Simvastatin (SV) repurposing has emerged as an alternative approach for the treatment of cancer. In this study, SV chitosan nanoparticles co-crosslinked with tripolyphosphate and chondroitin sulfate ...(SVCSChSNPs) were developed in order to maximize SV therapeutic efficiency. The hepatic targeting was realized using N-acetylgalactosamine (GalNAc) residues of ChS, which can be identified by the ASGPR receptors specifically expressed in hepatocytes. SV was repurposed as an anticancer agent against hepatocellular carcinoma (HCC). NPs were fabricated by the ionic gelation method, and the formulation variables (CS concentration, CS:ChS ratio, and CS solution pH) were optimized using a three-factor, three-level Box-Behnken design. The optimized NPs were investigated for particle size, size distribution, zeta potential, morphology, in vitro cytotoxicity, apoptotic effects against human hepatocellular carcinoma HepG2 cells, and detection of intracellular localization. The NPs were further evaluated for in vitro release behavior of SV and pharmacokinetics using Wister albino rats. Transmission electron microscopy (TEM) imaging showed a spherical shape with regular surface NPs of < 100 nm diameter. In vitro cytotoxicity testing showed that the SVCSChSNPs exhibited greater inhibition of proliferation in HepG2 cells and high cellular uptake through ASGPR-mediated endocytosis. The in vitro dissolution profile was 2.1-fold greater than that of pure SV suspension. Furthermore, in vivo oral pharmacokinetics revealed that the obtained NPs enhanced the bioavailability of SV by up to 2- and 1.6-fold for SV and SVA, respectively, compared to the pure SV suspension. These findings demonstrated that hepatic-targeted CSChSNPs delivering SV could potentially serve as a promising platform for HCC and other liver-related diseases.
Breast and colon carcinomas are two types of common cancers which lead to cancer-related deaths. Due to their cytotoxic potential against cancer cells, recently many studies of copper nanoparticles ...(CuNPs) have been conducted. In the current work, we aim to evaluate the cytotoxic and apoptosis-inducing effects of CuNPs on the human breast (MCF-7) and colon (LoVo) cancer cells. CuNPs were prepared in starch-stabilizing aqueous solution by electroless deposition technique in alkaline tartrate bath using formaldehyde as the reducing agent of copper sulfate. The obtained CuNPs were characterized by SEM, TEM, and XRD to confirm the particle size, morphology, and chemical composition. Standard colorimetric MTT and LDH assays were used to estimate the cytotoxic effect of CuNPs on MCF-7 and LoVo cells. Furthermore, CuNP-treated cells undergoing apoptosis were assessed based on the expression of apoptosis-related genes using qRT-PCR. The results indicate that the mean particle size of the synthesized CuNPs was ~ 50–60 nm, and they were spherical in shape with mainly the chemical structure of the copper metallic phase. MTT assay revealed that CuNPs induced cytotoxicity in tested cells with IC
50
rates of 16.4 (in MCF-7) and 21.6 μg/ml (in LoVo). Moreover, qRT-PCR analysis showed that CuNPs caused a significant increment of
Bax
,
P53
, and
Caspases
9, 8, and 3 genes. Overall, the anticancer potential of prepared CuNPs were reported through apoptotic induction which highlight the potential use of CuNPs as an efficient anticancer agent.
Here, we evaluated the antidiabetic and hypoglycaemic activities of Moricandia sinaica, a species of the Brassicaceae family, for the first time. The hypoglycaemic and antidiabetic activities of the ...M. sinaica shoot’s methanol extract (MOR-1), butanol fraction (MOR-2), and aqueous fraction (MOR-3) were examined against streptozotocin-induced diabetes model in albino Swiss mice. The mice were divided into eight groups (each group consisted of 6 mice). MOR-1 (100 and 200 mg/kg), MOR-2 (100 and 200 mg/kg), and MOR-3 (100 and 200 mg/kg) were administered to groups III, IV, V, VI, VII, and VIII, respectively, for 15 days (daily). The blood samples were haematologically and biochemically assessed at 0 days, 7 days, and 15 days. Mice in group I were kept untreated as control while group II was treated with glibenclamide as standard. Antidiabetic effects increased with MOR-1 and MOR-2 doses in a dose-dependent manner. MOR-2 treatment (200 mg/kg) yielded the best results (29.56% and 40.07% after 7 and 15 days, respectively) compared to the results obtained at zero days. MOR-2 (200 mg/kg) showed the greatest decline in glucose levels (27.67% and 41.13% after 7 and 15 days, respectively). The results concluded that M. sinaica exhibited potential hypoglycaemic activity.
Background: Diabetic neuropathy is a debilitating manifestation of long-term diabetes mellitus. The present study explored the effects of the roots of Rubia cordifolia L. (R. cordifolia L.) in the ...Wistar rat model for diabetic neuropathy and possible neuroprotective, antidiabetic, and analgesic mechanisms underlying this effect. Materials and Methods: Rats were divided into five experimental groups. An amount of 0.25% carboxy methyl cellulose (CMC) in saline and streptozotocin (STZ) (60 mg/kg) was given to group 1 and group 2, respectively. Group 3 was treated with STZ and glibenclamide simultaneously while groups 4 and 5 were simultaneously treated with STZ and hydroalcoholic extract of the root of R. cordifolia, respectively. Hot plate and cold allodynias were used to evaluate the pain threshold. The antioxidant effects of R. cordifolia were assessed by measuring Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). At the end of the study, sciatic nerve and brain tissues were collected for histopathological study. Bcl-2 proteins, cleaved caspase-3, and Bax were assessed through the Western blot method. Results: R. cordifolia significantly attenuated paw withdrawal and tail flick latency in diabetic neuropathic rats. R. cordifolia significantly (p < 0.01) improved the levels of oxidative stress. It was found to decrease blood glucose levels and to increase animal weight in R. cordifolia-treated groups. Treatment with R. cordifolia suppressed the cleaved caspase-3 and reduced the Bax:Bcl2 ratio in sciatic nerve and brain tissue compared to the diabetic group. Histopathological analysis also revealed a marked improvement in architecture and loss of axons in brain and sciatic nerve tissues at a higher dose of R. cordifolia (400 mg/kg). Conclusion: R. cordifolia attenuated diabetic neuropathy through its antidiabetic and analgesic properties by ameliorating apoptosis and oxidative stress.
Citrus fruits and juices have been studied extensively for their potential involvement in the prevention of various diseases. Flavanones, the characteristic polyphenols of citrus species, are the ...primarily compounds responsible for these studied health benefits. Using in silico and in vitro methods, we are exploring the possible antidiabetic action of narirutin, a flavanone family member. The goal of the in silico research was to anticipate how narirutin would interact with eight distinct receptors implicated in diabetes control and complications, namely, dipeptidyl-peptidase 4 (DPP4), protein tyrosine phosphatase 1B (PTP1B), free fatty acid receptor 1 (FFAR1), aldose reductase (AldR), glycogen phosphorylase (GP), alpha-amylase (AAM), peroxisome proliferator-activated receptor gamma (PPAR-γ), alpha-glucosidase (AGL), while the in vitro study looked into narirutin’s possible inhibitory impact on alpha-amylase and alpha-glucosidase. The results indicate that the studied citrus flavanone interacted remarkably with most of the receptors and had an excellent inhibitory activity during the in vitro tests suggesting its potent role among the different constituent of the citrus compounds in the management of diabetes and also its complications.
The present study aimed to engineer a nanoscale lipid-based lymphatic drug delivery system with D-α-Tocopherol polyethylene glycol 1000 succinate to combat the lymphatic metastasis of lung cancer. ...The nanoscale lipid-based systems including GEF-SLN, GEF-NLC, and GEF-LE were prepared and pharmaceutically characterized. In addition, the most stable formulation (GEF-NLC) was subjected to an in vitro release study. Afterward, the optimized GEF-NLC was engineered with TPGS (GEF-TPGS-NLC) and subjected to in vitro cytotoxicity, and apoptotic studies using the A549 cells line as a surrogate model for lung cancer. The present results revealed that particle size and polydispersity index of freshly prepared formulations were ranging from 198 to 280 nm and 0.106 to 0.240, respectively, with negative zeta potential ranging from − 14 to − 27.6.mV. An in vitro release study showed that sustained drug release was attained from GEF-NLC containing a high concentration of lipid. In addition, GEF-NLC and GEF-TPGS-NLC showed remarkable entrapment efficiency above 89% and exhibited sustained release profiles. Cytotoxicity showed that IC
50
of pure GEF was 11.15 μg/ml which decreased to 7.05 μg/ml for GEF-TPGS-NLC. The apoptotic study revealed that GEF-TPGS-NLC significantly decreased the number of living cells from 67 to 58% when compared with pure GEF. The present results revealed that the nanoscale and lipid composition of the fabricated SLN, NLC, and LE could mediate the lymphatic uptake of GEF to combat the lymphatic tumor metastasis. Particularly, GEF-TPGS-NLC is a promising LDDS to increase the therapeutic outcomes of GEF during the treatment of metastatic lung cancer.
Graphical abstract
Tarchonanthus Camphoratus L. is traditionally known for its various medicinal purposes. In this study, the T. camphoratus essential oil (TCEO) was isolated via steam distillation, and its chemical ...constituents were determined using GC–MS. The in vitro antiproliferative effects of TCEO on A549, HepG2, MCF-7 cancer cells, and HUVEC non-tumor cells was investigated using an MTT assay. Flow cytometry analysis was conducted to evaluate cell cycle distribution using propidium iodide staining, and cell death mode using Annexin V-FITC/PI assays. The expression of some apoptosis related genes was investigated using qRT-PCR. Major constituents of TCEO included fenchol, borneol, 3-cyclohexene-1-methanol and 3-ethyl-3-methyl. Cell viability test showed that TCEO is highly effective against MCF-7 cells with IC50 12.5 µg/mL. Cell cycle arrest at the G1/S phase, and apoptosis mediation were evident in the presence of TCEO. Gene expression analysis of several pro-apoptotic and anti-apoptotic genes revealed the initiation of apoptosis in TCEO-MCF-7 cells. In conclusion, our study confirms the antiproliferative activity of the T. camphoratus essential oil.
Epigenetics plays a vital role in the interaction between living organisms and their environment by regulating biological functions and phenotypic plasticity. Considering that most aquaculture ...activities take place in open or natural habitats that are vulnerable to environmental changes. Promising findings from recent research conducted on various aquaculture species have provided preliminary evidence suggesting a link between epigenetic mechanisms and economically valuable characteristics. Environmental stressors, including climate changes (thermal stress, hypoxia, and water salinity), anthropogenic impacts such as (pesticides, crude oil pollution, nutritional impacts, and heavy metal) and abiotic factors (infectious diseases), can directly trigger epigenetic modifications in fish. While experiments have confirmed that many epigenetic alterations caused by environmental factors have plastic responses, some can be permanently integrated into the genome through genetic integration and promoting rapid transgenerational adaptation in fish. These environmental factors might cause irregular DNA methylation patterns in genes related to many biological events leading to organs dysfunction by inducing alterations in genes related to oxidative stress or apoptosis. Moreover, these environmental issues alter DNA/histone methylation leading to decreased reproductive competence. This review emphasizes the importance of understanding the effects of environmentally relevant issues on the epigenetic regulation of phenotypic variations in fish. The goal is to expand our knowledge of how epigenetics can either facilitate or hinder species' adaptation to these adverse conditions. Furthermore, this review outlines the areas that warrant further investigation in understanding epigenetic reactions to various environmental issues.
The new asperorlactone (
), along with the known illudalane sesquiterpene echinolactone D (
), two known pyrones, 4-(hydroxymethyl)-5-hydroxy-2
-pyran-2-one (
) and its acetate
, and ...4-hydroxybenzaldehyde (
), were isolated from a culture of
, collected from Red Sea marine sediments. The structure of asperorlactone (
) was elucidated by HR-ESIMS, 1D, and 2D NMR, and a comparison between experimental and DFT calculated electronic circular dichroism (ECD) spectra. This is the first report of illudalane sesquiterpenoids from
fungi and, more in general, from ascomycetes. Asperorlactone (
) exhibited antiproliferative activity against human lung, liver, and breast carcinoma cell lines, with IC
values < 100 µM. All the isolated compounds were also evaluated for their toxicity using the zebrafish embryo model.
Lymphatic drug delivery (LDD) is an attractive option for the prevention and treatment of cancer metastasis. This study aims to develop TPGS decorated nanostructure lipid carrier gefitinib loaded ...(TPGS-NLC-GEF). Biocompatibility and cytotoxicity were studied using erythrocytes and A549 cell lines. Furthermore, cellular uptake of the prepared TPGS-NLC was studied using 5-carboxyfluorescein (5-CF). Pharmacokinetic, biodistribution, and chylomicron-block flow studies were performed using male Wister Albino rats to investigate the influence of TPGS-NLC on plasma concentration-time profile, organ deposition, and LDD of GEF. The present results indicated that the prepared TPGS-NLC and TPGS-NLC-GEF formulation had a particle size range of 268 and 288 nm with a negative zeta-potential value of − 29.3 and − 26.5 mV, respectively. The in-vitro release showed burst drug release followed by sustained release. In addition, the biosafety in the term of the hemocompatibility study showed that the prepared formulation was safe at the therapeutic level. Additionally, an in-vitro cytotoxicity study showed that the TPGS-NLC was able to enhance the activity of GEF against the A549 cell line. The cellular uptake study showed the ability of TPGS-NLC to enhance 5-CF internalization by 12.6-fold compared to the 5-CF solution. Furthermore, the in-vivo study showed that TPGS-NLC was able to enhance GEF bioavailability (1.5-fold) through lymphatic system which was confirmed via the indirect chylomicron-block flow method. The tissue distribution study showed the ability of lipid nanoparticles to enhance lung drug deposition by 5.8-fold compared to a GEF suspension. This study concluded that GEF-NLC-GEF is an encouraging approach for the treatment of metastatic lung cancer through lymphatic delivery, enhanced bioavailability, and reduced systemic toxicity.
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•TPGS decorated NLC loaded GEF were prepared and pharmaceutically characterized.•The biosafety, cytotoxicity, bioavailability, organ deposition, and LDD were studied.•TPGS-NLC-GEF have nanosize, negative ZP, sustained release, and biocompatible.•TPGS-NLC enhances cytotoxicity, bioavailability, LDD, and lung deposition of GEF.•GEF-NLC-GEF is promising approach for the treatment of metastatic lung cancer.
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