ABSTRACT
Senescence of cardiomyocytes is considered a key factor for the occurrence of doxorubicin (Dox)associated cardiomyopathy. The NODlike receptor family pyrin domaincontaining 3 (NLRP3) inflammasome is reported to be involved in the process of cellular senescence. Furthermore, thioredoxininteractive protein (TXNIP) is required for NLRP3 inflammasome activation and is considered to be a key component in the regulation of the pathogenesis of senescence. Studies have demonstrated that pretreatment with honokiol (Hnk) can alleviate Doxinduced cardiotoxicity. However, the impact of Hnk on cardiomyocyte senescence elicited by Dox and the underlying mechanisms remain unclear. The present study demonstrated that Hnk was able to prevent Doxinduced senescence of H9c2 cardiomyocytes, indicated by decreased senescenceassociated ßgalactosidase (SAßgal) staining, as well as decreased expression of p16INK4A and p21. Hnk also inhibited TXNIP expression and NLRP3 inflammasome activation in Doxstimulated H9c2 cardiomyocytes. When TXNIP expression was enforced by adenovirusmediated gene overexpression, the NLRP3 inflammasome was activated, which led to inhibition of the antiinflammation and antisenescence effects of Hnk on H9c2 cardiomyocytes under Dox treatment. Furthermore, adenovirusmediated TXNIPsilencing inhibited the NLRP3 inflammasome. Consistently, TXNIP knockdown enhanced the antiinflammation and antisenescence effects of Hnk on H9c2 cardiomyocytes under Dox stimulation. In summary, Hnk was found to be effective in protecting cardiomyocytes against Doxstimulated senescence. This protective effect was mediated via the inhibition of TXNIP expression and the subsequent suppression of the NLRP3 inflammasome. These results demonstrated that Hnk may be of value as a cardioprotective drug by inhibiting cardiomyocyte senescence.
Subject(s)
Biphenyl Compounds/pharmacology , Carrier Proteins/metabolism , Cellular Senescence/drug effects , Doxorubicin/pharmacology , Inflammasomes/metabolism , Lignans/pharmacology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Cell Line , Cell Survival/drug effects , Drug Antagonism , Humans , Oxidative Stress/drug effectsABSTRACT
Diabetes is associated with an increased risk of cardiovascular disease. A decrease in the number and functionality of endothelial progenitor cells (EPCs) leads to reduced endothelial repair and the development of cardiovascular disease. The aim of the present study was to explore the effect and underlying mechanisms of nuclear factor erythroid 2related factor 2 (Nrf2) on EPC dysfunction caused by diabetic mellitus. The biological functions of EPCs in streptozotocininduced diabetic mice were evaluated, including migration, proliferation, angiogenesis and the secretion of vascular endothelial growth factor (VEGF), stromalderived growth factor (SDF) and nitric oxide (NO). Oxidative stress levels in diabetic EPCs were also assessed by detecting intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). EPC senescence was evaluated by measuring p16 and bgal expression and observing the senescenceassociated secretory phenotype. In addition, the function of EPCs and level of oxidative stress were assessed following Nrf2 silencing or activation. Nrf2 silencing resulted in a decrease of EPC biological functions, accelerated cell senescence and increased oxidative stress, as indicated by ROS and MDA upregulation accompanied with decreased SOD activity. Furthermore, Nrf2 silencing inhibited migration, proliferation and secretion in EPCs, while it increased oxidative stress and cell senescence. Nrf2 activation protected diabetic EPCs against the effects of oxidative stress and cell senescence, ameliorating the biological dysfunction of EPCs derived from mice with diabetes. In conclusion, Nrf2 overexpression protected against oxidative stressinduced functional damage in EPCs derived from diabetic mice by regulating cell senescence.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Endothelial Progenitor Cells/cytology , Endothelial Progenitor Cells/metabolism , NF-E2-Related Factor 2/metabolism , Animals , Cell Movement/physiology , Cells, Cultured , Cellular Senescence/physiology , Diabetes Mellitus, Experimental/genetics , Male , Malondialdehyde/metabolism , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Oxidative Stress/physiology , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
OBJECTIVE: To study the protective effect of purariae isoflavone on apoptosis cells of atrophic nasal mucosas in ovariectomized rats. METHOD: 60 rats were divided into four groups as control, ovariectomized, ovariectomized + nylestriol (O + N) and ovariectomized + purariae isoflavone (O + P), each with 15 rats. Earlier apotosis cells of mucosas taken from nasal septum were measured with flow cytometry. RESULT: Compared with control group, and the number of apoptosis cells of mucosas increased after being ovariectomized,and the number of apoptosis cells of mucosas in O + N and O + D group didn't change. CONCLUSION: Nylestriol and purariae isoflavone might have effects on protecting cells of mucosas from lacking of estrogen by decreasing apoptosis cells in ovariectomized rats.
Subject(s)
Apoptosis/drug effects , Epithelial Cells/pathology , Isoflavones/pharmacology , Nasal Mucosa/pathology , Pueraria , Animals , Estradiol Congeners/pharmacology , Female , Isoflavones/isolation & purification , Ovariectomy , Plants, Medicinal/chemistry , Protective Agents/isolation & purification , Protective Agents/pharmacology , Pueraria/chemistry , Quinestrol/analogs & derivatives , Quinestrol/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: To study the protective effect of daizein on apoptosis cells of atrophic nasal mucosas in ovariectomized rats. METHODS: Sixty rats were divided into four groups as contrary, ovariectomized, ovariectomized + nylestriol (O + N) and ovariectomized + daizein (O + D), each with 15 rats. Earlier apotosis cells of nasal mucosas taken from nasal septum were measured with flow cytometry. RESULTS: Compared with contrary group, the number of apoptosis cells of mucosas increased after being ovariectomized, the number of apoptosis cells of mucosas in O + N and O + D groups didn't change. CONCLUSION: Estrogen replacement and daizein might have effects on protecting cells of mucosas from lacking of estrogen by decreasing apoptosis cells in ovariectomized rats.
Subject(s)
Apoptosis/drug effects , Epithelial Cells/pathology , Isoflavones/pharmacology , Nasal Mucosa/pathology , Quinestrol/analogs & derivatives , Animals , Atrophy , Female , Ovariectomy , Quinestrol/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: To study the effect of purariae isoflavone on estrogen level in ovariectomized rats. METHOD: 80 rats were divided into four groups randomly, every group with 20 rats: 1. Control group; 2. Normal + purariae isoflavone group; 3. Ovariectomized group; 4. Ovariectomized + purariae isoflavone group. Estrogen level and gonadotropin-releasing hormone level of all rats were measured. RESULT: Thirty days after being ovariectomized, E2, E3 level was significantly lower than that of the first group(P < 0.05). But Testerone, FSH, LH, PRL and GH increased(P < 0.05). After being gastrogavaged with purariae-isolfavone for thirty days, Estrogen level and gonadotropin-relasing hormone level of the second group were significantly lower in various degree than those of normal control group (P < 0.05). But in ovariectomized rats, the estrogen level was recovered (P > 0.05). The gonadotropin-releasing hormone level was increased (P < 0.05). CONCLUSION: Purariae-isoflavone can increase estrogen level to normal in ovariectomized rats by way of increasing the level of gonadotropin-releasing hormone. In normal rats, it has anti-estrogen effect.