ABSTRACT
Background: The NLRP3 inflammasome is overactivated in the brains of APP/PS1 transgenic mice and AD patients, and mitophagy has an obvious negative regulatory role on NLRP3 inflammasome activation. The protective effect of melatonin in AD may be related to the regulation of mitophagy and NLRP3 inflammasome activity. TFEB plays a critical role in maintaining autophagy/mitophagy. Studies have found that TFEB plays a protective role in AD. Methods: APP/PS1 transgenic mice were given melatonin in their drinking water for 3 months. Compared with mice without melatonin treatment, the mice given melatonin showed changes in the following features: (1) cognitive function, (2) mitophagy-related proteins in the brain, (3) ROS, (4) NLRP3 inflammasome and related proteins and the concentrations of inflammatory cytokines, and (5) Aß deposition. In in vitro experiments, effects of melatonin on mitophagy, NLRP3 inflammasome activity, and TFEB in SH-SY5Y cells with Aß 25-35 were observed. TFEB knockdown was implemented in combination with Aß 25-35 and melatonin treatment, and the expressions of TFEB, Parkin, p62, IL-1ß, caspase-1, ROS, and IL-18 were explored. Results: Melatonin improved cognitive function in APP/PS1 transgenic mice and decreased ROS and senile plaques. Melatonin promoted mitophagy in SH-SY5Y cells with Aß 25-35 and APP/PS1 transgenic mice. NLRP3 inflammasome activity was inhibited, and the concentrations of IL-18 and IL-1ßwere clearly reduced. Compared with C57/BL6J mice, the amount of TFEB in the brain nucleus of APP/PS1 transgenic mice was decreased. Melatonin treatment increased the nuclear translocation of TFEB in SH-SY5Y cells. TFEB knockout was implemented in combination with Aß 25-35 and MT treatment; the expressions of Parkin, p62, caspase-1, IL-1ß, IL-18, and ROS were accelerated. Conclusions: Melatonin promotes mitophagy by inducing TFEB nuclear translocation, downregulates NLRP3 inflammasome activation, and exerts protective effects in SH-SY5Y cells and APP/PS1 transgenic mice.
Subject(s)
Alzheimer Disease , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Melatonin , NLR Family, Pyrin Domain-Containing 3 Protein , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Caspase 1/genetics , Humans , Inflammasomes/metabolism , Interleukin-18 , Melatonin/pharmacology , Mice , Mice, Transgenic , Mitophagy , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Reactive Oxygen Species/metabolism , Ubiquitin-Protein Ligases/metabolismABSTRACT
Objective To evaluate the safety and validity of an early steroid withdrawal protocol including cyclosporine (CsA) and mycophenolate mofetil (MMF) in middle aged and elderly renal transplant patients. Methods Between September 2000 and April 2008, the prospective, randomized study design was used in 80 middle aged and elderly renal transplant patients. Steroid withdrawal group (n=39) with primary cadaveric kidney transplants received a protocol consisting of CsA 4～6 mg·kg~(-1)·d~(-1) beginning at postoperative day 3, MMF 0. 75 g twice a day from the next postoperative day, and methylprednisolone (MP) 500 mg daily from day 0 to 3. Then prednisone (Pred) 20 mg daily was gradually tapered and withdrawn after postoperative day 30. Conventional steroid treatment group (control group, n=41) received a regimen consisting of CsA, MMF and MP, and Pred 20 mg daily. Pred was tapered to 5 mg daily over a period of 6 months, then maintained thereafter. Outcome parameters were patient and graft survival rates, renal function, acute rejection ( AR), arterial hypertension, hyperlipidemia or diabetes mellitus, weight gain and infection. Results The incidence of AR in the steroid withdrawal group was similar to the control group (23. 1% vs. 19. 5%, χ~2=0. 15,P>0. 05). Patient survival rates at 12, 24, 36 months were 97. 4%, 94. 8% and 88.0% in the steroid withdrawal group and were 97.6%, 97.6 and 87.8% in the control group, respectively (χ~2=0. 17, P>0. 05). And graft survival rates were 94. 9%, 88. 6% and 83. 7% in the steroid withdrawal group and were 95. 1%, 91. 5% and 79. 5% in control group, respectively (χ~2 = 0.07, P>0. 05). Conclusions In middle aged and elderly renal transplant patients, early steroid withdrawal is feasible and may not significantly increase the risk of acute rejection episodes.
ABSTRACT
Objective To discuss the clinical application of noninvasive positive pressure ventila-tion for patients with acute respiratory distress syndrome (ARDS) as a result of cytomegalovirus (CMV) interstitial pneumonia after renaltransplantation. Methods There were 371 renal transplan-tation from March 2003 to October 2006, 27 patients were diagnosed as CMV pneumonia postopera-tion. Ten patients were treated with noninvasive positive pressure ventilation within the 11 patients who aggravated to ARDS. The clinical data of before and after mechanical ventilation were reviewed. Results Among patients received noninvasive positive pressure ventilation, 1 died of complication. Seven patients were cured by noninvasive positive pressure ventilation. Significant difference of the physiological index presented between the 7 patients cured with noninvasive positive pressure ventila-tion before and after the use of ventilation(P<0.05), and significant difference of the renal function also existed(P<0.05). Conclusion The major value of noninvasive positive pressure ventilation is to correct the hypoxemia.
