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Cover Illustration
2019, Vol.10  No.5
<b><span style="font-size:9.0pt;font-family:"">ISF drainage routes in normal rats and demyelinated rats.</span></b><span style="font-size:9.0pt;font-family:""> Due to the obstruction of the compact myelinated fibre tracts (yellow frame and yellow arrow), the traced ISF from the caudate nucleus (Cn)(pink arrow) could not drain to the ECS of the thalamus (Tha) and vice versa, even though these two regions are adjacent to one another. Myelin is identified as the transportation barrier to ISF drainage in the deep brain. At the meantime, it guides the ISF in the caudate nucleus draining to ipsilateral cortex and finally into the subarachnoid space, which maintains the pathway of ISF-CSF exchange. When the integrity of myelin is interrupted (white frame and white arrow), abnorm [Detail] ...

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  • Table of Content
      01 October 2019, Volume 10 Issue 5 Previous Issue   
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    Orginal Article
    A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology
    Dinesh Upadhya, Maheedhar Kodali, Daniel Gitai, Olagide W Castro, Gabriele Zanirati, Raghavendra Upadhya, Sahithi Attaluri, Eeshika Mitra, Bing Shuai, Bharathi Hattiangady, Ashok K Shetty
    Aging and disease. 2019, 10 (5): 915-936.   DOI: 10.14336/AD.2019.0720
    Abstract   HTML   PDF (1869KB) ( 817 )

    Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.

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    The Drainage of Interstitial Fluid in the Deep Brain is Controlled by the Integrity of Myelination
    Aibo Wang, Rui Wang, Dehua Cui, Xinrui Huang, Lan Yuan, Huipo Liu, Yu Fu, Lei Liang, Wei Wang, Qingyuan He, Chunyan Shi, Xiangping Guan, Ze Teng, Guomei Zhao, Yuanyuan Li, Yajuan Gao, Hongbin Han
    Aging and disease. 2019, 10 (5): 937-948.   DOI: 10.14336/AD.2018.1206
    Abstract   HTML   PDF (1529KB) ( 708 )

    In searching for the drainage route of the interstitial fluid (ISF) in the deep brain, we discovered a regionalized ISF drainage system as well as a new function of myelin in regulating the drainage. The traced ISF from the caudate nucleus drained to the ipsilateral cortex along myelin fiber tracts, while in the opposite direction, its movement to the adjacent thalamus was completely impeded by a barrier structure, which was identified as the converged, compact myelin fascicle. The regulating and the barrier effects of myelin were unchanged in AQP4-knockout rats but were impaired as the integrity of boundary structure of drainage system was destroyed in a demyelinated rat model. We thus proposed that the brain homeostasis was maintained within each ISF drainage division locally, rather than across the brain as a whole. A new brain division system and a new pathogenic mechanism of demyelination are therefore proposed.

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    Metformin Alters Locomotor and Cognitive Function and Brain Metabolism in Normoglycemic Mice
    Wenjun Li, Kiran Chaudhari, Ritu Shetty, Ali Winters, Xiaofei Gao, Zeping Hu, Woo-Ping Ge, Nathalie Sumien, Michael Forster, Ran Liu, Shao-Hua Yang
    Aging and disease. 2019, 10 (5): 949-963.   DOI: 10.14336/AD.2019.0120
    Abstract   HTML   PDF (1429KB) ( 862 )

    Metformin is currently the most effective treatment for type-2 diabetes. The beneficial actions of metformin have been found even beyond diabetes management and it has been considered as one of the most promising drugs that could potentially slow down aging. Surprisingly, the effect of metformin on brain function and metabolism has been less explored given that brain almost exclusively uses glucose as substrate for energy metabolism. We determined the effect of metformin on locomotor and cognitive function in normoglycemic mice. Metformin enhanced locomotor and balance performance, while induced anxiolytic effect and impaired cognitive function upon chronic treatment. We conducted in vitro assays and metabolomics analysis in mice to evaluate metformin’s action on the brain metabolism. Metformin decreased ATP level and activated AMPK pathway in mouse hippocampus. Metformin inhibited oxidative phosphorylation and elevated glycolysis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in vitro at therapeutic doses. In summary, our study demonstrated that chronic metformin treatment affects brain bioenergetics with compound effects on locomotor and cognitive brain function in non-diabetic mice.

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    Dl-3-n-butylphthalide Reduces Neurovascular Inflammation and Ischemic Brain Injury in Mice
    Chun-Sheng Yang, Ai Guo, Yulin Li, Kaibin Shi, Fu-Dong Shi, Minshu Li
    Aging and disease. 2019, 10 (5): 964-976.   DOI: 10.14336/AD.2019.0608
    Abstract   HTML   PDF (1140KB) ( 705 )

    Dl-3-n-butylphthalide (NBP) is a synthetic compound that has been approved for the treatment of ischemic stroke in China. The mechanisms underlying the treatment efficacy of NBP have been reported in multiple studies and remain controversial. Here, we show that NBP treatment attenuated ischemic brain injury in mice subjected to transient middle cerebral artery occlusion or photothrombosis-induced permanent cerebral ischemia. NBP induced downregulation of intercellular adhesion molecule 1 and protease-activated receptor 1 in cerebrovascular endothelial cells after cerebral ischemia and reperfusion. This effect was associated with the reduced brain infiltration of myeloid cells and improved cerebral blood flow after reperfusion. The beneficial effects of NBP were diminished in mice subjected to the depletion of Gr1+ myeloid cells before brain ischemia. Therefore, the restriction of neurovascular inflammation is a key mode of action for NBP in ischemic stroke.

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    Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours
    Artur Anisiewicz, Beata Filip-Psurska, Agata Pawlik, Anna Nasulewicz-Goldeman, Tomasz Piasecki, Konrad Kowalski, Magdalena Maciejewska, Joanna Jarosz, Joanna Banach, Diana Papiernik, Andrzej Mazur, Andrzej Kutner, Jeanette A Maier, Joanna Wietrzyk
    Aging and disease. 2019, 10 (5): 977-991.   DOI: 10.14336/AD.2018.0921
    Abstract   HTML   PDF (1691KB) ( 990 )

    Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.

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    Role of Regulatory T cells in Atorvastatin Induced Absorption of Chronic Subdural Hematoma in Rats
    Wei Quan, Zhifei Zhang, Pan Li, Qilong Tian, Jinhao Huang, Yu Qian, Chuang Gao, Wanqiang Su, Zengguang Wang, Jianning Zhang, Alex Zacharek, Poornima Venkat, Jieli Chen, Rongcai Jiang
    Aging and disease. 2019, 10 (5): 992-1002.   DOI: 10.14336/AD.2018.0926
    Abstract   HTML   PDF (1084KB) ( 718 )

    Chronic subdural hematoma (CSDH) is a neurological disorder with a substantial recurrence rate. Atorvastatin is an effective drug for treating hyperlipidemia and known to improve neurological outcome after intracerebral hemorrhage. Previous studies have reported that atorvastatin treatment promotes hematoma absorption in CSDH, while the underlying mechanisms remain unclear. In this study, we investigated whether the anti-inflammatory effects of atorvastatin mediate absorption of CSDH. 144 male, Wistar rats (6 months old) were randomly divided into the following groups: 1) sham surgery control, 2) treatment: CSDH + atorvastatin, and 3) vehicle control: CSDH + saline. Atorvastatin or saline was orally administered daily for 19 days after CSDH procedure. A T2WI MRI was used to evaluate CSDH volume changes during the time course of the study. Flow cytometry and immunohistochemical staining were used to measure the number of regulatory T cells (Treg). ELISA was used to measure cytokine level in the hematoma border. Neurological function and cognitive outcome were evaluated using Foot-Fault test and Morris Water Maze test, respectively. When compared to saline treatment, atorvastatin treatment accelerated the absorption of CSDH as indicated by decreased hematoma volume in T2WI MRI data on 14th and 21st day after CSDH (P<0.05). Atorvastatin treatment significantly increased the number of Treg in circulation and hematoma border from 3rd to 21st day after CSDH. Atorvastatin treatment significantly decreased the levels of interleukins (IL-6 and IL-8) and tumor necrosis factor-α (TNF-α), but increased IL-10 level in the hematoma border. Atorvastatin treatment also improved neurological function and cognitive outcome compared to vehicle treated group. Atorvastatin induced anti-inflammatory responses and increased Treg in circulation and brain which may contribute to the accelerated CSDH absorption in rats.

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    Clinical and Genetic Profiles in Chinese Patients with Huntington’s Disease: A Ten-year Multicenter Study in China
    Hong-Lei Li, Xiao-Yan Li, Yi Dong, Yan-Bin Zhang, Hong-Rong Cheng, Shi-Rui Gan, Zhi-Jun Liu, Wang Ni, Jean-Marc Burgunder, X. William Yang, Zhi-Ying Wu
    Aging and disease. 2019, 10 (5): 1003-1011.   DOI: 10.14336/AD.2018.0911
    Abstract   HTML   PDF (681KB) ( 809 )

    Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG triplet repeats expansion in exon 1 of the Huntingtin gene (HTT). In China, HD is considered to have a low prevalence. The goal of this study was to describe the clinical characteristic and genetic profiles of HD in a Chinese cohort. A total of 322 individuals with expanded CAG repeats were consecutively recruited from the neurologic clinics of three medical centers in Southeastern China between 2008 and 2018. Among them, 80 were pre-symptomatic mutation carriers and 242 were symptomatic patients. The mean age at onset (AAO), defined here as the age at motor symptom onset, of the 242 manifest HD individuals was 40.3 ± 11.9 years and the mean CAG repeat length was 46.1 ± 7.5 in the group of symptomatic patients. Initial symptoms were abnormal movements in 88.8% of the patients with psychiatric symptoms in 6.2%, cognitive impairment in 3.3% and others in 1.7%. The AAO of motor was negatively correlated with the CAG repeat length in an exponential regression analysis (R 2 = 0.74, P<0.001). Analysis of 46 parent-child pairs showed that the CAG repeat length was longer in the offspring group (45.8 ±7.6) than in the parent group (43.8 ±3.0) (p=0.005). Overall, this study provides clinical and genetic profiles in a cohort of Chinese patients with HD, which should contribute to a better understanding of this disorder.

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    Autoantibodies against AT1 Receptor Contribute to Vascular Aging and Endothelial Cell Senescence
    Meili Wang, Xiaochen Yin, Suli Zhang, Chenfeng Mao, Ning Cao, Xiaochun Yang, Jingwei Bian, Weiwei Hao, Qian Fan, Huirong Liu
    Aging and disease. 2019, 10 (5): 1012-1025.   DOI: 10.14336/AD.2018.0919
    Abstract   HTML   PDF (1161KB) ( 641 )

    Vascular aging predisposes the elderly to the progression of many aging-related vascular disorders and leads to deterioration of cardiovascular diseases (CVD). However, the underlying mechanisms have not been clearly elucidated. Agonistic autoantibodies against angiotensin II type 1 (AT1) receptor (AT1-AAs) have been demonstrated to be pro-inflammatory and contribute to the progression of atherosclerosis. However, the association between AT1-AAs and vascular aging has not been defined. Peripheral arterial disease (PAD) is an acknowledged vascular aging-related disease. In this study, AT1-AAs were detected in the sera of patients with PAD and the positive rate was 44.44% (n=63) vs. 17.46% in non-PAD volunteers (n=63). In addition, case-control analysis showed that AT1-AAs level was positively correlated with PAD. To reveal the causal relationship between AT1-AAs and vascular aging, an AT1-AAs-positive rat model was established by active immunization. The carotid pulse wave velocity was higher, and the aortic endothelium-dependent vasodilatation was attenuated significantly in the immunized rats. Morphological staining showed thickening of the aortic wall. Histological examination showed that levels of the senescent markers were increased in the aortic tissue, mostly located at the endothelium. In addition, purified AT1-AAs-IgGs from both the immunized rats and PAD patients induced premature senescence in cultured human umbilical vein endothelial cells. These effects were significantly blocked by the AT1 receptor blocker. Taken together, our study demonstrates that AT1-AAs contribute to the progression of vascular aging and induce EC senescence through AT1 receptor. AT1-AA is a novel biomarker of vascular aging and aging-related CVD that acts to accelerate EC senescence.

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    Characterization of Alzheimer’s Disease Using Ultra-high b-values Apparent Diffusion Coefficient and Diffusion Kurtosis Imaging
    Yingnan Xue, Zhenhua Zhang, Caiyun Wen, Huiru Liu, Suyuan Wang, Jiance Li, Qichuan Zhuge, Weijian Chen, Qiong Ye
    Aging and disease. 2019, 10 (5): 1026-1036.   DOI: 10.14336/AD.2018.1129
    Abstract   HTML   PDF (862KB) ( 843 )

    The aim of the study is to investigate the diffusion characteristics of Alzheimer’s disease (AD) patients using an ultra-high b-values apparent diffusion coefficient (ADC_uh) and diffusion kurtosis imaging (DKI). A total of 31 AD patients and 20 healthy controls (HC) who underwent both MRI examination and clinical assessment were included in this study. Diffusion weighted imaging (DWI) was acquired with 14 b-values in the range of 0 and 5000 s/mm2. Diffusivity was analyzed in selected regions, including the amygdala (AMY), hippocampus (HIP), thalamus (THA), caudate (CAU), globus pallidus (GPA), lateral ventricles (LVe), white matter (WM) of the frontal lobe (FL), WM of the temporal lobe (TL), WM of the parietal lobe (PL) and centrum semiovale (CS). The mean, median, skewness and kurtosis of the conventional apparent diffusion coefficient (ADC), DKI (including two variables, Dapp and Kapp) and ADC_uh values were calculated for these selected regions. Compared to the HC group, the ADC values of AD group were significantly higher in the right HIP and right PL (WM), while the ADC_uh values of the AD group increased significantly in the WM of the bilateral TL and right CS. In the AD group, the Kapp values in the bilateral LVe, bilateral PL/left TL (WM) and right CS were lower than those in the HC group, while the Dapp value of the right PL (WM) increased. The ADC_uh value of the right TL was negatively correlated with MMSE (mean, r=-0.420, p=0.019). The ADC value and Dapp value have the same regions correlated with MMSE. Compared with the ADC_uh, combining ADC_uh and ADC parameters will result in a higher AUC (0.894, 95%CI=0.803-0.984, p=0.022). Comparing to ADC or DKI, ADC_uh has no significant difference in the detectability of AD, but ADC_uh can better reflect characteristic alternation in unconventional brain regions of AD patients.

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    Hydroxyurea Facilitates Manifestation of Disease Relevant Phenotypes in Patients-Derived IPSCs-Based Modeling of Late-Onset Parkinson’s Disease
    Yuan Tan, Minjing Ke, Zhijian Huang, Cheong-Meng Chong, Xiaotong Cen, Jia-Hong Lu, Xiaoli Yao, Dajiang Qin, Huanxing Su
    Aging and disease. 2019, 10 (5): 1037-1048.   DOI: 10.14336/AD.2018.1216
    Abstract   HTML   PDF (1828KB) ( 1013 )

    Induced pluripotent stem cells (iPSCs)-derived dopaminergic neurons might be reset back to the fetal state due to reprogramming. Thus, it is a compelling challenge to reliably and efficiently induce disease phenotypes of iPSCs-derived dopaminergic neurons to model late-onset Parkinson’s disease (PD). Here, we applied a small molecule, hydroxyurea (HU), to promote the manifestation of disease relevant phenotypes in iPSCs-based modeling of PD. We established two iPS cell lines derived from two sporadic PD patients. Both patients-iPSCs-derived dopaminergic neurons did not display PD relevant phenotypes after 6 weeks culture. HU treatment remarkably induced ER stress on patients-iPSCs-derived dopaminergic neurons. Moreover, HU treatment significantly reduced neurite outgrowth, decreased the expression of p-AKT and its downstream targets (p-4EBP1 and p-ULK1), and increased the expression level of cleaved-Caspase 3 in patients-iPSCs-derived dopaminergic neurons. The findings of the present study suggest that HU administration could be a convenient and reliable approach to induce disease relevant phenotypes in PD-iPSCs-based models, facilitating to study disease mechanisms and test drug effects.

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    Intravenous Administration of Standard Dose Tirofiban after Mechanical Arterial Recanalization is Safe and Relatively Effective in Acute Ischemic Stroke
    Zhe Cheng, Xiaokun Geng, Jie Gao, Mohammed Hussain, Seong-Jin Moon, Huishan Du, Yuchuan Ding
    Aging and disease. 2019, 10 (5): 1049-1057.   DOI: 10.14336/AD.2018.0922
    Abstract   HTML   PDF (688KB) ( 970 )

    To investigate the safety and efficacy of intravenous administration of a standard dose of glycoprotein-IIb/IIIa inhibitor tirofiban after vessel recanalization by mechanical thrombectomy in acute ischemic stroke. A consecutive series of patients (n=112) undergoing endovascular ischemic stroke intervention therapy were enrolled. 81 patients were eligible for intravenous (IV) tirofiban treatment for 24 hours after mechanical thrombectomy. The incidence of symptomatic intracranial hemorrhage (sICH), death, National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) were assessed. In the 81 patients receiving tirofiban, 52 patients (64.2%) were treated with IV rt-PA before mechanical thrombectomy. sICH was found in 2 (2.5%) patients with no fatal ICH. Four patients died during 3 months after stroke onset. Successful recanalization with thrombolysis in cerebral infarction (TICI) score ≥2b was achieved in 75 of 81 patients (92.6%) after mechanical thrombectomy. The average number of passes with Solitaire stent retriever was 1.3. At 3 months, 55 of 81 patients (67.9%) had favorable outcomes (mRS<=2). The intravenous application of a standard dose of tirofiban post-Solitaire stent retriever thrombectomy and intravenous thrombolysis appears to be safe and relatively effective in acute ischemic stroke.

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    AMPK Signaling Regulates the Age-Related Decline of Hippocampal Neurogenesis
    Brian Z Wang, Jane J Yang, Hongxia Zhang, Charity A Smith, Kunlin Jin
    Aging and disease. 2019, 10 (5): 1058-1074.   DOI: 10.14336/AD.2019.0102
    Abstract   HTML   PDF (1870KB) ( 501 )

    The global incidence of age-associated neurological diseases is expected to rise with increasingly greying societies. In the aged brain, there is a dramatic decrease in the number of stem cells, which is a main cause for the decrease in brain function. Intrinsic factors, such as cell metabolism, have been studied but its role in neurogenesis is still unknown. Therefore, this study sought to establish whether AMP-activated protein kinase (AMPK) signaling does indeed regulate hippocampal neurogenesis in the aged brain. We found that i) AMPKα2 was the predominant catalytic subunit in the subgranular and subventricular zones; ii) AMPK activation was at a significantly higher level in the aged vs. young hippocampus; iii) short term (7 days) treatment with selective AMPK signaling inhibitor Compound C (10 mg/kg/day, i.p.) significantly increased the numbers of newborn (BrdU+), Type 2 (MCM2+), and Type 3 (DCX+) neural stem cells, but not Type 1 (GFAP+/Sox2+) cells, in the aged hippocampus. Taken together, our results demonstrate that AMPK signaling plays a critical role in the age-related decline of hippocampal neurogenesis.

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    Review Article
    Preclinical Evidence and Possible Mechanisms of Extracts or Compounds from Cistanches for Alzheimer’s Disease
    Xiao-Li Zhou, Meng-Bei Xu, Ting-Yu Jin, Pei-Qing Rong, Guo-Qing Zheng, Yan Lin
    Aging and disease. 2019, 10 (5): 1075-1093.   DOI: 10.14336/AD.2018.0815-1
    Abstract   HTML   PDF (2138KB) ( 810 )

    Currently, disease-modified strategies to prevent, halt or reverse the progress of Alzheimer’s disease (AD) are still lacking. Previous studies indicated extracts or compounds from Cistanches (ECC) exert a potential neuroprotective effect against AD. Thus, we conducted a preclinical systematic review to assess preclinical evidence and possible mechanisms of ECC in experimental AD. A systematical searching strategy was carried out across seven databases from their inceptions to July 2018. Twenty studies with 1696 rats or mice were involved. Neurobehavioral function indices as primary outcome measures were established by the Morris water maze test (n = 11), step-down test (n = 10), electrical Y-maze test (n = 4), step-through test (n = 3), open field test (n = 2) and passage water maze test (n = 1). Compared with controls, the results of the meta-analysis showed ECC exerted a significant effect in decreasing the escape latency, error times and wrong reaction latency in both the training test and the retention test, and in increasing the exact time and the percentage of time in the platform-quadrant and the number of platform crossings (all P<0.01). In conclusion, ECC exert potential neuroprotective effects in experimental AD, mainly through mechanisms involving antioxidant stress and antiapoptosic effects, inhibiting Aβ deposition and tau protein hyperphosphorylation and promoting synapse protection. Thus, ECC could be a candidate for AD treatment and further clinical trials.

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    Pyroptosis in Liver Disease: New Insights into Disease Mechanisms
    Jiali Wu, Su Lin, Bo Wan, Bharat Velani, Yueyong Zhu
    Aging and disease. 2019, 10 (5): 1094-1108.   DOI: 10.14336/AD.2019.0116
    Abstract   HTML   PDF (565KB) ( 1537 )

    There has been increasing interest in pyroptosis as a novel form of pro-inflammatory programmed cell death. The mechanism of pyroptosis is significantly different from other forms of cell death in its morphological and biochemical features. Pyroptosis is characterized by the activation of two different types of caspase enzymes—caspase-1 and caspase-4/5/11, and by the occurrence of a proinflammatory cytokine cascade and an immune response. Pyroptosis participates in the immune defense mechanisms against intracellular bacterial infections. On the other hand, excessive inflammasome activation can induce sterile inflammation and eventually cause some diseases, such as acute or chronic hepatitis and liver fibrosis. The mechanism and biological significance of this novel form of cell death in different liver diseases will be evaluated in this review. Specifically, we will focus on the role of pyroptosis in alcoholic and non-alcoholic fatty liver disease, as well as in liver failure. Finally, the therapeutic implications of pyroptosis in liver diseases will be discussed.

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    Handgrip Strength and Pulmonary Disease in the Elderly: What is the Link?
    Tatiana Rafaela Lemos Lima, Vívian Pinto Almeida, Arthur Sá Ferreira, Fernando Silva Guimarães, Agnaldo José Lopes
    Aging and disease. 2019, 10 (5): 1109-1129.   DOI: 10.14336/AD.2018.1226
    Abstract   HTML   PDF (1124KB) ( 1395 )

    Societies in developed countries are aging at an unprecedented rate. Considering that aging is the most significant risk factor for many chronic lung diseases (CLDs), understanding this process may facilitate the development of new interventionist approaches. Skeletal muscle dysfunction is a serious problem in older adults with CLDs, reducing their quality of life and survival. In this study, we reviewed the possible links between handgrip strength (HGS)—a simple, noninvasive, low-cost measure of muscle function—and CLDs in the elderly. Different mechanisms appear to be involved in this association, including systemic inflammation, chronic hypoxemia, physical inactivity, malnutrition, and corticosteroid use. Respiratory and peripheral myopathy, associated with muscle atrophy and a shift in muscle fiber type, also seem to be major etiological contributors to CLDs. Moreover, sarcopenic obesity, which occurs in older adults with CLDs, impairs common inflammatory pathways that can potentiate each other and further accelerate the functional decline of HGS. Our findings support the concept that the systemic effects of CLDs may be determined by HGS, and HGS is a relevant measurement that should be considered in the clinical assessment of the elderly with CLDs. These reasons make HGS a useful practical tool for indirectly evaluating functional status in the elderly. At present, early muscle reconditioning and optimal nutrition appear to be the most effective approaches to reduce the impact of CLDs and low muscle strength on the quality of life of these individuals. Nonetheless, larger in-depth studies are needed to evaluate the link between HGS and CLDs.

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    Subtyping of Parkinson’s Disease - Where Are We Up To?
    Elizabeth Qian, Yue Huang
    Aging and disease. 2019, 10 (5): 1130-1139.   DOI: 10.14336/AD.2019.0112
    Abstract   HTML   PDF (404KB) ( 851 )

    Heterogenous clinical presentations of Parkinson’s disease have aroused several attempts in its subtyping for the purpose of strategic implementation of treatment in order to maximise therapeutic effects. Apart from a priori classifications based purely on motor features, cluster analysis studies have achieved little success in receiving widespread adoption. A priori classifications demonstrate that their chosen factors, whether it be age or certain motor symptoms, do have an influence on subtypes. However, the cluster analysis approach is able to integrate these factors and other clinical features to produce subtypes. Differences in inclusion criteria from datasets, in variable selection and in methodology between cluster analysis studies have made it difficult to compare the subtypes. This has impeded such subtypes from clinical applications. This review analysed existing subtypes of Parkinson’s disease, and suggested that future research should aim to discover subtypes that are robustly replicable across multiple datasets rather than focussing on one dataset at a time. Hopefully, through clinical applicable subtyping of Parkinson’s disease would lead to translation of these subtypes into research and clinical use.

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    Short Communications
    The Peptide-Directed Lysosomal Degradation of CDK5 Exerts Therapeutic Effects against Stroke
    Ya-Fan Zhou, Jing Wang, Man-Fei Deng, Bin Chi, Na Wei, Jian-Guo Chen, Dan Liu, Xiaoping Yin, Youming Lu, Ling-Qiang Zhu
    Aging and disease. 2019, 10 (5): 1140-1145.   DOI: 10.14336/AD.2018.1225
    Abstract   HTML   PDF (954KB) ( 1085 )

    The aberrant activation of CDK5 has been implicated in neuronal death in stroke. The goal of this study is to determine whether knocking down CDK5 by a peptide-directed lysosomal degradation approach is therapeutically effective against stroke. We synthesized a membrane-permeable peptide that specifically binds to CDK5 with a chaperone-mediated autophagy targeting motif (Tat-CDK5-CTM) and tested its therapeutic effects on a mouse model of ischemic stroke. Our results showed that Tat-CDK5-CTM blocked the CDK5-NR2B interaction, resulting in the degradation of CDK5, which in turn prevented calcium overload and neuronal death in cultured neurons. Tat-CDK5-CTM also reduced the infarction area and neuronal loss and improved the neurological functions in MCAO (Middle cerebral artery occlusion) mice. The peptide-directed lysosomal degradation of CDK5 is a promising therapeutic intervention for stroke.

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Kunlin Jin, M.D., Ph.D., Professor
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