Colorectal cancer (CRC) is the third leading cause of death in men and the fourth in women worldwide and is characterized by deranged cellular energetics. Thymoquinone, an active component from Nigella sativa, has been extensively studied against cancer, however, its role in affecting deregulated cancer metabolism is largely unknown. Further, the phosphoinositide 3-kinase (PI3K) pathway is one of the most activated pathways in cancer and its activation is central to most deregulated metabolic pathways for supporting the anabolic needs of growing cancer cells. Herein, we provide evidence that thymoquinone inhibits glycolytic metabolism (Warburg effect) in colorectal cancer cell lines. Further, we show that such an abrogation of deranged cell metabolism was due, at least in part, to the inhibition of the rate-limiting glycolytic enzyme, Hexokinase 2 (HK2), via modulating the PI3/AKT axis. While overexpression of HK2 showed that it is essential for fueling glycolytic metabolism as well as sustaining tumorigenicity, its pharmacologic and/or genetic inhibition led to a reduction in the observed effects. The results decipher HK2 mediated inhibitory effects of thymoquinone in modulating its glycolytic metabolism and antitumor effects. In conclusion, we provide evidence of metabolic perturbation by thymoquinone in CRC cells, highlighting its potential to be used/repurposed as an antimetabolite drug, though the latter needs further validation utilizing other suitable cell and/or preclinical animal models.

Objective: This study aims to explore the relationships among hopelessness, cognitive flexibility, intolerance of uncertainty, and perceived stress in a non-clinical sample by proposing a multiple mediation model. It was suggested that hopeless individuals have low cognitive flexibility and high intolerance of uncertainty; consequently, they are more likely to perceive stress. Method: The participants of this study comprised 302 university students (46.7% female and 53.3% male) between 18 and 40 years of age who were recruited from a state university in Turkey. To collect data, Beck Hopelessness Scale, Cognitive Flexibility Inventory, Intolerance of Uncertainty Scale, and Perceived Stress Scale were applied. Results: The results showed that hopelessness is negatively correlated with cognitive flexibility and positively correlated with intolerance of uncertainty and perceived stress. Cognitive flexibility has been found to be negatively correlated with intolerance of uncertainty and perceived stress. There is also a positive correlation between intolerance of uncertainty and perceived stress. The mediation of cognitive flexibility and intolerance of uncertainty in the relationship between hopelessness and perceived stress is also statistically significant in the model, and all variables explain approximately 37.0% of the variance in perceived stress. Conclusion: The findings of the study are considered to provide a guide for mental health professionals and researchers. Amaç: Bu araştırma klinik olmayan bir örneklemde, çoklu aracılık modeli önererek umutsuzluk, bilişsel esneklik, belirsizliğe tahammülsüzlük ve algılanan stres arasındaki ilişkileri incelemeyi amaçlamaktadır. Araştırmada umutsuz bireylerin düşük düzeyde bilişsel esnekliğe ve yüksek düzeyde belirsizliğe tahammülsüzlüğe sahip olduğu; dolayısıyla algılanan stres düzeylerinin daha yüksek olacağı varsayılmıştır. Yöntem: Araştırmanın katılımcıları Türkiye’deki bir devlet üniversitesine devam eden ve yaşları 18 ile 40 arasında olan 302 öğrenciden (%46.7’si kadın % 53.3’ü erkek ) oluşmaktadır. Verilerin toplanmasında, Beck Umutsuzluk Ölçeği, Bilişsel Esneklik Envanteri, Belirsizliğe Tahammülsüz Ölçeği ve Algılanan Stres Ölçeği kullanılmıştır. Bulgular: Araştırma bulguları, umutsuzluğun bilişsel esneklik ile negatif yönde, belirsizliğe tahammülsüzlük ve algılanan stres ile pozitif yönde ilişkili olduğunu göstermiştir. Bilişsel esneklik; belirsizliğe tahammülsüzlük ve algılanan stres ile negatif yönde ilişkili bulunmuştur. Ayrıca belirsizliğe tahammülsüzlük ve algılanan stres arasında pozitif yönde ilişki vardır. Bilişsel esneklik ve belirsizliğe tahammülsüzlüğün, umutsuzluk ve algılanan stres arasındaki ilişkide aracılığı istatistiksel olarak anlamlıdır ve tüm değişkenler algılanan stresteki varyansın yaklaşık %37’sini açıklamaktadır. Tartışma: Araştırma sonuçlarının ruh sağlığı alanında çalışan profesyoneller ve araştırmacılar için yol gösterici olacağı düşünülmektedir.

The purpose of this study is to improve the solubility and dissolution of a poorly soluble drug, Irbesartan, using solid dispersion techniques. For that purpose, different polymers such as Soluplus^®, Kollidon^® VA 64, Kolliphor^® P 407, and Polyinylpyrrolidone (PVP-K30) were used as carriers at different concentrations to prepare solid dispersion formulations through the solvent evaporation method. In order to prepare binary dispersion formulations, Soluplus^® and Kollidon^® VA 64 were used at drug: polymer ratios of 1:1, 1:2, 1:3, and 1:4 (w/w). Saturation solubility of the drug in the presence of used carriers was performed to investigate the quantitative increase in solubility. Dissolution studies were performed to explore the drug release behavior from the prepared dispersions. Additionally, the characterization of the prepared formulations was carried out by performing DSC, SEM, XRD, and FTIR studies. The results revealed that among binary systems, K₄ formulation (Drug: Kollidon^® VA 64 at ratio of 1:4 w/w) exhibited optimal performance in terms of increased solubility, drug release, and other investigated parameters. Furthermore, ternary dispersion formulations of the optimized binary formulation were prepared with two more polymers, Kolliphor^® P 407 and Polyvinylpyrrolidone (PVP-K30), at (Drug: Kollidon^® VA 64:ternary polymer) ratios of 1:4:1, 1:4:2, and 1:4:3 (w/w). The results showed that KPVP (TD₃) exhibited the highest increase in solubility, as well as dissolution rate, among ternary solid dispersion formulations. Results of solubility enhancement by ternary solid dispersion formulations were also supported by FTIR, DSC, XRD, and SEM analysis. Conclusively, it was found that the ternary solid dispersion-based systems were more effective compared to the binary combinations in improving solubility as well as dissolution of a poorly soluble drug (Irbesartan).

Oral health is a key contributor to a person’s overall health and well-being. Oral microbiota can pose a serious threat to oral health. Thus, the present study aimed to develop a cinnamon oil (CO)-loaded nanoemulsion gel (NEG1) to enhance the solubilization of oil within the oral cavity, which will enhance its antibacterial, antifungal, and analgesic actions against oral microbiota. For this purpose, the CO-loaded nanoemulsion (CO-NE) was optimized using I-optimal response surface design. A mixture of Pluracare L44 and PlurolOleique CC 497 was used as the surfactant and Capryol was used as the co-surfactant. The optimized CO-NE had a globule size of 92 ± 3 nm, stability index of 95% ± 2%, and a zone of inhibition of 23 ± 1.5 mm. This optimized CO-NE formulation was converted into NEG1 using 2.5% hydroxypropyl cellulose as the gelling agent. The rheological characterizations revealed that the NEG1 formulation exhibited pseudoplastic behavior. The in vitro release of eugenol (the marker molecule for CO) from NEG1 showed an enhanced release compared with that of pure CO. The ex vivo mucosal permeation was found to be highest for NEG1 compared to the aqueous dispersion of CO-NE and pure cinnamon oil. The latency reaction time during the hot-plate test in rats was highest (45 min) for the NEG1 sample at all-time points compared with those of the other tested formulations. The results showed that the CO-NEG formulation could be beneficial in enhancing the actions of CO against oral microbiota, as well as relieving pain and improving overall oral health.

Agarose (AG) is a naturally occurring biocompatible marine seaweed extract that is converted to hydrocolloid gel in hot water with notable gel strength. Currently, its mucoadhesion properties have not been fully explored. Therefore, the main aim of this study was to evaluate the mucoadhesive potential of AG binary dispersions in combination with Carbopol 934P (CP) as mucoadhesive gel preparations. The gels fabricated via homogenization were evaluated for ex vivo mucoadhesion, swelling index (SI), dissolution and stability studies. The mucoadhesive properties of AG were concentration dependent and it was improved by the addition of CP. Maximum mucoadhesive strength (MS) (27.03 g), mucoadhesive flow time (FT) (192.2 min), mucoadhesive time in volunteers (MT) (203.2 min) and SI (23.6% at 4 h) were observed with formulation F9. The mucoadhesive time investigated in volunteers (MT) was influenced by AG concentration and was greater than corresponding FT values. Formulations containing 0.3%, w/v AG (F3 and F9) were able to sustain the release (~99%) for both drugs till 3 h. The optimized formulation (F9) did not evoke any inflammation, irritation or pain in the buccal cavity of healthy volunteers and was also stable up to 6 months. Therefore, AG could be considered a natural and potential polymer with profound mucoadhesive properties to deliver drugs through the mucosal route.

Alopecia areata is a scarless, localized hair loss disorder that is typically treated with topical formulations that ultimately only further irritate the condition. Hence, the goal of this study was to develop a nanoemulsion with a base of garlic oil (GO) and apple cider vinegar (APCV) and loaded with minoxidil (MX) in order to enhance drug solubilization and permeation through skin. A distance coordinate exchange quadratic mixture design was used to optimize the proposed nanoemulsion. Span 20 and Tween 20 mixtures were used as the surfactant, and Transcutol was used as the co-surfactant. The developed formulations were characterized for their droplet size, minoxidil steady-state flux (MX Jss) and minimum inhibitory concentration (MIC) against Propionibacterium acnes. The optimized MX-GO-APCV nanoemulsion had a droplet size of 110 nm, MX Jss of 3 μg/cm² h, and MIC of 0.275 μg/mL. The optimized formulation acquired the highest ex vivo skin permeation parameters compared to MX aqueous dispersion, and varying formulations lacked one or more components of the proposed nanoemulsion. GO and APCV in the optimized formulation had a synergistic, enhancing activity on the MX permeation across the skin membrane, and the percent permeated increased from 12.7% to 41.6%. Finally, the MX-GO-APCV nanoemulsion followed the Korsmeyer–Peppas model of diffusion, and the value of the release exponent (n) obtained for the formulations was found to be 1.0124, implying that the MX permeation followed Super case II transport. These results demonstrate that the MX-GO-APCV nanoemulsion formulation could be useful in promoting MX activity in treating alopecia areata.