Showing papers in "Experimental and Therapeutic Medicine in 2017"
TL;DR: The present review evaluates the current state of knowledge on MS with emphasis on the pathology itself, the diagnosis and common therapeutical approaches accurately used, particularly the exact neuroanatomical setting of plaques.
Abstract: Multiple sclerosis (MS) is a complex neurodegenerative disease affecting the central nervous system (CNS). The onset of MS has been typically observed in individuals aged from 20 to 40-years, with the female to male ratio of 1:2. MS appears as abrupt onset of focal sensory disturbances that is accompanied by unilateral painless damage of vision, double vision, limb weakness, unsteadiness of gait, and bowel or bladder symptoms. Whereas the exact etiology of the disease is unknown, observational research has suggested genetic and environment influences through an underlined pathophysiology widely believed to be autoimmune in nature. Indeed, plaque of demyelination inside of the CNS with relative conservation of axons remains the clinical symptoms of MS. However, considerable advances in understanding the pathology have contributed to an early diagnosis, particularly the exact neuroanatomical setting of plaques. Accordingly, magnetic resonance imaging has been considered as the primarily adjunctive modality for the constant detection of abnormal white matter. In addition, the analysis of cerebrospinal fluid contents has also been of interest for the diagnosis to discriminate other affections such infection or vasculitis. These resulted in a broad variety of therapies that considerably control the activity and change the course and prognosis of the disease. In the present review, we evaluate the current state of knowledge on MS with emphasis on the pathology itself, the diagnosis and common therapeutical approaches accurately used.
195 citations
TL;DR: The results of the present study demonstrated that Phascolarctobacterium faecium is abundantly colonized in the human gastrointestinal tract.
Abstract: Phascolarctobacterium can produce short-chain fatty acids, including acetate and propionate, and can be associated with the metabolic state and mood of the host. The present study investigated the colonization characteristics of Phascolarctobacterium faecium in healthy individuals 1 year old). The permillage of Phascolarctobacterium faecium in total bacteria ranged between 0.004-1.479. There was presence of Phascolarctobacterium faecium-like bacteria in younger individuals with a gradual increase in the number of bacteria maintained at a high level with increasing ages (between 1 and 60 years old), but with a decrease in elderly individuals (>60 years old). The results of the present study demonstrated that Phascolarctobacterium faecium is abundantly colonized in the human gastrointestinal tract.
178 citations
TL;DR: The findings of the present study suggested that biosynthesized CuNPs that utilize extracts of E. prostrata may be used for therapeutic application, and thus are a promising nanomaterial.
Abstract: The present study outlines the development of a method to synthesize copper nanoparticles (CuNPs) by mixing copper acetate solution with leaf extract of Eclipta prostrata without using any surfactant or external energy E prostrata leaf extract function as an excellent reducing agent of copper ions, and the biosynthesized CuNPs are safer for the environment The powder X-ray diffraction (XRD) pattern provided evidence for the formation of face-centered cubic structure ranging from 23 to 57 nm, with an average size of 31±12 nm Fourier transform infrared spectroscopy (FTIR) was used to identify the biomolecules and capping reagents in the E prostrata leaf extract that may be responsible for the reduction of copper ions and the stability of the bioreduced nanoparticles The biosynthesized CuNPs displayed considerable antioxidant capacity Similarly, in vitro anticancer studies demonstrated the cytotoxicity value of synthesized CuNPs against tested HepG2 cells The findings of the present study suggested that biosynthesized CuNPs that utilize extracts of E prostrata may be used for therapeutic application, and thus are a promising nanomaterial
137 citations
TL;DR: The renoprotective effects of metformin against the development and progression of T2DN in rats are clearly demonstrated, and the underlying mechanism of this protective effect may be associated with glycemic control, lipid metabolism, and anti-oxidative andAnti-inflammatory functions.
Abstract: The present study aimed to explore the renoprotective effect of metformin on diabetic nephropathy in type 2 diabetic rats A rat model of type 2 diabetic nephropathy (T2DN) was successfully induced via a high-fat diet combined with a single low-dose of streptozotocin Metformin was administered intragastrically for 13 weeks, and fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), HDL-c, LDL-c, urinary and serum creatinine levels were subsequently examined at the end of administration Renal function was determined after the treatment protocol Expression levels of transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF) were assessed via immunohistochemical analysis Superoxide dismutase activity, malondialdehyde content and glutathione peroxidase levels were assessed in kidney tissues using commercially available kits The results of the present study demonstrated that metformin administration significantly decreased the levels of serum blood urea nitrogen, serum creatinine, creatinine clearance, urinary albumin excretion and fasting blood glucose in rats with T2DN Furthermore, TG, TC and LDL-c levels were significantly decreased following metformin treatment, whereas HDL-c was increased Metformin treatment significantly increased SOD activity and significantly decreased malondialdehyde levels, as compared with the model group It was also demonstrated that metformin administration significantly decreased the expression levels of TGF-β1 and attenuated the morphological changes associated with T2DN in rats These data clearly demonstrated the renoprotective effects of metformin against the development and progression of T2DN in rats The underlying mechanism of this protective effect may be associated with glycemic control, lipid metabolism, and anti-oxidative and anti-inflammatory functions
96 citations
TL;DR: Berberine alleviates colitis principally by improving intestinal barrier function and promoting anti-inflammatory and antioxidative stress responses, and may be central to the anti-colitis activity of berberine.
Abstract: Berberine has demonstrated efficacy in alleviating experimental colitis in vivo and in vitro. However, the anti-colitis mechanisms of berberine that enable it to promote intestinal barrier function in vivo remain unclear. The present study aimed to evaluate the effect of berberine on intestinal epithelial barrier function, expression of tight junction proteins and the levels of inflammatory and oxidative stress factors in the intestinal mucosa of dextran sulfate sodium (DSS)-induced colitis mice. Berberine (100 mg/kg) was administered for five days to mice with established colitis, induced by administration of DSS (3% w/v) for six days. Intestinal barrier function and the presence of proinflammatory factors, oxidative stress and active signaling pathways in the colon were determined principally by western blotting and reverse transcription-quantitative polymerase chain reaction. It was observed that berberine reduced weight loss, shortening of the colon and colon damage in DSS-colitis mice. In addition, berberine significantly inhibited the increase of fluorescein isothiocyanate-dextran in serum and the decrease of zonula occluden-1 (also known as tight junction protein-1), occludin and epithelial cadherin expression in colonic tissue, relative to a DSS-treated control group. Berberine also significantly inhibited the expression of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α mRNA and phosphorylation of signal transducer and activator of transcription 3. Furthermore, berberine reduced the levels of myeloperoxidase and increased the levels of superoxide dismutase and catalase in colon and serum samples relative to the control group. The expression of cluster of differentiation 68 in the colon of colitis mice was also reduced by berberine. Collectively, these data suggest that berberine alleviates colitis principally by improving intestinal barrier function and promoting anti-inflammatory and antioxidative stress responses. In turn these effects inhibit macrophage infiltration into the colon and thus may be central to the anti-colitis activity of berberine.
74 citations
TL;DR: It is suggested that gut flora disorder results in the alteration of bacterial metabolism, which may be associated with the pathogenesis of colorectal cancer.
Abstract: Colorectal cancer is one of the most common types of cancer in the world and its morbidity and mortality rates are increasing due to alterations to human lifestyle and dietary habits. The relationship between human gut flora and colorectal cancer has attracted increasing attention. In the present study, a metabolic fingerprinting technique that combined pyrosequencing with gas chromatography-mass spectrometry was utilized to compare the differences in gut flora profiling and fecal metabolites between healthy individuals and patients with colorectal cancer. The results demonstrated that there were no significant differences in the abundance and diversity of gut flora between healthy individuals and patients with colorectal cancer (P>0.05) and the dominant bacterial phyla present in the gut of both groups included Firmicutes, Bacteroidetes and Verrucomicrobia. At the bacterial strain/genus level, significant differences were observed in the relative abundance of 18 species of bacteria (P<0.05). Analysis of fecal metabolites demonstrated that the metabolic profiles of healthy individuals and patients with colorectal cancer were distinct. The levels of short-chain fatty acid metabolites, including acetic acid, valeric acid, isobutyric acid and isovaleric acid, and of nine amino acids in patients with colorectal cancer were significantly higher than those in healthy individuals (P<0.05). However, the levels of butyrate, oleic acid, trans-oleic acid, linoleic acid, glycerol, monoacyl glycerol, myristic acid, ursodesoxycholic acid and pantothenic acid in patients with colorectal cancer were significantly lower than those in healthy individuals (P<0.05). Pearson rank correlation analysis demonstrated that there was a correlation between gut flora profiling and metabolite composition. These findings suggest that gut flora disorder results in the alteration of bacterial metabolism, which may be associated with the pathogenesis of colorectal cancer. The results of the present study are useful as a foundation for further studies to elucidate a potential colorectal cancer diagnostic index and therapeutic targets.
74 citations
TL;DR: The results suggest that ursolic acid inhibits the viability of breast cancer cells by inducing autophagy and apoptosis without inducing cell death, and may be used to develop novel therapeutic strategies for breast cancer treatment.
Abstract: Breast cancer, which is the second leading cause of cancer-associated mortality in women worldwide, develops from breast tissue. Chemotherapy is the most commonly used therapy to treat breast cancer. However, a number of natural plant-derived products have been suggested as alternative therapies to treat different types of cancer, such as breast cancer. The aim of the present study was to determine the anti-tumor effects of ursolic acid and its effect on apoptosis and inflammation in breast cancer cells. The anti-cancer effects of ursolic acid were evaluated in vitro using flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction. The results suggest that ursolic acid inhibits the viability of breast cancer cells by inducing autophagy and apoptosis without inducing cell death. Cellular migration assays demonstrated that ursolic acid was able to suppress the invasive ability of breast cancer cells (P<0.05). In addition, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was downregulated following ursolic acid administration (P<0.05), leading to an upregulation of glycogen synthase kinase activity (P<0.05) and downregulation of B-cell lymphoma 2 (P<0.05), subsequently causing autophagy and apoptosis via cyclin-D1 inhibition and caspase-3 stimulation (P<0.05). Furthermore, the inflammatory response of breast cancer cells was assessed by measuring levels of nuclear factor (NF)-κB. Ursolic acid was found to downregulate NF-κB in breast cancer cells, thus inhibiting inflammation and preventing the progression of breast cancer (P<0.05). To the best of our knowledge, the present study is the first to assess the effect of ursolic acid on breast cancer cells through PI3K/AKT-regulated GSK and caspase-3 accompanied by NF-κB signaling pathways. The results of the present study regarding the potential underlying molecular mechanisms of ursolic acid may be used to develop novel therapeutic strategies for breast cancer treatment.
71 citations
TL;DR: GFAP and 14-3-3ε expression remained elevated in AS 72 h after stress conditions, which is possibly related to the excessive activation and dysfunction of the CNS in chronic injuries.
Abstract: Glial fibrillary acidic protein (GFAP) is one of the best markers for the activation of astrocytes (AS) following injury or stress in the central nervous system (CNS). The purpose of this study was to examine the expression of GFAP and 14-3-3e in rat AS subjected to hypoxia. We established primary cultures of AS from cerebral cortex of neonatal Sprague-Dawley rats as a model of glucose deficiency and hypoxia/ischemia-reperfusion. We analyzed the activated astrocyte markers GFAP and 14-3-3e by western blot analysis and found that both increased over time, starting at 4 h and reaching the highest level at 72 h, at the end of the experiment. GFAP and 14-3-3e protein localization by double-labeling immunofluorescence showed elevated expression and co-localization in the cytoplasm of AS. GFAP and 14-3-3e expression remained elevated in AS 72 h after stress conditions, which is possibly related to the excessive activation and dysfunction of the CNS in chronic injuries.
70 citations
TL;DR: Therapeutic targeting of TGFβ signaling at ALK1-5 receptor activity level has met with limited success and extensive research is needed to develop therapies based on the components of T GFβ signaling pathway, for instance cardiac dysfunction and heart failure.
Abstract: Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational changes, through the active participation of transforming growth factor β (TGFβ) and its signaling pathways. TGFβ appears to be a 'Master of all trades', with respect to cardiac fibrosis, as it can promote cardiomyocyte apoptosis and cardiac hypertrophy. TGFβ signaling involves its binding to TGFβ receptor type II (TGFβRII), which recruits TGFβ receptor type I (TGFβRI), which are also known as activin receptor-like kinase (ALK) in five different isoforms. In canonical signaling pathways, ALK5 activates Smads 2 and 3, and ALK1 activates Smads 1 and 5. These pairs of Smads form a corresponding complex and then bind to Smad 4, to translocate into the nucleus, where transcriptional reprogramming is carried out to promote myofibroblast formation and ECM production, eventually leading to cardiac fibrosis. TGFβ levels are elevated in MI, thereby aggravating the myocardial injury further. Several microRNAs are involved in the regulation of TGFβ signaling at different steps, affecting different components. Therapeutic targeting of TGFβ signaling at ALK1-5 receptor activity level has met with limited success and extensive research is needed to develop therapies based on the components of TGFβ signaling pathway, for instance cardiac dysfunction and heart failure.
68 citations
TL;DR: Observations indicated that naringenin inhibited the migration of lung cancer A549 cells through several mechanisms, including the inhibition of AKT activities and reduction of MMP-2 and -9 activities.
Abstract: Lung cancer is among the most common causes of cancer-related mortality. It has a high mortality rate and resistance to chemotherapy due to its high metastatic potential. Naringenin, a bioactive compound identified in several fruits, displays anti-inflammatory and antitumor effects. Furthermore, naringenin mitigates the migration of several human cancer cell types. However, the effects of naringenin on lung cancer remain unclear. The current study investigated the mechanisms of naringenin on the migration of lung cancer A549 cells. The results indicate that significant alteration in A549 cell proliferation was observed in response to naringenin (0-300 µM) treatment for 24 and 48 h. Furthermore, a dose-dependent migration inhibition of A549 in the presence of naringenin was observed by healing and transwell migration assays. In addition, a zymography assay revealed that naringenin exhibited a concentration-dependent inhibition of matrix metalloproteinase (MMP)-2 and -9 activities. Furthermore, naringenin also inhibited the activities of AKT in a dose-dependent manner. These observations indicated that naringenin inhibited the migration of lung cancer A549 cells through several mechanisms, including the inhibition of AKT activities and reduction of MMP-2 and -9 activities.
64 citations
TL;DR: Therapeutic management of IBD-associated heart diseases cannot be achieved with simple anti-inflammatory drugs such as corticosteroids and anti-TNF-α antibodies, and further research is needed to assess their efficacy in IBD patients suffering from heart disease.
Abstract: Cardiovascular disease (CVD) can arise because of chronic inflammation and inflammatory bowel disease (IBD) is one such disease where the risk for CVD and eventual heart failure is increased considerably. The incidence of IBD, which refers to both ulcerative colitis and Crohn's disease, has been on the increase in several countries and is a potential risk factor for CVD. Although IBD can potentially cause venous thromboembolism, its significance in arterial stiffening, atherosclerosis, ischemic heart disease and myocardial infarction is only being realized now and it is currently under debate. However, several studies with large groups of patients have demonstrated the association of IBD with heart disease. It has been suggested that systemic inflammation as observed in IBD patients leads to oxidative stress and elevated levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), which lead to phenotypic changes in smooth muscle cells and sets into motion a series of events that culminate in atherosclerosis and CVD. Besides the endogenous factors and cytokines, it has been suggested that due to the compromised intestinal mucosal barrier, endotoxins and bacterial lipopolysaccharides produced by intestinal microflora can enter into circulation and activate inflammatory responses that lead to atherosclerosis. Therapeutic management of IBD-associated heart diseases cannot be achieved with simple anti-inflammatory drugs such as corticosteroids and anti-TNF-α antibodies. Treatment with existing medications for CVDs, aspirin, platelet aggregation inhibitors and statins is found to be acceptable and safe. Nevertheless, further research is needed to assess their efficacy in IBD patients suffering from heart disease.
TL;DR: It is indicated that AGE and LPS increase IL-6 secretion depending on NF-κB activation and ROS production through RAGE and/or TLR4 in the J774 murine macrophage cell line and resveratrol appears to be an effective regulator of the inflammatory responses associated with SIRT1 and AMPK activation in macrophages.
Abstract: Macrophages are essential for regulating the physiology of pregnancy; however, excessive inflammatory responses to macrophages, induced by infection and/or endogenous danger signals, may potentially result in complications during pregnancy. Advanced glycation end-products (AGE) and lipopolysaccharides (LPS) are known to induce inflammation and are associated with adverse developmental outcomes. The aim of the present study was to examine the effect of AGE and LPS on cytokines in the J774 murine macrophage cell line and the potential effect of resveratrol on AGE- and LPS-induced inflammation in macrophages. AGE and LPS significantly increased IL-6 mRNA expression and secretion in J774 macrophages (P<0.05). Although AGE and LPS significantly stimulated IL-1β mRNA expression (P<0.05), they had no significant effect on IL-1β secretion. To assess the receptors for AGE and LPS, including receptor for AGE (RAGE) and Toll-like receptor (TLR4), blocking reagents (RAGE antagonist or TLR4 inhibitor) were added to the J774 macrophages. IL-6 secretion induced by AGE or LPS was significantly inhibited by pretreatment with RAGE antagonist (P<0.05) or TLR4 inhibitor (P<0.05). IL-6 secretion was dependent on nuclear factor (NF)-κB activation and the production of reactive oxygen species (ROS; P<0.05). Resveratrol suppressed mRNA expression and intracellular IL-6 production, resulting in significantly decreased IL-6 secretion after treatment with LPS or AGE (P<0.01). Furthermore, treatment with Ex527, which is a sirtuin-1 (SIRT1) inhibitor, significantly attenuated the anti-inflammatory effect of resveratrol (P<0.05), and treatment with 5-aminoimidazole-4-carboxamide ribonucleotide, which is a 5' adenosine monophosphate-activated protein kinase (AMPK) activator, resulted in a significant decrease in IL-6 secretion in J774 macrophages (P<0.05). The results of the present study indicated that AGE and LPS increase IL-6 secretion depending on NF-κB activation and ROS production through RAGE and/or TLR4 in the J774 murine macrophage cell line. Based on the present study, resveratrol appears to be an effective regulator of the inflammatory responses associated with SIRT1 and AMPK activation in macrophages. These results suggest that resveratrol may have therapeutic applications for controlling immune responses during pregnancy.
TL;DR: It is suggested that RSV protected renal tissue from diabetes-induced injury and that this activity may be via inhibition of the p38 MAPK/TGF-β1 signaling pathway.
Abstract: Resveratrol (RSV) has been shown to have a renoprotective effect against diabetic nephropathy, but the underlying mechanisms of this have not been fully elucidated. The aim of the current study was to explore the mechanisms responsible for the therapeutic effects of RSV in rat mesangial cells in vitro and in a rat model of diabetic nephropathy. The viability of CRL-2573 rat mesangial cells and their expression levels of p38, phosphorylated (p)-p38, transforming growth factor beta 1 (TGF-β1) and fibronectin were assessed in response to treatment with high glucose, with or without RSV. Diabetic nephropathy was also induced in Sprague-Dawley rats by streptozotocin treatment. At 8 weeks, basic biochemical parameters and histopathological abnormalities as well as the expression of p38, p-p38, TGF-β1 and fibronectin in rat kidneys were compared between control diabetic rats and those treated with 20 mg/kg RSV daily for 4 weeks. In the mesangial cell line, RSV inhibited high glucose-induced increases in cell viability and fibronectin expression by significantly reducing p38 mitogen-activated protein kinase (MAPK) activation and TGF-β1 expression (P<0.05). In diabetic rats, RSV significantly decreased blood glucose, serum creatinine and urinary albumin levels, as well as the kidney weight and ratio of kidney weight/body weight compared with the control group (P<0.05). Moreover, RSV ameliorated renal histological changes and downregulated the expression of p-p38, TGF-β1 and fibronectin in the kidneys of diabetic rats. These data suggested that RSV protected renal tissue from diabetes-induced injury and that this activity may be via inhibition of the p38 MAPK/TGF-β1 signaling pathway.
TL;DR: Different roles of miRNAs in the development and diseases of the heart are addressed, including stress responsive cardiac hypertrophy, which is orchestrated among other factors, by specific mi RNAs.
Abstract: Heart disease-related deaths are the highest in most societies and congenital heart diseases account for approximately 40% of prenatal deaths and over 20% of mortality in the first few months after birth. Congenital heart disease affects approximately 1% of all newborns and is the causative factor for more deaths within the first year of life as compared to all other genetic defects. Advances in treatment approaches increased life expectancy and led to an expansion of adult population with clinical manifestation of congenital heart defects in up to 90% of the children born with congenital heart diseases. Regulation of cardiac gene expression involves multiple independent enhancers that play a critical role in maintaining a restricted and specific pattern of gene expression in the heart. Cardiac transcriptional pathways are intimately regulated by microRNAs (miRNAs), which are small, regulatory RNAs, approximately 22 nucleotides in length, also coded by specific genes. These miRNAs act as suppressors of gene expression by inhibiting translation and/or promoting degradation of target protein-coding mRNAs. There are several miRNAs involved in the development of heart and dysregulation of specific miRNAs is associated with congenital and other cardiac defects. Stress responsive cardiac hypertrophy is orchestrated among other factors, by specific miRNAs. miRNAs such as miR-499 are considered useful as biomarkers of a given heart disease. Therapeutic application of miRNAs is also envisaged considering the small size and specific effects of these molecules. In this review, we addressed different roles of miRNAs in the development and diseases of the heart.
TL;DR: It is suggested that naringenin pre-treatment ameliorated LPS-induced ALI through its anti-oxidative and anti-inflammatory activity and by inhibition of the PI3K/AKT pathway in mice.
Abstract: The aim of the present study was to explore the effect of naringenin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a mouse model, as well as the underlying mechanism. The animals were randomly assigned to four groups: PBS-treated healthy control (Control), LPS-induced ALI (LPS), vehicle-treated ALI (LPS + Vehicle), and naringenin-treated ALI (LPS + Nar) group. Naringenin (100 mg/kg) was administered orally for 4 consecutive days, starting 3 days prior to induction of ALI. The survival rates of mice, lung wet/dry weight ratios, lung injury score, protein levels of bronchoalveolar lavage fluid (BALF), lactate dehydrogenase (LDH) activity in the BALF, lung myeloperoxidase (MPO) activity, the number of infiltrated neutrophils and reactive oxygen species (ROS) levels (H2O2 and malondialdehyde) were assessed. In addition, the serum and BALF levels of inflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and macrophage inflammatory protein 2] were determined, along with the total and the phosphorylated protein levels of phosphatidylinositol 3-hydroxy kinase (PI3K) and AKT in lung tissues. The results showed that naringenin pre-treatment significantly increased the survival rate, improved histopathologic changes, alleviated pulmonary edema and lung vascular leak, downregulated the levels of ROS and reduced neutrophil infiltration as well as the levels of inflammatory cytokines in the serum and BALF. Moreover, naringenin pre-treatment reduced the total and the phosphorylated protein levels of PI3K and AKT. The present study suggested that naringenin pre-treatment ameliorated LPS-induced ALI through its anti-oxidative and anti-inflammatory activity and by inhibition of the PI3K/AKT pathway in mice.
TL;DR: The findings of the present study suggest that sesamol supplementation may serve as potent adjuvant in the treatment of focal cerebral ischemia/reperfusion injury due to its neuroprotective effects.
Abstract: The aim of the present study was to evaluate the therapeutic potential of sesamol treatment on focal ischemia/reperfusion (I/R) injury in the rat brain. The results demonstrated that pretreatment with sesamol seven days prior to focal cerebral I/R injury had significant positive effects, including improvements in neurological deficits (P<0.05), and a reduction in malondialdehyde content and elevation of antioxidant levels (superoxide dismutase, glutathione and glutatione peroxidase; both P<0.05). Furthermore, levels of B cell lymphoma-2 (Bcl-2)-associated X protein and caspase-3 were significantly downregulated, whereas the level of Bcl-2 was effectively increased. Conversely, the mRNA expression of proinflammatory cytokines were significantly reduced in focal cerebral I/R injury rats upon sesamol intervention. Therefore, the beneficial effects of sesamol on cerebral I/R injury may be due to the reduction of oxidative stress, inhibition of apoptosis and inflammation. The findings of the present study suggest that sesamol supplementation may serve as potent adjuvant in the treatment of focal cerebral ischemia/reperfusion injury due to its neuroprotective effects.
TL;DR: The clinical benefits of NAC were limited for ARDS based on the present meta-analysis, and additional trials are required to provide sufficient evidence for the efficacy of N-acetylcysteine in ARDS.
Abstract: Acute respiratory distress syndrome (ARDS) is a serious complication of acute lung injury. Severe systemic inflammation is the main cause of multiple organ dysfunction and high mortality. Removal of reactive oxygen species by anti-oxidants has been applied in clinical practice. N-acetylcysteine (NAC) is the most commonly used anti-oxidant. However, the benefit of anti-oxidant therapy was not consistently demonstrated by previous studies. In the present study, a meta-analysis was performed to evaluate the effects of NAC for adult patients with ARDS. The PubMed, Cochrane and EMBASE databases were searched to retrieve all of the available randomized controlled trials (RCTs) published until October 2015. Quality evaluation of included studies was performed according to the modified Jadad scale score. The Cochrane Collaboration Review Manager 5.3 software was used to perform the meta-analysis. Five RCTs comprising 183 patients were found to be eligible for inclusion in the meta-analysis. Pooled analysis showed that NAC did not contribute to reduce short-term mortality [risk ratio (RR)=0.73; 95% confidence interval (CI): 0.50-1.07; P=0.10] or 30-day mortality (RR=0.72; 95% CI: 0.44-1.19; P=0.20) when compared with those in the control group. However, duration of intensive care unit (ICU) stay in the NAC group was shortened [weighted mean difference (WMD), -4.56; 95% CI: (-7.32 to -1.80); P=0.001]. There was no significant difference in the ratio of partial arterial oxygen pressure to the fraction of inspired oxygen between the two groups [WMD, 54.34; 95% CI: (-30.50 to 139.17); P=0.21]. No severe adverse reactions were observed in the patients included. Although the duration of ICU stay was shortened, the clinical benefits of NAC were limited for ARDS based on the present meta-analysis. As the number of included trials and patients was small, additional trials are required to provide sufficient evidence for the efficacy of NAC in ARDS.
TL;DR: It is demonstrated that HOTAIR may be induced by gemcitabine and acts as a tumor promoter by inhibiting the chemosensitivity, and promoting the self-renewal capacity, proliferation and migration of PANC-1 CSCs, which supports its potential application as a novel therapeutic approach for pancreatic cancer.
Abstract: Gemcitabine is the first-line chemotherapeutic agent for advanced adenocarcinoma of the pancreas, despite the high risk of chemoresistance as a major disadvantage. In the past few years, significant advances have been made in the field of pancreatic cancer stem-like cells (CSCs) and their critical roles in drug resistance, invasion and metastasis, which are tightly regulated by long non-coding RNAs (lncRNAs). The present study demonstrated that HOX antisense intergenic RNA (HOTAIR) is not different between the pancreatic cancer cell line PANC-1 and its enriched CSC sub-population. However, after gemcitabine treatment, the expression levels of HOTAIR in CSCs were induced, but not in PANC-1 cells. HOTAIR induced by gemcitabine failed to cause chemoresistance, but promoted the clonogenicity, proliferation and migration of the cells. By introducing HOTAIR using lentivirus, chemoresistance was induced and the self-renewal capacity, proliferation and migration were significantly promoted. By contrast, HOTAIR knockdown in PANC-1 CSCs treated with or without gemcitabine decreased the cell proliferation, altered the cell cycle progression and induced apoptosis, demonstrating its critical roles in regulating the malignant character of PANC-1 CSCs. In conclusion, the present study demonstrated that HOTAIR may be induced by gemcitabine and acts as a tumor promoter by inhibiting the chemosensitivity, and promoting the self-renewal capacity, proliferation and migration of PANC-1 CSCs, which supports its potential application as a novel therapeutic approach for pancreatic cancer.
TL;DR: The utility of in vivo RCM as a promising technique for the non-invasive diagnosis of psoriasis vulgaris, for monitoring the evolution of lesions at a micromorphological level under various treatments and for gaining a better understanding of the pathophysiological processes that occur in the Evolution of this disease are pointed to.
Abstract: In vivo reflectance confocal microscopy (RCM) is a modern, non-invasive imaging technique, which allows for real-time examination of the upper layers of the skin at a resolution similar to that of classic microscopy. In addition, it has the advantage of real-time evaluation of blood flow and dynamic monitoring of cutaneous changes while preserving tissue integrity. The present study reported on the in vivo RCM technique as an objective method for the noninvasive assessment of psoriasis vulgaris that is potentially applicable in clinical studies and in monitoring the evolution of lesions under treatment. In psoriasis lesions, RCM virtual horizontal sections at the level of the dermo-epidermal junction featured numerous and prominent dermal papillae that were not surrounded by bright rings of basal cells. Micromorphological examination of the lesions using this technique revealed that mean values of the section area, the perimeter and the Feret's diameter of the dermal papillae were significantly higher in psoriatic lesions than in normal skin. An increased number of capillary vessels per lesional dermal papilla as compared to healthy skin was observed. Furthermore, micromorphological parameters of dermal capillaries were increased in psoriatic skin. These observations point to the utility of in vivo RCM as a promising technique for the non-invasive diagnosis of psoriasis vulgaris, for monitoring the evolution of lesions at a micromorphological level under various treatments and for gaining a better understanding of the pathophysiological processes that occur in the evolution of this disease.
TL;DR: It is validated that IN delivery of MSCs may be a potential safe, easy and cheap alternative route for stem cell treatment in neurodegenerative disorders.
Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. It affects the locomotor system, leading to a final severe disability through degeneration of dopaminergic neurons. Despite several therapeutic approaches used, no treatment has been proven to be effective; however, cell therapy may be a promising therapeutic method. In addition, the use of the intranasal (IN) route has been advocated for delivering various therapies to the brain. In the present study, the IN route was used for administration of mesenchymal stem cells (MSCs) in a mouse model of PD, with the aim to evaluate IN delivery as an alternative route for cell based therapy administration in PD. The PD model was developed in C57BL/6 mice using intraperitoneal rotenone administration for 60 consecutive days. MSCs were isolated from the mononuclear cell fraction of pooled bone marrow from C57BL/6 mice and incubated with micrometer-sized iron oxide (MPIO) particles. For IN administration, we used a 20 µl of 5×105 cell suspension. Neurobehavioral assessment of the mice was performed, and after sacrifice, brain sections were stained with Prussian blue to detect the MPIO-labeled MSCs. In addition, immunohistochemical evaluation was conducted to detect tyrosine hydroxylase (TH) antibodies in the corpus striatum and dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neurobehavioral assessment revealed progressive deterioration in the locomotor functions of the rotenone group, which was improved following MSC administration. Histopathological evaluation of brain sections in the rotenone+MSC group revealed successful delivery of MSCs, evidenced by positive Prussian blue staining. Furthermore, rotenone treatment led to significant decrease in dopaminergic neuron number in SNpc, as well as similar decrease in the corpus striatum fiber density. By contrast, in animals receiving IN administration of MSCs, the degeneration caused by rotenone treatment was significantly counteracted. In conclusion, the present study validated that IN delivery of MSCs may be a potential safe, easy and cheap alternative route for stem cell treatment in neurodegenerative disorders.
TL;DR: The tumor suppressor role of miR-223 was associated with the regulation of NLRP3 inflammasome components and provided insight into the association between the innate immune system and the genesis of HCC.
Abstract: Hepatocellular carcinoma (HCC) is a major malignant tumor type with a high incidence and mortality. Infection with hepatitis virus is a high-risk factor. Previous studies have demonstrated that microRNA (miR)-223 was downregulated in HCC tissues. NOD-like receptor family, pyrin domain containing 3 (NLRP3)-is a potential target of miR-223 and has a vital role in hepatitis infection. The present study was performed to investigate the role of miR-223 in the proliferation and apoptosis of HCC cells through regulating NLRP3. A dual luciferase reporter assay was performed to confirm the direct interaction between miR-223-3p and the 3' untranslated region of NLRP3 mRNA. Hep3B cells were then transfected with miR-223 mimics and the proliferation and apoptosis were determined by an MTT and a flow cytometric assay, respectively. The expression of NLRP3 and caspase-1 was analyzed at the mRNA as well as at the protein level by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The secretion of interleukin (IL)-1β and IL-18 in the culture supernatants was measured by ELISA. The dual luciferase assay confirmed NLRP3 as a direct target of miR-223. Overexpression of miR-223 in hep3B cells significantly suppressed cell proliferation and promoted apoptosis. Furthermore, the expression of NLRP3 was downregulated by miR-223 transfection. Certain downstream factors of the NLRP3 pathway were also downregulated following overexpression of miR-223. Caspase-1 was decreased at the transcriptional level and the cleaved caspase-1 was decreased at the protein level. Secretion of IL-1β and IL-18 into the culture medium by cells transfected with miR-223 was lower than that by the control cells. In conclusion, the tumor suppressor role of miR-223 was associated with the regulation of NLRP3 inflammasome components. miR-223 inhibited HCC cell proliferation and promoted apoptosis by directly targeting NLRP3. Downstream production of caspase-1, IL-1β and IL-18 were also repressed by miR-223. These results provided insight into the association between the innate immune system and the genesis of HCC.
TL;DR: The results provide further mechanistic evidence for the clinical efficacy of ICA in the treatment of OP and propose that ICA inhibits the differentiation of mesenchymal stem cells into adipocytes by inhibiting the expression of PPARγ, C/EBPα and FABP4 mRNA via the Notch signaling pathway.
Abstract: Icariin (ICA) is a pharmacologically active flavonoid glycoside that shows promise in the treatment and prevention of osteoporosis (OP). However, the mechanisms underlying the anti-osteoporotic effects of ICA remain largely unclear. The present study used quantitative polymerase chain reaction, western blot and immunohistochemical analysis to examine the effects of ICA on several key targets in the Notch signaling pathway in bone tissue in ovariectomized rats. It was observed that ICA has a pronounced beneficial effect on OP rats and inhibits the expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα) and fatty acid-binding protein 4 (FABP4) mRNA. In addition, it was identified that ICA downregulates the expression of notch1 intracellular domain (N1ICD) and Jagged1 proteins in bone tissue, and suppresses the effect of N1ICD on Notch2 mRNA expression. It is proposed that ICA inhibits the differentiation of mesenchymal stem cells into adipocytes by inhibiting the expression of PPARγ, C/EBPα and FABP4 mRNA via the Notch signaling pathway. In addition, it is proposed that ICA inhibits the expression of Notch2 mRNA by suppressing the effect of N1ICD. In conclusion, the results provide further mechanistic evidence for the clinical efficacy of ICA in the treatment of OP.
TL;DR: Hippocampal neuron apoptosis was induced by diabetes + SAH and expression levels of caspase-3, Bax and Bcl-2 were also increased, providing experimental basis for further studies of the relationship between SAh and cell apoptosis.
Abstract: The expression of caspase-3, Bax and Bcl-2 in hippocampus of rats with diabetes and subarachnoid hemorrhage (SAH) were investigated. Diabetes mellitus model was established by intraperitoneal injection of STZ. On the basis of diabetes mellitus model, SAH animal model was established by injecting fresh autologous femoral artery blood into cerebellomedullary cisten. Rats were divided into blank control group, diabetes control group and diabetes + SAH group. TUNEL method was used to detect cell apoptosis of hippocampus. Expression levels of caspase-3, Bax and Bcl-2 were detected by real-time quantitative reverse transcription PCR and western blot analysis at mRNA and protein levels, respectively. Apoptotic cells were not detected in blank control group and diabetes group, and number of apoptotic cells was the highest in the diabetic SAH group. Expression levels of caspase-3, Bax and Bcl-2 mRNA and protein were significantly higher in diabetes + SAH group than in blank control group and diabetes group. In conclusion, Hippocampal neuron apoptosis was induced by diabetes + SAH and expression levels of caspase-3, Bax and Bcl-2 were also increased. Our study provided experimental basis for further studies of the relationship between SAH and cell apoptosis.
TL;DR: The present study was the first to suggest that lncRNA MALAT1 may protect human brain vascular endothelial cells from OGD-R-induced apoptosis via a PI3K-dependent mechanism.
Abstract: Cerebral ischemia/reperfusion (I/R) injury leads to brain vascular dysfunction, which is characterized by endothelial cell injury or death. Long noncoding (lnc) RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is reportedly associated with endothelial cell functions and dysfunctions. In the present study, the role of MALAT1 in I/R-induced cerebral vascular endothelial cell apoptosis was explored using oxygen-glucose deprivation and reoxygenation (OGD-R) as an in vitro I/R injury model. Primary human brain microvascular endothelial cells were cultured under OGD-R, and the expression levels of MALAT1 and cell apoptosis were measured at 6, 9, 12, 24 and 36 h post-reoxygenation. The expression levels of MALAT1 and the apoptotic rate of cells exposed to OGD-R exhibited contrasting trends following reoxygenation. Following OGD-R, lentiviral overexpression of MALAT1 increased phosphatidylinositol 3-kinase (PI3K) activities and the activation of Akt phosphorylation, and decreased cell apoptosis and caspase 3 activities, which were successfully abolished by treatment with a PI3K inhibitor, Wortmannin. Conversely, lentiviral knockdown of MALAT1 decreased PI3K activities and the activation of Akt phosphorylation, and increased cell apoptosis and caspase 3 activity. Overexpression and knockdown of MALAT1 exhibited no significant effects on OGD-R-induced reactive oxygen species (ROS) production. In conclusion, to the best of our knowledge, the present study was the first to suggest that lncRNA MALAT1 may protect human brain vascular endothelial cells from OGD-R-induced apoptosis via a PI3K-dependent mechanism. These findings suggest that MALAT1 may be a potential novel therapeutic target for cerebral I/R injury.
TL;DR: The data suggest that emodin protects against DN and that the underlying mechanism may involve the suppression of inflammation, ICAM-1 and Bax, and activation of the PI3K/Akt/GSK-3β pathway.
Abstract: Emodin is the main active component of the Chinese medicine rhubarb, which has a variety of pharmacological effects and a high clinical value. Its anti-inflammatory and antitumor effects have been widely studied. The aim of the present study was to determine whether emodin has renoprotective effects, and to identify the potential underlying mechanisms in a rat model of diabetic nephropathy (DN). The changes in mean blood glucose levels, normalized kidney weight, urinary albumin excretion, serum creatinine levels and tubulointerstitial injury index (TII) scores of the rats with DN were significantly attenuated by emodin. Furthermore, treatment with emodin significantly inhibited inflammation-related factors and oxidative stress, suppressed the expression of intercellular adhesion molecule 1 (ICAM-1) and B-cell lymphoma 2-associated X protein (Bax), increased phosphorylated Akt and phosphorylated-glycogen synthase kinase 3 (p-GSK-3β) expression and inhibited caspase-3 activity in diabetic rats. These data suggest that emodin protects against DN and that the underlying mechanism may involve the suppression of inflammation, ICAM-1 and Bax, and activation of the PI3K/Akt/GSK-3β pathway.
TL;DR: This is the first experimental evaluation of the anti-hepatitis B virus (HBV) potential of the total ethanolic and sequential organic extracts of 60 candidate medicinal plants, which demonstrated novel anti-HBV activities in a time- and dose-dependent manner.
Abstract: Currently, >35 Saudi Arabian medicinal plants are traditionally used for various liver disorders without a scientific rationale This is the first experimental evaluation of the anti-hepatitis B virus (HBV) potential of the total ethanolic and sequential organic extracts of 60 candidate medicinal plants The extracts were tested for toxicity on HepG2215 cells and cytotoxicity concentration (CC50) values were determined The extracts were further investigated on HepG2215 cells for anti-HBV activities by analyzing the inhibition of HBsAg and HBeAg production in the culture supernatants, and their half maximal inhibitory concentration (IC50) and therapeutic index (TI) values were determined Of the screened plants, Guiera senegalensis (dichloromethane extract, IC50=1065), Pulicaria crispa (ethyl acetate extract, IC50=1445), Coccinea grandis (total ethanol extract, IC50=3157), Fumaria parviflora (hexane extract, IC50=3544), Capparis decidua (aqueous extract, IC50=6682), Corallocarpus epigeus (total ethanol extract, IC50=719), Indigofera caerulea (methanol extract, IC50=7321), Abutilon figarianum (dichloromethane extract, IC50=9976) and Acacia oerfota (total ethanol extract, IC50=10146) demonstrated novel anti-HBV activities in a time- and dose-dependent manner Further qualitative phytochemical analysis of the active extracts revealed the presence of alkaloids, tannins, flavonoids and saponins, which are attributed to antiviral efficacies In conclusion, P crispa, G senegalensis and F parviflora had the most promising anti-HBV potentials, including those of C decidua, C epigeus, A figarianum, A oerfota and I caerulea with marked activities However, a detailed phytochemical study of these extracts is essential to isolate the active principle(s) responsible for their novel anti-HBV potential
TL;DR: An upregulated expression of CTGF and TGF-β1 was revealed in the skeletal muscle of DMD patients, which were in positive correlation with the degree of pathology and clinical severity, which may be involved in the pathophysiology of fibrosis in DMD.
Abstract: The present study aimed to analyze the association of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) expression levels in skeletal muscle with the clinical manifestation of Duchenne muscular dystrophy (DMD). A total of 18 cases of DMD, which were confirmed by routine pathological diagnosis were recruited into the present study, along with 8 subjects who suffered from acute trauma but did not present any neuromuscular diseases and were enrolled as the healthy controls. Immunohistochemical staining was used to detect the expression levels of CTGF and TGF-β1 in muscle biopsy specimens. Furthermore, Spearman rank correlation analysis was conducted among the expression levels of CTGF and TGF-β1, age, clinical severity and pathological severity in DMD patients. The immunohistochemical staining results revealed that the expression levels of CTGF and TGF-β1 were significantly increased in the DMD group compared with those in the control group (P 0.05), but there was a significant correlation with the degree of pathology and clinical severity (P<0.05). In conclusion, an upregulated expression of CTGF and TGF-β1 was revealed in the skeletal muscle of DMD patients, which were in positive correlation with the degree of pathology and clinical severity. These two factors may be involved in the pathophysiology of fibrosis in DMD.
TL;DR: Both extraction methods are viable depending on whether high yield or high quality of extracted DNA is required, however, due to the increased degradation with age, storage time limits the available DNA in FFPE tissues regardless of the extraction method.
Abstract: Techniques for the extraction and use of nucleic acids from formalin-fixed and paraffin-embedded (FFPE) tissues, preserved over long time periods in libraries, have been developed. However, DNA extracted from FFPE tissues is generally damaged, and long-term storage may affect DNA quality. Therefore, it is important to elucidate the effect of long-term storage on FFPE tissues and evaluate the techniques used to extract DNA from them. In the present study, the yield, purity, and integrity of DNA in FFPE tissue samples was evaluated. Two DNA extraction techniques were used: A silica-binding DNA collection method using QIAamp DNA FFPE Tissue kit (QIA) and a total tissue DNA collection method using a WaxFree DNA extraction kit (WAX). A total of 25 FFPE tissues from lung adenocarcinomas were studied, which had been surgically resected and fixed at Okayama University Hospital prior to examination and subsequent storage at room temperature for 0.5, 3, 6, 9 and 12 years. Extracted DNA was quantified using ultraviolet absorbance, fluorescent dye, and quantitative polymerase chain reaction (qPCR). The quality of the DNA was defined by the absorbance ratio of 260 to 280 nm (A260/280) and Q-score, which is the quantitative value of qPCR product size ratio. The results demonstrated that the yield of total DNA extracted using WAX was significantly greater than when QIA was used (P<0.01); however, DNA extracted using WAX included more contaminants and was significantly more fragmented compared with DNA extracted using QIA (P<0.01). Aging had no significant effect on absolute DNA yield or DNA purity, although it did significantly contribute to increased DNA degradation for both QIA and WAX extraction (QIA P=0.02, WAX P=0.03; 0.5 years vs. 3 years, QIA P<0.01, WAX P=0.03; 9 years vs. 12 years). Both extraction methods are viable depending on whether high yield or high quality of extracted DNA is required. However, due to the increased degradation with age, storage time limits the available DNA in FFPE tissues regardless of the extraction method.
TL;DR: Considering its multiple properties, the present review has focused on the potential benefits of RSV as an antioxidant and chemopreventive agent.
Abstract: Health promotion strategies and lifestyle changes are important in disease prevention Oral health has received a large amount of attention previously as it is a fundamental component of general health and it contributes to the quality of life Therefore, the study of associations between diet, health and the presence of bioactive compounds in food is receiving a substantial amount of attention In the present review the effects and targets of a natural polyohenolic stilbenoid compound; resveratrol (3,5,4'-trihydroxystilbene; RSV) is assessed, and the future prospects for RSV in promoting oral health are considered RSV is a phytoalexin, synthesized by a wide range of plants and abundantly extracted in grape skin, it has been purported to exert a multiplicity of anti-inflammatory, anti-viral, anti-microbial, estrogenic, anticancer, cardioprotective, neuroprotective and immunomodulatory functions In this review, following an introduction documenting the biochemistry of RSV and RSV glucosides, the bioavailability and pharmacokinetics of RSV are described Considering its multiple properties, the present review has focused on the potential benefits of RSV as an antioxidant and chemopreventive agent
TL;DR: The ethanolic extracts of RO and SO exhibited antibacterial activity against Gram positive and Gram negative bacteria, suggesting that plant extracts from the Lamiaceae family may used in the clinic as natural antibacterial agents.
Abstract: The current study aimed to investigate ethanolic extracts from the following medicinal plant species cultivated in western Romania: Melissa officinalis L., Rosmarinus officinalis L. (RO) and Salvia officinalis L. (SO). Antioxidant activity, total phenolics content and a profile of the main hydroxycinnamic acids (HCAs), including caffeic, ferulic, coumaric and rosmarinic acids, was determined for each plant extract. The in vitro antimicrobial activity against four bacterial strains (Escherichia coli, Listeria-, Pseudomonas aeruginosa and Staphylococcus aureus), and the effect on cell viability in two melanoma cell lines (B164A5 murine melanoma and A375 human melanoma) was also assessed. The results indicated that total phenolics content was 73.76-274.73 mg GAE·g-1 and the antioxidant activity was 2.32-2.87 mM Fe2+·100 g-1. There was found a strong positive correlation (R=0.9691) between total phenolics content and the antioxidant activity in the investigated samples. Regarding the HCA profile obtained by high performance liquid chromatography, the results demonstrated that rosmarinic acid represents the main identified compound. The ethanolic extracts of RO and SO exhibited antibacterial activity against Gram positive and Gram negative bacteria. RO was the most effective in terms of decreasing the cell viability of murine and human melanoma cell lines, while the HCAs did not exhibit any effect on cell viability. These findings suggest that plant extracts from the Lamiaceae family may used in the clinic as natural antibacterial agents.