncovering key clinically-relevant mechanisms for combinatorial therapeutic targeting.