Predicting phase-I metabolism of piceatannol: an in silico study.

Piceatannol is a natural compound found in plants and can be derived from resveratrol. While resveratrol has been extensively researched for its effects and how the body processes it, there are concerns about its use. These concerns include its limited absorption in the body, the need for specific dosages, potential interactions with other drugs, lack of standardization, and limited clinical evidence to support its benefits. Interestingly, Piceatannol, another compound derived from resveratrol, has received less attention from researchers but appears to offer advantages. It has better bioavailability and seems to have a more favorable therapeutic profile compared to resveratrol. Surprisingly, no previous attempts have been made to explore or predict the metabolites of piceatannol when it interacts with the enzyme cytochrome P450. This study aims to fill that gap by predicting how piceatannol is metabolized by cytochrome P450 and assessing any potential toxicity associated with its metabolites. This research is interesting because it's the first of its kind to investigate the metabolic fate of piceatannol, especially in the context of cytochrome P450. The findings have the potential to significantly contribute to the field of piceatannol research, particularly in the food industry where this compound has applications and implications.

Piceatannol selectively inhibited the JNK3 enzyme and augmented apoptosis through inhibition of Bcl-2/Cyt-c/caspase-dependent pathways in the oxygen-glucose deprived SHSY-5Y cell lines: In silico and in vitro study.

JNK3, a neuronal kinase activated by stress, plays a role in stress-induced apoptosis, leading to neuronal cell death following cerebral ischemia. This study investigates the neuroprotective effects of piceatannol (PCT) in SHSY-5Y neuroblastoma cells after hypoxic injury and its interaction with JNK3. We analyzed the crystal coordinates, interaction energies, and amino acid interactions to determine PCT's selectivity for JNK3. The electrostatic potential was computed using density functional theory, while molecular dynamics assessed the stability and structural consistency of the JNK3-PCT complex. We used SP600125 (SP6), a JNK3 inhibitor, as a reference compound. Additionally, we performed cell-free JNK 1, 2, and 3 kinase assays to evaluate the isoform selectivity of PCT. Cytotoxicity and cell viability were determined by an MTT test. To assess apoptosis, we used acridine orange/ethidium bromide dual fluorescent labeling and ANNEXIN A5-FITC flow cytometry. Western blot was used to evaluate the attenuation of JNK3 and apoptotic proteins. In silico studies revealed a stronger binding affinity between PCT and JNK3 compared to JNK1 and JNK2, which was further supported by the in vitro kinase assay. PCT-treated cells exhibited a decrease in Cyt-c and caspase-3 expression and an increase in Bcl-2 level, compared to hypoxic control (p < .001). PCT also demonstrated superior efficacy over SP6 in inhibiting JNK3 phosphorylation (p < .001). Furthermore, PCT significantly increased the expression of neuronal genes, including NgN1, neuroD2, and survivin (p < .001). In conclusion, PCT is a potential JNK3 inhibitor, since it inhibited phosphorylation and the Bcl-2/Cyt-C/caspase-3-dependent apoptotic pathway after ischemic/hypoxic insult.

Piceatannol improved cerebral blood flow and attenuated JNK3 and mitochondrial apoptotic pathway in a global ischemic model to produce neuroprotection.

Cerebral ischemia is one of the leading causes of death and disability worldwide. The only FDA-approved treatment is recanalization with systemic tissue plasminogen activators like alteplase, although reperfusion caused by recanalization can result in neuroinflammation, which can cause brain cell apoptosis. Therefore, after an ischemic/reperfusion injury, interventions are needed to minimize the neuroinflammatory cascade. In the present study, piceatannol (PCT) was studied for its neuroprotective efficacy in a rat model of global ischemic injury by attenuating c-Jun N-terminal kinase 3 (JNK3) downstream signaling. PCT is a resveratrol analog and a polyphenolic stilbenoid naturally occurring in passion fruit and grapes. The neuroprotective efficacy of PCT (1, 5, 10 mg/kg) in ischemic conditions was assessed through pre- and post-treatment. Cerebral blood flow (CBF) and tests for functional recovery were assessed. Protein and gene expression were done for JNK3 and other inflammatory markers. A docking study was performed to identify the amino acid interaction. The results showed that PCT improved motor and memory function as measured by a functional recovery test believed to be due to an increase in cerebral blood flow. Also, the caspase signaling which promotes apoptosis was found to be down-regulated; however, nitric oxide synthase expression was up-regulated, which could explain the enhanced cerebral blood flow (CBF). According to our findings, PCT impeded c-Jun N-terminal kinase 3 (JNK3) signaling by suppressing phosphorylation and disrupting the mitochondrial apoptotic pathway, which resulted in the neuroprotective effect. Molecular docking analysis was performed to investigate the atomic-level interaction of JNK3 and PCT, which reveals that Met149, Leu206, and Lys93 amino acid residues are critical for the interaction of PCT and JNK3. According to our current research, JNK3 downstream signaling and the mitochondrial apoptosis pathway are both inhibited by PCT, which results in neuroprotection under conditions of global brain ischemia. Piceatannol attenuated JNK3 phosphorylation during the ischemic condition and prevented neuronal apoptosis.

C-Glucosyl Xanthone derivative Mangiferin downregulates the JNK3 mediated caspase activation in Almal induced neurotoxicity in differentiated SHSY-5Y neuroblastoma cells.

INTRODUCTION: C-Glucosyl Xanthone derivatives were assessed to inhibit the JNK3 mediated Caspase pathway in Almal (Aluminum Maltolate) induced neurotoxicity in SHSY-5Y cells. METHODS: Mangiferin was selected among 200 C-Glucosyl Xanthones based on molecular interaction, docking score (-10.22 kcal/mol), binding free energy (-71.12 kcal/mol), ADME/tox properties and by molecular dynamic studies. Further, it was noticed that glycone moiety of Mangiferin forms H-bond with ASN 194, SER 193, GLY 76, and OH group in the first position of the aglycone moiety shows interaction at Met 149 which is exceptionally crucial for JNK3 inhibitory activity. RESULTS AND DISCUSSION: Mangiferin (0.5, 1, 10, 20 and 30 µM) and standard SP600125 (20 µM) treatment increased the cell survival rate against Almal 200 µM, with EC50 of Mangiferin (8 µM) and standard SP600125 (4.9 µM) respectively. Mangiferin significantly impedes kinase activation, indicating suppression of JNK3 signaling with IC50 (98.26 nM). Mangiferin (10 and 15 µM) dose-dependently inhibits the caspase 3, 8, and 9 enzyme activation in comparison to Almal group. CONCLUSION: Mangiferin demonstrated neuroprotection in SHSY-5Y cells against apoptosis induced by Almal by adapting the architecture of the neurons and increasing their density. Among all Xanthone derivatives, Mangiferin could improve neuronal toxicity by inhibiting JNK3 and down-regulating the Caspase activation.

Identification and neuroprotective evaluation of a potential c-Jun N-terminal kinase 3 inhibitor through structure-based virtual screening and in-vitro assay.

The c-Jun N-terminal kinase 3 (JNK3) signaling cascade is activated during cerebral ischemia leading to neuronal damage. The present study was carried out to identify and evaluate novel JNK3 inhibitors using in-silico and in-vitro approach. A total of 380 JNK3 inhibitors belonging to different organic groups was collected from the previously reported literature. These molecules were used to generate a pharmacophore model. This model was used to screen a chemical database (SPECS) to identify newer molecules with similar chemical features. The top 1000 hits molecules were then docked against the JNK3 enzyme coordinate following GLIDE rigid receptor docking (RRD) protocol. Best posed molecules of RRD were used during induced-fit docking (IFD), allowing receptor flexibility. Other computational predictions such as binding free energy, electronic configuration and ADME/tox were also calculated. Inferences from the best pharmacophore model suggested that, in order to have specific JNK3 inhibitory activity, the molecules must possess one H-bond donor, two hydrophobic and two ring features. Docking studies suggested that the main interaction between lead molecules and JNK3 enzyme consisted of hydrogen bond interaction with methionine 149 of the hinge region. It was also observed that the molecule with better MM-GBSA dG binding free energy, had greater correlation with JNK3 inhibition. Lead molecule (AJ-292-42151532) with the highest binding free energy (dG = 106.8 Kcal/mol) showed better efficacy than the SP600125 (reference JNK3 inhibitor) during cell-free JNK3 kinase assay (IC50 = 58.17 nM) and cell-based neuroprotective assay (EC50 = 7.5 µM).

Design, Synthesis, and Biological Evaluation of 2-(2-Bromo-3-nitrophenyl)-5-phenyl-1,3,4-oxadiazole Derivatives as Possible Anti-Breast Cancer Agents.

Breast Cancer (BCa) is the most often diagnosed cancer among women who were in the late 1940's. Breast cancer growth is largely dependent on the expression of estrogen and progesterone receptor. Breast cancer cells may have one, both, or none of these receptors. The treatment for breast cancer may involve surgery, hormonal therapy (Tamoxifen, an aromatase inhibitor, etc.) and oral chemotherapeutic drugs. The molecular docking technique reported the findings on the potential binding modes of the 2-(2-bromo-3-nitrophenyl)-5-phenyl-1,3,4-oxadiazole derivatives with the estrogen receptor (PDB ID: 3ERT). The 1,3,4-oxadiazole derivatives 4a-4j have been synthesized and described by spectroscopic method. 2-(2-Bromo-6-nitrophenyl)-5-(4-bromophenyl)-1,3,4-oxadiazole (4c) was reconfirmed by single-crystal XRD. All the compounds have been tested in combination with generic Imatinib pharmaceutical drug against breast cancer cell lines isolated from Caucasian woman MCF-7, MDA-MB-453 and MCF-10A non-cancer cell lines. The compounds with the methoxy (in 4c) and methyl (in 4j) substitution were shown to have significant cytotoxicity, with 4c showing dose-dependent activation and decreased cell viability. The mechanism of action was reported by induced apoptosis and tested by a DNA enzyme inhibitor experiment (ELISA) for Methyl Transferase. Molecular dynamics simulations were made for hit molecule 4c to study the stability and interaction of the protein-ligand complex. The toxicity properties of ADME were calculated for all the compounds. All these results provide essential information for further clinical trials.

Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism.

CONTEXT: Soy is the main source of phytoestrogens, which has long been used as traditional food. One major subtype of phytoestrogens includes isoflavones and they are scientifically validated for their beneficial actions on many hormone-dependent conditions. OBJECTIVE: The present study examines the effect of soy isoflavones on letrozole-induced polycystic ovary syndrome (PCOS) rat model. MATERIALS AND METHODS: PCOS was induced in Sprague-Dawley rats with of 1 mg/kg letrozole, p.o. once daily for 21 consecutive days. Soy isoflavones (50 and 100 mg/kg) was administered for 14 days after PCOS induction. Physical parameters (body weight, oestrous cycle determination, ovary and uterus weight) metabolic parameters (oral glucose tolerance test, total cholesterol), steroidal hormone profile (testosterone and 17ß-oestradiol), steroidogenic enzymes (3ß-hydroxy steroid dehydrogenase (HSD) and 17ß-HSD), oxidative stress and histopathology of ovary were studied. RESULTS: Soy isoflavones (100 mg/kg) treatment significantly altered the letrozole-induced PCOS symptoms as observed by decreased body weight gain (p < 0.05), percentage diestrous phase (p < 0.001), testosterone (p < 0.001), 3ß-HSD (p < 0.01) and 17ß-HSD (p < 0.001) enzyme activity and oxidative stress. Histological results reveal that soy isoflavones treatment in PCOS rats resulted in well-developed antral follicles and normal granulosa cell layer in rat ovary. DISCUSSION: Treatment with soy isoflavones exerts beneficial effects in PCOS rats (with decreased aromatase activity) which might be due to their ability to decrease testosterone concentration in the peripheral blood. CONCLUSION: Analysis of physical, biochemical and histological evidences shows that soy isoflavones may be beneficial in PCOS.