Neuroprotective effects of curcumin via autophagy induction in 6-hydroxydopamine Parkinson's models.

Curcumin, a polyphenolic compound extracted from curcuma longa, acts as a nontoxic matter with anti-oxidant and anti-inflammatory effects as well as antiproliferative activities. Here, our research aimed to explore the neuroprotective effects of curcumin both in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) in vivo and 6-OHDA-lesioned PC12 cells in vitro. In vitro, 6-OHDA caused a distinct decrease in cell viability of PC12 cells (150 µM). With the incubation of curcumin (1 µM), 6-OHDA-induced apoptosis was suppressed, increasing the autophagy markers (LC3-II/LC3-I, Beclin-1) and inhibiting phosphor-AKT/AKT, phosphor-mTOR/mTOR. In vivo, curcumin (50 mg/kg) reduced the accumulation of a-synuclein and led to higher parkinsonian disability scores in 6-OHDA-lesioned PD rats, contributing to induction of autophagy through inhibiting AKT/mTOR signal pathway. Moreover, treatment with autophagy inhibitors, such as 3-MA and chloroquine, abolished the neuroprotective effects of curcumin as evidence by compromised autophagy and declined motor behavior in PD rats. In conclusion, the present study demonstrated that curcumin repressed PC12 cell death in vitro and improved parkinsonian disability scores in vivo by inhibiting AKT/mTOR signaling pathway which mediated by autophagy, indicating a potential value of curcumin in the therapeutic intervention of Parkinson's disease.

NAD+ in Alzheimer's Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo.

Mitochondria in neurons generate adenosine triphosphate (ATP) to provide the necessary energy required for constant activity. Nicotinamide adenine dinucleotide (NAD+) is a vital intermediate metabolite involved in cellular bioenergetics, ATP production, mitochondrial homeostasis, and adaptive stress responses. Exploration of the biological functions of NAD+ has been gaining momentum, providing many crucial insights into the pathophysiology of age-associated functional decline and diseases, such as Alzheimer's disease (AD). Here, we systematically review the key roles of NAD+ precursors and related metabolites in AD models and show how NAD+ affects the pathological hallmarks of AD and the potential mechanisms of action. Advances in understanding the molecular roles of NAD+-based neuronal resilience will result in novel approaches for the treatment of AD and set the stage for determining whether the results of exciting preclinical trials can be translated into the clinic to improve AD patients' phenotypes.

Defective Autophagy and Mitophagy in Alzheimer's Disease: Mechanisms and Translational Implications.

The main histopathology of Alzheimer's disease (AD) is featured by the extracellular accumulation of amyloid-ß (Aß) plaques and intracellular tau neurofibrillary tangles (NFT) in the brain, which is likely to result from co-pathogenic interactions among multiple factors, e.g., aging or genes. The link between defective autophagy/mitophagy and AD pathologies is still under investigation and not fully established. In this review, we consider how AD is associated with impaired autophagy and mitophagy, and how these impact pathological hallmarks as well as the potential mechanisms. This complicated interplay between autophagy or mitophagy and histopathology in AD suggests that targeting autophagy or mitophagy probably is a promising anti-AD drug candidate. Finally, we review the implications of some new insights for induction of autophagy or mitophagy as the new therapeutic way that targets processes upstream of both NFT and Aß plaques, and hence stops the neurodegenerative course in AD.

Delineating the Role of Mitophagy Inducers for Alzheimer Disease Patients.

Alzheimer's disease (AD) is the most common cause of dementia in elderly that serves to be a formidable socio-economic and healthcare challenge in the 21st century. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes contributing to the development of AD pathologies, namely amyloid-ß plaques (Aß) and neurofibrillary tangles (NFT). Here, we highlight the recent advances in the association between impaired mitophagy and AD, as well as delineate the potential underlying mechanisms. Furthermore, we conduct a systematic review the current status of mitophagy modulators and analyzed their relevant mechanisms, evaluating on their advantages, limitations and current applications in clinical trials for AD patients. Finally, we describe how deep learning may be a promising method to rapid and efficient discovery of mitophagy inducers as well as general guidance for the workflow of the process.

Administration of quercetin improves mitochondria quality control and protects the neurons in 6-OHDA-lesioned Parkinson's disease models.

Mounting evidence suggests that mitochondrial dysfunction and impaired mitophagy lead to Parkinson's disease (PD). Quercetin, one of the most abundant polyphenolic flavonoids, displays many health-promoting biological effects in many diseases. We explored the neuroprotective effect of quercetin in vivo in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and in vitro in 6-OHDA-treated PC12 cells. In vitro, we found that quercetin (20 µM) treatment improved mitochondrial quality control, reduced oxidative stress, increased the levels of the mitophagy markers PINK1 and Parkin and decreased α-synuclein protein expression in 6-OHDA-treated PC12 cells. Moreover, our in vivo findings demonstrated that administration of quercetin also relieved 6-OHDA-induced progressive PD-like motor behaviors, mitigated neuronal death and reduced mitochondrial damage and α-synuclein accumulation in PD rats. Furthermore, the neuroprotective effect of quercetin was suppressed by knockdown of either Pink1 or Parkin.

Current Treatment Modalities for Osteonecrosis of Femoral Head in Mainland China: A Cross-Sectional Study.

OBJECTIVE: To investigate the application of treatment modalities for patients with osteonecrosis of the femoral head (ONFH) in mainland China. METHODS: This cross-sectional study was based on the online application of China Osteonecrosis of the Femoral Head Database (CONFHD). Between July 2016 to December 2018, the CONFHD program planned to recruit ONFH patients from 12 administrative areas across mainland China. Real-world medical records of treatment regimens for these patients, including surgeries and prescriptions, were approved to upload to the CONFHD application for further analysis. The surgeries performed on these patients were classified into total hip arthroplasty and hip-preserving procedures, and the latter was further classified into core decompression, bone grafting, and tantalum rod implantation. Prescription medications were classified into chemical medicine and Chinese herbal medicine (CHM); chemical medicine was further classified according to their chemical compounds, and CHM was classified according to therapeutic functions based on traditional Chinese medicine theory. Descriptive analysis was performed to summarize the application of different treatment regimens on the overall sample. RESULTS: A total of 1491 patients (2381 hips) who fulfilled the protocol criteria were included. There were 1039 males and 452 females with a mean age of 47.29 ± 12.69 years. The causes of ONFH were alcoholism in 642 patients (43%), corticosteroid in 439 patients (29%), trauma in 239 patients (16%), and idiopathic ONFH in 171 patients (11%). Operative treatments (including total hip arthroplasty and hip-preserving procedures) were performed on 49% of patients (43% of hips), chemical medicine therapy (including bisphosphonate, statins, and prostacyclin) was given to 37% of patients (37% of hips), and CHM was administrated to 72% of patients (75% of hips). The aforementioned interventions were not always used alone, since 47% of patients (52% of hips) received combined regimens with multiple interventions. Among hips treated by surgery, all hips with ARCO stage IV ONFH received THA (305 hips), and THA was also performed on 63 hips with stage II ONFH. Over half of hips with stage I (81%), II (91%), and III (92%) ONFH had received pharmacological treatments. Prostacyclin and bisphosphonate were the top two most prescribed medicines used alone. CHM therapies with multiple CHM functions were more commonly prescribed. CONCLUSION: Current treatment modalities for ONFH patients in mainland China include operative treatment, chemical medicine, and CHM. Combined regimens with different treatment modalities are common in real-world clinical practices.

Prediction of Collapse Using Patient-Specific Finite Element Analysis of Osteonecrosis of the Femoral Head.

OBJECTIVE: To develop a prediction method for femoral head collapse by using patient-specific finite element analysis of osteonecrosis of the femoral head (ONFH). METHODS: The retrospective study recruited 40 patients with ARCO stage-II ONFH (40 pre-collapse hips). Patients were divided into two groups according to the 1-year follow-up outcomes: patient group without femoral head collapse (noncollapse group, n = 20) and patient group with collapse (collapse group, n = 20). CT scans of the hip were performed for all patients once they joined the study. Patient-specific finite element models were generated based on these original CT images following the same procedures: segmenting the necrotic lesion and viable proximal femur, meshing the computational models, assigning different material properties according to the Hounsfield unit distribution, simulating the stress loading of the slow walking gait, and measuring the distribution of the von Mises stress. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive performance of the maximum level of the von Mises stress. The optimal cut-off value was selected based on the Youden index and the corresponding predictive accuracy was reported as well. RESULTS: The mean level of the maximum von Mises stress in the collapse group was 2.955 ± 0.539 MPa, whereas the mean stress level in the noncollapse group was 1.923 ± 0.793 MPa (P < 0.01). ROC analysis of the maximum von Mises stress found that the area under the ROC curve was 0.842 (95% CI: 0.717-0.968, P < 0.01). The maximum Youden index was 0.60, which corresponded to two optimal cut-off values: 2.7801 MPa (sensitivity: 0.70; specificity: 0.90; predictive accuracy: 80.00%; LR+: 7), and 2.7027 MPa (sensitivity: 0.75; specificity: 0.85; predictive accuracy: 77.50%; LR+: 5). CONCLUSION: Finite element analysis is a potential method for femoral head collapse prediction among pre-collapse ONFH patients. The maximum level of the von Mises stress on the weight-bearing surface of the femoral head could be a good biomechanical marker to classify the collapse risk. The collapse prediction method based on patient-specific finite element analysis is, thus, suitable to apply to clinical practice, but further testing on a larger dataset is desirable.

Risk assessment of trace metal-polluted coastal sediments on Hainan Island: A full-scale set of 474 geographical locations covering the entire island.

Hainan Island is the second largest island and one of the most famous tourist destinations in China, but sediment contamination by trace metals in coastal areas is a major issue. However, full-scale risk assessments of trace metal-polluted coastal sediments are lacking. In this study, coastal surface sediments from 474 geographical locations covering almost the entire island were collected to identify risk-related variables. Controlling factors and possible sources of trace metals were identified, and the toxicity effects were carefully evaluated. Our results suggest that trace-metal pollution in coastal sediments, which was mainly caused by Pb, Zn and Cu emissions, has primarily resulted from industrial sewage and shipping activities and has threatened the offshore ecosystem of Hainan Island and warrants extensive consideration. This is the first study that has systematically investigated trace metal-polluted coastal sediments throughout the entirety of Hainan Island and provides solid evidence for sustainable marine management in the region.

[Study on optimization of a fewest layer measuring method of osteonecrotic area in femoral head].

OBJECTIVE: To optimize a measuring method of osteonecrotic area by analyzing the average osteonecrotic areas and osteonecritic volume using multi layer MR images. METHODS: The MRI images of 87 cases (120 hips) of ONFH(ARCO II) were collected retrospectively from January 2011 to January 2012 in Wangjing Hospital of China Academy of Chinese Medicine Science. PHILIPS Achieval 1.5T MR was used to obtain coronal TSE T1 weighted (T1W) images. The scanning parameters were shown as follows:slice thickness, 3.5 mm; gap, 0.3 mm; images repetition time(TR), 500 ms;echo time(TE), 20 ms;field of view (FOV), 374 mm;total 12 layers. According to the distribution rule of osteonecrotic lesion, the layer of coronal T1-weighted imaging showing most of femoral neck was marked as layer 0(L0). The layers before L0 were marked in sequence L1, L2, L3, L4... , and the layers after L0 were marked in sequence L-1, L-2, L-3, L-4... . Auto CAD 2007 was used to measure the percentage of osteonecrotic area and calcu late the average data, and then decreased the layer from low to high layer successively based on frequency of osteonecrotic occurrences. First, the layer with lowest frequency of osteonecrotic occurrenoses L3 was removed, then calculated the average osteonecrotic area of the ramaining 8 layers. L5, L4, L-2, L-1, L3 layers were gradually removed, resulting in the calculation of avereage osteonecrotic areas in 7, 6, 5, 4, 3 layers. These areas were compared to the osteonecrotic volume in MR imagings, leading to the optimization of the fewest layer measuring method of osteonecrotic area using a statistical analysis. RESULTS: The percentage of osteonecrotic volume in 120 hips was 0.333±0.151. The average osteonecrotic areas of 9 to 3 layers were 0.321±0.117, 0.317±0.136, 0.312±0.147, 0.333±0.153, 0.348±0.172, 0.365±0.174, 0.377±0.202 respectively. There were no statistical differences of the average osteonecrotic areas and osteonecrotic volume in 9 to 3 layers(P>0.05), but when the osteonecrotic layers were reduced to 3, there were statistical differences(P<0.05). Total 120 hips were grouped according to osteonecrotic volume based on ARCO staging criteria, among them, 12 hips were grade A, 43 were B, 65 were C. According to average osteonecrotic areas of 4 layers, 10 hips were A grade, 32 were B, 78 were C. There were no statistical differences between two methods(P>0.05). There was a high degree of concordance among two methods. CONCLUSIONS: The results of 4(L0, L1, L2, L3) layers measuring method and osteonecrotic volume measuring method are similar. The 4 layers measuring method is an accurate, convenient, valuable method measuring the esteonecrotic area with the fewest layers, which is worth to be popularized in clinical application.

[Treating early-to-middle stage nontraumatic osteonecrosis of femoral head patients by jianpi huogu recipe: a retrospective study].

OBJECTIVE: To observe the efficacy and features of treating early-to-middle stage nontraumatic osteonecrosis of femoral head (NONFH) patients by Jianpi Huogu Recipe (JHR). METHODS: Using retrospective paired control method, early-to-middle stage NONFH patients treated by JHR and followed-up for 2 years were recruited as the test group (47 cases). Those accepted surgery of core decompression, focus debridement and bone graft were recruited as the control group (48 cases). Radiographic images and clinical data of patients were collected before and after treatment. The stable rate and excellent rate of Harris score were taken as efficacy evaluation indicators. RESULTS: (1) There was no statistical difference in excellent rate of Harris score between the two groups (95.74% vs. 79.17%, P > 0.05). But better effects were obtained in the test group in relieving pain, improving joint deformation, joint mobility, and total Harris score (P < 0. 05, P < 0. 01). There was no statistical difference in the stable rate of radiography between the two groups (74.47% vs. 75.00%, P > 0.05). (2) There was no statistical difference in the stable rate of radiography at phase II and Ill [staging by Association Research Circulation Osseous (ARCO)] between the two groups (82.05% vs. 80.00%, 37.50% vs. 50.00%, P > 0.05). (3) The stable rate of radiography and excellent rate of Harris score were obviously higher in ARCO phase II patients than in ARCO phase Il patients (82.05% vs. 37.50%,97.44% vs. 87.50%, P < 0.01). CONCLUSIONS: Equivalent stable rate of radiography to that of surgery could be obtained in treating early-to-middle stage NONFH patients by JHR. But it was better than surgery in relieving pain, improving joint deformation and joint mobility.

[Effects of several ecological factors on the hatching of Sepiella maindroni wild and cultured eggs].

This paper compared the differences between Sepiella maindroni wild and cultured eggs, and studied the effects of temperature, salinity, hatching density, and egg type on the hatching rate and hatching time of the eggs. Wild eggs had better quality than cultured eggs. Among cultured eggs, small and black eggs had the best quality. For wild eggs, the optimum hatching temperature was 27 degrees C - 29 degrees C, and the optimum hatching salinity was 24.5-32.0. Hatching density had no significant effects on the hatching rate of wild eggs. For culturd Fol eggs, their hatching rate was 6.7% 30.0% when the temperature was 19 degrees C - 29 degrees C. No cultured eggs were hatched when the temperature was higher than 33 degrees C or lower than 17 degrees C. When the salinity was 19.5-32.0, the hatching rate of cultured eggs was 18.3%-25.0%. No hatching was observed when the salinity was below 17.0. Hatching density had no significant effects on the hatching rate of cultured eggs when air was provided, but the hatching rate was significantly affected when no air was provided.