ABSTRACT
In addition to providing energy for cells, mitochondria also participate in calcium homeostasis, cell information transfer, cell apoptosis, cell growth and differentiation. Therefore, maintaining mitochondrial homeostasis is very crucial for the body to carry out normal life activities. Ubiquitination, a post-translational modification of proteins, is involved in various physiological and pathological processes of cells by regulating mitochondrial homeostasis. However, the mechanism by which ubiquitination regulates mitochondrial homeostasis has not been summarized, especially the effect of Parkin protein on cardiovascular diseases. In this paper, the specific mechanism of mitochondrial homeostasis regulated by ubiquitination of Parkin protein is discussed, and the influence of mitochondrial homeostasis imbalance on cardiovascular diseases is reviewed, with a view to providing potential therapeutic strategies for the clinical treatment of cardiovascular diseases.
ABSTRACT
Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.
Subject(s)
Animals , Mice , Alzheimer Disease , Amyloid beta-Peptides , Monocytes , Cognition , Energy Metabolism , PhagocytosisABSTRACT
Deficits in the clearance of amyloid β protein (Aβ) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer's disease (AD). Impaired uptake of Aβ by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβ clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aβ uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aβ deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβ clearance by blood monocytes and alleviating AD-like pathology.
Subject(s)
Animals , Mice , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Cognition , Disease Models, Animal , Mice, Transgenic , Monocytes/pathology , Polysaccharides/therapeutic use , ProteoglycansABSTRACT
One hundred and ninety-three type 2 diabetic patients of average age of 70.3 years (96 males and 97 females), receiving insulin treatment at Diabetes Clinic of Caoyang Subdistrict Community Health Service Center from April to October 2018 were enrolled in the study. During the first visit, the average times of insulin injection pen needle use in the past month and the reason for repeated use were investigated; and the patients were informed that under the medical insurance policy in Shanghai, the reimbursement rate of the needles was increased to 80%. The patients were regularly instructed on the use of insulin needles in the follow-up visits. After 5 months the times of each insulin needle use were surveyed again. The first survey showed that 97.5% (188/193) of patients reused insulin needles, and each needle was used for (11.8±9.8) times; while the second survey showed that each needle was used for (4.4±4.4) times. Binary logistic regression analysis showed that the reuse behavior was affected by the frequency of education given by medical staff and the patient′s perception on expensiveness of the needles. It is suggested that clinical health education and fully informing medical insurance policy is important for the behavior change of reusing insulin injection pen needles in diabetic patients.
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To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer's disease (sAD) and pathological biomarkers in cerebrospinal fluid (CSF), 462 sAD patients and 463 age-matched cognitively normal (CN) controls were genotyped for 35 single-nucleotide polymorphisms (SNPs) that are significantly associated with sAD. Then, the alleles found to be associated with sAD were used to build polygenic risk score (PRS) models to represent the genetic risk. Receiver operating characteristic (ROC) analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset. We measured the CSF levels of Aβ42, Aβ42/Aβ40, total tau (T-tau), and phosphorylated tau (P-tau) in a subgroup (60 sAD and 200 CN participants), and analyzed their relationships with the PRSs. We found that 14 SNPs, including SNPs in the APOE, BIN1, CD33, EPHA1, SORL1, and TOMM40 genes, were associated with sAD risk in our cohort. The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls, and were able to predict the incidence rate of sAD and age at onset. Furthermore, the PRSs were correlated with the CSF levels of Aβ42, Aβ42/Aβ40, T-tau, and P-tau. Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD. As genetic risk profiles vary among populations, large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.
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Alzheimer's disease (AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD. In this review, we summarize the latest achievements, including diagnostic biomarkers, polygenic hazard score, amyloid and tau PET imaging, clinical trials targeting amyloid-beta (Aβ), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.
Subject(s)
Animals , Humans , Alzheimer Disease , Diagnosis , Therapeutics , Biomarkers , Blood , Biomedical Research , Methods , Disease Progression , Magnetic Resonance ImagingABSTRACT
<p><b>OBJECTIVE</b>To assess the effects of laparoscopic sleeve gastrectomy (LSG) on insulin secretion mode and metabolism of glucose and lipid in morbidly obese patients.</p><p><b>METHODS</b>Clinical data of 65 morbidly obese patients [body mass index (BMI) ≥30 kg/m] undergoing LSG at Shanghai 10th People's Hospital from August 2012 to December 2016 were retrospectively analyzed. According to the result of OGTT, these obese patients were divided into three groups: normal glucose tolerance (NGT, 23 cases), impaired glucose tolerance (IGT, 22 cases) and type 2 diabetes mellitus (DM, 20 cases) groups. Twenty-two healthy people [BMI (23.1±1.4) kg/m] were used as control group. The anthropometries parameters [weight, BMI, waist circumference, body fat percentage, excess weight loss(%EWL)], glucose metabolic indices [fasting plasma glucose (FPG), fasting insulin (FINS), glycosylated hemoglobin (HbA1c), homeostasis model assessment-insulin resistance index (HOMA-IR)], lipid profile (TC, TG, HDL-C, LDL-C) and inflammatory factor (UA, TNF-α) of 3 groups were detected before operation and at postoperative 1-, 3-, 6-month. These variables were analyzed among morbidly obese groups before and after surgery and compared to control group. Clinical registration number of this study was ChiCTROCSl2002381.</p><p><b>RESULTS</b>Body weight, waist circumference and BMI of morbidly obese patients all decreased at postoperative 1-, 3-, 6-month. Postoperative %EWL increased obviously to (71.5±24.7)% with the highest range in DM group. Percentage of successful weight loss (%EWL>50%) in NGT, IGT and DM groups was 63.6%, 83.9% and 90.0% at postoperative 6-month respectively, and DM group was also the highest. At postoperative 6-month, HbA1c of 3 morbidly obese groups became normal; FPG and postprandial 2-hour glucose of IGT and DM group decreased to normal level; insulin level of 3 morbidly obese groups decreased obviously compared to pre-operation (all P<0.05), especially FINS and postprandial 2-hour insulin became normal without significant difference of control group (P>0.05), while postprandial 30-minute and 60-minute insulin levels in 3 groups were still higher as compared to control group. The insulin secretion curves of morbidly obese groups showed hyperinsulinemia before surgery. The peak of insulin secretion curve in IGT and DM group moved back to postprandial 120-minute before operation, and returned to 60-minute after operation, with basic normal rhythm of secretion curve. Preoperative HOMA-IR in all 3 morbidly obese groups was higher than that in control group (all P<0.05) and remarkably lower at postoperative 6-month compared to pre-operation(P<0.05). In 3 morbidly obese groups after operation, TG decreased, HDL-C increased, UA and TNF-α decreased significantly compared to before operation (all P<0.05). At postoperative 6-month, the HOMA-IR of DM group was positively correlated with BMI (r=0.236, P=0.004) and TNF-α (r=0.228, P=0.033), and was not correlated with HDL-C(P>0.05).</p><p><b>CONCLUSIONS</b>LSG can effectively ameliorate hyperinsulinemia and insulin secretion curve, and improve metabolic disorder and insulin resistance of different stage in obesity patients with glucose metabolic disorder. Insulin resistance is correlated with body weight and inflammatory factors.</p>
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Objective This study aimed to explore clinical characteristics of four types of obesity based on metabolic classification. Methods Forty-eight obese patients were divided according to their clinical characteristics into 4 groups including metabolic healthy obesity (MHO), hypometabolic obesity (LMO), hypermetabolic obesity (HMO), and metabolic obesity with inflammation (IMO). 20 normal weight individuals were also recruited as a control group. Body fat, body weight, visceral index, and basal metabolism were measured by Omron body fat meter. Fat content and its distribution were measured by dual energy X-ray absorptiometry. All participating patients underwent various tests for 75 g oral glucose tolerance, blood glucose, insulin, C peptide. Lipid profile, thyroid function and sex hormones levels, and inflammation factors were also measured. Results (1)Patients in MHO group had higher body fat content, but had no metabolic disorder and inflammation. Their hormones levels were normal. (2) Lower metabolic rate and lower hormones levels were found in the patients in LMO group with increasing visceral fat. Trunk/subcutaneous fat mass was significantly higher than that in MHO group(1. 19 ± 0. 25 vs 0. 97 ± 0. 32, P<0. 05). There were abnormal lipid and glucose metabolism in LMO group. The insulin action index was significantly lower than that in MHO group(0. 006 6 ± 0. 002 7 vs 0. 012 1 ± 0. 009 5, P<0. 05). The area under the curve of glucoseconcentrationwassignificantlyhigherinLMOgroupthanthatinMHOgroup[(18.71±8.68vs12.70±4.63) mmol/L, P<0. 05]. (3)Heart rate and blood pressure were higher in HMO group. The heart rate was significantly increased compared with that in MHO group [(90. 50 ± 8. 24 vs 73. 20 ± 14. 11) beat/min, P<0. 05]. The waist circumference was significantly larger than that in MHO group [(111. 88 ± 10. 54 vs 98. 05 ± 15. 56) cm, P<0. 05]. (4) In IMO group, insulin action index was significantly lower than MHO group (0. 007 0 ± 0. 003 3 vs 0.0121±0.0095,P<0.05). ThetrunkfatmassanduricacidlevelsweresignificantlyhigherthanMHOgroup [(17236.38±4610.60vs15816.10±5453.42)gand(468.28±121.32vs376.84±97.14) μmol/L,bothP<0. 05]. Patients in IMO group had acanthosis nigricans, but their glucose level was relatively normal. Conclusion The metabolic-based obese diagnosis is essential for understanding the obesity etiology and providing individualized treatment.
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<p><b>OBJECTIVE</b>To study the functional and ultramicrostructural effects of alpha lipoic acid on hypothalamus-pituitary-adrenal (HPA) axis in normal and diabetic rats.</p><p><b>METHODS</b>Using radioimmunoassay we observed the effects of three doses (1, 20, and 100 mg/kg) of alpha lipoic acid injected intraperitoneally for 3 weeks on the plasma levels of CRH, ACTH and COR in normal and diabetic rats. The ultramicrostructural changes of the hypophysis and pituitary gland after alpha lipoic acid treatment were observed under transmission electron microscope.</p><p><b>RESULTS</b>Compared with the control group, CRH level in lipoicin-treated normal and diabetic rats was significantly reduced (P<0.05). ACTH level of the 3 lipoicin doses groups of normal rats decreased, and a significant reduction occurred in medium-dose lipoicin group of diabetic rats (P<0.05). COR level showed the same changes as CRH level in normal rats, but decreased significantly in high- and medium-dose lipoicin groups of diabetic rats. Lipoicin treatment produced no apparent effect on the ultramicrostructures of the hypophysis and pituitary gland cells, which were the targets of diabetic lesions with low metabolism functions. Lipoicin treatment obviously enhanced the hypophysis and pituitary gland cell metabolism function to resist diabetic oxidative stress.</p><p><b>CONCLUSION</b>Lipoicin can inhibit the HPA axis directly or indirectly in normal and diabetic rats.</p>
Subject(s)
Animals , Male , Rats , Diabetes Mellitus, Experimental , Pathology , Hypothalamo-Hypophyseal System , Physiology , Pituitary-Adrenal System , Diagnostic Imaging , Physiology , Random Allocation , Rats, Sprague-Dawley , Thioctic Acid , Pharmacology , UltrasonographyABSTRACT
Objective To study the functional and ultramicrostructural effects of melatonin on hypothalamus-pituitary-adrenal(HPA) axis in normal and diabetic rats.Methods By means of radioimmunoassay we observed the effects of three doses of melatonin(0.5mg/kg for low,10mg/kg for medium,50mg/kg for high) and lipoicin on level of CRH,ACTH and COR in normal and diabetic rats' plasma for three weeks respectively.The ultramicrostructural changes of hypophysis and pituitary gland after melatonin treatment were also observed under transmission electron microscope(TEM).Results 1.Compared with control groups,the CRH level of melatonin groups in normal and diabetic rats notably reduced(P