A bioanalytical assay for estimation of thymoquinone in rats cerebrospinal fluid and brain tissues of nasally administrated thymoquinone loaded lipo-polymeric nanoshells and its pharmacokinetic profiling.

Thymoquinone (TH) has been one of the major phytochemical used in the treatment of cancers since long time, especially in the management of glioblastoma multiforme (GBM). The formulation of lipo-polymeric nanoshells (LPNs) and their nasal delivery are fascinating approaches for overcoming the drawbacks of low solubility and poor bioavailability of TH. Hence targeting LPNs to the brain requires a validated bioanalytical method for the assessment of TH concentration in Cerebrospinal fluid (CSF) and brain tissue homogenates (BTH). Therefore, the current work focuses on the development and validation of high-performance liquid chromatography (HPLC) method in CSF by employing nasal simulated fluid (NSF) as one of the major components of the mobile phase. The developed method was checked for linearity in the range of 0.05 to 1.6 µg/mL, having an r2 value of 0.999 with mean % recovery >95% and % RSD values below <2.0%. The developed method gave a clear separation of TH at 6.021 ± 0.17 min with an internal standard at 4.102 ± 0.09 min and a CSF spike at 2.170 ± 0.12 min. The developed method assisted in determining the in-vitro and in-vivo drug release study of LPNs, pharmacokinetic profiling, qualitative in-vivo brain uptake study, in-vitro cellular uptake, and generating stability data of formulated LPNs proposed for intranasal administration in rats.

Uptake and Biotransformation of the Tire Rubber-derived Contaminants 6-PPD and 6-PPD Quinone in the Zebrafish Embryo (Danio rerio).

N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6-PPD) is a widely used antioxidant in tire rubber known to enter the aquatic environment via road runoff. The associated transformation product (TP) 6-PPD quinone (6-PPDQ) causes extreme acute toxicity in some fish species (e.g., coho salmon). To interpret the species-specific toxicity, information about biotransformation products of 6-PPDQ would be relevant. This study investigated toxicokinetics of 6-PPD and 6-PPDQ in the zebrafish embryo (ZFE) model. Over 96 h of exposure, 6-PPD and 6-PPDQ accumulated in the ZFE with concentration factors ranging from 140 to 2500 for 6-PPD and 70 to 220 for 6-PPDQ. A total of 22 TPs of 6-PPD and 12 TPs of 6-PPDQ were tentatively identified using liquid chromatography coupled to high-resolution mass spectrometry. After 96 h of exposure to 6-PPD, the TPs of 6-PPD comprised 47% of the total peak area (TPA), with 4-hydroxydiphenylamine being the most prominent in the ZFE. Upon 6-PPDQ exposure, >95% of 6-PPDQ taken up in the ZFE was biotransformed, with 6-PPDQ + O + glucuronide dominating (>80% of the TPA). Among other TPs of 6-PPD, a reactive N-phenyl-p-benzoquinone imine was found. The knowledge of TPs of 6-PPD and 6-PPDQ from this study may support biotransformation studies in other organisms.

Amino antioxidants: A review of their environmental behavior, human exposure, and aquatic toxicity.

Amino antioxidants (AAOs), a suite of emerging organic contaminants, have been widely used in numerous industrial and commercial products to inhibit oxidation and corrosion. Recently, their environmental ubiquity, health risks, bioaccumulative and toxic potential have led to mounting public concern. This review summarizes the current state of knowledge on the production and usage, environmental occurrence, bioavailability, human exposure, and aquatic toxicity of representative AAOs, and provides suggestions for future research directions. Previous studies have revealed widespread distribution of many AAOs in various environmental matrixes, including air, water, sediment, dust, and biota. In addition to parent compounds, their degradation products, such as 2-anilino-5-(1,3-dimethylbutylamino)-1,4-benzoquinone (6PPD-Q) and 4-nitrodiphenylamine (4-NO2-DPA), have also been detected at high levels in multiple compartments. Dust ingestion and air inhalation are the two most well-investigated routes for human exposure to AAOs and their transformation products, while studies on other pathways (e.g., skin contact and dietary intake) still remain extremely limited. Moreover, AAO burdens in human tissue have been poorly documented. Toxicological data have shown that a few AAOs may cause teratogenic, developmental, reproductive, endocrinic, neuronic, and genetic toxicity to aquatic organisms, and the toxic capacities of degradation products differ from their precursors. Future studies should focus on elucidating AAO exposure for humans and associated health risks. Additionally, more attention should be given to AAO transformation products (particularly those quinoid derivatives possessing substantial affinity with DNA) and to the effects of complex mixtures of these chemicals.

Thymoquinone Loaded Topical Nanoemulgel for Wound Healing: Formulation Design and In-Vivo Evaluation.

Thymoquinone is a natural bioactive with significant therapeutic activity against multiple ailments including wound healing. The poor aqueous solubility and low skin permeability limit its therapeutic efficacy. The present investigation aimed to improve the biopharmaceutical attributes of thymoquinone to enhance its topical efficacy in wound healing. A nanoemulsion-based hydrogel system was designed and characterized as a nanotechnology-mediated drug delivery approach to improve the therapeutic efficacy of thymoquinone, utilizing a high-energy emulsification technique. The black seed oil, as a natural home of thymoquinone, was utilized to improve the drug loading capacity of the developed nanoemulsion system and reduced the oil droplet size to <100 nm through ultrasonication. The influence of formulation composition, and the ultrasonication process conditions, were investigated on the mean globule size and polydispersity index of the generated nanoemulsion. Irrespective of surfactant/co-surfactant ratio and % concentration of surfactant/co-surfactant mixture, the ultrasonication time had a significant (p < 0.05) influence on the mean droplet size and polydispersity index of the generated nanoemulsion. The developed nanoemulgel system of thymoquinone demonstrated the pseudoplastic behavior with thixotropic properties, and this behavior is desirable for topical application. The nanoemulgel system of thymoquinone exhibited significant enhancement (p < 0.05) in skin penetrability and deposition characteristics after topical administration compared to the conventional hydrogel system. The developed nanoemulgel system of thymoquinone exhibited quicker and early healing in wounded Wistar rats compared to the conventional hydrogel of thymoquinone, while showing comparable healing efficacy with respect to marketed silver sulfadiazine (1%) cream. Furthermore, histopathology analysis of animals treated with a developed formulation system demonstrated the formation of the thick epidermal layer, papillary dermis along with the presence of extensive and organized collagen fibers in newly healed tissues. The outcome of this investigation signifies that topical delivery of thymoquinone through nanoemulgel system is a promising candidate which accelerates the process of wound healing in preclinical study.

Therapeutic perspectives of the black cumin component thymoquinone: A review.

The dietary phytochemical thymoquinone (TQ), belonging to the family of quinones, mainly obtained from the black and angular seeds of Nigella sativa, is one of the promising monoterpenoid hydrocarbons, which has been receiving massive attention for its therapeutic potential and pharmacological properties. It plays an important role as a chemopreventive and therapeutic agent in the treatment of various diseases and illnesses. The aim of this review is to present a summary of the most recent literature pertaining to the use of TQ for the prevention and treatment of various diseases along with possible mechanisms of action, and the potential use of this natural product as a complementary or alternative medicine. Research findings indicated that TQ exhibits numerous pharmacological activities including antioxidant, anti-inflammatory, cardioprotective, hepatoprotective, antidiabetic, neuroprotective, and anticancer, among others. Conclusions of this review on the therapeutic aspects of TQ highlight the medicinal and folk values of this compound against various diseases and ailments. In short, TQ could be a novel drug in clinical trials, as we hope.

Thymoquinone-entrapped chitosan-modified nanoparticles: formulation optimization to preclinical bioavailability assessments.

The major limitation with the oral administration of most of the phytochemicals is their low aqueous solubility and bioavailability. Thymoquinone (THQ) is one of the most widely used phytochemicals used to treat a variety of diseases. However, strong lipophilic characteristics limit its clinical application. Therefore, this study was aimed to design novel chitosan (C) modified polycaprolactone (PL) nanoparticles (NPs) for improved oral bioavailability of THQ. THQ-CPLNPs was optimized 33-Box-Behnken design. After that, the optimized THQ-CPLNPs was characterized by different parameters. THQ-CPLNPs showed the size, PDI, and ZP of 182.32 ± 6.46 nm, 0.179 ± 0.012, and +21.36 ± 1.22 mV, respectively. The entrapment and loading capacity were found to be 79.86 ± 4.36%, and 13.45 ± 1.38%, respectively. THQ-CPLNPs exhibited burst release in initial 2 h followed by prolonged release up to 24 h in simulated intestinal fluids. THQ-CPLNPs showed excellent mucoadhesion properties which were further confirmed with the intestinal permeation study as well as confocal microscopy. The study revealed higher permeation of THQ-CPLNPs compared to neat THQ suspension (THQ-S). Moreover, in vivo gastric irritation study revealed good compatibility of THQ-CPLNPs with the gastric mucosa. Furthermore, pharmacokinetic results depicted ∼3.53-fold improved oral bioavailability of THQ from THQ-CPLNPs than THQ-S. Therefore, from the findings, it was concluded that the prepared polymeric NPs could be an effective delivery system for improved oral bioavailability of THQ.

Anticancer Activity of Thymoquinone Cubic Phase Nanoparticles Against Human Breast Cancer: Formulation, Cytotoxicity and Subcellular Localization.

INTRODUCTION: Triple negative breast cancer is an aggressive disorder which accounts for at least 15% of breast cancer diagnosis and a high percentage of breast cancer morbidity, hence intensive research efforts are focused on the development of effective therapies to overcome the disease. Thymoquinone (TQ), the bioactive constituent of Nigella sativa, exhibits anticancer activity, yet its translation to the clinic is hindered by its poor bioavailability and lack of quantification method in blood and tissues. To overcome these limitations, cubosomes were utilized for the encapsulation and delivery of this anticancer molecule. METHODS: Thymoquinone loaded cubosomes were prepared through the emulsification homogenization method. The physicochemical characteristics, including particle size, zeta potential, morphology and entrapment efficiency, were studied. Moreover, the in vitro antitumor activity was tested on breast cancer cell lines (MCF-7 and MDA-MB-231) and compared to non-tumorigenic cell line (MCF-10A). Subcellular localization, cellular uptake and apoptotic effects of the formulations were assessed. RESULTS: The results revealed that the TQ loaded cubosomal formulation exhibited a mean particle size of 98.0 ± 4.10 nm with narrow unimodal distribution. The high entrapment efficiency (96.60 ± 3.58%) and zeta potential (31.50 ±4.20 mV) conceived the effectiveness of this nanosystem for TQ encapsulation. Cell viability in both breast cancer cell lines demonstrated a dose-dependent decrease in response to treatment with free TQ or TQ-loaded cubosomes, with enhanced antitumor activity upon treating with the latter formulation. A significant increase in apoptotic bodies and cleaved caspase 3 was observed upon treatment of MDA-MB-231 cells with either TQ or TQ-loaded cubosomes. Localization and trafficking studies unveiled that cubosomes accumulate in the cytoplasm of the studied breast cancer cell lines. DISCUSSION: Our results show that thymoquinone encapsulation in cubosomal nanoparticles provides a promising anticancer drug delivery system with the ability to label, detect and subsequently trace it within the human cells.

Thymoquinone-Loaded Soluplus®-Solutol® HS15 Mixed Micelles: Preparation, In Vitro Characterization, and Effect on the SH-SY5Y Cell Migration.

Thymoquinone (TQ) is the main active ingredient of Nigella sativa essential oil, with remarkable anti-neoplastic activities with anti-invasive and anti-migratory abilities on a variety of cancer cell lines. However, its poor water solubility, high instability in aqueous solution and pharmacokinetic drawbacks limits its use in therapy. Soluplus® and Solutol® HS15 were employed as amphiphilic polymers for developing polymeric micelles (SSM). Chemical and physical characterization studies of micelles are reported, in terms of size, homogeneity, zeta potential, critical micelle concentration (CMC), cloud point, encapsulation efficiency (EE%), load capacity (DL), in vitro release, and stability. This study reports for the first time the anti-migratory activity of TQ and TQ loaded in SSM (TQ-SSM) in the SH-SY5Y human neuroblastoma cell line. The inhibitory effect was assessed by the wound-healing assay and compared with that of the unformulated TQ. The optimal TQ-SSM were provided with small size (56.71 ± 1.41 nm) and spherical shape at ratio of 1:4 (Soluplus:Solutol HS15), thus increasing the solubility of about 10-fold in water. The entrapment efficiency and drug loading were 92.4 ± 1.6% and 4.68 ± 0.12, respectively, and the colloidal dispersion are stable during storage for a period of 40 days. The TQ-SSM were also lyophilized to obtain a more workable product and with increased stability. In vitro release study indicated a prolonged release of TQ. In conclusion, the formulation of TQ into SSM allows a bio-enhancement of TQ anti-migration activity, suggesting that TQ-SSM is a better candidate than unformulated TQ to inhibit human SH-SY5Y neuroblastoma cell migration.

Pharmacokinetics and Biodistribution of Thymoquinone-loaded Nanostructured Lipid Carrier After Oral and Intravenous Administration into Rats.

BACKGROUND: Thymoquinone (TQ), an active compound isolated from Nigella sativa, has been proven to exhibit various biological properties such as antioxidant. Although oral delivery of TQ is valuable, it is limited by poor oral bioavailability and low solubility. Recently, TQ-loaded nanostructured lipid carrier (TQ-NLC) was formulated with the aim of overcoming the limitations. TQ-NLC was successfully synthesized by the high-pressure homogenization method with remarkable physiochemical properties whereby the particle size is less than 100 nm, improved encapsulation efficiency and is stable up to 24 months of storage. Nevertheless, the pharmacokinetics and biodistribution of TQ-NLC have not been studied. This study determined the bioavailability of oral and intravenous administration of thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) in rats and its distribution to organs. MATERIALS AND METHODS: TQ-NLC was radiolabeled with technetium-99m before the administration to the rats. The biodistribution and pharmacokinetics parameters were then evaluated at various time points. The rats were imaged at time intervals and the percentage of the injected dose/gram (%ID/g) in blood and each organ was analyzed. RESULTS: Oral administration of TQ-NLC exhibited greater relative bioavailability compared to intravenous administration. It is postulated that the movement of TQ-NLC through the intestinal lymphatic system bypasses the first metabolism and therefore enhances the relative bioavailability. However, oral administration has a slower absorption rate compared to intravenous administration where the AUC0-∞ was 4.539 times lower than the latter. CONCLUSION: TQ-NLC had better absorption when administered intravenously compared to oral administration. However, oral administration showed greater bioavailability compared to the intravenous route. This study provides the pharmacokinetics and biodistribution profile of TQ-NLC in vivo which is useful to assist researchers in clinical use.

A Sensitive Rapid and Environmentally Friendly UHPLC Assay Method for the Determination of Thymoquinone in Plasma Samples and Its Analytical Application.

A precise, swift and environmental-friendly reverse phase ultra-high performance liquid chromatographic assay for the determination of thymoquinone (TQ) in plasma samples using thymol (TM) as an internal standard was developed and validated. The method used a high strength silica C18 1.7 µm column (100 × 2.1 mm) with an isocratic mobile phase consisting of a blend of methanol and 20 mM potassium dihydrogen ortho-phosphate (90:10 v/v; pH of 4.2). The selected eluent provided a short run time (≤2 min), better peak symmetry, lower limit of quantification of 10 ng/mL and satisfactory values of other chromatographic parameters including resolution (Rs = 1), capacity factor (k = 21.5 and 14.5 for TQ and TM, respectively), selectivity (α = 1.482) and number of theoretical plates (N = 1653 and 784 for TQ and TM, respectively). The method was efficiently applied to a pharmacokinetic study of TQ following an intraperitoneal administration of 2 mg/kg in mice. The concentrations of TQ in plasma were measurable up to 12 h with Cmax of 404.08 ± 28.91 ng/mL, T1/2 of 2.31 ± 0.10 h and area under plasma concentration-time curve of 1527.00 ± 46.61 ng/mL × h.

Naphthoquinones, benzoquinones, and anthraquinones: Molecular docking, ADME and inhibition studies on human serum paraoxonase-1 associated with cardiovascular diseases.

Paraoxonase-1 (PON1) has essential roles such as protecting low-density lipoprotein against detoxification and oxidation of highly toxic compounds. Quinones are a class of compounds and a type of plant-derived secondary metabolites. Here, PON1 was purified using very simple methods and evaluation of the interactions between the enzyme and some quinones. It was found that these quinones displayed effective inhibitor properties for PON1 with the IC50 values in the range of 3.27-82.90 µM and the K i values in the range of 2.50 ± 0.65 to 30.90 ± 7.20 µM. These quinones displayed distinct inhibition mechanisms. It was determined that except for 5-hydroxy-2-methyl-1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone all quinones exhibit competitive inhibition effects. Also, molecular docking and in silico ADME studies were performed. Usage of drugs including quinone derivatives in structure with biological activity would be hazardous in some cases.

Effect of compromised liver function and acute kidney injury on the pharmacokinetics of thymoquinone in a rat model.

The current research explored the effect of hepatic and renal dysfunctions on the pharmacokinetics of thymoquinone (TQ) in a rat model.An acute kidney injury was induced using gentamicin and a liver damage was elicited using a single dose of d-galactosamine. For the pharmacokinetic studies, TQ was administered as IV injection or and PO route to rats.The concentrations of TQ and pharmacokinetic parameters were calculated using a non-compartmental analysis. The systemic clearance (Cl) of TQ after IV dosing was slightly reduced in the liver dysfunction group compared to healthy controls (p = 0.0013). Similarly, the estimated volume of distribution at steady state (Vss) was marginally decreased (p = 0.001). However, in rats with acute kidney injury exhibited a larger Vss as opposed to normal renal function (511.28 ± 21.03 ml/kg vs. 442.25 ± 31.43 ml/kg; p = 0.0001). Whereas oral Cl and terminal volume of distribution (Vz) of TQ were reduced by ∼50% in the liver dysfunction group (p = 0.0001). These changes were associated with more systemic exposure as measured by AUC0-∞ in rats with compromised liver functions. The estimated plasma protein binding TQ was 99.84 ± 0.03% in healthy controls, 97.05 ± 0.57% with kidney injury rats, and 95.75 ± 0.64% in liver dysfunctionThe findings of the present study suggest that liver dysfunction could potentially modify the disposition of TQ administered orally, and therefore, a smaller maintenance dose is probably required to avoid accumulation.

Enhanced oral bioavailability and hepatoprotective activity of thymoquinone in the form of phospholipidic nano-constructs.

Background: The poor biopharmaceutical properties of thymoquinone (TQ) obstruct its development as a hepatoprotective agent. To surmount the delivery challenges of TQ, phospholipid nanoconstructs (PNCs) were constructed.Method: PNCs were constructed employing microemulsification technique and systematic optimization by three-factor three level Box-Behnken design.Result: Optimized PNC composition exhibited nano size (<100 nm), spherical morphology, within acceptable range of polydispersity index (0.55), high drug entrapment efficiency (>90%), controlled drug release pattern, and neutral surface charge (zeta potential of -0.65 mV). After oral administration of a single dose of PNC, it showed a relative bioavailability of 386.03% vis-à-vis plain TQ suspension. Further, TQ-loaded PNC demonstrated significant enhanced hepato-protective effect vis-à-vis pure TQ suspension and silymarin, as evidenced by reduction in the ALP, ALT, AST, bilirubin, and albumin level and ratified by histopathological analysis.Conclusion: TQ-loaded PNCs can be efficient nano-platforms for the management of hepatic disorders and promising drug delivery systems to enhance oral bioavailability of this hydrophobic molecule.

Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women.

BACKGROUND AND OBJECTIVE: Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy. METHODS: PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (Css,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated. RESULTS: PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest Css,avg in the third trimester (median [interquartile range]: 4.5 [3.8-5.1] mg/L), while Css,avg was 6.7 [5.9-7.4], 5.6 [4.7-6.3], and 4.9 [4.1-5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1-13.4%]), followed by the second (9.0% [7.5-11.0%]) and third trimester (8.2% [6.8-10.1%]), compared with non-pregnant women (7.7% [6.4-9.4%]). CONCLUSION: Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model.

Molecular Docking and Dynamics Simulation Analysis of Thymoquinone and Thymol Compounds from Nigella sativa L. that Inhibits P38 Protein: Probable Remedies for Hepatocellular Carcinoma.

BACKGROUND: Currently, a novel antagonist against p38 is being designed and applied to inhibit hepatocellular carcinoma. Protein-ligand interaction plays a major role in the identification of the possible mechanism for the pharmacological action. The involvement of p38 remains an important target for anticancer drug development as its activation induces apoptosis in hepatoma cells. OBJECTIVE: The aim is to identify the best candidate from the plants of N. sativa which binds with the hepatocellular carcinoma (HCC) targets by computational approach. MATERIALS AND METHODS: The reported phytoconstituents such as thymoquinone and thymol present in the plant, N. sativa were docked with the HCC target such as p38. Structures of phytoconstituents were prepared using ChemDraw Ultra 10 software and converted into its 3D PDB structure and minimized using Discovery Studio client 2.5. The target protein, p38 was retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling were carried out on the phytoconstituents of the N. sativa, and the compounds were further promoted for molecular docking and MD simulation analysis. RESULTS: The docking results revealed promising inhibitory potential of thymoquinone against p38 with binding energy of -7.67 kcal/mole as compared to its known standard doxorubicin having binding energy of -6.68 kcal/mol respectively. Further, molecular dynamic (MD) simulations for 5ns were conducted for optimization, flexibility prediction, and determination of folded p38 stability. The p38-thymoquinone complex was found to be quite stable with RMSD value of 0.2 nm. CONCLUSION: Obtained results propose thymoquinone binding energy on the selected targets. Hence, this compound bears outstanding potential against hepatocellular carcinoma and has to be taken up for experimental work against hepatocellular carcinoma.

A Tumor Microenvironment-Responsive Biodegradable Mesoporous Nanosystem for Anti-Inflammation and Cancer Theranostics.

A nanoplatform that integrates diagnostic and therapeutic functions with intrinsic tumor microenvironment-responsive biodegradability is highly desired. Herein, a biodegradable nanotheranostic agent based on hollow mesoporous organosilica nanoparticles (HMONs), followed by encapsulating of heat shock protein 90 (Hsp 90) inhibitor is described. Then, the pore-engineering including gating with bovine serum albumin-iridium oxide nanoparticles (BSA-IrO2 ) and conjugation of polyethylene glycol (PEG) is conducted to yield 17AAG@HMONs-BSA-IrO2 -PEG (AHBIP) nanotheranostics for multimode computed tomography (CT)/photoacoustic (PA) imaging-guided photodynamic therapy (PDT) and low-temperature photothermal therapy (PTT). Such nanoplatforms show extraordinary photothermal conversion efficiency, high cargo loading (35.4% for 17AAG), and stimuli-responsive release of 17AAG for inhibition of Hsp90, which induces cell apoptosis at low-temperatures (≈41 °C). Also, the IrO2 simultaneously endows the nanotheranostics with catalytic activity in triggering the decomposition of H2 O2 into O2 and thus reducing the tumor hypoxia, as well as protecting normal tissues against H2 O2 -induced inflammation. AHBIP shows good photocatalysis activity for PDT as a result of the generation of superoxide anion by laser irradiation. The resulting AHBIP-mediated synergistic PTT/PDT offers an outstanding therapeutic outcome both in vitro and in vivo. Overall, the incorporation of the BSA-IrO2 and biodegradable HMONs into one nanoplatform has great potential for clinical applications.

Thymoquinone-loaded lipid vesicles: a promising nanomedicine for psoriasis.

BACKGROUND: Psoriasis, a recurrent, chronic inflammatory disorder of skin, is a common problem in middle age and elderly people. Thymoquinone (TQ), a lipid soluble benzoquinone is the major active ingredient of volatile oil of Nigella sativa (NS), possesses good anti-psoriatic activity. However, its hydrophobicity, poor aqueous solubility, and photosensitive nature obstructs its development. Therefore, in the present research work, ethosomal vesicles (EVs) loaded with TQ were assessed for its anti-psoriatic potential employing mouse-tail model. METHODS: TQ-loaded EVs were prepared by cold method, and characterized for various essential attributes, viz. particle size, morphology, percent drug entrapment, flexibility, rheological and textural analysis, and skin absorption. The optimized formulation was finally evaluated for anti-psoriatic activity on Swiss albino mice employing mouse-tail model for psoriasis. RESULTS: The spherical shaped vesicles were in the nanosize range, and had high flexibility. The EVs incorporated hydrogel was rheologically acceptable and resulted in substantial TQ retention in the skin layers. The % anti-psoriatic drug activity was observed to be substantially better in the case of TQ-loaded ethosomal gel vis-à-vis plain TQ, NS extract, and marketed formulation. CONCLUSIONS: The promising outcomes of the current studies ratify the superiority of TQ-loaded phospholipid-based vesicular systems for the management of psoriasis over other studied test formulations. This study, thus open promising avenues for topical application of TQ in the form of EV hydrogel.

Fabrication of Thymoquinone-Loaded Albumin Nanoparticles by Microfluidic Particle Synthesis and Their Effect on Planarian Regeneration.

Thymoquinone is the main bioactive component of the plant Nigella sativa, which is commonly known as black seeds and has several therapeutic effects. However, clinical applications of thymoquinone are limited due to its hydrophobic nature. In this study, thymoquinone is encapsulated in albumin nanoparticles by using a microfluidic platform to overcome this limitation. The mean particle sizes of empty and thymoquinone-loaded nanoparticles are determined as 271.3 and 315.6 nm, respectively, with polydispersity index values both lower than 0.25. In addition to particle size distribution measurements, characterizations of the prepared nanoparticles such as zeta potential measurements, in vitro release studies, as well as scanning electron microscopy, Fourier-transform infrared, and differential scanning calorimetry analyses are also carried out. To determine the effect of thymoquinone on neural regeneration, planarians are used as the model organism. After application of free and encapsulated thymoquinone, planarians are amputated and the fragments are observed in terms of head and tail regeneration, swimming pattern, and behavior. The results indicate that thymoquinone affects their behavior and primarily enhances head regeneration of planarians. In addition, it is shown that encapsulation of thymoquinone not only enhances the thermal stability of the molecule but also decreases its toxicity.

Pharmacokinetics of thymoquinone in layer chickens following oral and intravenous administration.

Thymoquinone (TQ) is the major constituent of Nigella sativa and known to possess a variety of pharmacological effects. This study was designed to evaluate the pharmacokinetic profile of TQ following oral (PO) and intravenous (IV) administration in layer chickens. The layer chickens were equally divided into two groups (six chickens in each group, total 12 chickens), and TQ was administered via PO and IV routes. For PO route, the dose was 20 mg/kg b.w. and for IV route, 5 mg/kg b.w. was administered, respectively. A sensitive and accurate High-Performance Liquid Chromatography (HPLC) technique was validated for the quantification of TQ from plasma. The limit of detection (LOD) and limit of quantification (LOQ) were 0.02 µg/ml and 0.05 µg/ml, respectively with >80% recovery. Maximum plasma concentration (Cmax ) following PO and IV administration was 8.805 and 4.497 µg/ml, respectively, while time to reach at maximum concentration (Tmax ) was 1 and 0.1 hr, respectively. The elimination half-lives were recorded as 1.02 and 0.978 hr, whereas the mean residence times were 1.79 and 1.036 hr following both PO and IV administration, respectively. The 85% PO bioavailability was indicative that TQ could be used for various therapeutic purposes in layer chickens.

SkQThy, a novel and promising mitochondria-targeted antioxidant.

Since thymoquinone (2-isopropyl-5-methylbenzoquinone) isolation from Nigella sativa in 1963, various studies have reported on its diverse pharmacological properties. However, despite its versatile healing abilities, clinical trials involving the use of thymoquinone have not been initiated due to its poor bioavailability. Many attempts have been made to improve the therapeutic efficacy of thymoquinone by synthesizing analogs, as well as by developing nanotechnology-based delivery systems. We hypothesized that some of the issues with thymoquinone delivery and bioavailability could be resolved by targeted delivery to mitochondria of thymoquinone derivatives conjugated to the penetrating lipophilic cationic triphenylphosphonium fragment. As mitochondria are the major site of reactive oxygen species generation in the cell, such a membranotropic thymoquinone derivative can act as an efficient antioxidant or prooxidant depending on the concentration used. Based on these theoretical considerations, a novel mitochondria-targeted compound, SkQThy, was synthesized and its effects on rat liver mitochondria and yeast cells were examined. SkQThy was found to exhibit pronounced antioxidant activity in mammalian mitochondria and yeast cells, decreasing hydrogen peroxide production in mitochondria, as well as preventing prooxidant-induced oxidative stress and mitochondrial fragmentation in yeast cells and increasing cell viability. Moreover, SkQThy proved itself to be the most efficient mitochondria-targeted antioxidant within the SkQs family, showing good therapeutic potential.