Graphical abstract

Hydroxyphenylalkanes and diarylheptanoids possess potential therapeutic value in different pathophysiological conditions, such as malignancy. In the current study, naturally isolated hydroxyphenylalkane and diarylheptanoid compounds were investigated for potential chemo-modulatory effects in addition to potential vascular protective roles with doxorubicin. Diarylheptanoids showed stronger antioxidant effects, in comparison to hydroxyphenylalkanes, as demonstrated by DPPH assay and amelioration of CCl 4 -induced disturbed intracellular GSH/GSSG balance. Shogaol and 4 1 -methoxygingerol showed considerable cytotoxic effects against HCT116, HeLa, HepG2 and MCF7 cells, with IC 50 values ranging from 3.1 to 19.4 µM. Gingerol significantly enhanced the cytotoxic profile of doxorubicin against HepG 2 and Huh7, cells decreasing its IC 50 s by 10-and 4-fold, respectively. Cell cycle distribution was studied using DNA cytometry. Doxorubicin alone induced cell accumulation at S-phase and G 2 /M-phase, while in combination with gingerol it significantly induced cell cycle arrest at the G 2 /M-phase. Additionally, the vascular protective effect of gingerol against doxorubicin (10 µM) was examined on isolated aortic rings. Co-incubation with 6-gingerol (30 µM) completely blocked the exaggerated vasoconstriction and impaired vascular relaxation induced by doxorubicin. In conclusion, despite its relatively weak antioxidant properties, gingerol protected from DOX-induced vascular damage, apparently not through a ROS scavenging mechanism. Besides, gingerol synergized the cytotoxic effects of DOX against liver cancer cells without influencing the cellular pharmacokinetics.

Benign prostatic hyperplasia (BPH) is a common disorder in the male population. 2-Methoxyestradiol (2ME) is an end metabolite of estrogens with pleiotropic pharmacological properties. This study aimed to explore the potential ameliorative effects of 2ME against testosterone-induced BPH in rats. 2-Methoxyestradiol (50 and 100 mg/kg, dissolved in DMSO) prevented the rise in prostatic index and weight in comparison to testosterone-alone-treated animals for 2 weeks. Histological examination indicated that 2ME ameliorated pathological changes in prostate architecture. This was confirmed by the ability of 2ME to decrease the glandular epithelial height when compared to the testosterone group. Also, 2ME improved testosterone-induced oxidative stress as it inhibited the rise in lipid peroxide content and the exhaustion of superoxide dismutase (SOD) activity. The beneficial effects of 2ME against the development of BPH were substantiated by assessing proliferation markers, preventing the rise in cyclin D1 protein expression and enhancing Bax/Bcl2 mRNA ratio. It significantly reduced prostate content of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), nuclear factor κB (NF-κB), and transforming growth factor β (TGF-β). In addition, 2ME reduced hypoxia-inducible factor 1-α (HIF-1α) and phospho-Smad2 (p-Smad2) protein expression compared to the testosterone group. In conclusion, 2ME attenuates experimentally induced BPH by testosterone in rats through, at least partly, inhibition of HIF-1α/TGF-β/Smad2 axis.

High glucose levels in diabetic patients are implicated in delay wound healing that could lead to more serious clinical complications. The aim of the present work was to examine the formulation of ceftriaxone (CTX) and melittin (MEL) as nanoconjugate (nanocomplex)-loaded hydroxypropyl methylcellulose (HPMC) (1.5% w/v)-based hydrogel for healing of acute wounds in diabetic rats. The CTX–MEL nanoconjugate, formulated by ion-pairing at different molar ratio, was characterized for size and zeta potential and investigated by transmission electron microscopy. CTX–MEL nanoconjugate was prepared, and its preclinical efficacy evaluated in an in vivo model of acute wound. In particular, the potential ability of the innovative CTX–MEL formulation to modulate wound closure, oxidative status, inflammatory markers, and hydroxyproline was evaluated by ELISA, while the histopathological examination was obtained by using hematoxylin and eosin or Masson’s trichrome staining techniques. Quantitative real-time PCR (qRT-PCR) of the excised tissue to measure collagen, type I, alpha 1 (Col1A1) expression and immunohistochemical assessment of vascular endothelial growth factor A (VEGF-A) and transforming growth factor beta 1 (TGF-β1) were also carried out to shed some light on the mechanism of wound healing. Our results show that the CTX–MEL nanocomplex has enhanced ability to regenerate epithelium, also giving better keratinization, epidermal proliferation, and granulation tissue formation, compared to MEL, CTX, or positive control. The nanocomplex also significantly ameliorated the antioxidant status by decreasing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) levels. The treatment of wounded skin with the CTX–MEL nanocomplex also showed a significant reduction in interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) pro-inflammatory cytokines combined with a substantial increase in hydroxyproline, VEFG-A, and TGF-β1 protein expression compared to individual components or negative control group. Additionally, the CTX–MEL nanocomplex showed a significant increase in mRNA expression levels of Col1A1 as compared to individual compounds. In conclusion, the ion-pairing nanocomplex of CTX–MEL represents a promising carrier that can be topically applied to improve wound healing.

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.