Optimized Ribociclib nanostructured lipid carrier for the amelioration of skin cancer: Inferences from ex-vivo skin permeation and dermatokinetic studies.

Current research focuses on explicitly developing and evaluating nanostructured lipidic carriers (NLCs) for the chemotherapeutic drug Ribociclib (RCB) via the topical route to surmount the inherent bioavailability shortcomings. The absolute oral bioavailability has not been determined, but using a physiologically based pharmacokinetic model it was predicted that 65.8 % of the standard dose of RCB (600 mg) would be absorbed mainly in the small intestine. RCB-NLCs were produced using the solvent evaporation method, and Box-Behnken Design (BBD) was employed to optimize composition. The prepared NLCs had an average PS of 79.29 ± 3.53 nm, PDI of 0.242 ± 0.021, and a %EE of 86.07 ± 3.14. The TEM analysis disclosed the spherical form and non-aggregative nature of the NLCs. The outcomes of an in-vitro release investigation presented cumulative drug release of 84.97 ± 3.37 % in 24 h, significantly higher than that from the RCB suspension (RCB-SUS). Ex-vivo skin permeation investigations on rodent (Swiss albino mice) revealed that RCB-NLCs have 1.91 times increases in skin permeability comparable to RCB-SUS. Compared to RCB-SUS, RCB-NLCs were able to penetrate deeper into the epidermis membrane than RCB-SUS as per the findings of confocal microscopy. In dermatokinetic study, higher amount of RCB was maintained in both the layers of mice's skin when treated with RCB-NLCs gel comparable to the RCB-SUS gel preparation. The in-vitro, ex-vivo, CLSM, and dermatokinetics data demonstrated a significant possibility for this novel RCB formulation to be effective against skin cancer.

Exploring the promising potential of noscapine for cancer and neurodegenerative disease therapy through inhibition of integrin-linked kinase-1.

Integrin-linked kinase (ILK), a ß1-integrin cytoplasmic domain interacting protein, supports multi-protein complex formation. ILK-1 is involved in neurodegenerative diseases by promoting neuro-inflammation. On the other hand, its overexpression induces epithelial-mesenchymal transition (EMT), which is a major hallmark of cancer and activates various factors associated with a tumorigenic phenotype. Thus, ILK-1 is considered as an attractive therapeutic target. We investigated the binding affinity and ILK-1 inhibitory potential of noscapine (NP) using spectroscopic and docking approaches followed by enzyme inhibition activity. A strong binding affinity of NP was measured for the ILK-1 with estimated Ksv (M-1) values of 1.9 × 105, 3.6 × 105, and 4.0 × 105 and ∆G0 values (kcal/mol) -6.19554, -7.8557 and -8.51976 at 298 K, 303 K, and 305 K, respectively. NP binds to ILK-1 with a docking score of -6.6 kcal/mol and forms strong interactions with active-site pocket residues (Lys220, Arg323, and Asp339). The binding constant for the interaction of NP to ILK-1 was 1.04 × 105 M-1, suggesting strong affinity and excellent ILK-1 inhibitory potential (IC50 of ∼5.23µM). Conformational dynamics of ILK-1 were also studied in the presence of NP. We propose that NP presumably inhibits ILK-1-mediated phosphorylation of various downstream signalling pathways that are involved in cancer cell survival and neuroinflammation.

Identification of mitogen-activated protein kinase 7 inhibitors from natural products: Combined virtual screening and dynamic simulation studies.

Mitogen-activated protein kinase 7 (MAPK7) is a serine/threonine protein kinase that belongs to the MAPK family and plays a vital role in various cellular processes such as cell proliferation, differentiation, gene transcription, apoptosis, metabolism, and cell survival. The elevated expression of MAPK7 has been associated with the onset and progression of multiple aggressive tumors in humans, underscoring the potential of targeting MAPK7 pathways in therapeutic research. This pursuit holds promise for the advancement of anticancer drug development by developing potential MAPK7 inhibitors. To look for potential MAPK7 inhibitors, we exploited structure-based virtual screening of natural products from the ZINC database. First, the Lipinski rule of five criteria was used to filter a large library of ~90,000 natural compounds, followed by ADMET and pan-assay interference compounds (PAINS) filters. Then, top hits were chosen based on their strong binding affinity as determined by molecular docking. Further, interaction analysis was performed to find effective and specific compounds that can precisely bind to the binding pocket of MAPK7. Consequently, two compounds, ZINC12296700 and ZINC02123081, exhibited significant binding affinity and demonstrated excellent drug-like properties. All-atom molecular dynamics simulations for 200 ns confirmed the stability of MAPK7-ZINC12296700 and MAPK7-ZINC02123081 docked complexes. According to the molecular mechanics Poisson-Boltzmann surface area investigation, the binding affinities of both complexes were considerable. Overall, the result suggests that ZINC12296700 and ZINC02123081 might be used as promising leads to develop novel MAPK7 inhibitors. Since these compounds would interfere with the kinase activity of MAPK7, therefore, may be implemented to control cell growth and proliferation in cancer after required validations.

Aegle marvels (L.) Correa Leaf Essential Oil and Its Phytoconstituents as an Anticancer and Anti-Streptococcus mutans Agent.

Aegle mamelons (A. marmelos) or Indian Bael leaves possess anti-cancerous and antibacterial properties and are used in the traditional medicine system for the treatment of oral infections. In the present study, the essential oil of the leaves of A. marmelos was explored for its anticancer, antioxidant, and anti-cariogenic properties. The hydro-distilled oil of A. marmelos leaves was analyzed using gas chromatography coupled with mass spectrometry (GC-MS). Monoterpene limonene (63.71%) was found to have the highest percentage after trans-2-Hydroxy-1,8-cineole and p-Menth-2,8-dien-1-ol. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was used to investigate the anticancer activity of the extracted oil against human oral epidermal carcinoma (KB), and the results showed significantly higher (**** p < 0.0001) anticancer activity (45.89%) in the doxorubicin (47.87%) when compared to the normal control. The antioxidant activity of the essential oil was evaluated using methods of DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)). The results showed a significant (*** p < 0.001) percentage of inhibition of DPPH-induced free radical (70.02 ± 1.6%) and ABTS-induced free radical (70.7 ± 1.32%) at 100 µg/mL with IC50, 72.51 and 67.33 µg/mL, respectively, comparatively lower than standard compound ascorbic acid. The results of the molecular docking study of the significant compound limonene with the receptors tyrosinase and tyrosine kinase 2 supported the in vitro antioxidant potential. The anti-cariogenic activity was evaluated against Streptococcus mutans (S. mutans). Results showed a significant minimum inhibitor concentration of 0.25 mg/mL and the killing time was achieved at 3 to 6 h. The molecular-docking study showed that limonene inhibits the surface receptors of the S. mutans c-terminal domain and CviR protein. The study found that A. marmelos leaves have potential anti-carcinoma, antioxidant, and anti-cariogenic effects on human oral epidermal health, making them a valuable natural therapeutic agent for managing oral cancer and infections.

Preparation and Evaluation of Nanoemulsion of Citronella Essential Oil with Improved Antimicrobial and Anti-Cancer Properties.

The development of new pharmaceutical solutions for treating various diseases results from a growing understanding of the benefits of using essential oils. One of the most often used volatile materials among essential oils is the oil of the citronella plant, termed citronella essential oil (CITEO), which has potential for use in food and medicine. Its wide use is limited due to lipophilicity, high volatility and poor physicochemical stability. With this background, the present study aims to evaluate the properties of CITEO-nanoemulsion (CITEO-NE) by analyzing its antimicrobial activities against Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) and its anticancer activity against, human skin adenocarcinoma cell line (A431). The CITEO-NE was prepared and evaluated for the size range of 130 ± 5 nm, polydispersity index (PDI) of 0.127 and zeta potential -12.6 mV. The percentage % of entrapment efficiency (%EE) of nanoemulsions loaded with CIT was very high at the beginning of the study, at 95.5 ± 4.775%. The MIC was observed to be 500 µg/mL for CITEO and 250 µg/mL for CITEO-NE against S. aureus and 250 µg/mL for CITEO and 125 µg/mL for CITEO-NE against C. albicans. The time-kill assay also suggests the effectiveness of CITEO-NE against the test pathogens as a novel alternative therapy. The IC50 values of CITEO and CITEO-NE exhibited significant cytotoxic properties against the A431 cell line, with 41.20 µg/mL and 37.71 µg/mL, respectively. Hence, our findings revealed that encapsulation of CITEO increased the pharmacological properties.

Formulation, In Vitro and In Silico Evaluations of Anise (Pimpinella anisum L.) Essential Oil Emulgel with Improved Antimicrobial Effects.

Over the past decade, researchers have made several efforts to develop gel-based formulations that provide an alternative to traditional hydrogels and emulgel. Due to its excellent antibacterial properties, anise, the main constituent of Pimpinella anisum L., widely used in pharmaceuticals, was selected as the active ingredient in this study. Since many bacteria have developed considerable antibiotic resistance, this research aimed to develop an herbal emulgel for treating skin infections caused by bacteria. Given these obstacles, we developed and evaluated a new, cost-effective topical emulgel solution containing anise essential oil against Escherichia coli (E. coli). Anise-based emulgels, potential drug delivery platforms, have been evaluated for various parameters, including physical properties, viscosity, pH, rheology, encapsulation efficiency, and in vitro release research. The AEOs emulgel demonstrated remarkable colloidal stability, with a zeta potential of 29 mV, a size of 149.05 nm, and considerable polydispersity. The efficacy of anise-loaded emulgels as antibacterial formulations was evaluated in vitro. E. coli was used as a model microbial organism for the antibacterial study. Human keratinocytes (HaCaT) were used to examine the biocompatibility of the emulgel. Molecular docking revealed that the essential oil components of Pimpinella anisum L. possess a high affinity for the bacterial adhesin protein FimH of E. coli. These findings indicate that the developed AEOs have the potential to be analyzed using E. coli as a model organism.

Composition, Antibacterial Efficacy, and Anticancer Activity of Essential Oil Extracted from Psidium guajava (L.) Leaves.

Essential oils (EO) are used as a natural remedy to treat various chronic diseases, although clinical evidence is lacking. In this context, we have endeavored to measure the percentage of chemical composition and biological efficacy of Psidium guajava (guava) leaf essential oil in treating oral infections and oral cancer. The essential oil obtained from hydrodistillation of P. guajava L. leaves was analyzed by gas chromatography−mass spectrometry (GC−MS). The activities of selected oral pathogens Candida albicans (C. albicans) and Streptococcus mutans (S. mutants) were studied in vitro and in silico. MTT assay was used to test for anticancer activity against human oral epidermal carcinoma (KB). GC−MS showed that the main components of PGLEO were limonene (38.01%) and ß-caryophyllene (27.98%). Minimum inhibitory concentrations (MICs) of 0.05−0.1% were demonstrated against C. albicans and S. mutans. Antimicrobial activity against C. albicans and S. mutans, as shown by molecular linkage analysis, revealed that the main metabolites, limonene and ß-caryophyllene, potentially inhibited the receptors of C. albicans and S. mutans. PGLEO showed significant (p < 0.001) anticancer activity (45.89%) at 200 µg/mL compared to doxorubicin (47.87%) with an IC50 value of 188.98 µg/mL. The outcomes of the present study suggest that PGLEO has promising antimicrobial and anticancer activities and could be a useful source for developing a natural therapeutic agent for oral infections and oral cancer.

Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery.

The 3-phosphoinositide-dependent protein kinase 1 (PDPK1) has a significant role in cancer progression and metastasis as well as other inflammatory disorders, and has been proposed as a promising therapeutic target for several malignancies. In this work, we conducted a systematic virtual screening of natural compounds from the IMPPAT database to identify possible PDPK1 inhibitors. Primarily, the Lipinski rules, ADMET, and PAINS filter were applied and then the binding affinities, docking scores, and selectivity were carried out to find effective hits against PDPK1. Finally, we identified two natural compounds, 11-Hydroxytephrosin and Torosaflavone A, bearing substantial affinity with PDPK1. Both compounds showed drug-likeness as predicted by the ADMET analysis and their physicochemical parameters. These compounds preferentially bind to the ATP-binding pocket of PDPK1 and interact with functionally significant residues. The conformational dynamics and complex stability of PDPK1 with the selected compounds were then studied using interaction analysis and molecular dynamics (MD) simulations for 100 ns. The simulation results revealed that PDPK1 forms stable docked complexes with the elucidated compounds. The findings show that the newly discovered 11-Hydroxytephrosin and Torosaflavone A bind to PDPK1 in an ATP-competitive manner, suggesting that they could one day be used as therapeutic scaffolds against PDPK1-associated diseases including cancer.

Hepatoprotective activity of depsidone enriched Cladonia rangiferina extract against alcohol-induced hepatotoxicity targeting cytochrome P450 2E1 induced oxidative damage.

Alcoholic liver disease (ALD) is a broad-spectrum disorder, covering fatty liver, cirrhosis, alcoholic hepatitis and in extreme untreated condition hepatocellular carcinoma (HCC) may also develop. Cladonia rangiferina (CR) is a class of lichen having a broad spectrum of pharmacological activity. It is used like traditional natural sources in ancient times in India, China, Sri Lanka, etc. Folkloric record about CR has reported their use as an antimicrobial, antitumor, antioxidant, anti-inflammatory activities, etc. Hence, the present study was requested to ascertain the effect of the ethanolic extract of Cladonia rangiferina (CRE) on alcohol-induced hepatotoxicity. The animals were evaluated for the estimation of the liver in vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity. The results of this study reveal that CRE proves to be helpful in the treatment of alcohol-induced hepatotoxicity and oxidative stress. Results of different markers have shown that among all, CRE has demonstrated the best hepatoprotective activity. These observations say about the importance of the components of the extract. The ameliorative action of CRE in alcoholic liver damage may exist due to antioxidant, anti-inflammatory, and anti-apoptotic activities.

Oxidative free radicals scavenging activity (in vitro and in vivo assay) of standardized fractions from the seeds of Argyreia speciosa (Ghav-patta) a traditional Indian medicine.

TRADITIONAL PERTINENCE: Argyreia speciosa Sweet (Linn.), belongs to the family convolvulaceae, a traditional Indian medicinal herb, has been used to treat acute/chronic ulcers, gonorrhea, rheumatoid arthritis and several nervous disorders having a long history. AIM OF THE STUDY: A broad spectrum approach of this work was to find out the antioxidant activity of Argyreia speciosa seeds, in vitro and in vivo antioxidant assay were performed. MATERIAL AND METHODS: Total phenolic content (TPC), reducing power (RP), antioxidant activity (AOA), O 2 · - (superoxide anion), DPPH (1,1-diphenyl-2-picrylhydrazyl) and ˙OH (hydroxyl) radicals scavenging activities, GSH (glutathione), CAT (catalase), SOD (superoxide dismutase) and LPO (lipid peroxidase) are the major parameters which were studied for determining in vitro and in vivo antioxidant property of seed extract & their six fractions obtained from A. speciosa. Carbon tetrachloride (CCl4) induced rat model was used to determine in vivo antioxidant assay of extract and its fractions. RESULTS: Butanol fraction (AS-BF) showed strong antioxidant property and protected oxidative DNA damage. AS-BF was found best as compared to all other fraction for determining antioxidant property of seeds with the reduction in lipid peroxide formation and increment in GSH, CAT and SOD. AS-BF showed the presence of phenolic compounds viz. gallic acid, chlorogenic acid, and ellagic acid. CONCLUSION: From these results, it was proved that A. speciosa seeds prevent tissue damage due to oxidative stress with strong antioxidant activity.

Identification of Hydroxamic Acid Based Selective HDAC1 Inhibitors: Computer Aided Drug Design Studies.

BACKGROUND: Overexpression of Histone deacetylase 1 (HDAC1) is responsible for carcinogenesis by promoting epigenetic silence of tumour suppressor genes. Thus, HDAC1 inhibitors have emerged as the potential therapeutic leads against multiple human cancers, as they can block the activity of particular HDACs, renovate the expression of several tumour suppressor genes and bring about cell differentiation, cell cycle arrest and apoptosis. METHODS: The present research work comprises atom-based 3D-QSAR, docking, molecular dynamic simulations and DFT (density functional theory) studies on a diverse series of hydroxamic acid derivatives as selective HDAC1 inhibitors. Two pharmacophoric models were generated and validated by calculating the enrichment factors with the help of the decoy set. The Four different 3D-QSAR models i.e., PLS (partial least square) model, MLR (multiple linear regression) model, Field-based model and GFA (Genetic function approximation) model were developed using 'PHASE' v3.4 (Schrödinger) and Discovery Studio (DS) 4.1 software and validated using different statistical parameters like internal and external validation. RESULTS AND DISCUSSION: The results showed that the best PLS model has R2=0.991 and Q2=0.787, the best MLR model has R2= 0.993 and Q2= 0.893, the best Field-based model has R2= 0.974 and Q2= 0.782 and the best GFA model has R2= 0.868 and Q2= 0.782. Cross-validated coefficients, (rcv 2) of 0.967, 0.926, 0.966 and 0.829 was found for PLS model, MLR, Field based and GFA model, respectively, indicated the satisfactory correlativity and prediction. The docking studies were accomplished to find out the conformations of the molecules and their essential binding interactions with the target protein. The trustworthiness of the docking results was further confirmed by molecular dynamics (MD) simulations studies. Density Functional Theory (DFT) study was performed which promptly optimizes the geometry, stability and reactivity of the molecule during receptor-ligand interaction. CONCLUSION: Thus, the present research work provides spatial fingerprints which would be beneficial for the development of potent HDAC1 inhibitors.

Evaluation of Cucurbita maxima extract against scopolamine-induced amnesia in rats: implication of tumour necrosis factor alpha.

Cucurbita maxima (CM) seed oil is commonly used in Indian folk medicine to treat various ailments. We have investigated the effect of CM seed oil on memory impairment induced by scopolamine in rats. Male adult Wistar rats were administered scopolamine 1 mg/kg body weight, i.p. or 1.25 mg/kg body weight, s.c. to induce memory impairment. The nootropic agent piracetam 100 mg/kg body weight, i.p. and CM seed oil 100 and 200 mg/kg body weight, p.o. were administered daily for five consecutive days. The memory function was evaluated in the Morris water maze (MWM) test, the social recognition test (SRT), the elevated plus maze (EPM) test, and the pole climbing test (PCT). Acetylcholinesterase (AChE) activity and oxidative stress parameters were estimated in the cortex, hippocampus, and cerebellum of the brains after completion of the behavioural studies. The effects of scopolamine on the levels of the tumour necrosis factor alpha (TNF-α) transcript were also investigated. Scopolamine caused memory impairment in all the behavioural paradigms along with a significant increase in the AChE activity and oxidative stress in the brain. Scopolamine also caused a significant increase in the expression of TNF-α in the hippocampus. CM seed oil exhibited antiamnesic activity as indicated by a significant reduction in the latency time in the MWM test and decreased social interaction during trial 2 in the SRT. Further, treatment with CM seed oil significantly decreased the AChE activity and malondialdehyde levels and increased the glutathione level in brain regions. CM seed oil also significantly decreased the expression of TNF-α in the hippocampus. The effect of CM seed oil on behavioural and biochemical parameters was comparable to that observed in rats treated with piracetam. These results indicate that CM seed oil may exert antiamnesic activity which may be attributed to the inhibition of AChE and inflammation as well as its antioxidant activity in the brain.