Treatment Of PD Research Articles

MO701: Origin of Proteins in Peritoneal Dialysis Explained by a Transcriptomics/Proteomics Cross-Over Analysis

Abstract BACKGROUND AND AIMS Peritoneal dialysis effluent (PDE) is a rich but underexplored source of molecular markers for therapy monitoring and investigation of deregulated processes during PD. Modern high performance mass spectrometry (MS) and sequencing methods allow monitoring of hundreds of analytes in parallel. For understanding PD related processes on a systems biology level, a multilevel omics approach is particularly attractive. Here, we investigate the cellular transcriptome and cell-free proteome of PDE samples in combination with the publicly available Human Plasma Proteome Database to investigate the origin of proteins found in peritoneal dialysis effluent. METHOD Samples were obtained from clinically stable patients on chronic peritoneal dialysis during a highly standardized clinical routine check. The effluent material was separated into a cellular and cell-free component. Soluble proteins in the cell-free compartment were processed using our equalizing and TMT-labeling workflow followed by LC-MS. The cellular material was subjected to RNA sequencing. The Human Plasma Proteome database (peptideatlas.org/hupo/hppp) was used for referencing plasma proteins and estimating plasma concentration. A bioinformatic workflow conjoined information from the datasets to reveal novel insights into the ‘PD effluentome,’ especially clarifying the source of proteins found in PDE. RESULTS Combining two targeted metabolomics methods enabled detecting 207 unique metabolites in cell-free PDE. Metabolites not detected in our samples were included in the panel for in vitro studies of cellular systems. A mixed-effect ANOVA of all metabolites demonstrated dwell time-dependent concentration changes in 173 metabolites. Post-hoc testing revealed most metabolites to be changed between 1 and 16 h [ON] of fluid dwell (160), followed by 114 and 46 differently concentrated metabolites between 4 and 16 h and 1 and 4 h of dwell, respectively. We quantified 9797 transcripts in PD-effluent cells and 2729 solved proteins in PD effluent. A total of 342 proteins were filtered from plasma, while 800 proteins were attributable to local production. A quantitative analysis of the interaction proteome and cellular transcripts of roughly 1700 protein-transcript pairs showed clusters of proteins explained by overexpression in peritoneal cells compared to plasma concentrations. CONCLUSION Multi-omic profiling of PD effluent proved to be a valuable approach for revealing small molecule related changes during PD treatment. The exploitation of PD effluent information on multiple omics levels as identified by our bioinformatic approach has been shown to improve our understanding of the molecular processes in the peritoneal cavity and their role in development of complications for ultimately improving PD therapy. The combinatorial investigation of proteome and transcriptome of PD effluent represents a first step in identifying locally produced proteins for further validation as biomarkers of peritoneal health in peritoneal dialysis patients. Proteins of plasma origin could be tested for their value as diagnostic tools in monitoring treatment success and protein transport over the peritoneal barrier. Our work suggests feasibility of multi-omics approaches to investigate cell-derived biomarkers for their involvement in pathomechanisms relevant in PD.

MO711: Evaluation of an in Vitro Co-Culture Model for Studying Modulation of Cross-Talk between Endothelial and Mesothelial Cells by Cytoprotective Additives in Peritoneal Dialysis Fluids

Abstract BACKGROUND AND AIMS Peritoneal dialysis (PD) is a life-saving renal replacement therapy. The composition of all currently available peritoneal dialysis fluids (PDF) triggers morphological and functional changes in the peritoneal membrane. Periodic exposure leads to vasculopathy, hypervascularization and diabetes-like damage of vessels, eventually leading to failure of the technique. In vitro and in vivo studies have shown that cytoprotective additives [e.g. dipeptide alanyl-glutamine (AlaGln) or kinase inhibitor lithium chloride (LiCl)] to PDF reduce peritoneal damage in mesothelial (MC) and endothelial (EC) cells. However, it is yet unclear if potential cross talk between cells present in the peritoneal membrane mediates the observed modulation of PD-associated changes. Currently, there is no model system available to study relevant processes in these cells when in close proximity. Here, we aimed to develop a co-culture model for investigating cell-to-cell communication in a PD-relevant setting using cellular proteome and secretome analyses and investigate the effects of cytoprotective additives. METHOD For modelling the peritoneal membrane in vitro, MCs and ECs were co-cultured in transwell plates. MCs were grown in the upper compartment and primary microvascular ECs were grown in the lower compartment. PDF with or without additives, was added to the upper compartment to expose MCs directly, while the ECs below were kept in medium. Cellular proteome and secretome profiles were analysed for both cell types cultured individually or together by a quantitative mass spectrometry approach. Prior to analysis of the secretome, a combinatorial peptide ligand library coupled to beads was employed to enrich low abundant proteins and deplete high abundant proteins. RESULTS Proteome analysis revealed perturbation of major cellular processes including cytoskeleton reorganization, stress response, and regulation of cell death that characterize PDF cytotoxicity. Co-cultured cells yielded differently regulated pathways following PDF exposure compared to individual cultures. Several pathways relevant for PD, such as VEGF signaling in ECs or oxidative stress response in MCs were found only under co-culture conditions. Combined analysis of proteome and secretome showed specific ligand–receptor pairs expressed only under co-culture conditions regulating some of these pathways. Differentially regulated cellular and secreted proteins after PDF exposure were related to processes like angiogenesis, immune response, or and extracellular processes such as integrin signaling. Addition of 10 mM LiCl to PDF led to modulation of VEGF and oxidative stress response pathways in ECs as well as ligand–receptor pairs involved in these pathways, possibly explaining MC–EC crosstalk during PDF exposure of these cells and the cytoprotective effect of LiCl. CONCLUSION Harmful effects of PDF on MCs may also affect ECs, as demonstrated by our data. Interestingly, both cells type react differently when co-cultured compared to individual culture models, showing the importance of models that allow cell type interaction to mimic the in vivo conditions. We identified potential signaling axes between the cell types that could explain pathophysiological changes of the peritoneal membrane during PD treatment. We have also elucidated potential mechanisms by which the cytoprotective additive LiCl may modulate crosstalk between MCs and ECs to counteract adverse PDF effects in the local peritoneal environment. Linking local peritoneal damage with systemic vasculopathy through perturbations of PD-induced cellular crosstalk, may identify therapeutic targets to reduce the cardiovascular risk of PD patients and current limitations of the therapy.

Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism

Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson’s disease (PD) are also observed in other neurodegenerative diseases. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is caused by mutations in the human PANK2 gene, which catalyzes the initial step of de novo CoA synthesis. Here, we show that fumble (fbl), the human PANK2 homolog in Drosophila, interacts with PINK1 genetically. fbl and PINK1 mutants display similar mitochondrial abnormalities, and overexpression of mitochondrial Fbl rescues PINK1 loss-of-function (LOF) defects. Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype. Mechanistically, Fbl regulates Ref(2)P (p62/SQSTM1 homolog) by acetylation to promote mitophagy, whereas PINK1 regulates fbl translation by anchoring mRNA molecules to the outer mitochondrial membrane. In conclusion, Fbl (or PANK2) acts downstream of PINK1, regulating CoA/acetyl-CoA metabolism to promote mitophagy, uncovering a potential therapeutic intervention strategy in PD treatment.

MO704: Prognostic Factors of Serological Response to the Sars-Cov 2 Vaccine in Peritoneal Dialysis: Our Experience

BACKGROUND AND AIMSThe severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) pandemic has had a massive impact in health systems worldwide, taking an important toll on dialysis patients as they are more comorbid, have higher mortality and an impaired immune system. Vaccines against SARS-Cov-2 proved to reduce mortality and hospitalization, but serological response in the dialysis population is weaker. Therefore, predictors of response would be useful to assess their level of protection and evaluate the need for further booster doses of the vaccine.METHOD- We retrospectively analysed all peritoneal dialysis (PD) patients fully vaccinated (two doses) in our PD Unit between February and June 2021.- Clinical data, vaccine brand and anti SARS-Cov-2 IgG antibodies (Ab) measured by enzyme immunoassay were recorded.- The linear correlation between Ab level and all other variables was analysed using the Pearson correlation coefficient.RESULTS- In the study period, 22 of 32 prevalent patients were fully vaccinated with two vaccine doses, 70.8% Moderna, 20.8% Pfizer/BioNTech and 8.3% AstraZeneca. A total of 50% were male and 36.4% had diabetes mellitus, with mean age 61.4 ± 12.3 years. Median time on PD was 15.6 months (IQR 4.9–25.1). Up to 22.7% were on immunosuppression (IS) after a kidney graft dysfunction (prednisolone, tacrolimus or both) and 22.7% had a previous diagnosis of coronavirus disease (COVID).- A total of 072.7% had an immediate minor adverse event after the second dose of the vaccine, mostly headache/malaise (31.8%) and puncture site pain (22.7%).- Ab levels were significantly higher in those patients with previous COVID (r = 0.452; P = 0.035). Male gender and Moderna vaccine had a positive correlation with higher Ab titers, although not statistically significant (r = 0.401, P = 0.064 and r = 0.215, P = 0.337, respectively). Those with longer duration of PD treatment before vaccination had a weaker serological response (r = −0.228, P = 0.307). Ab levels did not correlate with age (r = −0.046, P = 0.837), diabetes (r = −0.121, P = 0.600) or IS medications (r = −0.070, P = 0.756).- Shows Ab levels at 7.4 ± 4 weeks after the second dose:CONCLUSIONIn our experience, PD patients have an adequate serological response to the SARS-Cov-2 vaccines, being previous COVID exposure the main predictor of a good response. Conversely, longer duration of PD treatment was a prognostic factor of seroconversion failure. We believe this should be kept in mind to assess the need for booster vaccination doses in those patients.Table 1.Ab levels (AU/mL)%<1000100–100031.81001–10 00027.310 001–40 00022.7>40.00018.2

Peyronie's Disease - Outcomes of collagenase clostridium histolyticum injection: A systematic review

ABSTRACT Introduction Peyronie's Disease (PD) is a condition characterized by abnormal and excessive wound repair causing fibrous plaquing of the tunica albuginea. Intralesional (IL) therapies are for patients who prefer to avoid surgical intervention and associated adverse complications. Currently, among available IL injection therapies (Collagenase Clostridium histolyticum (CCh) (Xiaflex, Endo Pharmaceuticals, Dublin, Ireland), verapamil, IFN-a-2b, OnabotulinumtoxinA (Botox) (AbbVie, Chicago, Illinois), Hyaluronic acid). The only FDA approved intralesional treatment option is CCh, which recently expanded its indications for atypical PD. Objective This study aims to review recent literature pertaining to CCh and other intralesional therapies in treatment of PD. Methods A systematic search of literature using exclusively PubMed was performed. There were no specific inclusion or exclusion criteria, however a preference was placed on recent and high impact articles. The review represents many types of studies including randomized control trials, meta-analyses, as well as phase 2 and 3 clinical trials. The use of CCh was compared to other IL therapies and evaluated for efficacy. This included Lastly, CCh use in atypical Peyronie's Disease was assessed for rate of success and complication. Results Recent literature supports the notion that CCh is the most superior IL treatment for typical and atypical PD patients. The capstone CCh study was the IMPRESS trial that showed a 34% reduction in curvature with a mean -17.0 ± 14.8 angle reduction with IL CCh, while men in the placebo saw an average 18.2% decrease in penile bend with a mean -9.3 ± 13.6 degree of change per person (p&amp;lt;0.0001). A shortened protocol for IL CCh treatment offered a 31.4% reduction in curvature while decreasing cost and office visits, potentially increasing patient compliance. Lastly, the literature shows CCh is used most commonly in atypical cases with about 64.8% of patients being treated with CCh – this is probably because of the high efficacy and superb safety profile that it offers. The most serious complications associated with CCh including urethral injury, corporal rupture and penile fracture are rare in all types of PD. Conclusion Since the approval of CCh by the FDA in 2013, it has been a staple in the treatment of PD, and here we report the continued success and superiority of this therapy. CCh is an effective, minimally invasive therapeutic option in most PD populations, however recent changes have made CCh unavailable for commercial use out of the United States, thus impacting many patients who have previous benefited from it. Disclosure Work supported by industry: no.

A Systematic Review of Machine Learning Based Gait Characteristics in Parkinson's Disease.

Parkinson's disease is a pervasive neuro disorder that affects people's quality of life throughout the world. The unsatisfactory results of clinical rating scales open the door for more research. PD treatment using current biomarkers seems a difficult task. So automatic evaluation at an early stage may enhance the quality and time period of life. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and population, Intervention, Comparison, and Outcome (PICO) search methodology schemes are followed to search the data and eligible studies for this survey. Approximate 1500 articles were extracted using related search strings. After the stepwise mapping and elimination of studies, 94 papers are found suitable for the present review. After the quality assessment of extracted studies, nine inhibitors are identified to analyze people's gait with Parkinson's disease, where four are critical. This review also differentiates the various machine learning classification techniques with their PD analysis characteristics in previous studies. The extracted research gaps are described as future perspectives. Results can help practitioners understand the PD gait as a valuable biomarker for detection, quantification, and classification. Due to less cost and easy recording of gait, gait-based techniques are becoming popular in PD detection. By encapsulating the gait-based studies, it gives an in-depth knowledge of PD, different measures that affect gait detection and classification.

Extracellular Alpha-Synuclein: Mechanisms for Glial Cell Internalization and Activation.

Alpha-synuclein (α-syn) is a small protein composed of 140 amino acids and belongs to the group of intrinsically disordered proteins. It is a soluble protein that is highly expressed in neurons and expressed at low levels in glial cells. The monomeric protein aggregation process induces the formation of oligomeric intermediates and proceeds towards fibrillar species. These α-syn conformational species have been detected in the extracellular space and mediate consequences on surrounding neurons and glial cells. In particular, higher-ordered α-syn aggregates are involved in microglial and oligodendrocyte activation, as well as in the induction of astrogliosis. These phenomena lead to mitochondrial dysfunction, reactive oxygen and nitrogen species formation, and the induction of an inflammatory response, associated with neuronal cell death. Several receptors participate in cell activation and/or in the uptake of α-syn, which can vary depending on the α-syn aggregated state and cell types. The receptors involved in this process are of outstanding relevance because they may constitute potential therapeutic targets for the treatment of PD and related synucleinopathies. This review article focuses on the mechanism associated with extracellular α-syn uptake in glial cells and the consequent glial cell activation that contributes to the neuronal death associated with synucleinopathies.

Multi-Omics Integration in Mice With Parkinson's Disease and the Intervention Effect of Cyanidin-3-O-Glucoside.

BackgroundParkinson’s disease (PD) is a multifactorial degenerative disease of the central nervous system, which affects mostly older adults. To date, research has focused on the progression of PD. Simultaneously, it was confirmed that the imbalances in gut microbiota are associated with the onset and progression of PD. Accurate diagnosis and precise treatment of PD are currently deficient due to the absence of effective biomarkers.MethodsIn this study, the pharmacodynamic study of cyanidin-3-O-glucoside in PD mice was used. It intends to use the “imbalance” and “balance” of intestinal microecology as the starting point to investigate the “gut-to-brain” hypothesis using metabolomic-combined 16S rRNA gene sequencing methods. Simultaneously, metabolomic analysis was implemented to acquire differential metabolites, and microbiome analysis was performed to analyze the composition and filter the remarkably altered gut microbiota at the phylum/genera level. Afterward, metabolic pathway and functional prediction analysis of the screened differential metabolites and gut microbiota were applied using the MetaboAnalyst database. In addition, Pearson’s correlation analysis was used for the differential metabolites and gut microbiota. We found that cyanidin-3-O-glucoside could protect 1-methyl-4-phenyl-1,2,3,6− tetrahydropy ridine (MPTP)-induced PD mice.ResultsMetabolomic analysis showed that MPTP-induced dysbiosis of the gut microbiota significantly altered sixty-seven metabolites. The present studies have also shown that MPTP-induced PD is related to lipid metabolism, amino acid metabolism, and so on. The 16S rRNA sequencing analysis indicated that 5 phyla and 22 genera were significantly altered. Furthermore, the differential gut microbiota was interrelated with amino acid metabolism, and so on. The metabolites and gut microbiota network diagram revealed significant correlations between 11 genera and 8 differential metabolites.ConclusionIn combination, this study offers potential molecular biomarkers that should be validated for future translation into clinical applications for more accurately diagnosing PD. Simultaneously, the results of this study lay a basis for further study of the association between host metabolisms, gut microbiota, and PD.

Differences in Patient Characteristics and Surgical Outcomes in Inpatient vs Outpatient Surgery for Peyronie's Disease: Contemporary Data from the National Surgical Quality Improvement Program Database

ABSTRACT Introduction Peyronie's disease (PD) is a fibrotic condition of the tunical layer of corporal penis that can cause deformity, erectile dysfunction, and reduced quality of life in men. Surgical therapy remains an integral treatment of the condition in severe cases. However, there is a paucity of data describing trends in surgical practices. Objective To characterize the differences between inpatient (IP) and outpatient (OP) practice patterns for PD surgery. We utilized the National Surgical Quality Improvement Program (NSQIP) database to identify and compare factors and outcomes associated with each approach. Methods NSQIP database was queried for men undergoing PD surgery between 2005-2019. Patients were classified as either OP (&amp;lt;24 hours) or IP(&amp;gt;24 hours). Baseline demographics, operating time, and complications were compared between the two groups. Multivariate logistic regression evaluated factors associated with discharge times and 30-day complications. Results A total of 924 patients were identified and classified as IP in 157 and OP in 767 patients. Operative time was shorter in OP (89 minutes) compared to IP (126 minutes, p&amp;lt;0.001). A statistically significant difference was noted in comorbidities favoring IP surgery between the groups including chronic obstructive pulmonary disease, anemia, and pre-operative dyspnea. The 30-day complication rates between both groups differed notably for any complication (9.6% IP, 1.6% OP, p&amp;lt; 0.001), any readmission (3.8% IP, 0.7% OP, p 0.005) superficial incisional surgical site infection (5.1% IP, 0.7% IP, p&amp;lt; 0.001), and unplanned intubation (1.3% IP, 0 % OP, p 0.029). Conclusions Surgical treatment for PD is increasingly utilized as an OP procedure. Patients with shorter operative times and fewer comorbidities appear to be the best suited candidates OP procedures. Beginning in 2015, trends began to shift toward OP procedures. In the era of increasing hospital costs, a shift toward OP surgery for PD has been rising. Disclosure No

The use of a polyglycolic acid polymer graft in Peyronie's disease - preliminary outcomes.

Plaque incision and grafting is indicated for patients with Peyronie's Disease [PD] and severe curvature, complex deformities or for patients with significant penile shortening. To date, no graft studied has been considered ideal. The aim of this study is to conduct a descriptive analysis about functional results with the use of a bioabsorbable graft for PD treatment. A single-center, retrospective evaluation of a cohort of patients who were treated by plaque incision and grafting with a polyglycolic acid polymer graft (Gore® Bio-A®) between 2018 and 2021 was conducted. Correction of penile curvature was the main outcome. Loss of penile sensitivity, de novo erectile dysfunction and any other adverse event were the secondary endpoints. 14 patients were included in this study (mean age 59.5 ± 7.2 years). The median follow-up time was 12 months (range 3-12). The curvature correction rate was 78.5%. Glans hypoesthesia was present in one of 14 patients (7.1%) and refractory erectile dysfunction was reported in 64.2%. None of the patients presented any major adverse event based on Clavien-Dindo classification. Curvature correction and changes in penile sensitivity rates were similar to those found in the literature. No major surgical complications, such as graft rejection, infection, and extrusion, occurred in this sample. Although a population with a higher prevalence of erectile dysfunction was included in this sample, higher rates of refractory erectile dysfunction were observed and these findings should be confirmed in further studies.

Change in the incidence of Parkinson\u2019s disease in a large UK primary care database

Parkinson’s disease (PD) has the fastest rising prevalence of all neurodegenerative diseases worldwide. However, it is unclear whether its incidence has increased after accounting for age and changes in diagnostic patterns in the same population. We conducted a cohort study in individuals aged ≥50 years within a large UK primary care database between January 2006 and December 2016. To account for possible changes in diagnostic patterns, we calculated the incidence of PD using four case definitions with different stringency derived from the combination of PD diagnosis, symptoms, and treatment. Using the broadest case definition, the incidence rate (IR) per 100,000 person years at risk (PYAR) was 149 (95% CI 143.3–155.4) in 2006 and 144 (95% CI 136.9–150.7) in 2016. In conclusion, the incidence of PD in the UK remained stable between 2006 and 2016, when accounting for age and diagnostic patterns, suggesting no major change in underlying risk factors for PD during this time period in the UK.

Dopamine receptor agonists: standard and non-standard applications in medicine

Dopamine receptor agonists (DRA) are a class of therapeutic drugs able to directly stimulate dopaminergic receptors facilitating a stronger effect of the endogenous dopamine, which is widely used in treatment of diseases that are accompanied with dopaminergic neurotransmission deficiency. A classical hypodopaminergic condition is Parkinson’s disease and DRA are traditionally associated with it. However, even the first DRA, Bromocriptine, widely adopted in PD treatment, was initially registered as a medication for treatment of prolactinaemia and associated pituitary adenomas and is still widely used in gynecology and endocrinology. In several countries DRA are used in treatment of diabetes, eating disorders, and addictions. Dopamine is the cardinal neurotransmitter of the emotional control and the main neurotransmitter of the reward system, and that defines the interest for researching the dopaminergic agents in treatment of primarily mental illnesses, as well as correction of secondary affective disorders. The experimental effectiveness of ADR in slowing down the rate of progression of the neurodegenerative process in severe incurable diseases, as well as potential neuroprotection in cerebrovascular insufficiency, will allow in the future to determine the criteria for the use of ADR in these non-standard situations, which may even lead to a change in clinical recommendations for the treatment of individual nosologies. Presented in this article are both traditional uses of DRA and an overview of non-standard applications of this class of medications with a discussion of recent studies. In the future, the likelihood of a rethinking of ADRs as a class of only antiparkinsonian drugs, with the expansion of their therapeutic indications.

Identifying the hub gene and immune infiltration of Parkinson’s disease using bioinformatical methods

BackgroundParkinson’s disease (PD) is a common neurodegenerative disorder that affects 1%–2% of the population over 60 years old. Immune response dysfunction in the brain contributes to the occurrence and development of PD. This study aimed to uncover the potential diagnostic genes for PD and characterize the immune cell infiltrates. MethodsWe downloaded the microarray data of patients with PD samples from the Gene Expression Omnibus (GEO) database. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify the modules linked to PD in the GSE20163 dataset. Meanwhile, differentially expressed genes (DEGs) between the healthy control samples and PD samples were also identified. Then the PD-related genes were integrated based on the genes in the key module and DEGs. Functional enrichment analysis was used to explore the molecular mechanisms of these PD-related genes. Protein-protein interaction (PPI) network and least absolute shrinkage and selection operator (LASSO) analysis were used to further screen candidate genes for PD. Gene set enrichment analysis (GSEA) was applied to explore the biological functions of these candidate genes. The infiltration of immune cells was detected by single-sample gene set enrichment analysis (ssGSEA) algorithm in the GSE20163 dataset, and Pearson analysis was used to investigate the correlation of candidate genes with immune cells and immune checkpoint proteins. The expression of candidate genes in clinical samples was verified by qPCR. ResultsAltogether, we found a unique gene module related to PD, where 109 DEGs were identified in the GSE20163 dataset. Following these results, we screened 68 genes associated with PD. Gene Expression Omnibus (GEO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that these genes were markedly enriched in the pathway of synthesis and transport of neurons. Three candidate genes (SLC18A2, CALB1, and SYNGR3) were further identified in PD patients through PPI network and LASSO analysis. The receiver operating characteristic (ROC) curve indicated that the three candidate genes had a good performance in distinguishing the PD samples from healthy control samples. The proportions of the aDC, DC, NK CD56dim cells, and follicular helper T cells (TFH) were obviously different between the healthy control and PD samples. Moreover, CTLA4, LAG3, CEACAM1, and CD27 were highly expressed in the PD group. GSEA analysis for candidate genes revealed that they were all closely related to the neurogenic disease. Additionally, the three candidate genes were all strongly correlated with the above immune cells and immune checkpoint proteins. The qPCR results validated the expression differences of SLC18A2 and SYNGR3 in the clinical PD and control samples. ConclusionThe three candidate genes may be a useful tool for diagnosing PD patients. These findings provide a reference for exploring new therapeutic targets and strategies for PD treatment.

Protective effects of functional foods against Parkinson's disease: A narrative review on pharmacology, phytochemistry, and molecular mechanisms.

In Persian Medicine (PM), PD (brain-based tremor) is a known CNS disorder with several therapeutic and preventive options. In their medical textbooks and pharmacopeias, Persian great scientists such as Rhazes (854-925 AD), Avicenna (980-1037 AD), and Jorjani (1042-1136 AD), have discussed pharmacological and nutritional strategies for the prevention, slowing progression, and treatment of PD. In the present study, we surveyed plant- and animal-based foods recommended by PM for the prevention and treatment of CNS-related tremors. In vivo and in-vitro pharmacological evidence supporting the beneficial effects of PM-recommended foods in prevention and alleviating PD, major active phytochemicals along with the relevant mechanisms of action were studied. Several PM plants possess potent antioxidant, antiinflammatory, and PD preventing properties. Garlic and allicin, cabbage and isothiocyanates, chickpea seed and its O-methylated isoflavones biochanin A and formononetin, cinnamon, and cinnamaldehyde, saffron and its crocin, crocetin, and safranal, black cumin and its thymoquinone, black pepper and piperine, pistachio and genistein and daidzein, and resveratrol are among the most effective dietary itemsagainst PD. They act through attenuating neurotoxin-induced memory loss and behavioral impairment, oxidative stress, and dopaminergic cell death. PM-recommended foods can help alleviate PD progression and also discovering and developing new neuroprotective anti-PD pharmaceuticals.

Psychosocial treatment for panic disorder: An umbrella review of systematic reviews and meta-analyses.

Panic disorder is a common and disabling psychiatric condition marked by sudden onset of physiological sensations that are appraised as dangerous. A number of studies and reviews have examined the efficacy of psychosocial treatments for PD; however, there is a lack of overarching reports that discuss the strength of evidence for the different psychosocial treatments for PD. This umbrella review provides an overview of systematic reviews and meta-analyses on psychosocial treatments for PD. A systematic search and review of the literature was conducted according to PRISMA guidelines. A total of 38 reviews (31 meta-analyses and 7 systematic reviews) were included in the umbrella review. Most of the 38 reviews were focused on the use of CBT, both in-person and internet-based, to treat PD among adults, generally finding it to be an efficacious treatment compared to control conditions. A limited number of the 38 reviews included other age ranges or examined other forms of psychosocial treatments. The methodological quality of most included reviews was rated as critically low according to the AMSTAR-2 rating system. Future reviews should focus on improving their methodological quality. Although the included reviews supported CBT as an efficacious treatment for reducing panic symptoms among adults, future research could focus on how CBT compares to other psychosocial treatments and the efficacy of CBT for PD among other populations (e.g., children and adolescents) and among diverse cultural groups.

Long-term retinal protection by MEK inhibition in Pax6 haploinsufficiency mice

Aniridia is a panocular condition characterized by impaired eye development and vision, which is mainly due to the haploinsufficiency of the paired-box-6 (PAX6) gene. Like what is seen in aniridia patients, Pax6-deficient mice Pax6Sey-Neu/+ exhibit a varied degree of ocular damage and impaired vision. Our previous studies showed that these phenotypes were partially rescued by PD0325901, a mitogen-activated protein kinase kinase (MEK or MAP2K) inhibitor. In this study, we assessed the long-term efficacy of PD0325901 treatment in retinal health and visual behavior. At about one year after the postnatal treatment with PD0325901, Pax6Sey-Neu/+ mice showed robust improvements in retina size and visual acuity, and the elevated intraocular pressure (IOP) was also alleviated, compared to age-matched mice treated with vehicles only. Moreover, the Pax6Sey-Neu/+ eyes showed disorganized retinal ganglion cell (RGC) axon bundles and retinal layers, which we termed as hotspots. We found that the PD treatment reduced the number and size of hotspots in the Pax6Sey-Neu/+ retinas. Taken together, our results suggest that PD0325901 may serve as an efficacious intervention in protecting retina and visual function in aniridia-afflicted subjects.

Novel anti-apoptotic L-DOPA precursors SuperDopa and SuperDopamide as potential neuroprotective agents for halting/delaying progression of Parkinson\u2019s disease

Parkinson’s disease (PD) is characterized by a gradual degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpC). Levodopa, the standard PD treatment, provides the missing dopamine in SNpC, but ultimately after a honeymoon with levodopa treatment the neurodegenerative process and the progression of the disease continue. Aimed at prolonging the life of dopaminergic cells, we prepared the levodopa precursors SuperDopa (SD) and SueprDopamide (SDA), in which levodopa is merged with the antioxidant N-acetylcysteine (NAC) into a single molecule. Rotenone is a mitochondrial complex inhibitor often used as experimental model of PD. In vivo, SD and SDA treatment show a significant relief of motor disabilities in rotenone-injected rats. SD and SDA also lower rotenone-induced-α-synuclein (α-syn) expression in human SH-SY5Y cells, and α-syn oligomerization in α-syn-overexpressing-HEK293 cells. In the neuronal SH-SY5Y cells, SD and SDA reverse oxidative stress-induced phosphorylation of cJun-N-terminal kinase (JNK) and p38-mitogen-activated kinase (p38MAPK). Attenuation of the MAPK-inflammatory/apoptotic pathway in SH-SY5Y cells concurrent with protection of rotenone-triggered motor impairment in rats, is a manifestation of the combined antioxidant/anti-inflammatory activity of SD and SDA together with levodopa release. The concept of joined therapies into a single molecule, where levodopa precursors confer antioxidant activity by enabling NAC delivery across the BBB, provides a potential disease-modifying treatment for slowing PD progression.

Extracts of Portulaca oleracea promote wound healing by enhancing angiology regeneration and inhibiting iron accumulation in mice

ObjectiveTo investigate the role of Portulaca oleracea (POL) in promoting revascularization and re-epithelization as well as inhibiting iron aggregation and inflammation of deep tissue pressure injury (DTPI). MethodsThe hydroalcoholic extract of POL (P) and aqueous phase fraction of POL (PD) were prepared based on maceration and liquid–liquid extraction. The number of new blood vessels and VEGF-A expression level were assessed using H&E stain and Western blot on injured muscle to examine the role of POL different extracts in vascularization. The iron distribution and total elemental iron of injured muscle were detected using laser ablation inductively coupled plasma mass spectrometry (ICP-MS) and Perls’ staining to determine whether POL extracts can inhibit the iron accumulation. Besides, the ability of POL extracts to promote wound healing by combining re-epithelization time, inflammation degree and collagen deposition area were comprehensively evaluated. ResultsIn vitro, we observed a significant increase in HUVEC cell viability, migration rate and the number of the tube after P and PD treatment (P < 0.05). In vivo, administration of P and PD impacted vascularization and iron accumulation on injured tissue, evident from more new blood vessels, higher expression of VEGF-A and decreased muscle iron concentration of treatment groups compared with no-treatment groups (P < 0.05). Besides, shorter re-epithelization time, reduced inflammatory infiltration and distinct collagen deposition were associated with administration of P and PD (P < 0.05). ConclusionPOL extract administration groups have high-quality wound healing, which is associated with increased new blood vessels, collagen deposition and re-epithelization, along with decreased iron accumulation and inflammatory infiltration. Our results suggest that that POL extract is beneficial to repair injured muscle after ischemia–reperfusion, highlighting the potential of POL in the DTPI treatment.

The clinical efficacy of the stratification medical treatment based on the risk estimation of motor complications in Parkinson's disease

Objectives: To evaluate the clinical efficacy of the stratification medical treatment based on the motor complications risk estimation in improving the quality of life, motor symptoms and delaying the motor complications in Parkinson's patients. Methods: Outpatients and inpatients from Xinhua Hospital, Shanghai Jiao Tong University, were recruited between November 2019 and June 2020. The participants were all clinically diagnosed with PD and treated with anti-PD medications, but had no history of motor complications, with the 8-item Parkinson's disease questionnaire summary index (PDQ-8 SI)>18.59. At baseline, the demographic characteristics, PD medical history, levodopa dosage (LD) and levodopa equivalent dosage (LED) were collected, and the evaluation of PDQ-8, Unified Parkinson's disease rating scale (UPDRS)-Ⅱ and Ⅲ, Hoehn and Yahr (H&Y) grade, Hamilton anxiety scale-14 (HAMA-14), Hamilton depression scale-24 (HAMD-24), mini-mental state examination (MMSE), Pittsburgh sleep quality index (PSQI), and Epworth sleepiness scale (ESS) tools was accomplished in all participants. Meanwhile, a Parkinson's disease risk estimation scale for motor complications was used to assess patients' risk of motor complications, and thus the medication was stratified in PD patients accordingly. During the 6-month and 12-month follow-ups, the evaluation of the above-mentioned parameters was repeated in all participants. At the 3-month and 9-month follow-ups, the information of anti-PD medications, the occurrence of motor complications (motor fluctuations and dyskinesia) and adverse drug reactions were recorded, and PDQ-8 was also evaluated. Results: Two hundred and fifty-one patients completed the 1-year follow-up, with 135 males and 116 females. At baseline, the median age of the patients was 66 (60, 71) years and the median PDQ-8 SI was 31.2 (21.9, 40.6). Additionally, 15.9% (40/251) of the patients were at high risk of motor fluctuation, and 7.2% (18/251) were at high risk of dyskinesia. There were significant differences in the age of onset, disease duration, PD treatment duration, the scores of UPDRS-Ⅱ and Ⅲ, H&Y Grade, and PDQ-8 SI among PD patients of different risk groups (all P<0.05). In the 12th month, the median of PDQ-8 SI, Δ PDQ-8 SI and Δ UPDRS-Ⅲ was 12.5 (9.4, 18.8), -15.6 (-21.9, -9.4) and -9(-16, -4), respectively, which was statistically different from that of baseline (all P<0.05). The change of UPDRS-Ⅱ scores in the group with high risk of motor fluctuation was statistically different from that in the groups with low and moderate risk (P<0.05). The changes of PSQI score, LD and LED in the group with high risk of dyskinesia was statistically different from those in the groups with low and moderate risk (all P<0.05). During the follow-up, the incidence of motor fluctuation and dyskinesia was 9.56% (24/251) and 5.97% (15/251), respectively. Conclusion: The stratification medical treatment might have a positive intervention effect on promoting a better quality of life, improving motor symptoms and delaying motor complications in PD patients.

Neurotensin agonist PD 149163 modulates the neuroinflammation induced by bacterial endotoxin lipopolysaccharide in mice model

Objective The disruption of bidirectional communication between neuroendocrine and immune components by stressors leads to mental problems. The immunomodulation therapy of neuroinflammation-led psychiatric illness is an emerging area of research. Therefore, the present study aimed to evaluate immune modulation efficacy of PD 149163 (PD) against the lipopolysaccharide (LPS)-induced neuroinflammation. Materials and methods The Swiss albino mice (female/12 weeks) were divided into six groups (6 mice/group): (I) Control: 0.9% NaCl; (II) LPS: 1 mg/kg BW, for 5 days; (III) LPS + PD Low: LPS 1 mg/kg BW (for 5 days) after that PD 100 µg/kg BW (for 21 days); (IV) LPS + PD High: LPS 1 mg/kg BW (for 5 days) after that PD 300 µg/kg BW (for 21 days); (V) PD Low: PD 100 µg/kg BW (for 21 days); (VI) PD High: PD 300 µg/kg BW (for 21 days). All treatments were given intraperitoneal. Results The LPS-induced weight loss (body and brain) was normalized to control after PD treatment. The PD enhanced superoxide dismutase (SOD) activity while decreased lipid hydroperoxide (LOOH) level altered in LPS-exposed mice. The significantly increased pro-inflammatory cytokines (IL-6 and TNF-α) in LPS exposure were also decreased by PD. Likewise, the LPS-induced HPA axis activation was stabilized by PD. In the hippocampus, the pyramidal cell layer thickness, pyramidal neurons number and size of CA1 and CA3 regions were reduced along with misalignment, shrinkage, and impairment of cytoarchitecture. In the co-treated group, the LPS-induced hippocampus disruption was reversed after PD exposure. Conclusion We suggested that the PD modulates the LPS-induced neuroinflammation and psychiatric illness in a dose-dependent manner.