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Modulating stemness of mesenchymal stem cells from exfoliated deciduous and permanent teeth by IL-17 and bFGF
No full textMesenchymal stem cells (MSCs) have been identified within dental pulp tissues of exfoliated deciduous (SHEDs) and permanent (DPSCs) teeth. Although differences in their proliferative and differentiation properties were revealed, variability in SHEDs and DPSCs responsiveness to growth factors and cytokines have not been studied before. Here, we investigated the influence of interleukin-17 (IL-17) and basic fibroblast growth factor (bFGF) on stemness features of SHEDs and DPSCs by analyzing their proliferation, clonogenicity, cell cycle progression, pluripotency markers expression and differentiation after 7-day treatment. Results indicated that IL-17 and bFGF differently affected SHEDs and DPSCs proliferation and clonogenicity, since bFGF increased proliferative and clonogenic potential of both cell types, while IL-17 similarly affected SHEDs, exerting no effects on adult counterparts DPSCs. In addition, both factors stimulated NANOG, OCT4, and SOX2 pluripotency markers expression in SHEDs and DPSCs showing diverse intracellular expression patterns dependent on MSCs type. As for the differentiation capacity, both factors displayed comparable effects on SHEDs and DPSCs, including stimulatory effect of IL-17 on early osteogenesis in contrast to the strong inhibitory effect showed for bFGF, while having no impact on SHEDs and DPSCs chondrogenesis. Moreover, bFGF combined with IL-17 reduced CD90 and stimulated CD73 expression on both types of MSCs, whereas each factor induced IL-6 expression indicating its' role in IL-17/bFGF-modulated properties of SHEDs and DPSCs. All these data demonstrated that dental pulp MSCs from primary and permanent teeth exert intrinsic features, providing novel evidence on how IL-17 and bFGF affect stem cell properties important for regeneration of dental pulp at different ages
Mechanisms of Hydroxyurea-Induced Cellular Senescence: An Oxidative Stress Connection?
Get PDFHydroxyurea (HU) is a water-soluble antiproliferative agent used for decades in neoplastic and nonneoplastic conditions. HU is considered an essential medicine because of its cytoreduction functions. HU is an antimetabolite that inhibits ribonucleotide reductase, which causes a depletion of the deoxyribonucleotide pool and dramatically reduces cell proliferation. The proliferation arrest, depending on drug concentration and exposure, may promote a cellular senescence phenotype associated with cancer cell therapy resistance and inflammation, influencing neighboring cell functions, immunosuppression, and potential cancer relapse. HU can induce cellular senescence in both healthy and transformed cells in vitro, in part, because of increased reactive oxygen species (ROS). Here, we analyze the main molecular mechanisms involved in cytotoxic/genotoxic HU function, the potential to increase intracellular ROS levels, and the principal features of cellular senescence induction. Understanding the mechanisms involved in HU's ability to induce cellular senescence may help to improve current chemotherapy strategies and control undesirable treatment effects in cancer patients and other diseases
Tumorigenic Aspects of MSC Senescence—Implication in Cancer Development and Therapy
Get PDFAs an organism ages, many physiological processes change, including the immune system. This process, called immunosenescence, characterized by abnormal activation and imbalance of innate and adaptive immunity, leads to a state of chronic low-grade systemic inflammation, termed inflammaging. Aging and inflammaging are considered to be the root of many diseases of the elderly, as infections, autoimmune and chronic inflammatory diseases, degenerative diseases, and cancer. The role of mesenchymal stromal/stem cells (MSCs) in the inflammaging process and the age-related diseases is not completely established, although numerous features of aging MSCs, including altered immunomodulatory properties, impeded MSC niche supporting functions, and senescent MSC secretory repertoire are consistent with inflammaging development. Although senescence has its physiological function and can represent a mechanism of tumor prevention, in most cases it eventually transforms into a deleterious (para-)inflammatory process that promotes tumor growth. In this review we are going through current literature, trying to explore the role of senescent MSCs in making and/or sustaining a microenvironment permissive to tumor development and to analyze the therapeutic options that could target this process
Systematic Review of the Application of Perinatal Derivatives in Animal Models on Cutaneous Wound Healing
Get PDFKnowledge of the beneficial effects of perinatal derivatives (PnD) in wound healing goes back to the early 1900s when the human fetal amniotic membrane served as a biological dressing to treat burns and skin ulcerations. Since the twenty-first century, isolated cells from perinatal tissues and their secretomes have gained increasing scientific interest, as they can be obtained non-invasively, have anti-inflammatory, anti-cancer, and anti-fibrotic characteristics, and are immunologically tolerated in vivo. Many studies that apply PnD in pre-clinical cutaneous wound healing models show large variations in the choice of the animal species (e.g., large animals, rodents), the choice of diabetic or non-diabetic animals, the type of injury (full-thickness wounds, burns, radiation-induced wounds, skin flaps), the source and type of PnD (placenta, umbilical cord, fetal membranes, cells, secretomes, tissue extracts), the method of administration (topical application, intradermal/subcutaneous injection, intravenous or intraperitoneal injection, subcutaneous implantation), and the type of delivery systems (e.g., hydrogels, synthetic or natural biomaterials as carriers for transplanted cells, extracts or secretomes). This review provides a comprehensive and integrative overview of the application of PnD in wound healing to assess its efficacy in preclinical animal models. We highlight the advantages and limitations of the most commonly used animal models and evaluate the impact of the type of PnD, the route of administration, and the dose of cells/secretome application in correlation with the wound healing outcome. This review is a collaborative effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the preclinical application of PnD in wound healing
Climate change as a challenge in Malaria Drug Discovery
No full textMalaria, a disease which affects millions of people worldwide, is a parasitic infection caused by protozoans of the Plasmodium genus. Five species are known to cause human malaria, including P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi. The vectors responsible for the transmission of this disease are female mosquitoes of the Anopheles genus. Malaria is the greatest health problem facing developing countries, with the highest morbidity and mortality rates in Africa and Southeast Asia. Moreover, due to climate change and mass human migration, autochthonous cases of malaria are increasingly appearing sporadically (Corsica, Italy, Spain) or even as local epidemics (Greece), in countries or regions in which the disease was considered eradicated. Plasmodium parasites are developing resistance to nearly all conventional antimalarials, Anopheles vectors are becoming resistant to insecticides, and no vaccine exists to date. Given the current situation, there is an urgent need for new antimalarial compounds. Synthetic quinoline derivatives hold the most promise, with 4- aminoquinolines being the most suitable for chemical modifications. Here we report on the antimalarial efficacy of ten novel benzothiophene, thiophene and benzene aminoquinolines. In vitro efficacy was evaluated by a lactate dehydrogenase assay in cultures of a chloroquine (CQ)-sensitive P. falciparum strain 3D7 and CQ-resistant (CQR) P. falciparum strain Dd2. Nine of the ten compounds had a lower 50% inhibitory concentration than CQ against the CQR strain. Five compounds, available for in vivo evaluation, were nontoxic in preliminary experiments. Those compounds were evaluated in C57BL/6 mice infected with P. berghei ANKA strain using a modified Thompson test. All five compounds administered at a dose of 160 mg/kg/day for 3 days prolonged the survival of treated compared with untreated mice. Untreated control mice died by Day 7 with a mean parasitaemia of 15%. Among treated mice, a dichotomous outcome was observed, with a two-third majority of treated mice dying by Day 17 with a low mean parasitaemia of 5%, whereas one-third survived longer with a mean hyperparasitaemia of 70%; specifically, five of these mice survived a mean of 25 days, whilst two even survived past Day 31. The significant antimalarial potential of this aminoquinoline series is illustrated by its excellent in vitro activity against the CQR P. falciparum strain and significant in vivo activity. Most importantly, compounds ClAQ7, ClAQ9 and ClAQ11 were able to confer resistance to cerebral malaria and afford a switch to hyperparasitaemia to mice prone to the neurological syndrome.2nd Scientific Symposium of the Pharmaceutical Association of Serbia entitled „Pharmacy and the Nature - complex relationships and mutual impacts
Olive leaf extract attenuates adriamycin-induced focal segmental glomerulosclerosis in spontaneously hypertensive rats via suppression of oxidative stress, hyperlipidemia, and fibrosis
No full textOlive (Olea europaea L.) leaf extract (OLE) possesses powerful antioxidant, antihyperlipidemic, and anti-inflammatory properties. The aim was to investigated the effects of OLE on the hyperlipidemia, antioxidant defense, heme oxygenase/biliverdin reductase (HO/BVR) pathway, inflammation, and fibrosis in spontaneously hypertensive rats with focal segmental glomerulosclerosis (FSGS, a progressive form of chronic kidney disease) induced by adriamycin (2 mg/kg, i.v., twice in a 21-day period). Daily treatment of OLE (80 mg/kg, p.o.) for 6 weeks suppressed protein oxidation and lipid peroxidation (p lt .01 and p lt .001, respectively), significantly increased antioxidant enzymes activities and normalized antioxidant capacity, leading to the improvement of antioxidant defense independently of the HO/BVR pathway. Furthermore, the values of triglycerides (p lt .01), total, and low-density lipoprotein cholesterol (p lt .05, both) were improved by OLE. OLE strongly prevented glomerulosclerosis, interstitial inflammation, and fibrosis (renal injury score, FSGS: 8 +/- 0.45 vs. FSGS+OLE: 4.20 +/- 1.07; p lt .01), as evidenced by normalized fibronectin content (p lt .001), suppressed interstitial inflammatory cells infiltration and collagen deposition, without changing cytokines expressions. OLE decreased blood pressure with a tendency to reduce urine albumin loss. These data suggest that OLE may be effective in slowing down the progression of FSGS
Calorie-Restricted Mediterranean and Low-Fat Diets Affect Fatty Acid Status in Individuals with Nonalcoholic Fatty Liver Disease
Get PDFLifestyle modifications are the main support of nonalcoholic fatty liver disease (NAFLD) therapy. Weight loss is one of the primary goals in NAFLD, but the effects of different calorie-restricted diets remain unclear. Thus, we evaluated the effects of two calorie-restricted diets-the Mediterranean diet (Med diet) and low-fat diet-on liver status, cardiometabolic markers, and fatty acid profiles in patients with NAFLD. Twenty-four overweight/moderately obese men were randomly assigned to consume one of these diets. Lipid levels, glucose, insulin, liver enzymes, steatosis, and fatty acid profiles of serum and erythrocytes phospholipids were assessed. After 3 months, all participants had a significant weight loss ( gt 9%), with improvements in waist circumference, body fat %, index of visceral adiposity (VAI), lipid accumulation product, fatty liver (FLI), and hepatic steatosis (HSI) index (p lt 0.001). Both diets significantly lowered triglycerides, total and LDL-cholesterol, liver enzymes, fasting glucose, insulin, and HOMA-IR index. Fatty acid profiles were enhanced after both diets, with a significantly decreased n-6/n-3 ratio. Participants on the Med diet had higher levels of HDL-cholesterol and monounsaturated and n-3 docosahexaenoic acids in serum phospholipids and lower levels of saturated fatty acids, triglycerides, TG/HDL ratio, and FLI when compared to participants on the low-fat diet. Our results indicate that dietary patterns and calorie restriction represent central therapeutic issues in the improvement of obesity-related cardiometabolic alterations that are involved in the mechanism of hepatic steatosis. The Med diet may contribute to disease treatment even more than the low-fat diet since it leads to decreased saturated and increased monounsaturated and n-3 polyunsaturated fatty acid status and improved FLI in NAFLD patients
Changes in long-term properties and natural cycles of the Danube river level and flow induced by damming
No full textIn this paper we assessed changes in scaling properties of the river Danube level and flow data, associated with building of Djerdap/Iron Gates hydrological power plants positioned on the border of Romania and Serbia. We used detrended fluctuation analysis (DFA), wavelet transform spectral analysis (WTS) and wavelet modulus maxima method (WTMM) to investigate time series of measurements from hydrological stations in the vicinity of dams and in the area of up to 480 km upstream from dams, and time series of simulated NOAA-CIRES 20th Century Global Reanalysis precipitation data for the Djerdap/Iron Gates region. By comparing river dynamics during the periods before and after construction of dams, we were able to register changes in scaling that are different for recordings from upstream and from downstream (from dams) areas. We found that damming caused appearance of human-made or enhancement of natural cycles in the small time scales region, which largely influenced the change in temporal scaling in downstream recording stations. We additionally found disappearance or decline in the amplitude of large-time-scale cycles as a result of damming, which changed the dynamics of upstream data. The most prominent finding of our paper is a demonstration of a complete or partial loss of annual cycles in the upstream stations' data that stems from the operation of the artificial water reservoir and extends as far as 220 km from dams. We discussed probable sources of such found changes in scaling, aiming to provide explanations that could be of use in future environmental assessments
Theta-modulated oscillatory transcranial direct current stimulation over posterior parietal cortex improves associative memory
Get PDFAssociative memory (AM) reflects the ability to remember and retrieve multiple pieces of information bound together thus enabling complex episodic experiences. Despite growing interest in the use of transcranial direct current stimulation (tDCS) for the modulation of AM, there are inconsistent evidence regarding its benefits. An alternative to standard constant tDCS could be the application of frequency-modulated tDCS protocols, that mimic natural function-relevant brain rhythms. Here, we show the effects of anodal tDCS oscillating in theta rhythm (5 Hz; 1.5 ± 0.1 mA) versus constant anodal tDCS and sham over left posterior parietal cortex on cued recall of face-word associations. In a crossover design, each participant completed AM assessment immediately following 20-min theta-oscillatory, constant, and sham tDCS, as well as 1 and 5 days after. Theta oscillatory tDCS increased initial AM performance in comparison to sham, and so did constant tDCS. On the group level, no differences between oscillatory and constant tDCS were observed, but individual-level analysis revealed that some participants responded to theta-oscillatory but not to constant tDCS, and vice versa, which could be attributed to their different physiological modes of action. This study shows the potential of oscillatory tDCS protocols for memory enhancement to produce strong and reliable memory-modulating effects which deserve to be investigated further