Combating Parkinson's disease with plant-derived polyphenols: Targeting oxidative stress and neuroinflammation.

Parkinson's disease (PD) is a devastating neurodegenerative disorder predominantly affecting the elderly, characterized by the loss of dopaminergic neurons in the substantia nigra. Reactive oxygen species (ROS) generation plays a central role in the pathogenesis of PD and other neurodegenerative diseases. An imbalance between cellular antioxidant activity and ROS production leads to oxidative stress, contributing to disease progression. Dopamine metabolism, mitochondrial dysfunction, and neuroinflammation in dopaminergic neurons have been implicated in the pathogenesis of Parkinson's disease. Consequently, there is a pressing need for therapeutic interventions capable of scavenging ROS. Current pharmacological approaches, such as L-dihydroxyphenylalanine (levodopa or L-DOPA) and other drugs, provide symptomatic relief but are limited by severe side effects. Researchers worldwide have been exploring alternative compounds with less toxicity to address the multifaceted challenges associated with Parkinson's disease. In recent years, plant-derived polyphenolic compounds have gained significant attention as potential therapeutic agents. These compounds exhibit neuroprotective effects by targeting pathophysiological responses, including oxidative stress and neuroinflammation, in Parkinson's disease. The objective of this review is to summarize the current understanding of the neuroprotective effects of various polyphenols in Parkinson's disease, focusing on their antioxidant and anti-inflammatory properties, and to discuss their potential as therapeutic candidates. This review highlights the progress made in elucidating the molecular mechanisms of action of these polyphenols, identifying potential therapeutic targets, and optimizing their delivery and bioavailability. Well-designed clinical trials are necessary to establish the efficacy and safety of polyphenol-based interventions in the management of Parkinson's disease.

Pioneering a paradigm shift in tissue engineering and regeneration with polysaccharides and proteins-based scaffolds: A comprehensive review.

In the realm of modern medicine, tissue engineering and regeneration stands as a beacon of hope, offering the promise of restoring form and function to damaged or diseased organs and tissues. Central to this revolutionary field are biological macromolecules-nature's own blueprints for regeneration. The growing interest in bio-derived macromolecules and their composites is driven by their environmentally friendly qualities, renewable nature, minimal carbon footprint, and widespread availability in our ecosystem. Capitalizing on these unique attributes, specific composites can be tailored and enhanced for potential utilization in the realm of tissue engineering (TE). This review predominantly concentrates on the present research trends involving TE scaffolds constructed from polysaccharides, proteins and glycosaminoglycans. It provides an overview of the prerequisites, production methods, and TE applications associated with a range of biological macromolecules. Furthermore, it tackles the challenges and opportunities arising from the adoption of these biomaterials in the field of TE. This review also presents a novel perspective on the development of functional biomaterials with broad applicability across various biomedical applications.

Unveiling the impact of aging on BBB and Alzheimer's disease: Factors and therapeutic implications.

Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that has devastating effects on individuals, often resulting in dementia. AD is primarily defined by the presence of extracellular plaques containing insoluble ß-amyloid peptide (Aß) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (P-tau). In addition, individuals afflicted by these age-related illnesses experience a diminished state of health, which places significant financial strain on their loved ones. Several risk factors play a significant role in the development of AD. These factors include genetics, diet, smoking, certain diseases (such as cerebrovascular diseases, obesity, hypertension, and dyslipidemia), age, and alcohol consumption. Age-related factors are key contributors to the development of vascular-based neurodegenerative diseases such as AD. In general, the process of aging can lead to changes in the immune system's responses and can also initiate inflammation in the brain. The chronic inflammation and the inflammatory mediators found in the brain play a crucial role in the dysfunction of the blood-brain barrier (BBB). Furthermore, maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. Therefore, in this review, we discussed the role of age and its related factors in the breakdown of the blood-brain barrier and the development of AD. We also discussed the importance of different compounds, such as those with anti-aging properties, and other compounds that can help maintain the integrity of the blood-brain barrier in the prevention of AD. This review builds a strong correlation between age-related factors, degradation of the BBB, and its impact on AD.

C-5401331 identified as a novel T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) inhibitor to control acute myeloid leukemia (AML) cell proliferation.

T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is a checkpoint protein expressed in exhausted T-cells during cancer scenarios. This exhaustion may end in T-cell effector dysfunction, resulting in suboptimal control of cancers like acute myeloid leukemia (AML). Use of immune checkpoint inhibitors (ICIs) to block checkpoint receptors such as Tim-3 is an emerging, revolutionary concept in the immuno-oncology therapeutic arena; however, ICIs are not effective on myeloid malignancies. Here, a multifaceted approach is utilized to identify novel compounds that target and inhibit Tim-3 with improved efficacy. High-throughput virtual screening of the ChemBridge small molecule library and molecular dynamics simulation yielded a lead molecule C-5401331 predicted to bind with high affinity and inhibit the activity of Tim-3. In vitro evaluations demonstrated the compound to have anti-proliferative effects on Tim-3-positive populations of THP-1 and HC-5401331 AML cells, inducing early and late phase apoptosis. With further development, the lead molecule identified in this work has potential to aid the natural "gatekeeper" functions of the body in immunocompromised AML cancer patients by successfully hampering the binding of Tim-3 to T-cells.

Nanozymes and carbon-dots based nanoplatforms for cancer imaging, diagnosis and therapeutics: Current trends and challenges.

Cancer patients face a significant clinical and socio-economic burden due to increased incidence, mortality, and poor survival. Factors like late diagnosis, recurrence, drug resistance, severe side effects, and poor bioavailability limit the scope of current therapies. There is a need for novel, cost-effective, and safe diagnostic methods, therapeutics to overcome recurrence and drug resistance, and drug delivery vehicles with enhanced bioavailability and less off-site toxicity. Advanced nanomaterial-based research is aiding cancer biologists by providing solutions for issues like hypoxia, tumor microenvironment, low stability, poor penetration, target non-specificity, and rapid drug clearance. Currently, nanozymes and carbon-dots are attractive due to their low cost, high catalytic activity, biocompatibility, and lower toxicity. Nanozymes and carbon-dots are increasingly used in imaging, biosensing, diagnosis, and targeted cancer therapy. Integrating these materials with advanced diagnostic tools like CT scans and MRIs can aid in clinical decision-making and enhance the effectiveness of chemotherapy, photothermal, photodynamic, and sonodynamic therapies, with minimal invasion and reduced collateral effects.

Augmented least squares, a powerful chemometric approach for the spectroscopic analysis of the antiretroviral therapy abacavir, lamivudine and dolutegravir in their ternary mixture.

Augmented least squares models such as concentration residual augmented classical least squares (CRACLS) and spectral residual augmented classical least squares (SRACLS) are powerful chemometric approaches that can be applied for spectroscopic analysis of many pharmaceutical compounds. Herein, both CRACLS and SRACL have been employed for UV spectral analysis of three antiretroviral therapy namely abacavir (ACV), lamivudine (LMV) and dolutegravir (DTG) in their ternary mixture. A partial factorial design has been utilized for calibration set construction then both CRACLS and SRACLS models have been optimized regarding the number of iterations and principal components, respectively, using a leave-one-out cross-validation procedure. It was found that a higher number of iterations and principal components were required for modelling the minor component DTG indicating more augmentation procedures to improve the models' accuracy. Validation of the proposed models was performed using external validation set of 13 mixtures and different validation parameters have been evaluated regarding models' predictive abilities. Both models showed excellent performance for analyzing ACV and LMV with relative root mean square error of prediction (RRMSEP) below 2 %. However, higher RRMSEP values around 5 % were observed for the minor component DTG suggesting that these models should be utilized with caution when analyzing minor components in mixtures. Furthermore, the suggested models have been applied for analyzing ACV, LMV and DTG in their pharmaceutical formulation and excellent agreement was observed between the suggested models and the reported chromatographic method posing these models as powerful chemometric approaches for quality control analysis of many pharmaceutical compounds.

Identification of potential inhibitors targeting Ebola virus VP35 protein: a computational strategy.

Ebola virus (EBOV) poses a severe threat as a highly infectious pathogen, causing devastating hemorrhagic fever in both humans and animals. The EBOV virus VP35 protein plays a crucial role in viral replication and exhibits the ability to suppress the host interferon cascade, leading to immune system depletion. As a potential drug target, VP35 protein inhibition holds promise for combating EBOV. To discover new drug candidates, we employed a computer-aided drug design approach, focusing on compounds capable of inhibiting VP35 protein replication. In this connection, a pharmacophore model was generated using molecular interactions between the VP35 protein and its inhibitor. ZINC and Cambridge database were screened using validated pharmacophore model. Further the compounds were filtered based on Lipinski's rule of five and subjected to MD simulation and relative binding free energy calculation. Six compounds manifest a significant docking score and strong binding interaction towards VP35 protein. MD simulations further confirmed the remarkable stability of these six complexes. Relative binding free energy calculations also showed significant ΔG value in the range of -132.3 and -49.3 kcal/mol. This study paves the way for further optimization of these compounds as potential inhibitors of VP35, facilitating subsequent experimental in vitro studies.Communicated by Ramaswamy H. Sarma.

Green spectrofluorimetric quantification of aspirin, olmesartan, and metoprolol in spiked human plasma.

Low dose aspirin is routinely taken with antihypertensive drugs such as olmesartan and metoprolol to avoid the cardiovascular and renal outcomes associated with high blood pressure. The first spectrofluorimetric method for quantifying aspirin, olmesartan, and metoprolol in spiked human plasma is described here. The emission/excitation wavelengths of Aspirin, olmesartan, and metoprolol were 404 nm/290 nm, 372 nm/250 nm, and 302 nm/230 nm, respectively. The native fluorescence spectra of metoprolol do not overlap with those of aspirin or olmesartan, although the spectra of aspirin and olmesartan overlap. As a result, metoprolol could be measured directly in a mixture at 302 nm following excitation at 230 nm. Using synchronous fluorescence spectrometry at Δλ = 110 allowed for the determination of olmesartan at 364 nm with no interference from aspirin and metoprolol. Coupling the synchronous fluorescence spectrometry with second-order derivative allowed for the determination of aspirin at 426 nm with no interference from olmesartan and metoprolol. The suggested approach has been validated using ICH M10 criteria for bioanalytical method validation and was effectively utilized for quantification of tested medications in human plasma with reasonable accuracy and precision findings. Furthermore, using two greenness metrics, the Green Analytical Procedure Index and the Analytical GREEnness, the suggested method obtained a high greenness score.

Identification by molecular dynamic simulation and in vitro validation of SISB-A1, N-[1-(4-bromophenyl)-3-methyl-1H-pyrazol-5-yl]-2-[(2-oxo-4-phenyl-2H-chromen-7-yl) oxy], as an inhibitor of the AblT315I mutant kinase to combat imatinib resistance in chronic myeloid leukemia.

The discovery of imatinib, a specific inhibitor of Abl kinase, revolutionized the therapeutic approach to chronic myeloid leukemia (CML); however, its efficacy can be impeded by the emergence of novel mutations within the kinase domain, particularly AblT315I, that lead to the development of drug resistance. It therefore remains necessary to identify specific inhibitors that can effectively target imatinib-resistant CML harboring the AblT315I mutation. A natural product library sourced from the ZINC database was screened against the experimental structure of AblT315I kinase to identify compounds that selectively target the mutated kinase. The top-scoring compound was empirically tested for inhibition of AblT315I kinase using a luminescence-based kit and for impact on cellular proliferation using the BaF3-BCR-ABL-T315I stable cell line. Computational docking and molecular dynamic simulations identified the compound SISB-A1, N-[1-(4-bromophenyl)-3-methyl-1H-pyrazol-5-yl]-2-[(2-oxo-4-phenyl-2H-chromen-7-yl)oxy] acetamide, to effectively bind the catalytic domain of the mutant AblT315I kinase. Moreover, SISB-A1 exhibited greater preference than imatinib for amino acid residues of the mutant kinase's active site, including isoleucine 315. MMPBSA-based Gibbs binding free energy estimation predicted SISB-A1 to have a free energy of -51.5 versus -65.0 kcal/mol for the conventional AblT315I inhibitor ponatinib. Cell proliferation assays showed SISB-A1 to have a GI50 of 164.0 nM against the ABL-T315I stable cell line, whereas imatinib had a GI50 of 5035 nM. The IC50 value obtained for SISB-A1 against the AblT315I kinase was 197.9 nM. The results indicate SISB-A1 to have a notable ability to bind the catalytic domain of the AblT315I mutant kinase and effectively suppress its activity, thereby surpassing the associated resistance to imatinib. Continued advancement of this lead compound has the potential to yield innovative therapeutics for imatinib-resistant CML.

Association of serum leptin and resistin levels among obese Saudi patients with acute myocardial infarction in Asir region.

In the current scenario, the importance of cardiac biomarkers in diagnosing, assessing, and managing people with cardiovascular discomfort is required. This cross-sectional study examined the relationship between serum leptin and resistin levels among obese people with acute myocardial infarction (AMI) with varying body mass index (BMI). The cardio and diabetic biomarkers among the 77 Saudi patients with hypoxia who lived in the Asir region were analyzed in the study. The patients were categorized into three groups, namely, group 1 (control), group 2 (AMI with normal BMI), and group 3 (AMI with varying BMI). Our results showed a positive correlation between serum glucose, HbA1C, triglycerides, Troponin-I (cTnI), creatine kinase MB (CK-MB), leptin, and resistin in patients with AMI. We also observed significantly lower HbA1C, cholesterol, and insulin values in groups 2 and 3. A statistical difference between the groups with and without AMI and between the genders was noticed. BMI with leptin showed a positive connection in group 3 but no association was observed for groups 1 and 2. A stronger relationship between BMI and leptin levels in men in Group 3 than in women was observed. In all three groups, resistin levels did not correlate with BMI. Thus, circulating leptin concentrations do not significant impact AMI compared to participants with and without AMI. However, resistin levels were considerably higher in obese individuals with AMI. Therefore, we suggest that resistin can be used as a pro-inflammatory marker to detect AMI disorder with varying BMI and as a prognostic marker associated with AMI.

5-Fluorouracil-Loaded PLGA Nanoparticles: Formulation, Physicochemical Characterisation, and In VitroAnti-Cancer Activity.

The major goal of this investigation was to prepare a drug delivery of polymeric nanoparticles (NPs) from 5-fluorouracil (FU) that could be delivered intravenously and improve the therapeutic index of the FU. In order to achieve this, interfacial deposition method was used to prepare FU entrapped poly-(lactic-co-glycolic acid) nanoparticles (FU-PLGA-NPs). The influence of various experimental settings on the effectiveness of FU integration into the NPs was assessed. Our findings show that the technique used to prepare the organic phase and the ratio of the organic phase to the aqueous phase had the greatest impact on the effectiveness of FU integration into NPs. The results show that the preparation process produced spherical, homogenous, negatively charged particles with a nanometric size of 200 nm that are acceptable for intravenous delivery. A quick initial release over 24 h and then slow and steady release of FU from the formed NPs, exhibiting a biphasic pattern. Through the human small cell lung cancer cell line (NCI-H69), the in vitro anti-cancer potential of the FU-PLGA-NPs was evaluated. It was then associated to the in vitro anti-cancer potential of the marketed formulation Fluracil®. Investigations were also conducted into Cremophor-EL (Cre-EL) potential activity on live cells. The viability of NCI-H69 cells was drastically reduced when they were exposed to 50 µg·mL-1 Fluracil®. Our findings show that the integration of FU in NPs significantly increases the drug cytotoxic effect in comparison to Fluracil®, with this potential effect being particularly important for extended incubation durations.

Computational and Preclinical Analysis of 2-(4-Methyl)benzylidene-4,7-dimethyl Indan-1-one (IPX-18): A Novel Arylidene Indanone Small Molecule with Anti-Inflammatory Activity via NF-κB and Nrf2 Signaling.

Background: The adverse effects of anti-inflammatory drugs urges the search for new anti-inflammatory agents. This study aims at the preclinical analysis of the in-house synthesized small molecule IPX-18. Human whole blood (HWB), peripheral blood mononuclear cells (PBMCs), and neutrophils were used. Rat basophil cells (RBL-2H3) were used to assess degranulation. Binding stability to NF-κB-p50 was predicted using computational docking and molecular dynamic simulations. Essential signaling proteins were evaluated through flow cytometry. Results: IPX-18 inhibited the release of TNF-α with an IC50 value of 298.8 nM and 96.29 nM in the HWB and PBMCs, respectively. The compound depicted an IC50 value of 217.6 nM in the HWB and of 103.7 nM in the PBMCs for IFN-γ inhibition. IL-2 release and IL-8 release were inhibited by IPX-18 in the HWB and PBMCs. The compound controlled the migration of and the elastase in the activated neutrophils. The IC50 value for basophil activation through the FcεRI receptor assay was found to be 91.63 nM. IPX-18 inhibited RBL-2H3-degranulation with an IC50 value of 98.52 nM. The computational docking analysis predicted that IPX-18 would effectively bind NF-κB-p50. NF-κB-phosphorylation in the activated RBL-2H3 cells was decreased, and the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were increased with IPX-18 treatment. Conclusions: IPX-18 demonstrated efficacy in mediating the effector cells' inflammatory responses through NF-κB/Nrf2 signaling.

Design, Physical Characterizations, and Biocompatibility of Cationic Solid Lipid Nanoparticles in HCT-116 and 16-HBE Cells: A Preliminary Study.

In this study, pEGFP-LUC was used as a model plasmid and three distinct cationic lipids (dioleyloxy-propyl-trimethylammonium chloride [DOTMA], dioleoyl trimethylammonium propane [DOTAP], and cetylpyridinium chloride [CPC]) were tested along with PEG 5000, as a nonionic surfactant, to prepare glyceryl monostearate (GMS)-based cationic solid lipid nanoparticles (cSLNs). Both the type and quantity of surfactant had an impact on the physicochemical characteristics of the cSLNs. Thermal analysis of the greater part of the endothermic peaks of the cSLNs revealed they were noticeably different from the individual pure compounds based on their zeta potential (ZP ranging from +17 to +56 mV) and particle size (PS ranging from 185 to 244 nm). The addition of cationic surfactants was required to produce nanoparticles (NPs) with a positive surface charge. This suggested that the surfactants and extensive entanglement of the lipid matrix GMS provided support for the behavioral diversity of the cSLNs and their capacity to interface with the plasmid DNA. Additionally, hemolytic assays were used to show that the cSLNs were biocompatible with the human colon cancer HCT-116 and human bronchial epithelial 16-HBE cell lines. The DOTMA 6-based cSLN was selected as the lead cSLN for further ex vivo and in vivo investigations. Taken together, these new findings might provide some guidance in selecting surfactants to prepare extremely efficient and non-toxic cSLN-based therapeutic delivery systems (e.g., gene therapy).

Therapeutic Efficacy of a Formulation Prepared with Linum usitatissimum L., Plantago ovata Forssk., and Honey on Uncomplicated Pelvic Inflammatory Disease Analyzed with Machine Learning Techniques.

A single-blind double-dummy randomized study was conducted in diagnosed patients (n = 66) to compare the efficacy of Linseeds (Linum usitatissimum L.), Psyllium (Plantago ovata Forssk.), and honey in uncomplicated pelvic inflammatory disease (uPID) with standard drugs using experimental and computational analysis. The pessary group received placebo capsules orally twice daily plus a per vaginum cotton pessary of powder from linseeds and psyllium seeds, each weighing 3 gm, with honey (5 mL) at bedtime. The standard group received 100 mg of doxycycline twice daily and 400 mg of metronidazole TID orally plus a placebo cotton pessary per vaginum at bedtime for 14 days. The primary outcomes were clinical features of uPID (vaginal discharge, lower abdominal pain (LAP), low backache (LBA), and pelvic tenderness. The secondary outcomes included leucocytes (WBCs) in vaginal discharge on saline microscopy and the SF-12 health questionnaire. In addition, we also classified both (pessary and standard) groups using machine learning models such as Decision Tree (DT), Random Forest (RF), Logistic Regression (LR), and AdaBoost (AB). The pessary group showed a higher percentage reduction than the standard group in abnormal vaginal discharge (87.05% vs. 77.94%), Visual Analogue Scale (VAS)-LAP (80.57% vs. 77.09%), VAS-LBA (74.19% vs. 68.54%), McCormack pain scale (McPS) score for pelvic tenderness (75.39% vs. 67.81%), WBC count of vaginal discharge (87.09% vs. 83.41%) and improvement in SF-12 HRQoL score (94.25% vs. 86.81%). Additionally, our DT 5-fold model achieved the maximum accuracy (61.80%) in the classification. We propose that the pessary group is cost-effective, safer, and more effective as standard drugs for treating uPID and improving the HRQoL of women. Aucubin, Plantamajoside, Herbacetin, secoisolariciresinol diglucoside, Secoisolariciresinol Monoglucoside, and other various natural bioactive molecules of psyllium and linseeds have beneficial effects as they possess anti-inflammatory, antioxidant, antimicrobial, and immunomodulatory properties. The anticipated research work is be a better alternative treatment for genital infections.

Antioxidant and Gastroprotective Activity of Suaeda fruticosa Forssk. Ex J.F.Gmel.

Suaeda fruticosa Forssk. Ex J.F.Gmel is traditionally used for inflammatory and digestive disorders, as a carminative, and for diarrhea. This plant is widely distributed in Asia, Africa, and the Mediterranean region. Aqueous methanolic extract of S. fruticosa (Sf.Cr) was prepared and screened for phytoconstituents through qualitative and GC-MS analysis. Quantification of total phenolic and flavonoid contents was performed, while antioxidant capacity was determined by DPPH, CUPRAC, FRAP, and ABTS assays. The gastroprotective activity was assessed in an ethanol-induced ulcer model. Gastric secretory parameters and macroscopic ulcerated lesions were analyzed and scored for ulcer severity. After scoring, histopathology was performed, and gastric mucus contents were determined. Oral pre-treatment of Sf.Cr demonstrated significant gastroprotection. The gastric ulcer severity score and ulcer index were reduced while the %-inhibition of ulcer was increased dose-dependently. The Sf.Cr significantly elevated the pH of gastric juice, while a decrease in total acidity and gastric juice volume was observed. Histopathology demonstrated less oedema and neutrophil infiltration in gastric mucosa of rats pre-treated with the Sf.Cr in comparison to ethanol-intoxicated animals. Furthermore, the gastric mucus contents were increased as determined by alcian blue binding. Sf.Cr showed marked gastroprotective activity, which can be attributed to antioxidant, antisecretory, and cytoprotective effects.

Pharmacological Validation for the Folklore Use of Ipomoea nil against Asthma: In Vivo and In Vitro Evaluation.

Oxidative stress is the key factor that strengthens free radical generation which stimulates lung inflammation. The aim was to explore antioxidant, bronchodilatory along with anti-asthmatic potential of folkloric plants and the aqueous methanolic crude extract of Ipomoea nil (In.Cr) seeds which may demonstrate as more potent, economically affordable, having an improved antioxidant profile and providing evidence as exclusive therapeutic agents in respiratory pharmacology. In vitro antioxidant temperament was executed by DPPH, TFC, TPC and HPLC in addition to enzyme inhibition (cholinesterase) analysis; a bronchodilator assay on rabbit's trachea as well as in vivo OVA-induced allergic asthmatic activity was performed on mice. In vitro analysis of 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH) expressed as % inhibition 86.28 ± 0.25 with IC50 17.22 ± 0.56 mol/L, TPC 115.5 ± 1.02 mg GAE/g of dry sample, TFC 50.44 ± 1.06 mg QE/g dry weight of sample, inhibition in cholinesterase levels for acetyl and butyryl with IC50 (0.60 ± 0.67 and 1.5 ± 0.04 mol/L) in comparison with standard 0.06 ± 0.002 and 0.30 ± 0.003, respectively, while HPLC characterization of In.Cr confirmed the existence with identification as well as quantification of various polyphenolics and flavonoids i.e., gallic acid, vanillic acid, chlorogenic acid, quercetin, kaempferol and others. However, oral gavage of In.Cr at different doses in rabbits showed a better brochodilation profile as compared to carbachol and K+-induced bronchospasm. More significant (p < 0.01) reduction in OVA-induced allergic hyper-responses i.e., inflammatory cells grade, antibody IgE as well as altered IFN-α in airways were observed at three different doses of In.Cr. It can be concluded that sound mechanistic basis i.e., the existence of antioxidants: various phenolic and flavonoids, calcium antagonist(s) as well as enzymes' inhibition profile, validates folkloric consumptions of this traditionally used plant to treat ailments of respiration.

Anticancer efficacy of 3-(4-isopropyl) benzylidene-8-ethoxy, 6-methyl, chroman-4-one (SBL-060), a novel, dual, estrogen receptor-Akt kinase inhibitor in acute myeloid leukemia cells.

Estrogen receptor (ER) α is expressed in a subset of patient-derived acute myeloid leukemia (AML) cells, whereas Akt is predominantly expressed in most types of AML. Targeting AML with dual inhibitors is a novel approach to combat the disease. Herein, we examined a novel small molecule, 3-(4-isopropyl) benzylidene-8-ethoxy,6-methyl, chroman-4-one (SBL-060), capable of targeting AML cells by inhibiting ERα and Akt kinase. The chemical properties of SBL-060 were identified by proton nuclear magnetic resonance (1H-NMR), 13C-NMR, and mass spectroscopy. In silico docking was performed using an automated protocol with AutoDock-VINA. THP-1 and HL-60 cell lines were differentiated using phorbol 12-myristate 13-acetate. ERα inhibition was assessed using ELISA. The MTT assay assessed cell viability. Flow cytometry was performed for cell cycle, apoptosis, and p-Akt analyses. Chemical analysis identified the compound as 3-(4-isopropyl) benzylidene-8-ethoxy,6-methyl, chroman-4-one, which showed high binding efficacy toward ER, with a ΔGbinding score of -7.4 kcal/mol. SBL-060 inhibited ERα, exhibiting IC50 values of 448 and 374.3 nM in THP-1 and HL-60 cells, respectively. Regarding inhibited cell proliferation, GI50 values of SBL-060 were 244.1 and 189.9 nM for THP-1 and HL-60 cells, respectively. In addition, a dose-dependent increase in sub G0/G1 phase cell cycle arrest and total apoptosis was observed after treatment with SBL-060 in both cell types. SBL-060 also dose-dependently increased the p-Akt-positive populations in both THP-1 and HL-60 cells. Our results indicate that SBL-060 has excellent efficacy against differentiated AML cell types by inhibiting ER and Akt kinase, warranting further preclinical evaluations.

Computational high-throughput screening and in vitro approaches identify CB-006-3; A novel PI3K-BRAFV600E dual targeted inhibitor against melanoma.

Malignant melanoma is characterized by both genetic and molecular alterations that activate phosphoinositide 3-kinase (PI3K), and RAS/BRAF pathways. In this work, through diversity-based high-throughput virtual screening we identified a lead molecule that selectively targets PI3K and BRAFV600E kinases. Computational screening, Molecular dynamics simulation and MMPBSA calculations were performed. PI3K and BRAFV600E kinase inhibition was done. A375 and G-361 cells were used for in vitro cellular analysis to determine antiproliferative effects, annexin V binding, nuclear fragmentation and cell cycle analysis. Computational screening of small molecules indicates compound CB-006-3 selectively targets PI3KCG (gamma subunit), PI3KCD (delta subunit) and BRAFV600E. Molecular dynamics simulation and MMPBSA bases binding free energy calculations predict a stable binding of CB-006-3 to the active sites of PI3K and BRAFV600E. The compound effectively inhibited PI3KCG, PI3KCD and BRAFV600E kinases with respective IC50 values of 75.80, 160.10 and 70.84 nM. CB-006-3 controlled the proliferation of A375 and G-361 cells with GI50 values of 223.3 and 143.6 nM, respectively. A dose dependent increase in apoptotic cell population and sub G0/G1 phase of cell cycle were also observed with the compound treatment in addition to observed nuclear fragmentation in these cells. Furthermore, CB-006-3 inhibited BRAFV600E, PI3KCD and PI3KCG in both melanoma cells. Collectively, based on the computational modeling and in vitro validations, we propose CB-006-3 as a lead candidate for selectively targeting PI3K and mutant BRAFV600E to inhibit melanoma cell proliferation. Further experimental validations, including pharmacokinetic evaluations in mouse models will identify the druggability of the proposed lead candidate for further development as a therapeutic agent for treating melanoma.