Childhood asthma was associated with the presence of cardio-cerebrovascular diseases in US middle-aged and elderly.

Background: Asthma and cardio-cerebrovascular diseases (CVDs) share a common etiology of chronic systemic inflammation. Our manuscript was to investigate the association between childhood asthma and CVDs in middle-aged and elderly. Methods: A total of 12,070 US middle-aged and elder were enrolled in the National Health and Nutrition Examination Survey. Childhood asthma was defined as a previous diagnosis of asthma at <18 years of age. Associations between childhood asthma and overall and cause-specific CVDs were evaluated using multivariable logistic regression models and subgroup analyses, including coronary artery disease (CAD), angina, and stroke. Results: The prevalence of CVDs, including CAD (p = 0.031) and angina (p < 0.001), was significantly higher in patients with asthma (p = 0.008). Asthma was independently associated with a higher risk of CVDs (odds ratio [OR]:1.50, 95 % confidence interval [CI]: 1.22-1.84, p < 0.001), CAD (OR: 1.55, 95 %CI: 1.17-2.02, p = 0.002), and angina (OR: 1.93, 95 %CI: 1.42-2.58, p < 0.001) while not related to stroke (p = 0.233). Subgroup analysis suggested that the association was consistent across sex, race, and the presence of obesity, chronic obstructive pulmonary disease, and diabetes. Conclusions: Childhood asthma was significantly associated with the presence of cardiocerebrovascular diseases, including CAD and angina in middle-aged and elderly. These findings underscore the importance of addressing childhood asthma as a potential risk factor for cardiovascular morbidity in middle-aged and elderly populations.

Neuromuscular Electrical Stimulation of Peroneal Longus on Balance Control Ability in Young Adults with Chronic Ankle Instability: A Randomized Controlled Trial.

OBJECTIVE: This study aimed to investigate the effects of six weeks of peroneal longus neuromuscular electrical stimulation (NMES) on the balance control ability in young adults with chronic ankle instability (CAI). DESIGN: This study is a double blind randomized controlled trial. Six weeks of NMES and placebo intervention were conducted in the NMES and control groups for 20 minutes, three times a week, respectively. Thirty-eight participants successfully completed the whole intervention and single-leg standing tests. The kinetics data of the center of pressure (COP) trajectory during static single-leg stance were measured using a Kistler force platform. Two-way repeated measures ANOVA was used to analyze the electrical stimulation effects. RESULTS: Significant interactions were detected in CAIT scores and all balance parameters including Displacement X (Dx), Displacement Y(Dy), 95% confidence ellipse area (95%AREA), root-mean-square (RMS) and COP mean displacement velocity (MV) (p < 0.05, 0.103 ≤ η2 ≤ 0.201). Significant between-group differences were found in CAIT scores (p = 0.003, Cohen's d = 0.215), Dx (p = 0.045, Cohen's d = 0.107), RMS-ml (p = 0.019, Cohen's d = 0.143) and 95%AREA (p = 0.031, Cohen's d = 0.123) after the six weeks interventions. CONCLUSION: Six weeks of NMES on the peroneus longus can improve static balance control ability in young adults with CAI, especially the stability of ankle frontal plane.

Relationship between syncopal symptoms and head-up tilt test modes.

OBJECTIVE: Head-up tilt test (HUTT) is an important tool in the diagnosis of pediatric vasovagal syncope. This research will explore the relationship between syncopal symptoms and HUTT modes in pediatric vasovagal syncope. METHODS: A retrospective analysis was performed on the clinical data of 2513 children aged 3-18 years, who were diagnosed with vasovagal syncope, from Jan. 2001 to Dec. 2021 due to unexplained syncope or pre-syncope. The average age was 11.76 ± 2.83 years, including 1124 males and 1389 females. The patients were divided into the basic head-up tilt test (BHUT) group (596 patients) and the sublingual nitroglycerine head-up tilt test (SNHUT) group (1917 patients) according to the mode of positive HUTT at the time of confirmed pediatric vasovagal syncope. RESULTS: (1) Baseline characteristics: Age, height, weight, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and composition ratio of syncope at baseline status were higher in the BHUT group than in the SNHUT group (all P < 0.05). (2) Univariate analysis: Age, height, weight, HR, SBP, DBP, and syncope were potential risk factors for BHUT positive (all P < 0.05). (3) Multivariate analysis: syncope was an independent risk factor for BHUT positive, with a probability increase of 121% compared to pre-syncope (P<0.001). CONCLUSION: The probability of BHUT positivity was significantly higher than SNHUT in pediatric vasovagal syncope with previous syncopal episodes.

Neuromuscular electrical stimulation improves frontal ankle motor control in individuals with chronic ankle instability during drop-landing.

OBJECTIVE: This study investigated the effect of neuromuscular electrical stimulation (NMES) on the frontal ankle motor control in individuals with chronic ankle instability (CAI) during drop-landing. DESIGN: This was a randomized, controlled, double-blind trial. Thirty-six individuals with CAI were randomly assigned to each group. Participants received 6-week NMES intervention and sham stimulation in the NMES and control groups, respectively. Data was collected at week0 and week6. A mixed-effects model and analysis of covariance were employed to investigate the between-group differences in continuous and discrete outcome variables at week6, with the outcome variables at week0 as covariates. RESULTS: Compared to control group, NMES group exhibited a 2.66° (2.45, 2.86) reduction in frontal ankle inversion angle, a 47.41°/s (-16.05, -78.77) decrease in peak ankle inversion angular velocity, and a 0.43 Nm/kg (0.18, 0.68) increase in peak ankle eversion moment during drop-landing at week6. CONCLUSION: Applying 6-week NMES to the fibularis longus resulted in decreased ankle inversion angle and ankle inversion angular velocity, and increased peak ankle eversion moment during drop-landing. Consequently, NMES could be considered an effective modality for individuals with CAI to enhance the frontal ankle movement patterns and overall ankle motor control.

Current status and prospect of immunotherapy for colorectal cancer.

PURPOSE: Colorectal cancer is the most common gastrointestinal tumor in China. While significant progress has been achieved in traditional chemotherapy, radiotherapy, and targeted therapy, the prognosis of advanced colorectal cancer is poor, and the five-year survival rate is unsatisfactory. There is an urgent need to explore new treatment modalities. In this review, we examined the latest progress of colorectal cancer immunotherapy and discussed its future prospects. METHODS: We conducted a literature review to sort out the current status of immunotherapy for different types of colorectal cancer and discussed potential combination therapy options. Results Subsequent line therapy, first-line therapy and neoadjuvant therapy for MSI-H/dMMR colorectal cancer are discussed. In addition, combination therapy options for patients with MSS/pMMR colorectal cancer are presented. Finally, current valuable biomarkers for immunotherapy are highlighted. RESULTS: Subsequent line therapy, first-line therapy and neoadjuvant therapy for MSI-H/dMMR colorectal cancer are discussed. In addition, combination therapy options for patients with MSS/pMMR colorectal cancer are presented. Finally, current valuable biomarkers for immunotherapy are highlighted. CONCLUSION: This review discussed the current status of immunotherapy for different types of colorectal cancer and biomarkers for immunotherapy.

Association between ankle-brachial blood pressure index with all-cause and cardiovascular mortality in adults without arterial stiffness.

PURPOSE: To explore the relationship between ankle-brachial blood pressure index (ABPI) and all-cause or cardiovascular mortality in adults without arterial stiffness. METHODS: A total of 6784 participants without arterial stiffness were enrolled from National Health and Nutrition Examination Survey 1999-2004. The hazard ratio (HR) and 95% confidence interval (CI) of ABPI associating with the risk of all-cause and cardiovascular mortality was calculated by Cox proportional regression models adjusted for demographic and traditional risk factors. Dose-response relationship was explored with restricted cubic spines. RESULTS: After an average follow-up of 12.1 years, 1844 all-cause deaths and 299 cardiovascular deaths occurred. Compared with the lowest ABPI quartile, the second quartile was associated with the lowest risk of all-cause mortality (HR 0.89, 95%CI 0.79-0.98; p = 0.036) and cardiovascular mortality (HR 0.75, 95%CI 0.56-0.98; p = 0.048). Besides, dose-response analysis revealed that ABPI was nonlinearly correlated to all-cause mortality (p for nonlinearity < 0.001) and linearly correlated to cardiovascular mortality (p for nonlinearity = 0.459). CONCLUSIONS: The relationship between ABPI and all-cause and cardiovascular mortality followed a L-shape curve. A lower ABPI was independently associated with an increased risk of all-cause and cardiovascular mortality in adults without arterial stiffness.

Functional and structural alterations as diagnostic imaging markers for depression in de novo Parkinson's disease.

Background: Depression in Parkinson's disease (PD) is identified and diagnosed with behavioral observations and neuropsychological measurements. Due to the large overlaps of depression and PD symptoms in clinical manifestations, it is challenging for neurologists to distinguish and diagnose depression in PD (DPD) in the early clinical stage of PD. The advancement in magnetic resonance imaging (MRI) technology provides potential clinical utility in the diagnosis of DPD. This study aimed to explore the alterations of functional and structural MRI in DPD to produce neuroimaging markers in discriminating DPD from non-depressed PD (NDPD) and healthy controls (HC). Methods: We recruited 20 DPD, 37 NDPD, and 41 HC matched in age, gender, and education years. The patients' diagnosis with PD was de novo. The differences in regional homogeneity (ReHo), voxel-wise degree centrality (DC), cortical thickness, cortical gray matter (GM) volumes, and subcortical GM volumes among these groups were detected, and the relationship between altered indicators and depression was analyzed. Moreover, the receiver operating characteristic (ROC) analysis was performed to assess the diagnostic efficacy of altered indicators for DPD. Results: Compared to NDPD and HC, DPD showed significantly increased ReHo in left dorsolateral superior frontal gyrus (DSFG) and DC in left inferior temporal gyrus (ITG), and decreased GM volumes in left temporal lobe and right Amygdala. Among these altered indicators, ReHo value in left DSFG and DC values in left ITG and left DSFG were significantly correlated with the severity of depression in PD patients. Comparing DPD and NDPD, the ROC analysis revealed a better area under the curve value for the combination of ReHo value in left DSFG and DC value in left ITG, followed by each independent indicator. However, the difference is not statistically significant. Conclusion: This study demonstrates that both functional and structural impairments are present in DPD. Among them, ReHo value of left DSFG and DC value of left ITG are equally well suited for the diagnosis and differential diagnosis of DPD, with a combination of them being slightly preferable. The multimodal MRI technique represents a promising approach for the classification of subjects with PD.

Association of GBA genotype with motor and cognitive decline in Chinese Parkinson's disease patients.

Objective: Variants in the glucocerebrosidase (GBA) gene are the most common and significant risk factor for Parkinson's disease (PD). However, the impact of GBA variants on PD disease progression in the Chinese population remains unclear. This study aimed to explore the significance of GBA status on motor and cognitive impairment in a longitudinal cohort of Chinese patients with PD. Methods: The entire GBA gene was screened by long-range polymerase chain reaction (LR-PCR) and next generation sequencing (NGS). A total of 43 GBA-related PD (GBA-PD) and 246 non-GBA-mutated PD (NM-PD) patients with complete clinical data at baseline and at least one follow-up were recruited for this study. The associations of GBA genotype with rate of motor and cognitive decline, as measured by Unified PD Rating Scale (UPDRS) motor and Montreal Cognitive Assessment (MoCA), were assessed by linear mixed-effect models. Results: The estimated (standard error, SE) UPDRS motor [2.25 (0.38) points/year] and MoCA [-0.53 (0.11) points/year] progression rates in the GBA-PD group were significantly faster than those in the NM-PD group [1.35 (0.19); -0.29 (0.04) points/year; respectively]. In addition, the GBA-PD group showed significantly faster estimated (SE) bradykinesia [1.04 (0.18) points/year], axial impairment [0.38 (0.07) points/year], and visuospatial/executive [-0.15 (0.03) points/year] progression rates than the NM-PD group [0.62 (0.10); 0.17 (0.04); -0.07 (0.01) points/year; respectively]. Conclusion: GBA-PD is associated with faster motor and cognitive decline, specifically greater disability in terms of bradykinesia, axial impairment, and visuospatial/executive function. Better understanding of GBA-PD progression may help predict prognosis and improve clinical trial design.

Predictive Value of the Ankle-Brachial Index for All-Cause and Cardio-Cerebrovascular Mortality.

The present study explored the relationship between the ankle-brachial index (ABI) (>.9) and all-cause or cardio-cerebrovascular mortality. Participant details were obtained from the National Health and Nutrition Examination Survey 1999-2004. The association between baseline ABI and the risk of mortality was evaluated by a priori defined quartile categories and on a continuous scale (per .1-unit change) with Cox regression models adjusted for demographic and traditional risk factors. A total of 7087 individuals (age: 59.6 ± 12.8 years) were included; 3612 (51.0%) were male. After an average follow-up of 12.2 years, 1926 deaths occurred. Kaplan-Meier analysis showed that the lowest ABI quartile (<1.06) was associated with the highest risk of all-cause, cardio-cerebrovascular and cancer mortality (all P < .001). However, after adjusting for potential confounders, ABI ranging between 1.06 and 1.12 was associated with the lowest risk of all-cause mortality (hazard ratio .88, 95% confidence interval .78-1.00, P < .05) compared with the reference group (<1.06). Besides, splines showed the relationship was nonlinear (P < .05) and the inflection point was 1.11. In conclusion, the level of ABI associated with the lowest risk of all-cause mortality was 1.11, under which a lower ABI was independently associated with an increased risk of all-cause mortality.

The Lower Limb Stiffness, Moments, and Work Mode During Stair Descent Among the Older Adults.

OBJECTIVE: Lower limb stiffness strategies and work mode changes between young and older adults during stair descent are unclear. This study investigated the effect of aging on the lower limb stiffness, moments, and joint work mode during stair descent. DESIGN: Twenty young adults and 20 older adults were recruited from the local community for stair descent test. Kinematics and kinetics data were collected by Vicon system and Kistler force plate. The lower limb stiffness, moments, and work mode were calculated and assess between groups. RESULTS: No significant differences in gait parameters were detected between groups. Compared with young adults, older adults have decreased leg stiffness, knee and ankle stiffness, increased peak hip extension moment, hip stiffness, and ankle work contribution. CONCLUSIONS: The older adults actively reduce the lower limb stiffness to reduce the risk of injury during stair descent. The hip joint strategy reduces the risk of forwarding falls and ankle joint compensation work mode to make up for the lack of knee extension strength. This provides a reference for the focus of exercise intervention and rehabilitation strategies for older adults.

Zishen pingchan granules combined with pramipexole in the improvement of depressive symptoms in Parkinson's disease: a prospective, multicenter, randomized, double-blind, controlled clinical study.

BACKGROUND AND OBJECTIVE: Zishen Pingchan granule (ZPG), a traditional Chinese herbal recipe for treating Parkinson's disease (PD), is usually used as an add-on drug with some antiparkinsonian drugs in China. The objectives of this study were to evaluate the efficacy, safety, and tolerability of ZPG combined with pramipexole in the treatment of depression in PD (dPD). METHODS: A 12-week, multicenter, randomized, double-blind, and placebo-controlled study on ZPG was performed on a total of 200 patients who were treated with pramipexole but still had mild to moderate depressive symptoms. Patients were randomly divided into ZPG (n = 100) or placebo (n = 100). The primary effective result was the mean change from the baseline on the Hamilton Depression Scale 17 items (HAM-D-17) over 12 weeks and the clinical efficacy rate. Secondary endpoints were the mean change from the baseline in the Geriatric Depression Scale (GDS-15), Unified Parkinson's disease rating scale Part III (UPDRS III), Parkinson's quality of life scale (PDQ-8), and Parkinson's disease sleep scale (PDSS-2) over 12 weeks. RESULTS: After 12 weeks of treatment, ZPG significantly reduced the mean [95% confidence interval] HAMD score vs. placebo (- 1.43 scores [- 2.50, - 0.36]; p = 0.009). The clinical remission rate and responders of the ZPG group were higher than those of the placebo (46.1% vs. 31.0%; p = 0.041; 34.8% vs. 18.4%; p = 0.014). A significant improvement in the PDSS-2 score was also observed in the ZPG group compared with that in the placebo group (- 3.56 scores [- 5.77, - 1.35]; p = 0.002). A total of 7 patients (7.1%) in the ZPG group had mild adverse events (AEs) vs 9 patients (9%) in the placebo group. No severe AEs were observed in either group. The randomization and controlled clinical study revealed that ZPG was effective, safe, and well-tolerated. CONCLUSION: ZPG combined with pramipexole further reduced the depressive symptoms and improved the sleeping quality of PD patients. Trial registration The protocol was retrospectively registered at the Chinese Clinical Trial Registry, Unique identifier: ChiCTR1800019942, date of registration: December 9, 2018; http://www.chictr.org.cn/showproj.aspx?proj=30432.

Research progress review on long non-coding RNA in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies globally, and the morbidity and mortality rates associated with it are among the highest around the world. Not even great advances in colorectal cancer diagnosis and treatment technologies have been able to increase the 5-year survival rate in this disease. Recidivation and metastasis are the main causes of death in CRC, although the underlying mechanism remains unknown. Long non-coding RNA (lncRNA) is a type of non-coding RNA that is greater than 200 nt in length. LncRNAs are involved in cell proliferation, apoptosis, metastasis, and differentiation. Abnormal expression of lncRNAs is reported in various diseases. Relevant studies have demonstrated that lncRNAs are capable of interacting with DNAs, RNAs, and proteins, thereby regulating the Wnt, p53, and other signaling pathways and playing an important role in the biogenesis, progression, metastasis, and drug resistance in CRC. In the present report, recent progress in the research related to lncRNAs in colorectal cancer is reviewed.

miR-122 promotes diabetic retinopathy through targeting TIMP3.

Diabetic retinopathy (DR) is a primary complication of diabetes mellitus. DR can cause severe vision loss for patients. miR-122 is elevated in DR patients, while its role in DR is unclear. Hence, the purpose of this study was to analyze the effect of miR-122 on the function of high glucose-induced REC cells and the underlying molecular mechanisms. In this study, our results revealed that miR-122 was up-regulated in high glucose-induced human retinal pigment epithelial cells (ARPE-19). High glucose decreased the cell viability of ARPE-19 cells, which was then restored by miR-122 knockdown. In addition, miR-122 knockdown suppressed apoptosis of high glucose-induced ARPE-19 cells. High glucose also inhibited B-cell lymphoma-2 (Bcl-2) level and increased cleaved caspase-3 level in ARPE-19 cells, which were reversed by miR-122 knockdown. Tissue inhibitor of metalloproteinases-3 (TIMP3) was a direct target of miR-122. TIMP3 was decreased in high glucose-induced ARPE-19 cells, and the decrease was abrogated by miR-122 knockdown. In addition, the effects of miR-122 overexpression in cell viability and apoptosis of high glucose-induced ARPE-19 were abolished by overexpression of TIMP3. In conclusion, the effect and mechanism of miR-122 on high glucose-induced ARPE-19 cells were demonstrated for the first time. miR-122 promoted diabetic retinopathy through targeting TIMP3, making miR-122 a promising target for diabetic retinopathy therapy.

The effect of text-based math task on dynamic stability control during stair descent

Stair descent imposes a significant challenge for dynamic stability among young adults. The effect of a concurrent text-based math task on dynamic stability control remains unclear during stair descent when considering the influence of gait velocity. Twenty-six participants performed three successful stair descent trials under TEXTING or NO-TEXTING conditions at their preferred speed. Synchronous kinematics and kinetics were collected by an eight-camera Vicon infrared motion capture system and two force platforms. Repeated measures analysis of covariance and Wilcoxon signed rank test were used to analyze the differences between the two different task conditions with gait velocity as a covariate. The outcomes indicated that under TEXTING condition, sagittal margin of stability increased at right-foot-landing; step cadence, double-support percentage, sagittal and frontal joint moment decreased; and sagittal and frontal joint angles were also modified. It is concluded that concurrent TEXTING impaired sagittal and frontal stability control during stair descent despite slowing down the step cadence. Knee and ankle joint adjustment strategies were mainly adopted in response to stability control in the sagittal plane with the interference of TEXTING, whereas the hip joint adjustment strategy was adopted in the frontal plane. In conclusion, texting behaviors on mobile phones should be minimized during stair descent.

Comparative diagnostic accuracy of ACE-III and MoCA for detecting mild cognitive impairment.

OBJECTIVE: The aim of this study was to validate the reliability of the Chinese version of Addenbrooke's Cognitive Examination III (ACE-III) for detecting mild cognitive impairment. Furthermore, the present study compares the diagnostic accuracy of ACE-III with that of Montreal Cognitive Assessment (MoCA). METHODS: One hundred and twenty patients with MCI and 136 healthy controls were included in the study. All patients were evaluated by the Chinese version of ACE-III, MoCA and MMSE. RESULTS: Subjects in the control group showed better performance in ACE-III total score and its subdomain scores than those in the MCI group. There was a significantly positive correlation between ACE-III total score and MoCA score. Meanwhile, there was also a significantly positive correlation between ACE-III total score and MMSE score. For ACE-III total score, a cut-off point of 85 yielded a sensitivity of 97.3% and a specificity of 90.7%. The AUC for ACE-III total score was 0.978. For MoCA, a cut-off point of 23 yielded a sensitivity of 86.5% and a specificity of 97.7%. The AUC for MoCA was 0.961. There were no significant differences in diagnostic accuracy between ACE-III and MoCA. CONCLUSION: The present findings support that both ACE-III and MoCA are useful for detecting MCI in early stages.

[Design and implementation of postoperative evaluation pipeline of deep brain stimulation by multimodality imaging].

Deep brain stimulation (DBS) surgery is an important treatment for patients with Parkinson's disease in the middle and late stages. The accuracy of the implantation of electrode at the location of the nuclei directly determines the therapeutic effect of the operation. At present, there is no single imaging method that can obtain images with electrodes, nuclei and their positional relationship. In addition, the subthalamic nucleus is small in size and the boundary is not obvious, so it cannot be directly segmented. In this paper, a complete end-to-end DBS effect evaluation pipeline was constructed using magnetic resonance (MR) data of T1, T2 and SWI weighted by DBS surgery. Firstly, the images of preoperative and postoperative patients are registered and normalized to the same coordinate space. Secondly, the patient map is obtained by non-rigid registration of brain map and preoperative data, as well as the preoperative nuclear cluster prediction position. Then, a three-dimensional (3D) image of the positional relationship between the electrode and the nucleus is obtained by using the electrode path in the postoperative image and the result of the nuclear segmentation. The 3D image is helpful for the evaluation of the postoperative effect of DBS and provides effective information for postoperative program control. After analysis, the algorithm can achieve a good registration between the patient's DBS surgical image and the brain map. The error between the algorithm and the expert evaluation of the physical coordinates of the center of the thalamus is (1.590 ± 1.063) mm. The problem of postoperative evaluation of the placement of DBS surgical electrodes is solved.

Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy.

Hydrogen sulfide has recently been found decreased in chronic kidney disease. Here we determined the effect and underlying mechanisms of hydrogen sulfide on a rat model of unilateral ureteral obstruction. Compared with normal rats, obstructive injury decreased the plasma hydrogen sulfide level. Cystathionine-ß-synthase, a hydrogen sulfide-producing enzyme, was dramatically reduced in the ureteral obstructed kidney, but another enzyme cystathionine-γ-lyase was increased. A hydrogen sulfide donor (sodium hydrogen sulfide) inhibited renal fibrosis by attenuating the production of collagen, extracellular matrix, and the expression of α-smooth muscle actin. Meanwhile, the infiltration of macrophages and the expression of inflammatory cytokines including interleukin-1ß, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in the kidney were also decreased. In cultured kidney fibroblasts, a hydrogen sulfide donor inhibited the cell proliferation by reducing DNA synthesis and downregulating the expressions of proliferation-related proteins including proliferating cell nuclear antigen and c-Myc. Further, the hydrogen sulfide donor blocked the differentiation of quiescent renal fibroblasts to myofibroblasts by inhibiting the transforming growth factor-ß1-Smad and mitogen-activated protein kinase signaling pathways. Thus, low doses of hydrogen sulfide or its releasing compounds may have therapeutic potentials in treating chronic kidney disease.

Autophagic impairment contributes to systemic inflammation-induced dopaminergic neuron loss in the midbrain.

BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as α-synuclein (α-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown. RESULTS: Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of α-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-α induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-α (50 ng/ml) increased the expression of LC3-II, p62, and α-SYN, implying that TNF-α triggered autophagic impairment in cells. CONCLUSION: Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.

Crosstalk between the proteasome system and autophagy in the clearance of α-synuclein.

AIM: A growing body of evidence suggests that α-synuclein accumulation may play an important role in the pathogenesis of Parkinson's disease. The aim of this study was to investigate the roles of the proteasome and autophagy pathways in the clearance of wild-type and mutant α-synuclein in PC12 cells. METHODS: PC12 cells overexpressing either wild-type or A30P mutant α-synuclein were treated with the proteasome inhibitor epoxomicin, the macroautophagy inhibitor 3-MA and the macroautophagy activator rapamycin alone or in combination. The cell viability was assessed using MTT assay. Immunofluorescence and Western blot analysis were used to detect the level of α-synuclein, LAMP-2A, E1 activase, and E2 ligase in the cells. Chymotrypsin-like proteasomal activity was measured using a commercial kit. RESULTS: When the proteasome and macroautophagy in the wild-type and mutant cells were inhibited with epoxomicin and 3-MA, respectively, the cell viability was significantly decreased, and the α-synuclein level was increased. Both epoxomicin and 3-MA activated the chaperone-mediated autophagy (CMA) by increasing the level of the CMA-limiting enzyme LAMP-2A. Furthermore, 3-MA or epoxomicin significantly decreased chymotrypsin-like proteasomal activity. 3-MA or epoxomicin did not change E1 activase expression in either mutant or wild-type cells, but increased E2 ligase expression, especially when used together. Macroautophagy inducer rapamycin increased the cell viability and reduced epoxomicin-induced α-synuclein accumulation. Interestingly, CMA was also activated by rapamycin. CONCLUSION: Our results demonstrate the existence of complex crosstalk between different forms of autophagy and between autophagy and the proteasome pathway in the clearance of α-synuclein in PC12 cells.

Application and interpretation of current autophagy inhibitors and activators.

Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.