Multiple types of inflammations caused by foreign pathogens or chemicals and mutations that upregulate inflammation enhancers kindle the need of developing new vectors for the treatment of inflammation. Nanoparticles have been used in various fields ranging from the food industry, cosmetic industry and agricultural industry to devices like sensors, solar cells, and batteries. Nanoparticles have been used in the medical and research fields due to their high penetration power even inside cells and have the excellent ligand-binding properties due to their high surface area to volume ratio. Mechanistic study of anti-inflammatory activities of various metal and metal oxide nanoparticles like silver, gold, zinc oxide, titanium dioxide, and selenium have been discussed in the following literature review. The present study focuses on the differential uptake of nanoparticles into cells and the anti-inflammatory mechanism adopted by the nanoparticles synthesized by green routes. It also gives a concise literature review of the various green sources used for the synthesis of nanoparticles and the mechanism of action of each nanoparticle.
Melanoma is one of the most aggressive and treatment-resistant tumors that responsible for majority of skin-cancer related deaths. Here we propose a combination of MEK inhibitor binimetinib with metformin as a promising therapy against human melanoma cells in vitro, including BRAF -mutated A375, Mel Z, and Mel IL cells, and NRAS-mutated Mel MTP and Mel Me cells. Additionally, we obtained two close to clinical practice models of melanoma progression. The first one was vemurafenib-resistant Mel IL/R melanoma cells with acquired resistance to BRAF inhibition-targeted therapy, and the second one was tumor spheroids, which are 3D in vitro model of small-size solid tumors in vivo. The cytotoxicity of binimetinib and metformin was synergistic in both 2D and 3D melanoma culture and mediated through apoptotic pathway. The combination reduced the number of melanoma-formed colonies, inhibited cell invasion and migration, and led to G0/G1 cell cycle arrest through cyclin D/CDK4/CDK6 pathway. The mechanism of metformin and binimetinib synergy in melanoma cells was associated with increased activation of p-AMPK alpha and decreased p-ERK, but not with alterations in p-mTOR. In summary, the combination of metformin and binimetinib resulted in stronger anti-proliferative effects on melanoma cells compared to binimetinib alone, and therefore could be promising for clinical applications.
Mesoporous silica nanoparticles (MSNs) represent one of the most promising drug delivery systems. MSNs have attracted considerable attention in recent years both in industry and biomedicine due to their unique properties. Thus, evaluation of the toxic effects of MSNs is necessary before the biomedical and clinical applications. We investigated the in vivo effect of MSNs on the production of reactive oxygen species (ROS), antioxidant defenses and histology of the heart and lung. Rats received 25, 50, 100 and 200 mg/kg body weight of synthesized MSNs intraperitoneally for 30 days and samples were collected for analysis. MSNs induced significant increase in serum cardiac function markers, tumor necrosis factor alpha and lipids. MSNs-induced rats exhibited anemia, thrombocytopenia, leukocytosis, significantly increased ROS, malondialdehyde and nitric oxide, and declined antioxidant defenses in the heart and lung of rats. In addition, MSNs induced histological alterations in the heart and lung of rats. In conclusion, our results demonstrated that MSNs induce cardiotoxicity and pulmonary toxicity via excessive generation of ROS, suppressed antioxidants, inflammation and histological alterations. Further investigations are recommended to understand the molecular mechanism underlying the toxic effects of MSNs and to improve the performance of nanomedicine.
Novel drug development is onerous, time consuming and overpriced process with particularly low success and relatively high enfeebling rates. To overcome this burden, drug repositioning approach is being used to predict the possible therapeutic effects of FDA approved drugs in different diseases. Herein, we designed a computational and enzyme inhibitory mechanistic approach to fetch the promising drugs from the pool of FDA approved drugs against AD. The binding interaction patterns and conformations of screened drugs within active region of AChE were confirmed through molecular docking profiles. The possible associations of selected drugs with AD genes were predicted by pharmacogenomics analysis and confirmed through data mining. The stability behaviour of docked complexes (Drugs-AChE) were checked by MD simulations. The possible therapeutic potential of repositioned drugs against AChE were checked by in vitro analysis. Taken together, Cinitapride displayed a comparable results with standard and can be used as possible therapeutic agent in the treatment of AD.
We analyzed whether ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, clinically used for angina and arrhythmia, had anticonvulsant, antioxidant and neuroprotective properties against classical seizure models. Potential molecular targets to IVA anticonvulsant effects were evaluated by molecular docking. Mice were treated with IVA (1, 10 or 20 mg/kg, IP) for 3 days, and 30 min after the last administration were injected with pentylenetetrazole (PTZ - 85 mg/kg, IP), pilocarpine (PILO 400 mg/kg, SC), picrotoxin (PICRO 10 mg/kg, IP). The following measures were performed: presence of seizures, latency for the first seizure, latency for death, percentage of survival. Antioxidant activity was investigated by determination of lipid peroxidation (MDA), reduced glutathione (GSH) and nitrite levels in the prefrontal cortex (PFC), hippocampus and striatum (ST). Immunohistochemistry analysis for cleaved caspase-3, a pro-apoptotic and degenerative marker, in hippocampal subregions namely cornu ammonis (CA)1, CA3 and dentate gyrus (DG), were also performed. IVA attenuated PTZ- and PICRO-induced seizures while presented an antioxidant effect in all brain areas studied. IVA markedly reduced cleaved caspase-3 expression in the CA1 and DG region of PICRO- and PTZ-treated mice, respectively. Molecular docking demonstrated that IVA has high energetic affinity and binding compatibility for GABA(A) receptor without causing channel obstruction. However, no reproducibility in the binding of IVA to N-methyl-D-aspartate (NMDA) receptor was detected. In conclusion, IVA has anticonvulsant, antioxidant and neuroprotective effects against PTZ- and PICRO-induced seizures. Also, a high affinity of IVA to GABA(A) receptor was predicted, representing a potential underlying mechanism to these observable effects.
The objective of this study was to evaluate potential of two chemically characterized edible wild onion species, Allium flavum and Allium carinatum, to reduce side effects of cytostatic doxorubicin (Dox). Since Dox application is mainly limited due to its high cardiotoxicity, while there are no approved cardioprotective agents for the prevention of Dox adverse effects, new co-treatments are urgently needed. Here, we showed that methanol extracts expressed high antioxidant activity and synergistically increased Dox anticancer activity against human hepatoma (HepG2) and lung carcinoma (A549) cells, while protected normal human fibroblasts (MRC-5) from Dox cytotoxicity. Analysis of the antioxidative enzymes level (catalase and superoxide dismutases) showed that the catalase level was differently altered in cancer cells compared to normal cells upon applied treatments. In vivo toxicity evaluation in the zebrafish model revealed significantly lower toxicity of extracts compared to Dox, and no teratogenic effects at applied doses. We found that extracts successfully rescued the Dox-treated embryos of life-threating cardiomyopathy, while at the same time reduced developmental toxicity and neutropenia. Further analysis demonstrated that extracts had higher anti-angiogenic activity than sunitinib or auranofin, clinically used anti-angiogenic drugs. In addition, angiogenesis was markedly more suppressed in Dox-extract cotreatments than upon single treatments.
Background: White adipose tissue (WAT) have a relevant metabolic and inflammatory function, in overweight or obesity conditions. In this regard, the WAT under over feeding nutrition present a significant increment in oxidative stress, pro-inflammatory status and depletion of n-3 long chain polyunsaturated fatty acid. Hydroxytyrosol (HT) is a polyphenol with important cytoprotective effects, and this molecule can modulate the gene expression, transcription factors and enzymatic activity. Objective: Therefore, the purpose of this study was evaluate the anti-inflammatory, anti-oxidant and anti-lipogenic effects of HT supplementation mice and the molecular adaptations involved, on dysfunctional WAT from high-fat diet (HFD)-fed mice. Methods and results: Male C57BL/6 J mice received (i) control diet (10% fat); (ii) control diet + HT (daily doses of 5 mg kg body weight), (iii) HFD (60% fat); or (iv) HFD+ HT for 12 weeks. HFD-fed mice exhibited: (i) WAT hypertrophy; (ii) oxidative stress and depletion of antioxidant defenses, (iii) increased lipogenesis and proinflammatory status, (iv) depletion of n-3 LCPUFA and (v) up-regulation of NF-kappa B and SREBP 1c with downregulation Nrf2, and PPAR-gamma. HT supplementation attenuated the metabolic impairment produced by HFD in WAT, attenuating increment of NF-kappa B and SREBP 1c, and increasing the activity of Nrf2 and PPAR-gamma. Conclusion: Supplementation with HT improve the WAT dysfunction induced by HDF in mice through the modulation of transcription factors NF-kappa B, Nrf2, SREBP-1c and PPAR-gamma as well as their target genes, involved in inflammation, antioxidant defenses and lipogenesis.
Cartilage degeneration is a basic pathological feature of osteoarthritis (OA), and there is growing evidence that it is associated with inflammation. ACY-1215, a selective HDAC6 inhibitor, has been reported to have anti-inflammatory effects. Here, we investigated the anti-inflammatory and chondroprotective effects of ACY-1215 in IL-1 beta-stimulated human primary chondrocytes and C28/I2 cells. The results suggested that ACY-1215 can markedly suppress the expression of inflammatory factors, including IL-1 beta and IL-6 in human primary chondrocytes and C28/I2 cells. Furthermore, ACY-1215 exerts potent chondroprotection through the amelioration of cartilage degradation by inhibiting the expression of matrix-degrading proteases, including MMP-1 and MMP-13 in chondrocytes. These effects may be related to ACY-1215 induced down-regulation of NF-kappa B and STAT3 pathways in OA chondrocytes. Taken together, our results show that ACY-1215 may be a potential and promising therapeutic drug for the management of OA.
Thyroid cancer (TC) is a familiar cancer, which accounts for approximately 1% of the malignant tumors of all cancers worldwide. Recently, icariin (ICA) has been reported to play an anti-tumor role in different cancers. The study aimed to investigate the effect of ICA on TC cells to uncover the regulatory mechanism. The different concentrations of ICA were stimulated SW579 and TPC1 cells, and cell viability, apoptosis, migration, invasion and main factors of these processes were detected by CCK-8, flow cytometry, Transwell and western blot. The expression of miR-625-3p in TC tissues or in ICA-treated cells was examined by qRT-PCR. MiR-625-3p mimic and the negative control were transfected into SW579 and TPC1 cells to investigate the effect of miR-625-3p on TC. Finally, the signaling pathways of PI3K/AKT and MEK/ERK were examined by western blot. ICA significantly suppressed cell viability in a dose-dependent manner and induced apoptosis by regulating Bcl-2, Bax and cleaced-Caspase-3/-9 expression in SW579 and TPC1 cells (p < 0.001). Moreover, ICA inhibited cell migration and invasion by down-regulating MMP-9 and Vimentin in SW579 and TPC1 cells (p < 0.01 or p < 0.001). The expression level of miR-625-3p was decreased by ICA, and miR-625-3p overexpression reversed the anti-tumor effect of ICA on SW579 and TPC1 cells (p < 0.05, p < 0.01 or p < 0.001). Furthermore, ICA inactivated PI3K/AKT and MEK/ERK signaling pathways by mediating miR-625-3p in SW579 and TPC1 cells. ICA exerted antitumor effect by inhibiting cell proliferation, migration and invasion by down-regulating miR-625-3p in TC cells.
Zerumbone has been reported to maintain the anti-cancer effects in many malignant cells. However, the effect and mechanism of Zerumbone on esophageal squamous cell carcinomas (ESCC) is rarely investigated. Here we report the inhibitory effect of Zerumbone (hereinafter referred to as ZER) on ESCC migration and the underlying molecular mechanism. ZER could inhibit the migration of human esophageal squamous cancer KYSE-30 cells and KYSE-150 cells. ZER induced Rac1 protein down-regulation in a dose-and time-dependent manner. The reduction of Rac1 protein was crucial for ZER-induced inhibition of cell migration, as Rac1 knockdown could enhance ZER-induced inhibition of cell migration. We further demonstrated that the decrease of Rac1 after ZER treatment is via proteasome-dependent degradation pathway, and ZER treatment drastically enhanced ubiquitination of Rac1, which finally caused Rac1 degradation. Collectively, our results indicated that ZER inhibits cell migration by suppressing Rac1 expression. This suppresion is achieved through promoting Rac1 ubiquitination and degradation. Thus, the study raises the possibility of ZER as a potential drug for ESCC due to its ability to inhibit cell migration.
Diabetes mellitus is characterized by hyperglycaemia that results from defects in insulin secretion or insulin action and is accompanied by general disturbances metabolism. Psidium guajava (PG) leaf is known to have antidiabetic effects that include lowering of blood glucose. The aim of the study was to investigate the effect of PG leaf extract on tissue activity of glycogen synthase (GS) and glycogen phosphorylase (GP); tissue activity of hormone sensitive lipase (HSL); serum lipid profile; and serum enzyme biomarkers of tissue damage. Diabetes was induced in male Sprague-Dawley rats with a single dose of 40 mg/kg body weight streptozotocin. The aqueous extract of PG leaves was used to treat both normal and diabetic animals (400 mg/kg body weight) for 2 weeks while control animals were treated with the vehicle. At the end of the treatment period, blood, liver and adipose tissue samples were collected from the euthanized animals. The results show that PG extract significantly decreased (P < 0.05) HSL activity in adipose tissue and liver of diabetic animals which was accompanied by increased glycogen levels, reduced serum triglycerides, total cholesterol, LDL-cholesterol and increased HDL-cholesterol. This study demonstrates that P. guajava has significant anti-diabetic effects that include increased glycogen storage and reduced HSL activity in the liver and adipose tissue with an improved serum lipid profile.
Background: Acute respiratory distress syndrome is associated with a mortality of 45%. The authors investigated the possible mechanisms and effect of vascular endothelial growth factor on alveolar epithelial barrier permeability in acute respiratory distress syndrome mice model. Methods: Eighty Male BALB/c mice were randomly assigned to four group: PBS group, LPS group, sFlt group, or LPS+ sFlt group. The levels of vascular endothelial growth factor and total protein in bronchoalveolar lavage fluid were compared, together with lung injury score and the histopathology of alveolar epithelial barrier. The expressions of vascular endothelial growth factor and tight junction proteins mRNA in lung tissue were also studied. Results: Lipopolysaccharide (LPS) inhaling was accompanied with increasing lung vascular endothelial growth factor (VEGF) expression. Anti-VEGF with soluble fms-like tyrosine kinase-1 (sFlt-1) attenuated the lung injury effectively. Conclusions: Our data indicate that anti-vascular endothelial growth factor with soluble fms-like tyrosine kinase1 could maintain the normal structure and function of respiratory membrane in acute respiratory distress syndrome mice model and might be a suitable therapeutic tool for the treatment of acute respiratory distress syndrome.
A self-nanoemulsifying drug delivery system (SNEDDS) was developed as a novel route to enhance the efficacy of docetaxel lipophilic drug. SNEDDS comprised ethyl oleate, Tween 80 and poly(ethylene glycol) 600, as oil, surfactant and co-surfactant, and formed stabilized monodispersed oil nanodroplets upon dilution in water. SNEDDS represented encapsulation efficiency and loading capacity of 21.4 and 52.7%, respectively. The docetaxel release profile from the drug-loaded SNEDDS was recorded, its effectiveness against MCF-7 cell line was investigated, and an IC50 value of 0.98 +/- 0.05 mu g mL(-1) was attained. The drug-loaded SNEDDS was administrated in rats, and the pharmacokinetic parameters of maximum concentration of 22.2 +/- 0.8 mu g mL(-1), time to attain this maximum concentration of 230 min, and area under the curve of 1.71 +/- 0.18 mu g min mL(-1) were obtained. The developed SNEDDS formulation can be represented as an alternative to docetaxel administration.
B-lymphocyte antigen CD20 (called CD20) is known as an activated-glycosylated phosphoprotein which is expressed on the surface of all B-cells. CD20 is involved in the regulation of trans-membrane Ca2+ conductance and also play critical roles in cell-cycle progression during human B cell proliferation and activation. The appearance of monoclonal antibody (mAb) technology provided an effective field for targeted therapy in treatment of a variety of diseases such as cancer, and autoimmune diseases. Anti-CD20 is one of important antibodies which could be employed in treatment of several diseases. Increasing evidences revealed that efficacy of different anti-CD20 antibodies is implicated by their function. Hence, evaluation of anti-CD20 antibodies function could provide and introduce new anti-CD20 based therapies. In the present study, we summarized several applications of anti-CD20 antibodies in various immune related disorders including B-CLL (B-cell chronic lymphocytic leukemia), rheumatoid arthritis (RA), multiple sclerosis (MS) and melanoma.