Pioglitazone (PGL) is an effective insulin sensitizer, however, side effects such as accumulation of subcutaneous fat, edema, and weight gain as well as poor oral bioavailability limit its ...therapeutic potential for oral delivery. Recent studies have shown that combination of both, PGL and fish oil significantly reduce fasting plasma glucose,improve insulin resistance, and mitigate pioglitazone-induced subcutaneous fat accumulation and weight gain. Nevertheless, developing an effective oral drug delivery system for administration of both medications have not been explored yet. Thus, this study aimed to develop a self-micro emulsifying drug delivery system (SMEDDS) for the simultaneous oral administration of PGL and fish oil. SMEDDS was developed using concentrated fish oil,Tween® 80, and Transcutol HP and optimized by central composite design (CCD). The reconstituted, optimized PGL-SMEDDS exhibited a globule size of 142 nm, a PDI of 0.232, and a zeta potential of −20.9 mV. The in-vitro drug release study of the PGL-SMEDDS showed a first-order model kinetic release and demonstrated remarkable 15-fold enhancement compared to PGL suspension. Additionally, following oral administration in fasting albino Wistar rats, PGL-SMEDDS exhibited 3.4-fold and 1.4-fold enhancements in the AUC0–24h compared to PGL suspension and PGL marketed product. The accelerated stability testing showed that the optimized SMEDDS formulation was stable over a three-month storage period. Taken together, our findings demonstrate that the developed fish oil-based SMEDDS for PGL could serve as effective nanoplatforms for the oral delivery of PGL, warranting future studies to explore its synergistic therapeutic potential in rats.
is a medicinal plant that is widely used in Saudi folklore medicine for treatment of various diseases.
fruit powder was sequentially extracted with
-hexane, chloroform, ethyl acetate, and methanol ...using a Soxhlet extractor. The cytotoxic effects of these fractions on human breast cancer cells (MDA-MB-231 and MCF-7) and non-tumorigenic control cells (MCF-10A) were evaluated via cell viability measurements, microscopy, gene expression, and migration assays. Moreover, the effect of the most promising extract on 7,12-dimethyl-benzaanthracene (DMBA)-induced breast cancer was investigated in rats. The promising extract was also subjected to gas chromatography-mass spectrometry. Fruit extracts of
were significantly cytotoxic toward all tested cell lines, as demonstrated by MTT and LDH assays. Treatment of MDA-MB-231 cells with fruit ethyl acetate fraction (RSF EtOAc) increased expression 11of P53, Bax and activation of caspase 3/7. A cell migration scratch assay demonstrated that extracts at non-cytotoxic concentrations exerted a potent anti-migration activity against the highly invasive MDA-MB-231 cell line. Moreover, RT-PCR results showed that RSF EtOAc significantly downregulated MMP-2 and MMP-9 expression, which play an important role in breast cancer metastasis. Histological studies of breast tissue in experimental animals showed a slight improvement in tissue treated with fruit ethyl acetate extract. GC-MS chromatogram showed thirteen peaks with major constituents were camphor, trichosenic acid and guanidine. Our current study demonstrates that fruit extracts of
are cytotoxic toward breast cancer cell lines through apoptotic mechanisms.
The goal of this study was to assess the anticancer efficacy of chlorojanerin against various cancer cells. The effects of chlorojanerin on cell cytotoxicity, cell cycle arrest, and cell apoptosis ...were examined using MTT assay, propidium iodide staining, and FITC Annexin V assay. RT-PCR was employed to determine the expression levels of apoptosis-related genes. Furthermore, docking simulations were utilized to further elucidate the binding preferences of chlorojanerin with Bcl-2. According to MTT assay, chlorojanerin inhibited the proliferation of all tested cells in a dose-dependent manner with a promising effect against A549 lung cancer cells with an IC
of 10 µM. Cell growth inhibition by chlorojanerin was linked with G2/M phase cell cycle arrest in A549 treated cells. Flow cytometry analysis indicated that the proliferation inhibition effect of chlorojanerin was associated with apoptosis induction in A549 cells. Remarkably, chlorojanerin altered the expression of many genes involved in apoptosis initiation. Moreover, we determined that chlorojanerin fit into the active site of Bcl-2 according to the molecular docking study. Collectively, our results demonstrate that chlorojanerin mediated an anticancer effect involving cell cycle arrest and apoptotic cell death and, therefore, could potentially serve as a therapeutic agent in lung cancer treatment.
is an important source of valuable phytoconstituents, which are widely used in traditional medicine system of Indo-Pak sub-continent. In this study we investigated the distribution of phenolic ...compounds in the fruit pericarps of six different genotypes (ZNP01-06) of
growing in the unexplored hilly areas of Pakistan. The methanolic extracts of these genotypes were screened for total phenolic content (TPC), total flavonoid content (TFC), antioxidant, and cholinesterase inhibitory potentials. The observed biological potentials were explained in terms of the outcome of molecular docking and HPLC analyses. Among them, genotype ZNP02 displayed high TPC (88.50 ± 1.23 μg/mL) and showed potent scavenging activity against DPPH (67.03 ± 1.04 μg/mL) and ABTS (65.3 ± 1.74 μg/mL) in comparison to ascorbic acid (68.7 ± 0.47 μg/mL). Moreover, genotypes ZNP01, ZNP02, and ZNP04 displayed potent inhibition against acetyl and butyryl cholinesterases (AChE and BChE) with IC
values of 21.2, 20.5, and 23.7 μg/mL (AChE) and 22.7, 24.4, and 33.1 μg/mL (BChE), respectively. Furthermore, the individual compounds in the most potent species ZNP01 responsible for potent enzyme inhibition (identified through HPLC-UV analysis), were computed via docking simulation software to the enzyme structures. Among these compounds rutin exhibited significant binding affinity with value of -9.20 kcal/mol. The differences amongst the phytochemical compositions of the selected genotypes highlighted the genotypic variations in them. Based on our results it was concluded that the selected plant can be used as remedy of oxidative stress and neurodegenerative diseases. However, further studies are needed to isolate responsible compounds and test the observed potential in vivo, along with toxicological evaluations in animal models.
Calendula arvensis
L. is used in traditional folk medicine for the treatment of several diseases. Leaves, stems, and flowers of
C. arvensis
were extracted using a Soxhlet extractor with different ...solvents (i.e., hexane, chloroform, ethyl acetate, and methanol). The ethyl acetate extract of
C. arvensis flowers
(CAF EtOAC) had cytotoxic activity against MCF-7 and MDA-MB-231 breast cancer cells, with IC
50
values of 70 and 78 µg/mL, respectively. Microscopic examination revealed concentration-dependent cell shrinkage, cell detachment, nuclear fragmentation, and chromatin condensation. The CAF EtOAC inhibited the migration of cultured cells in a scratch wounding assay, indicating a possible defense against metastasis. The same extract also caused apoptosis by downregulating Bcl-2 and upregulating Bax and caspase 3/7 activity. Phytochemical analyses revealed the presence of phenols and flavonoids, and gas chromatography-mass spectroscopy (GC-MS) revealed a high content of linolenic acid in the extract. Based on our data, the CAF EtOAC may provide active ingredients for the development of novel chemotherapeutics for breast cancer therapy.
In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position
-
. The ...structure of the newly prepared compounds was proved by microanalysis, IR,
H-NMR,
C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds
and
were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds
and
exerted the strongest cytotoxicity against MCF-7 cells with an IC
value of 2.5 and 5 μM, respectively. Flow cytometry data revealed the ability of compounds
and
to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both
and
activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds
and
fit perfectly into Bcl2's active site. Based on the biological properties, we conclude that both compounds
and
could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.
Janerin is a cytotoxic sesquiterpene lactone that has been isolated and characterized from different species of the
genus. In this study, janerin was isolated form
, and its cytotoxic molecular ...mechanism was studied in THP-1 human leukemic cells. Janerin inhibited the proliferation of THP-1 cells in a dose-dependent manner. Janerin caused the cell cycle arrest at the G2/M phase by decreasing the CDK1/Cyclin-B complex. Subsequently, we found that janerin promoted THP-1 cell death through apoptosis as indicated by flow cytometry. Moreover, apoptosis induction was confirmed by the upregulation of Bax, cleaved PARP-1, and cleaved caspase 3 and the downregulation of an anti-apoptotic Bcl-2 biomarker. In addition, immunoblotting indicated a dose dependent upregulation of P38-MAPK and ERK1/2 phosphorylation during janerin treatment. In conclusion, we have demonstrated for the first time that janerin may be capable of inducing cell cycle arrest and apoptosis through the MAPK pathway, which would be one of the mechanisms underlying its anticancer activity. As a result, janerin has the potential to be used as a therapeutic agent for leukemia.
Many quinazoline derivatives with pharmacological properties, such as anticancer activity, have been synthesized. Fourteen quinazoline derivatives bearing a substituted sulfonamide moiety (
) were ...previously synthesized and fully characterized. These compounds exerted antiproliferative activity against cell lines derived from solid tumors. Herein, the antileukemic activities of these compounds (
) against two different leukemia cell lines (Jurkat acute T cell and THP-1 acute monocytic) were investigated. Our investigation included examining their activity in vivo in a zebrafish embryo model. Remarkably, compounds
and
were the most potent in suppressing cell proliferation, with an IC
value range of 4-6.5 µM. Flow cytometry analysis indicated that both compounds halted cell progression at the G2/M phase and induced apoptosis in a dose-dependent manner. RT-PCR and Western blot analyses also showed that both compounds effectively induced apoptosis by upregulating the expression of proapoptotic factors while downregulating that of antiapoptotic factors. In vivo animal toxicity assays performed in zebrafish embryos indicated that compound
was more toxic than compound
, with compound
inducing multiple levels of teratogenic phenotypes in zebrafish embryos at a sublethal concentration. Moreover, both compounds perturbed the hematopoiesis process in developing zebrafish embryos. Collectively, our data suggest that compounds
and
have the potential to be used as antileukemic agents.
The accumulation of body fat due to an imbalance between calorie intake and energy expenditure is called obesity. Metabolic syndrome increases the risk of heart disease, type 2 diabetes, and stroke. ...The purpose of this study was to determine the effect of
(J.T.) and
(F.M.) leaf extracts on high-fat diet-induced obesity in rats. Normal control, high-fat diet (HFD) control, orlistat standard, and test groups were created using male Albino Wistar rats (n = 6 per group) weighing 190 ± 15 g. Except for the control group, all regimens were administered orally and continued for 6 weeks while on HFD. Evaluation criteria included body weight, food intake, blood glucose, lipid profile, oxidative stress, and liver histology. High-Performance Thin Layer Chromatography (HPTLC) analysis was performed using a solvent system (7:3 hexane: ethyl acetate for sitosterol solution and
extracts and 6:4 hexane: ethyl acetate: 1 drop of acetic acid for esculetin and
extracts). There were no deaths during the 14 days before the acute toxicity test, indicating that aqueous and ethanolic extracts of both J.T. and F.M. did not produce acute toxicity at any dose (5, 50, 300, and 2000 mg/kg). The ethanolic and aqueous extracts of J.T. and F.M. leaves at 200 and 400 mg/kg/orally showed a reduction in weight gain, feed intake, and significant decreases in serum glucose and lipid profile. As compared to inducer HFD animals, co-treatment of aqueous and ethanolic extract of both J.T. and F.M. and orlistat increased the levels of antioxidant enzymes and decreased lipid peroxidation. The liver's histological findings showed that the sample had some degree of protection. These results indicate that ethanolic samples of J.T. have antidiabetic potential in diabetic rats fed an HFD. The strong antioxidant potential and restoration of serum lipid levels may be related to this. Co-treatment of samples JTE, JTAQ, FME, FMAQ and orlistat resulted in an increase in antioxidant enzymes and reduction in lipid peroxidation as compared to inducer HFD animals. We report, for the first time, on using these leaves to combat obesity.
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