Dual loading of Nigella sativa oil-atorvastatin in chitosan-carboxymethyl cellulose nanogel as a transdermal delivery system.

Both Nigella sativa oil and atorvastatin possess anti-inflammatory, immunomodulatory, antioxidant, and antibacterial properties that benefit wound healing. In this work, chitosan-carboxymethyl cellulose was loaded on N. sativa oil to synthesize oil nanogel (ONG) which was later used to load with atorvastatin to obtain atorvastatin-oil nanogel (ATONG). Evaluation of the particle size of ONG and ATONG proved the average of 172 and 193 nm, and their surface charges were found to be 32.2 and 34.7 mV, respectively. Transmission electron microscopy of the sample showed that the particles had homogeneous size distributions with spherical structures. Moreover, drug loading efficiency, drug release, and stability of ATONG were investigated, and their results confirmed the appropriate loading and release of atorvastatin. Cytotoxicity evaluation demonstrated that ATONG can safely release atorvastatin intracellularly in fibroblasts. Results from in vitro skin permeation of ONG and ATONG also revealed that the nanogels (NGs) has proper flux through the skin layers. The in vitro wound closure assay for ATONG verified the proliferation and migration capabilities of fibroblasts, confirming the positive effect on wound-healing applications. In scratch model of fibroblasts, the treatment with ATONG resulted in an increase in the expression of the FGF2, TGF-ß1, and VEGF genes involved in fibroblast proliferation and migration aimed at wound healing (p < .001). ATONG, also demonstrated bactericidal effects against Staphylococcus, S. aureus, and S. epidermidis species. Based on the results, ONG and ATONG exhibited great potential to be used as a transdermal drug carrier and skin wound healing NG, respectively.

Tribulus terrestris and female reproductive system health: A comprehensive review.

BACKGROUND: Tribulus terrestris L. (T. terrestris) positive performance on the male sexual system has been confirmed, but little is known about its effects on the female reproductive system. PURPOSE: This review discussed in detail the beneficial impact of T. terrestris and its secondary metabolites on the female reproductive system. STUDY DESIGN AND METHODS: In this review, the scientific Databases of Science direct, Pubmed, Web of Science, Google, Google Scholar, Researchgate, EMBASE, Scientific Information (SID), and Elsevier were searched profoundly. Studies about the pharmacological activities of T. terrestris on the female reproductive system in each aspect of investigations: human, in vivo, and in vitro studies, in the period from 1998 to 2020 were admitted. Our study was not limited by the language of publications. RESULTS: 23 articles about the effects of T. terrestris on the female reproductive system were found. These studies approved the T. terrestris efficacy on improvements in histological features of the ovary and uterus of polycystic ovary syndrome patients as well as the well-working of normal ovaries, enhancements in the sexual desire of postmenopausal syndrome, improve ovarian and breast cancers. CONCLUSION: These studies showed that the positive effect of T. terrestris on the female reproductive system was due to the presence of a secondary metabolite called protodioscin; a steroidal saponin compound, as the dominant active component of this plant.

Generation of Scalable Hepatic Micro-Tissues as a Platform for Toxicological Studies.

BACKGROUND: Currently, there is an urgent need for scalable and reliable in vitro models to assess the effects of therapeutic entities on the human liver. Hepatoma cell lines, including Huh-7, show weakly resemblance to human hepatocytes, limiting their significance in toxicity studies. Co-culture of hepatic cells with non-parenchymal cells, and the presence of extracellular matrix have been shown to influence the biological behavior of hepatocytes. The aim of this study was to generate the scalable and functional hepatic micro-tissues (HMTs). METHODS: The size-controllable HMTs were generated through co-culturing of Huh-7 cells by mesenchymal stem cells and human umbilical vein endothelial cells in a composite hydrogel of liver-derived extracellular matrix and alginate, using an air-driven droplet generator. RESULTS: The generated HMTs were functional throughout a culture period of 28 days, as assessed by monitoring glycogen storage, uptake of low-density lipoprotein and indocyanine green. The HMTs also showed increased secretion levels of albumin, alpha-1-antitrypsin, and fibrinogen, and production of urea. Evaluating the expression of genes involved in hepatic-specific and drug metabolism functions indicated a significant improvement in HMTs compared to two-dimensional (2D) culture of Huh-7 cells. Moreover, in drug testing assessments, HMTs showed higher sensitivity to hepatotoxins compared to 2D cultured Huh-7 cells. Furthermore, induction and inhibition potency of cytochrome P450 enzymes confirmed that the HMTs can be used for in vitro drug screening. CONCLUSION: Overall, we developed a simple and scalable method for generation of liver micro-tissues, using Huh-7, with improved hepatic-specific functionality, which may represent a biologically relevant platform for drug studies.

Thymoquinone and its therapeutic potentials.

Herbal medicine has attracted great attention in the recent years and is increasingly used as alternatives to chemical drugs. Several lines of evidence support the positive impact of medicinal plants in the prevention and cure of a wide range of diseases. Thymoquinone (TQ) is the most abundant constituent of the volatile oil of Nigella sativa seeds and most properties of N sativa are mainly attributed to TQ. A number of pharmacological actions of TQ have been investigated including anti-oxidant, anti-inflammatory, immunomodulatory, anti-histaminic, anti-microbial and anti-tumor effects. It has also gastroprotective, hepatoprotective, nephroprotective and neuroprotective activities. In addition, positive effects of TQ in cardiovascular disorders, diabetes, reproductive disorders and respiratory ailments, as well as in the treatment of bone complications as well as fibrosis have been shown. In addition, a large body of data shows that TQ has very low adverse effects and no serious toxicity. More recently, a great deal of attention has been given to this dietary phytochemical with an increasing interest to investigate it in pre-clinical and clinical researches for assessing its health benefits. Here we report on and analyze numerous properties of the active ingredient of N. sativa seeds, TQ, in the context of its therapeutic potentials for a wide range of illnesses. We also summarize the drug's possible mechanisms of action. The evidence reported sugests that TQ should be developed as a novel drug in clinical trials.

Tranilast: a review of its therapeutic applications.

Tranilast (N-[3',4'-dimethoxycinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite. Initially, tranilast was identified as an anti-allergic agent, and used in the treatment of inflammatory diseases, such as bronchial asthma, atypical dermatitis, allergic conjunctivitis, keloids and hypertrophic scars. Subsequently, the results showed that it could be also effective in the management of a wide range of conditions. The beneficial effects of tranilast have also been seen in a variety of disease states, such as fibrosis, proliferative disorders, cancer, cardiovascular problems, autoimmune disorders, ocular diseases, diabetes and renal diseases. Moreover, several trials have shown that it has very low adverse effects and it is generally well tolerated by patients. In this review, we have attempted to accurately summarize previously published studies relating to the use of tranilast for a range of disorders and discuss the drug's possible mode of action. The major mode of the drug's efficacy appears to be the suppression of the expression and/or action of the TGF-ß pathway, but the drug affects other factors as well. The findings presented in this review demonstrate the potential of tranilast for the control of a vast array of pathological situations, furthermore, it is a prescribed drug without severe side effects.

The Effects of Tamoxifen in Combination with Tranilast on CXCL12-CXCR4 Axis and Invasion in Breast Cancer Cell Lines.

It has been reported that CXCL12 binding to CXCR4 induces several intracellular signaling pathways, and enhances survival, proliferation, and migration of malignant cells. In the present study, we examined the effects of anti-estrogen tamoxifen and anti-allergic tranilast drugs as a single or in combination on invasion by two in-vitro invasion assays, wound-healing and matrigel invasion on MCF-7 and MDA-MB-231 human breast cancer cell lines. The mRNA expression levels of CXCR4 and CXCL12 were measured by quantitative real time-RT PCR and CXCL12 protein levels were evaluated by ELISA assay. The data showed that treatment with tamoxifen and tranilast as a single or in combination resulted in decreased CXCR4 and CXCL12 mRNA and CXCL12 protein expression levels. Both in-vitro invasion assays markedly showed synergistic effect of tamoxifen when combined with tranilast drug. Either ER-positive or ER-negative breast cancer cells were sensitive to this combination therapy. In conclusion, Tranilast increases antimetastatic effect of tamoxifen. The synergistic effect of tranilast is not estrogen dependent; however tamoxifen may sensitize the cells for the action of tranilast. The data also support the importance of the CXCR4/CXCL12 interaction in breast cancer metastasis, and further suggest that CXCR4 and CXCL12 are critical targets for tamoxifen and tranilast in combination or alone.

Tranilast enhances the anti-tumor effects of tamoxifen on human breast cancer cells in vitro.

BACKGROUND: Tamoxifen is the most widely used anti-estrogen for the treatment of breast cancer. Studies show that the combination therapy with other substances that helps the activity of tamoxifen. The objective of this study was to evaluate the effect of tamoxifen when used in combination with tranilast on human breast cancer cells. RESULTS: Two MCF-7 and MDA-MB-231 human breast cancer cell lines were treated with tamoxifen and/or tranilast. The cell viability and cytotoxicity was assessed using MTT and LDH assays; the apoptotic effects were examined by TUNEL assay, acridine orange/ethidium bromide staining and DNA laddering, also the expression levels of bax and bcl-2 genes were detected by real-time RT-PCR. The mRNA expression of TGF-ß ligands and receptors examined using real-time RT-PCR and TGF-ß1 protein secretion levels were also evaluated by ELISA assay. Inhibitory effect of these drugs on invasion and metastasis were tested by wound healing and matrigel invasion assay. CONCLUSIONS: These findings indicate that tranilast, by synergistic effect, enhances the activity of tamoxifen and the TGF-ß pathway is a target for this combination therapy, therefore; we propose that this combined treatment may be suitable selection in prevention of breast cancer.

Synergistic effects of tamoxifen and tranilast on VEGF and MMP-9 regulation in cultured human breast cancer cells.

BACKGROUND: Vascular endothelial growth factor and matrix metalloproteinases are two important factors for angiogenesis associated with breast cancer growth and progression. The present study was aimed to examine the effects of tamoxifen and tranilast drugs singly or in combination on proliferation of breast cancer cells and also to evaluate VEGF and MMP-9 expression and VEGF secretion levels. MATERIALS AND METHODS: Human breast cancer cell lines, MCF-7 and MDA-MB-231, were treated with tamoxifen and/or tranilast alone or in combination and percentage cell survival and proliferative activity were evaluated using LDH leakage and MTT assays. mRNA expression and protein levels were examined by real-time RT-PCR and ELISA assay, respectively. RESULTS: LDH and MTT assays showed that the combined treatment of tamoxifen and tranilast resulted in a significant decrease in cell viability and cell proliferation compared with tamoxifen or tranilast treatment alone, with significant decrease in VEGF mRNA and protein levels. We also found that tamoxifen as a single agent rarely increased MMP-9 expression. A decrease in MMP-9 expression was seen after treatment with tranilast alone and in the combined treatment MMP-9 mRNA level was decreased. CONCLUSIONS: This combination treatment can able to inhibit growth, proliferation and angiogenesis of breast cancer cells.