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.

Prognostic significance of urinary protein and urinary ketone bodies in acute ischemic stroke.

BACKGROUND AND AIMS: Prior studies have shown an association between positive urinary protein and an elevated risk of long-term mortality in patients with acute ischemic stroke (AIS); however, data on the short-term prognostic significance of urinary protein and urinary ketone bodies in patients with AIS is sparse. METHODS AND RESULTS: A total of 2842 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included. Patients were divided into urinary protein positive and negative, urinary ketone bodies positive and negative by urine dipstick. Cox and logistic regression models were used to estimate the effect of urinary protein and urinary ketone bodies on all cause in-hospital mortality and poor outcome upon discharge (modified Rankin Scale score ≥3) in AIS patients. Patients with positive urinary protein was associated with a 2.74-fold and 1.62-fold increase in the risk of in-hospital mortality (adjusted HR 2.74; 95% CI, 1.54-4.89; P-value = 0.001) and poor outcome upon discharge (aOR, 1.62; 95% CI 1.26-2.08; P-value <0.001) in comparison to negative urinary protein after adjusting for potential covariates. Moreover, Patients with positive urinary ketone bodies was associated with 2.11-fold in the risk of poor outcome upon discharge (aOR 2.11; 95% CI 1.52-2.94; P-value <0.001) but not in-hospital mortality (P-value = 0.066) after adjusting for potential covariates. CONCLUSIONS: Urinary protein at admission was independently associated with in-hospital mortality and poor functional outcome at hospital discharge in acute stroke patients and urinary ketone bodies also associated with poor functional outcome at hospital discharge.

Cancer-associated fibroblasts support bone tropic metastasis by acting as coordinators between the tumor microenvironment and bone matrix in breast cancer.

Bone is a common site of metastasis for various types of cancer cells, including breast cancer, and the consequent skeleton-related events observed in patients are severe and often fatal. Currently, it is widely accepted that cancer-associated fibroblasts (CAFs) confer a metastasis-promoting property to breast cancer cells. Furthermore, clinical observations suggest that CAFs mediate the bone tropism of metastatic breast cancer cells. Therefore, a deeper understanding of the mechanism by which CAFs are involved in the bone-tropic metastasis of breast cancer can facilitate the study of the novel and effective therapeutic drugs for the corresponding targets. In this review, we focused on the coordinator role of CAFs in remolding breast cancer cells and remodeling the bone marrow during metastasis. We discussed the potential roles of the CXCL12/CXCR4 axis, the CAFs-CSCs reinforcing loop, and exosomes in this malignant process. In summary, in agreement with Paget's theory, CAFs play a pivotal role in bone colonization by breast cancer cells by providing a "fertile soil" for the "selected seeds" by influencing tumor-intrinsic characteristics and microenvironment (ME).

Serum Alkaline Phosphatase, Phosphate, and In-Hospital Mortality in Acute Ischemic Stroke Patients.

BACKGROUND: The clinical impacts of serum alkaline phosphatase (ALP) and phosphate on early death are not fully understood in patients with acute ischemic stroke. We examined the associations between serum ALP, phosphate, and in-hospital mortality after ischemic stroke. METHODS: Serum ALP and phosphate were measured in 2944 ischemic stroke patients from 22 hospitals in Suzhou City from December 2013 to May 2014. Cox proportional hazard models and restricted cubic splines were used to estimate the relationships between serum ALP and phosphate (both as categorical and continuous variables) and risk of in-hospital mortality. RESULTS: During hospitalization, 111 patients (3.7%) died from all causes. After multivariable adjustment, the hazard ratio (HR) of the highest quartile compared with the lowest quartile of ALP was 2.19 (95% confidence interval [CI], 1.20-4.00) for early death. Restricted cubic spline analysis indicated a significant linear association between ALP and death (P-linearity = .017). A U-shaped association of phosphate with in-hospital mortality was observed (P-nonlinearity = .011). Compared with the third quartile of phosphate (1.08-1.21 mmol/L), HRs of the lowest and highest quartiles for early death were 2.17 (1.15-4.08) and 1.70 (.88-3.30), respectively. Sensitivity analyses further confirmed our findings. CONCLUSIONS: We observed a graded relationship between serum ALP levels and risk of early death in patients with acute ischemic stroke. There was a U-shaped association between phosphate and all-cause mortality with significantly increased risk among patients with lower phosphate levels.

Parkinson's disease patients with pain suffer from more severe non-motor symptoms.

Non-motor symptoms, including pain, depression, sleep disorder, and olfactory dysfunction, occur frequently in patients with Parkinson's disease (PD), even before the onset of motor symptoms. Although studies have examined the correlation between pain and depression or sleep disorder in PD, few studies have investigated the correlation between pain and a range of other non-motor symptoms of PD. PD patients (n = 142) with or without pain were included in the study. PD severity was evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H/Y) staging scale. Pain severity was analyzed with the Visual Analog Scale. The Hamilton Rating Scale for Depression (HRSD; 24 items), Montreal Cognitive Assessment Beijing Version (MoCA), and non-motor questionnaire (NMSQT) measured symptoms of depression, cognitive function, and non-motor symptoms. The incidence of pain was 47.9% in patients with PD, most of whom had moderate pain levels. Patients with pain showed higher HRSD, UPDRS, H/Y, and NMSQT scores and lower MoCA scores compared to those of patients without pain. HRSD and NMSQT scores were closely related with pain (P < 0.001). Non-motor symptoms were more prominent in patients with pain compared to that of controls and PD patients without pain.

[Sleep disorders associated with essential tremor and Parkinson's disease].

OBJECTIVE: To evaluate the sleep quality and explore the manifestations of sleep disorders for 62 essential tremor (ET) patients, 60 normal controls and 62 Parkinson's disease (PD) patients. METHODS: A total of 62 ET patients, 60 normal controls and 62 PD patients from June 2009 to December 2013 were recruited. All of them were outpatients at Second Affiliated Hospital, Soochow University and Hospital of Changshu Hospital of Traditional Chinese Medicine. Sleep was assessed with Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). RESULTS: The global PSQI score was 4.7 ± 2.5 in controls, 6.0 ± 4.0 in ET cases and 7.4 ± 3. 7 in PD cases. PD cases had the highest PSQI score, followed by ET (intermediate) and lowest scores in controls (F = 9.022, P = 0.000). A poor quality of sleep was observed in normal controls (23/62, 38.3%) compared to ET cases (34/62, 54.8%) and PD cases (40/62, 64.5%) (χ² = 8.555, P = 0.014 when comparing all three groups and χ² = 1.206, P = 0.272 when ET vs PD). The ESS score increased from normal controls (4.4 ± 2.5) to ET cases (6.3 ± 4.8) and PD cases (8.2 ± 4.2). An ESS score ≥ 10 (an indicator of greater than normal levels of daytime sleepiness) was observed in 6 (10.0%) normal controls, compared to ET cases (16, 25.8%) and PD cases (20, 32.3%) (χ² = 9.047, P = 0.011 when comparing all three groups and χ² = 0.626, P = 0.429 when ET vs PD). For normal controls, ET and PD patients, the factor scores of subjective sleep were 0.6 ± 0.7, 0.8 ± 0.8 and 1.1 ± 0.7; the factor scores of quality sleep latency 0.6 ± 0.7, 0.9 ± 0.9 and 1.1 ± 1.0; the factor scores of sleep duration 0.6 ± 0.8, 0.7 ± 1.0 and 1.0 ± 0.9; the factor scores of sleep efficiency 0.6 ± 0.8, 0.9 ± 0.9 and 1.0 ± 1.0; the factor scores of sleep disturbances 1.2 ± 0.6, 1.2 ± 0.5 and 1.7 ± 0.7; the factor scores of daytime dysfunction 1.2 ± 1.0, 1.3 ± 1.0 and 2.0 ± 1.1 respectively. There were inter-group statistical differences in subjective sleep (F = 7.709, P = 0.001), quality sleep latency (F = 4.414, P = 0.013), sleep duration (F = 4.464, P = 0.013), sleep efficiency (F = 3.201, P = 0.043), sleep disturbances (F = 12.594, P = 0.000) and daytime dysfunction (F = 9.022, P = 0.000) . However, no inter-group statistical differences existed in use of sleeping medication (F = 1.200, P = 0.304). There were statistical differences in subjective sleep (P < 0.05), sleep efficiency (P < 0.05) and daytime dysfunction (P < 0.05) between ET and PD patients. CONCLUSION: Some sleep scores in ET are intermediate between those of PD cases and normal controls. And it suggests that a mild form of sleep dysregulation may be present in ET.

[Cognitive dysfuctions associated with essential tremor and Parkinson's disease].

OBJECTVE: To explore the incidence of cognitive dysfunction and associated factors in 62 essential tremor (ET) cases, 60 normal controls and 61 Parkinson's disease (PD) cases. METHODS: A total of 62 ET and 61 PD patients from September 2009 to September 2013 were recruited from our outpatient clinic. ET patients received the Tremor Rating Scale for Tremor-motor examination (items 1-15 of rating scale) while 61 PD patients were examined with the Unified Parkinson's Disease Rating Scale (UPDRS)-motor examination and a modified Hoehn and Yahr scale for staging disorder severity. All participants completed Montreal Cognitive Assessment (MoCA) Beijing version for measuring cognitive functions. And depression was evaluated by the Hamilton Depression Scale (HAMD). The serum levels of uric acid were tested. RESULTS: A MoCA score <26 (at least mildly cognitive) was observed in 14 (23.3%) normal controls, compared to 24 (38.7%) ET cases and 27 (44.3%) PD cases (P = 0.045 when comparing all 3 groups, and P = 0.532 when comparing ET and PD). The factor scores of visual space/execution were 4.1 ± 1.0, 3.8 ± 1.1 and 3.2 ± 1.6 in normal controls, ET and PD patients, the factor scores of naming 2.9 ± 0.4, 2.8 ± 0.6 and 2.3 ± 0.8 in control, ET and PD patients, the factor scores of delay memory 3.9 ± 0.9, 2.7 ± 1.3 and 2.5 ± 1.7 in control, ET and PD patients. Statistical differences existed in visual space/execution, naming and delay memory (P < 0.05) among 3 groups. Yet there were no statistical differences in attention, language, abstract and directional among 3 groups. Statistical differences existed in visual space/execution and naming between ET and PD patients (P < 0.05). PD cases had the lowest visual space/execution score, followed by ET (intermediate) and highest scores in controls (P < 0.05). In ET patients, cognitive scores were correlated with serum levels of uric acid, education, tremor Rating Scale for Tremor-motor subscale score and depression levels (r = 0.589, P = 0.000; r = 0.449, P = 0.010; r = 0.452, P = 0.009; r = 0.466, P = 0.025). In PD patients, cognitive scores correlated with serum levels of uric acid, education, score of UPDRS-III and depression levels (r = 0.694, P = 0.000; r = 0.614, P = 0.000; r = 0.604, P = 0.000; r = 0.376, P = 0.000). CONCLUSION: The incidence of cognition is higher in ET and PD. There were no significant inter-group differences for cognition frequency. The most frequently endorsed symptoms were poor visual spatial ability, execution disturbance and delayed recall disorders. Some connition scores in ET were intermediate between those of PD cases and normal controls. Thus a mild form of connition dysregulation may be present in ET. The degree of cognition symptoms is correlated with serum levels of uric acid, education and serious motor.

Diffusion tensor imaging parameters for the early diagnosis of radiation-induced brain injury in patients with nasopharyngeal carcinoma: a meta-analysis.

PURPOSE: To estimate diffusion tensor imaging (DTI) parameters for early diagnosis during the stage of radiation-induced brain injury (RBI) in nasopharyngeal carcinoma (NPC) patients.PubMed, Embase, Web of Science and Cochrane Library were searched up to March 2019. Eligible studies comparing early brain injuries with controls of temporal lobe in NPC patients before and after radiotherapy which collected the DTI parameters such as apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial diffusibility (λa), radial diffusibility (λr), mean diffusion (MD) were included. CONCLUSION: Seven studies (N = 21) were selected from the studies in the databases. Overall, FA, λa, λr values were significant difference between early RBI and healthy control (HC) in NPC patients after radiotherapy (MD= -0.03, 95% CI= -0.05∼-0.01; p = .008 in FA, MD= -0.07, 95% CI= -0.11∼-0.02; p = .002 in λa and MD = 0.02, 95% CI = 0.00 ∼ 0.04; p = .04 in λr). The meta regression analysis about dose dependence with FA value was: -0.057 ∼ 0.0003 in 95% CI, I2=74.70%, P = 0.052 (adjust p = .029). The overall heterogeneity is p < .001, I2=91% in FA, P = 0.08, I2=61% in λa and p = .04, I2=69% in λr. DTI parameters such as the reduced FA value, the decreased λa value, and the increased λr value were significant in the early period of RBI in NPC patients after radiotherapy, which becoming a more sensitive method in diagnosing the early stage of RBI.

Comparison of results and age-related changes in establishing reference intervals for CEA, AFP, CA125, and CA199 using four indirect methods.

•The reference intervals calculated using RefineR, Kosmic, TMC, and non-parametric methods are similar.•TMC algorithm is more robust, demonstrates a high pass rate among the four methods and has the ability to automatically isolate outliers.•The reference intervals of CA125 and CA199 showed significant differences between age and sex.

Albiflorin alleviates neuroinflammation of rats after MCAO via PGK1/Nrf2/HO-1 signaling pathway.

Ischemic stroke is acknowledged as one of the most frequent causes of death and disability, in which neuroinflammation plays a critical role. Emerging evidence supports that the PGK1/Nrf2/HO-1 signaling can modulate inflammation and oxidative injury. Albiflorin (ALB), a main component of Radix paeoniae Alba, possesses anti-inflammatory and antioxidative properties. However, how it exerts a protective role still needs further exploration. In our study, the middle cerebral artery occlusion (MCAO) model was established, and the Longa score was applied to investigate the degree of neurological impairment. Dihydroethidium (DHE) staining and Malondialdehyde (MDA) assay were used to detect the level of lipid peroxidation. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining was used to measure the infarct area. Evans blue staining was employed to observe the integrality of the blood-brain barrier (BBB). The injury of brain tissue in each group was observed via HE staining. Immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA) and western blot assay were used for the measurement of inflammatory factors and protein levels. We finally observed that ALB relieved cerebral infarction symptoms, attenuated oxidative damage in brain tissues, and reduced neuroinflammation and cell injury in MCAO rats. The overexpression of PGK1 abrogated the protective effect of ALB after experimental cerebral infarction. ALB promoted PGK1 degradation and induced Nrf2 signaling cascade activation for subsequent anti-inflammatory and antioxidant damage. Generally speaking, ALB exerted a protective role in treating cerebral ischemia, and it might target at PGK1/Nrf2/HO-1 signaling. Thus, ALB might be a potential therapeutic agent to alleviate neuroinflammation and protect brain cells after cerebral infarction.

Tongqiao Huoxue Decoction inhibits ferroptosis by facilitating ACSL4 ubiquitination degradation for neuroprotection against cerebral ischemia-reperfusion injury.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) refers to brain tissue injury caused by the temporary interruption of cerebral blood flow ischemia followed by the restoration of reperfusion, which is the main cause of post-stroke brain injury. A traditional Chinese herbal preparation called Tongqiao Huoxue Decoction (TQHX) has shown promise in reducing CIRI in rats. However, the mechanism of this herbal preparation for CIRI remains unclear. PURPOSE: This study aimed to evaluate the therapeutic effect of TQHX extract on rats with CIRI and to further explore the underlying mechanisms. METHODS: The active ingredients of TQHX extract were quantified by the high-performance liquid chromatography (HPLC) condition. We conducted thorough investigations to assess the effects of TQHX on CIRI and ferroptosis using oxygen-glucose deprivation/reperfusion (OGD/R)-treated PC12 cells as an in vitro model and transient middle cerebral artery occlusion (tMCAO) animals as an in vivo model. The neurological score assessment was performed to evaluate the neuroprotective effects of TQHX extract on tMCAO rats. Using histologic methods to study the extent of cerebral infarction, blood-brain barrier, and rat brain tissue. We examined the impact of TQHX on ferroptosis-related markers of Fe2+, superoxide dismutase (SOD), reactive oxygen species (ROS), and malondialdehyde (MDA) in the brain tissue. In addition, the expression of key proteins and markers of ferroptosis, as well as key factors associated with Acyl-CoA synthetase long-chain family member 4 (ACSL4) were detected by Western blot and quantitative real-time PCR (RT-qPCR). RESULTS: TQHX extract could decrease the Longa score and extent of cerebral infarction of tMCAO rats, which exerted the function of neuroprotection. Additionally, TQHX treatment efficiently decreased levels of MDA and ROS while increasing the expression of SOD and ferroptosis-related proteins including ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) at the transcription and translation level. Meanwhile, TQHX provided strong protection against oxidative stress and ferritin accumulation by increasing the ubiquitination and degradation of ACSL4. The injection of OE-ACSL4 reversed the effects of TQHX on neuroprotection and ferroptosis inhibition in PC12 cells. The injection of shACSL4 reversely validate the crucial role of ACSL4 in CIRI rat treatment. CONCLUSION: This work shows that TQHX promotes the ubiquitination-mediated degradation of ACSL4, which improves oxidative stress and inhibits the beginning of ferroptosis in cells. TQHX provides a possible path for additional research in CIRI therapies, advancing translational investigations.

[Depression associated with movement disorders].

OBJECTIVE: To explore the incidence of depression in movement disorders and associated factors. METHODS: A total of 121 Parkinson's disease (PD) patients from August 2010 to June 2011 and 62 ET patients from July 2009 to June 2010 were recruited. All of them were outpatients of our hospital. PD patients received the unified Parkinson's disease rating scale (UPDRS) -motor examination and a modified Hoehn and Yahr scale to stage the severity of their disorders while 62 essential tremor (ET) patients were evaluated with tremor rating scale for tremor-motor examination (items 1 - 15 of rating scale). All participants completed Hamilton depression rating scale (24 items) to measure the presence and degree of symptoms of depression. RESULTS: It was found that 56.2% of PD patients and 53.2% of ET patients were depressed (HAMD score of 8 or higher). Among them, the rates of mild depression were 38.9% and 35.5%, moderate depression 15.7% and 17.7% and severe depression 1.7% and 0% in PD and ET patients respectively. No significant differences existed between each group. The factor scores of cognitive impairment were 1.81 ± 1.86 and 1.04 ± 1.07 in PD and ET patients while those of sense of despair were 2.95 ± 1.97 and 4.09 ± 2.08 in each group. The differences had statistical significance in two factor scores of two groups (P < 0.05). No differences in anxiety/somatization, lose weight, day-and-night changes, block and sleep disorders between two groups. For PD patients, the motor score of UPDRS-III was positively correlated with total HAMD score (r = 0.511, P < 0.01). Similarly, for ET patients, tremor rating scale for tremor-motor subscale score and HAMD score were positively correlated (r = 0.828, P < 0.01). CONCLUSION: As two common movement disorders, PD and ET have a high incidence of depression. The severity of depression is similar in two groups. There is no significant intra-group difference in severity and frequency of depression. The most common symptoms are anxiety somatization, anhedonia, working difficulty, slowness and sleep disturbance. The depression and motor symptoms are positively correlated. Like the non-motor symptoms in PD, we should also pay attention to the non-motor symptoms in ET.

High expression level of homocitrulline is correlated with seborrheic keratosis and skin aging.

BACKGROUD: Homocitrulline (Hcit), is involved in the pathological processes of some diseases. However, the role and function of Hcit (CBL) in human skin remains largely obscure. OBJECTIVE: To investigate the correlation of the level of Hcit in seborrheic keratosis, skin aging, and its clinical significance. METHODS: Immunohistochemistry was used to analyze the level of Hcit in skin lesions of seborrheic keratosis (SK), unaffected skin (distant 0.5 centimeters from SK lesion), and normal skin of healthy subjects in the control group. ELISA test was used to detect the serum level of CBL in SK patients and healthy subjects of different ages. RESULTS: Hcit was mainly localized in the nucleus of epidermal cells. In healthy control skin, the expression of Hcit increased with age and showed a positive correlation with age (the correlation coefficient was 0.806, p = 0.0002). The expressional level of Hcit in SK lesions was higher than that in healthy control skin (Z = -3.703, p = 0.0002). The serum level of CBL in healthy subjects and in SK patients increased with age (the correlation coefficient were 0.5763, p = 0.0032; 0.682, p = 0.004. respectively). The serum level of CBL in SK patients was higher than that in healthy subjects (Z = -2.19, p = 0.030). STUDY LIMITATIONS: The small serum sample size in the study. CONCLUSION: The high expressional level of Hcit is correlated with seborrheic keratosis and skin aging. HCit may be one of the potential biomarkers of skin aging.

Huangqi Guizhi Wuwu decoction promotes M2 microglia polarization and synaptic plasticity via Sirt1/NF-κB/NLRP3 pathway in MCAO rats.

Huangqi Guizhi Wuwu decoction (HGWD) has been demonstrated to ameliorate cerebral ischemia-reperfusion injury in clinical application. Nevertheless, the exact mechanisms of HGWD have not been conclusively elucidated. This study aimed to investigate the potential role and mechanism of HGWD on neurological deficits in a rat model of middle cerebral artery occlusion (MCAO). Our results showed that HGWD significantly alleviated neurological deficits in MCAO rats, evidenced by high mNSS score, reduced cerebral infarction area, and improved brain pathological injury. Besides, HGWD reduced the levels of TNF-α, IL-1ß, IL-6, SOD, MDA and GSH in the brain tissue. Further study suggested that HGWD promoted microglia polarization towards M2 by inhibiting M1 activation (Iba1+/CD16+, iNOS) and enhancing M2 activation (Iba1+/CD206+, Arg-1). Additionally, HGWD increased dendritic spine density and enhanced levels of synapse marker proteins (PSD95, Synapsin I). HGWD also up-regulated Sirt1 expression while inhibited p-NF-κB, NLRP3, ASC, and cleaved caspase-1 level in the hippocampus of MCAO rats. Sirt1 specific inhibitor EX527 notably weakened the neuroprotective efficacy of HGWD against cerebral ischemia, and significantly abolished its modulation on microglia polarization and synaptic plasticity in vivo. Collectively, our findings suggested that HGWD ameliorated neuronal injury in ischemic stroke by modulating M2 microglia polarization and synaptic plasticity, at least partially, via regulating Sirt1/NF-κB/NLRP3 pathway, further supporting HGWD as a potential therapy for neuroprotection after ischemic stroke.

Astragaloside IV promotes angiogenesis by targeting SIRT7/VEGFA signaling pathway to improve brain injury after cerebral infarction in rats.

Cerebral infarction (CI) has become one of the leading causes of death and acquired disability worldwide. Astragaloside IV (AST IV), one of the basic components of Astragalus membranaceus, has a protective effect on CI. However, the underlying mechanism has not been conclusively elucidated. Therefore, this study aims to explore the underlying mechanism of AST IV improving brain injury after CI. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) were used to simulate cerebral infarction injury in SD rats and HUVECs cells. Neurologic score, Evans blue, TTC and HE staining were used to observe brain injury in rats. Cell viability and migration were measured in vitro. Angiogenesis was detected by immunofluorescence and tube formation assay, and cell cycle was detected by flow cytometry. Western blot was used to find the expression of related proteins. Molecular docking, virtual mutation, site-directed mutagenesis, MST, and lentivirus silencing were used for target validation. The results showed that AST IV alleviated neurological impairment and promoted angiogenesis after CI. Moreover, AST IV greatly increased the transcription levels of SIRT6 and SIRT7, but had no effect on SIRT1-SIRT5, and promoted cell viability, migration, angiogenesis and S phase ratio in OGD/R-induced HUVECs. Furthermore, AST IV up-regulated the protein expressions of CDK4, cyclin D1, VEGFA and VEGF2R. Interestingly, AST IV not only bound to SIRT7, but also increased the expression of SIRT7. Silencing SIRT7 by lentivirus neutralizes the positive effects of AST IV. Taken together, the present study revealed that AST IV may improve brain tissue damage after CI by targeting SIRT7/VEGFA signaling pathway to promote angiogenesis.

Endothelial cell-derived RSPO3 activates Gαi1/3-Erk signaling and protects neurons from ischemia/reperfusion injury.

The current study explores the potential function and the underlying mechanisms of endothelial cell-derived R-spondin 3 (RSPO3) neuroprotection against ischemia/reperfusion-induced neuronal cell injury. In both neuronal cells (Neuro-2a) and primary murine cortical neurons, pretreatment with RSPO3 ameliorated oxygen and glucose deprivation (OGD)/re-oxygenation (OGD/R)-induced neuronal cell death and oxidative injury. In neurons RSPO3 activated the Akt, Erk and ß-Catenin signaling cascade, but only Erk inhibitors reversed RSPO3-induced neuroprotection against OGD/R. In mouse embryonic fibroblasts (MEFs) and neuronal cells, RSPO3-induced LGR4-Gab1-Gαi1/3 association was required for Erk activation, and either silencing or knockout of Gαi1 and Gαi3 abolished RSPO3-induced neuroprotection. In mice, middle cerebral artery occlusion (MCAO) increased RSPO3 expression and Erk activation in ischemic penumbra brain tissues. Endothelial knockdown or knockout of RSPO3 inhibited Erk activation in the ischemic penumbra brain tissues and increased MCAO-induced cerebral ischemic injury in mice. Conversely, endothelial overexpression of RSPO3 ameliorated MCAO-induced cerebral ischemic injury. We conclude that RSPO3 activates Gαi1/3-Erk signaling to protect neuronal cells from ischemia/reperfusion injury.

How sleep quality affects activities of daily living in Parkinson's disease: the mediating role of disease severity and the moderating role of cognition.

Objective: The aim of this study was to explore the influential mechanism of the relationship between sleep quality and activities of daily living (ADL) in patients with Parkinson's disease (PD), we hypothesized disease severity as a mediator and assumed the mediating process was regulated by cognition. Methods: 194 individuals with PD (95 women and 99 men) were enrolled in study. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality of PD patients. Patients' ADL, disease severity and cognition were measured by the Unified Parkinson's Disease Rating Scale-II (UPDRSII), Hoehn-Yahr (H-Y) Scale, and Mini-Mental State Examination (MMSE). We investigated the mediating role of disease severity and the moderating effect of cognition on the association between sleep quality and ADL in PD patients. Results: The score of UPDRSII was positively correlated with the score of PSQI and H-Y stage, while the score of MMSE was negatively correlated with the score of H-Y stage and UPDRSII. Sleep quality predicts disease severity, and disease severity predicts ADL. Disease severity mediated the relationship between sleep quality and ADL, and the mediating effect was 0.179. Cognition alone did not affect ADL, but the interaction between disease severity and cognition was significantly affected ADL, confirming the moderating effect of cognition in PD patients. Conclusion: Disease severity mediated the association between sleep quality and ADL, good cognition significantly reduced disease severity's mediating influence on the relationship between sleep quality and ADL. Our study indicated a close relationship between ADL and sleep and cognition in PD, and also provided new insights into the overall management of PD and a better quality of life of PD patients.

Proton Magnetic Resonance Spectroscopy for the Early Diagnosis of Parkinson Disease in the Substantia Nigra and Globus Pallidus: A Meta-Analysis With Trial Sequential Analysis.

This study aimed to investigate the metabolic changes in globus pallidus (GP) and substantia nigra (SN) during the early stage of Parkinson disease (PD) using magnetic resonance spectroscopy (MRS). PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure were searched till November 2018. Eligible trials comparing early metabolic changes in GP and SN in patients with PD vs. controls were included. The mean differences with 95% confidence intervals were estimated with either fixed- or random-effects models using Review Manager 5.3 software. Trial sequential analysis was performed using TSA 0.9.5.10 beta software. Finally, 16 studies were selected from the search. Overall, the N-acetyl aspartate-to-creatine ratio showed a significant difference between patients with early-stage PD and healthy controls. The overall heterogeneity was P < 0.00001, I 2 = 94% in GP and P = 0.0002, I 2 = 74% in SN. The results revealed that MRS could be a more sensitive imaging biomarker in the diagnosis of early-stage PD. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=125731, registration number: CRD42019125731.

Treatment of melasma by a combination of intense pulsed light with advanced optimal pulse technology and human-like collagen repair dressing: A case series study.

To observe the efficacy and safety of a combination of intense pulsed light (IPL) with advanced optimal pulse technology (AOPT) and human-like collagen repair dressing in the treatment of melasma. Ten patients with melasma were treated using IPL with AOPT once a month for a total of 8 times, and received the treatment of external human-like collagen repair dressing after each operation. The efficacy was evaluated with the modified Melasma Area Severity Index (mMASI) score and satisfaction score, respectively, before treatment, after each treatment and at 4 months after the end of the whole treatment course. The melasma was significantly lightened in all 10 patients after 8 times of treatments. The mMASI score before treatment was (8.6 ± 3.8) points, which decreased significantly to (5.1 ± 2.7) points after 8 times of treatments, and there was a significant difference in mMASI score between before and after 8 times of treatments (P = .001). The mMASI score was (3.3 ± 2.2) points at 4 months after the end of whole treatment course, and there was no significant difference in mMASI score between after 8 times of treatments and 4 months after the end of whole treatment course (P > .05). The satisfaction score was (7.2 ± 1.4) points after 8 times of treatments and (7.1 ± 1.4) points at 4 months after the end of whole treatment course, there was no significant difference in satisfaction score between after 8 times of treatments and 4 months after the end of whole treatment course (P > .05). A combination of IPL with AOPT and human-like collagen repair dressing can effectively decrease the severity of melasma, and is associated with a higher patient satisfaction score and a lower risk of relapse after discontinuation of treatment.

Treatment of Modified Dahuang Fuzi Decoction on Cognitive Impairment Induced by Chronic Kidney Disease through Regulating AhR/NF-κB/JNK Signal Pathway.

Aim: An increasing widespread of chronic kidney disease (CKD) has been established lately around the globe. In addition to renal function loss, CKD can also cause cognitive impairment (CI). Modified Dahuang Fuzi Decoction (MDFD) is used as a traditional Chinese therapy for CKD. The effect of MDFD on cognitive impairment induced by chronic kidney disease (CKD-CI), and therapeutic mechanisms were investigated. Methods: The CKD animals' model was developed in the 5/6 nephrectomized mice. Sham operation and model groups received normal saline, while positive control and MDFD high/medium/low dose received Aricept (10 mg/kg/day) and different doses of MDFD (24, 16, and 8 g/kg/day), respectively. Cognitive function was detected with the Morris water maze test, while related factors were determined by ELISA. Histopathology and mechanism were studied using HE, western blot, and qRT-PCR. Results: In the CKD-CI mice model, escape latency decreased significantly, whereas time of crossing platform and time spent within the platform quadrant increased substantially (P < 0.05) after MDFD treatment. Moreover, renal function and brain injury in CKD-CI improved dose-dependently, while the effect of MDFD-L was worse. Proteins such as aryl hydrocarbon receptor, nuclear factor-kappa B and c-Jun-N-terminal kinase, and mRNA in the kidney and brain of all the treatment groups decreased substantially (P < 0.05). Expression of tropomyosin receptor kinase B and brain-derived neurotrophic factor at protein and mRNA levels in the brain were significantly enhanced (P < 0.05). Conclusion: MDFD presumably activated the BDNF/TrkB pathway by inhibiting the AhR/NF-κB/JNK signaling pathway to treat CKD-CI.