Troxerutin Delays Skin Keratinocyte Senescence Induced by Ionizing Radiation Both In Vitro and In Vivo.

BACKGROUNDS: With the increasing demand for beauty and a healthy lifespan, studies regarding anti-skin aging have drawn much more attention than ever before. Skin cellular senescence, the primary cause of skin aging, is characterized by a cell cycle arrest in proliferating cells along with a senescence-associated secretory phenotype (SASP), which can be triggered by various internal or external stimuli. AIMS: Recent studies have made significant progress in the fields of anti-senescence and anti-aging. However, little is known about the roles and functions of natural compounds, particularly flavonoids, in skin cellular senescence studies. METHODS: In this study, using strategies including ionizing radiation (IR), senescence-associated ß galactosidase assay (SA-ß-Gal), immunofluorescence (IF), flow cytometry, PCR array, as well as in vivo experiments, we investigated the effects and roles of troxerutin (Trx), a natural flavonoid, in skin keratinocyte senescence. RESULTS: We found that Trx delays skin keratinocyte senescence induced by IR. Mechanistically, Trx protects the skin keratinocyte cells from senescence by alleviating reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and DNA damage caused by IR. In addition, Trx was also proved to relieve skin senescence and SASP secretion in vivo induced by IR stimulation. CONCLUSIONS: Altogether, our findings pointed to a new function of Trx in delaying stress-induced skin keratinocyte senescence, and should thus provide theoretical foundations for exploring novel strategies against skin aging.

Associations of prognostic nutritional index with risk of all-cause and cardiovascular disease mortalities in persons with gestational diabetes mellitus: A NHANES-based analysis.

OBJECTIVE: To investigate relationships between prognostic nutritional index (PNI) during pregnancy and risk of all-cause mortality (ACM) and cardiovascular disease (CVD) mortality in persons with gestational diabetes mellitus (GDM). METHODS: A cross-sectional study was conducted using NHANES data from 2007 to 2018, and weighted Cox regression models were established. Restricted cubic spline analysis was used to unveil associations of PNI with risk of ACM and CVD mortalities in individuals with GDM. Receiver operating characteristic curve was employed for determination of threshold value for association of PNI with mortality. Sensitivity analysis was performed to verify the stability of the results. RESULTS: 734 GDM individuals and 7987 non-GDM individuals were included in this study. In GDM population, after adjusting for different categorical variables, PNI was significantly negatively correlated with ACM risk. Subgroup analysis showed that among GDM populations with no physical activity, moderate physical activity, parity of 1 or 2, negative correlation between PNI and risk of ACM was stronger than other subgroups. Sensitivity analysis results showed stable negative correlations between PNI and ACM and CVD mortality of total population, and between PNI and ACM of GDM. CONCLUSION: In individuals with GDM, PNI was negatively correlated with ACM risk, especially in populations with no physical activity, moderate physical activity, and parity of 1 or 2. PNI = 50.75 may be an effective threshold affecting ACM risk in GDM, which may help in risk assessment and timely intervention for individuals with GDM.

Inhibition of transglutaminase 2 inhibits ionizing radiation-induced cellular senescence in skin keratinocytes in vitro.

Senescent cells are typically characterized by a stable proliferation arrested in dividing cells accompanied with a senescence-associated secretory phenotype (SASP). Skin cellular senescence is the primary cause of skin aging, whereas the lack of identified skin senescence markers limits our understanding of the mechanisms involved in skin aging. Recent studies have revealed that intracellular calcium signaling has emerged as a key player in regulating cellular senescence and aging. However, the implication and roles of calcium signaling in skin keratinocyte senescence remain only partially understood. In this study, we developed a model for skin keratinocyte senescence using ionizing radiation (I/R) stimulation and found that the calcium-associated gene transglutaminase 2 (TGM2) was significantly induced compared with normal control. Interestingly, inhibition of TGM2 was found to delay skin keratinocyte senescence by suppressing I/R-promoted intracellular calcium signaling, accumulation of reactive oxygen species (ROS), DNA damage, as well as NF-κB-mediated SASP secretion. Taken together, our findings demonstrate that inhibition of TGM2 contributes to bypassing I/R-induced skin keratinocyte senescence and sheds light on novel strategies against skin stresses caused by I/R.

TRPM7 controls skin keratinocyte senescence by targeting intracellular calcium signaling.

Cellular senescence is described as an irreversible cell cycle arrest for proliferating cells and is associated with the secretion of senescence associated secretory phenotype factors. It has been known to accumulate with age and is regarded as a key driver of aging-associated skin pathologies. However, the lack of markers of skin senescence and partially understood skin cellular senescence mechanisms has limited the exploration of skin aging and anti-skin aging strategies. Recently, intracellular calcium signaling has emerged as an important regulator of cellular senescence and aging. However, little is known about the modulation of skin cellular senescence by calcium-associated factors. Here, we found that the expression of calcium channel transient receptor potential melastatin 7 (TRPM7) is elevated during skin keratinocyte senescence and aging. Importantly, TRPM7 promotes skin keratinocyte senescence by triggering intracellular calcium transfer from the endoplasmic reticulum to the mitochondria; accumulation of mitochondrial calcium then induces a drop in mitochondrial membrane potential and reactive oxygen species production, leading to subsequent nuclear enlargement and DNA damage. Altogether, these findings indicate that TRPM7 controls skin keratinocyte senescence through regulating intracellular calcium signaling, and thus, shed light on novel strategies for anti-skin aging therapy.

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.

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.

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.

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.

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.

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.

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

Abstract 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.

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.

Study on the correlation of high expression level of HuD with seborrheic keratosis and skin aging.

BACKGROUND: Currently, most studies of ELAV (Embryonic Lethal, Abnormal Vision, Drosophila)-like protein 4 (Hu antigen D, HuD) focus on nervous system-related diseases; the role of HuD in the occurrence of skin aging and seborrheic keratosis (SK) has not been reported. OBJECTIVE: To explore the role of HuD in the occurrence of SK and skin aging and its related clinical significance. METHODS: The expression levels of HuD in the skin and blood of healthy people at different ages, SK lesions, and perilesional skin of SK patients were detected by both immunohistochemistry and Western blotting. The mRNA expression levels of HuD in the skin and blood of healthy peoples at different ages were detected by quantitative real-time reverse transcription-polymerase chain reaction. The expression level of HuD was compared with the skin of healthy people, SK lesion, and perilesional skin of SK patients of the same age. RESULTS: The immunohistochemistry and Western blotting showed that the expression levels of HuD in SK lesions were higher than those in healthy skin and perilesional skin. The immunohistochemical staining intensity, protein and mRNA expression levels of HuD in the skin and blood of healthy people were correlated with age, which gradually increased with increasing age. CONCLUSION: HuD is highly expressed in SK lesion and aged skin, indicating that a higher HuD expression level is correlated with occurrence of SK and aging skin; however, its mechanism needs to be further studied.

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.

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.

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 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.