The Potential of Targeting Autophagy-Related Non-coding RNAs in the Treatment of Alzheimer's and Parkinson's Diseases.

Clearance of accumulated protein aggregates is one of the functions of autophagy. Recently, a clearer understanding of non-coding RNAs (ncRNAs) functions documented that ncRNAs have important roles in several biological processes associated with the development and progression of neurodegenerative disorders. Subtypes of ncRNA, including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), are commonly dysregulated in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Dysregulation of these non-coding RNAs has been associated with inhibition or stimulation of autophagy. Decreased miR-124 led to decreased/increased autophagy in experimental model of Alzheimer and Parkinson diseases. Increased BACE1-AS showed enhanced autophagy in Alzheimer disease by targeting miR-214-3p, Beclin-1, LC3-I/LC3-II, p62, and ATG5. A significant increase in NEAT1led to stimulated autophagy in experimental model of PD by targeting PINK1, LC3-I, LC3-II, p62 and miR-374c-5p. In addition, increased BDNF-AS and SNHG1 decreased autophagy in MPTP-induced PD by targeting miR-125b-5p and miR-221/222, respectively. The upregulation of circNF1-419 and circSAMD4A resulted in an increased autophagy by regulating Dynamin-1 and miR-29c 3p, respectively. A detailed discussion of miRNAs, circRNAs, and lncRNAs in relation to their autophagy-related signaling pathways is presented in this study.

Non-coding RNAs and Aquaporin 4: Their Role in the Pathogenesis of Neurological Disorders.

Neurological disorders are a major group of non-communicable diseases affecting quality of life. Non-Coding RNAs (ncRNAs) have an important role in the etiology of neurological disorders. In studies on the genesis of neurological diseases, aquaporin 4 (AQP4) expression and activity have both been linked to ncRNAs. The upregulation or downregulation of several ncRNAs leads to neurological disorder progression by targeting AQP4. The role of ncRNAs and AQP4 in neurological disorders is discussed in this review.

Therapeutic Potential of Fingolimod on Psychological Symptoms and Cognitive Function in Neuropsychiatric and Neurological Disorders.

Neuropsychiatric and neurological disorders pose a significant global health burden, highlighting the need for innovative therapeutic approaches. Fingolimod (FTY720), a common drug to treat multiple sclerosis, has shown promising efficacy against various neuropsychiatric and neurological disorders. Fingolimod exerts its neuroprotective effects by targeting multiple cellular and molecular processes, such as apoptosis, oxidative stress, neuroinflammation, and autophagy. By modulating Sphingosine-1-Phosphate Receptor activity, a key regulator of immune cell trafficking and neuronal function, it also affects synaptic activity and strengthens memory formation. In the hippocampus, fingolimod decreases glutamate levels and increases GABA levels, suggesting a potential role in modulating synaptic transmission and neuronal excitability. Taken together, fingolimod has emerged as a promising neuroprotective agent for neuropsychiatric and neurological disorders. Its broad spectrum of cellular and molecular effects, including the modulation of apoptosis, oxidative stress, neuroinflammation, autophagy, and synaptic plasticity, provides a comprehensive therapeutic approach for these debilitating conditions. Further research is warranted to fully elucidate the mechanisms of action of fingolimod and optimize its use in the treatment of neuropsychiatric and neurological disorders.

Probiotics and the Treatment of Parkinson's Disease: An Update.

Parkinson's disease (PD) is a progressive neurological disorder characterized by motor and non-motor features. Although some progress has been made in conventional PD treatments, these breakthroughs have yet to show high efficacy in treating this neurodegenerative disease. Probiotics are live microorganisms that confer health benefits on the host when administered in adequate amounts. Probiotics have putative anticancer, antioxidative, anti-inflammatory, and neuroprotective effects. Multiple lines of evidence show that probiotics control and improve several motor and non-motor symptoms in patients and experimental animal models of PD. Probiotic supplementation mediates these pharmacological effects by targeting a variety of cellular and molecular processes, i.e., oxidative stress, inflammatory and anti-inflammatory pathways, as well as apoptosis. Herein, we summarize the effects of probiotics on motor and non-motor symptoms as well as various cellular and molecular pathways in PD.

Aquaporin 4 in Traumatic Brain Injury: From Molecular Pathways to Therapeutic Target.

Traumatic brain injury (TBI) is known as an acute degenerative pathology of the central nervous system, and has been shown to increase brain aquaporin 4 (AQP4) expression. Various molecular mechanisms affect AQP4 expression, including neuronal high mobility group box 1, forkhead box O3a, vascular endothelial growth factor, hypoxia-inducible factor-1 α (HIF-1 α) sirtuin 2, NF-κB, Malat1, nerve growth factor and Angiotensin II receptor type 1. In addition, inhibition of AQP4 with FK-506, MK-801 (indirectly by targeting N-methyl-D-aspartate receptor), inactivation of adenosine A2A receptor, levetiracetam, adjudin, progesterone, estrogen, V1aR inhibitor, hypertonic saline, erythropoietin, poloxamer 188, brilliant blue G, HIF-1alpha inhibitor, normobaric oxygen therapy, astaxanthin, epigallocatechin-3-gallate, sesamin, thaliporphine, magnesium, prebiotic fiber, resveratrol and omega-3, as well as AQP4 gene silencing lead to reduced edema upon TBI. This review summarizes current knowledge and evidence on the relationship between AQP4 and TBI, and the potential mechanisms involved.

The role of aquaporin 4 in brain tumors: implications for pathophysiology, diagnosis and therapy.

Primary brain tumors are a heterogeneous group of tumors that arise from cells intrinsic to the central nervous system (CNS). Aquaporin-4 (AQP4) has been implicated in the pathogenesis of brain tumors. Previous reports have documented a relationship between AQP4 and several molecular pathways associated with the etiology of brain tumors, such as apoptosis, invasion and cell migration. AQP4 affects apoptosis via cytochrome C, Bad and Bcl-2, as well as invasion and migration via IDO1/TDO-Kyn-AhR axis, lncRNA LINC00461, miR-216a, miRNA-320a and MMPs. In addition, inhibition of AQP4 mitigates the progression of brain tumors. This review summarizes current knowledge and evidence regarding the relationship between AQP4 and brain tumors, and the mechanisms involved.

The role of vitamin D in the age of COVID-19: A systematic review and meta-analysis.

BACKGROUND: Evidence recommends that vitamin D might be a crucial supportive agent for the immune system, mainly in cytokine response regulation against COVID-19. Hence, we carried out a systematic review and meta-analysis in order to maximise the use of everything that exists about the role of vitamin D in the COVID-19. METHODS: A systematic search was performed in PubMed, Scopus, Embase and Web of Science up to December 18, 2020. Studies focused on the role of vitamin D in confirmed COVID-19 patients were entered into the systematic review. RESULTS: Twenty-three studies containing 11 901 participants entered into the meta-analysis. The meta-analysis indicated that 41% of COVID-19 patients were suffering from vitamin D deficiency (95% CI, 29%-55%), and in 42% of patients, levels of vitamin D were insufficient (95% CI, 24%-63%). The serum 25-hydroxyvitamin D concentration was 20.3 ng/mL among all COVID-19 patients (95% CI, 12.1-19.8). The odds of getting infected with SARS-CoV-2 are 3.3 times higher among individuals with vitamin D deficiency (95% CI, 2.5-4.3). The chance of developing severe COVID-19 is about five times higher in patients with vitamin D deficiency (OR: 5.1, 95% CI, 2.6-10.3). There is no significant association between vitamin D status and higher mortality rates (OR: 1.6, 95% CI, 0.5-4.4). CONCLUSION: This study found that most of the COVID-19 patients were suffering from vitamin D deficiency/insufficiency. Also, there is about three times higher chance of getting infected with SARS-CoV-2 among vitamin-D-deficient individuals and about five times higher probability of developing the severe disease in vitamin-D-deficient patients. Vitamin D deficiency showed no significant association with mortality rates in this population.

Melatonin and Parkinson Disease: Current Status and Future Perspectives for Molecular Mechanisms.

Parkinson disease (PD) is a chronic and neurodegenerative disease with motor and nonmotor symptoms. Multiple pathways are involved in the pathophysiology of PD, including apoptosis, autophagy, oxidative stress, inflammation, α-synuclein aggregation, and changes in the neurotransmitters. Preclinical and clinical studies have shown that melatonin supplementation is an appropriate therapy for PD. Administration of melatonin leads to inhibition of some pathways related to apoptosis, autophagy, oxidative stress, inflammation, α-synuclein aggregation, and dopamine loss in PD. In addition, melatonin improves some nonmotor symptom in patients with PD. Limited studies, however, have evaluated the role of melatonin on molecular mechanisms and clinical symptoms in PD. This review summarizes what is known regarding the impact of melatonin on PD in preclinical and clinical studies.

The effects of quercetin supplementation on lipid profiles and inflammatory markers among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials.

Aims: This systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to determine the effect of quercetin administration on lipid profiles and inflammatory markers among patients with metabolic syndrome (MetS) and related disorders.Methods: We searched systematically online databases including Cochrane Library, EMBASE, MEDLINE, and Web of Science to identify the relevant RCTs until November 2018. Q-test and I2 statistics were applied to assess heterogeneity among included studies. Data were combined using fixed- or random-effects model and presented as standardized mean difference (SMD) with 95% confidence interval (CI).Results: Out of 591 citations, 16 RCTs were included in the meta-analysis. The pooled findings showed that quercetin consumption significantly decreased total-cholesterol (SMD = -0.98; 95% CI, -1.48, -0.49; p < 0.001; I2: 94.0), LDL-cholesterol (SMD = -0.88; 95% CI, -1.35, -0.41; p < 0.001; I2: 92.7) and C-reactive protein (CRP) levels (-0.64; 95% CI, -1.03, -0.25; p = 0.001; I2: 90.2). While, quercetin supplementation did not significantly affect triglycerides (TG) (SMD = -0.32; 95% CI, -0.68, 0.04; p = 0.08; I2: 84.8), HDL-cholesterol (SMD = 0.20; 95% CI, -0.20, 0.24; p = 0.84; I2: 70.6), interleukin 6 (IL-6) (SMD = -0.69; 95% CI, -1.69, 0.31; p = 0.17; I2: 94.5) and tumor necrosis factor-alpha (TNF-α) levels (SMD = -0.06; 95% CI, -0.25, 0.14; p = 0.58; I2: 35.6)Conclusions: In summary, the current meta-analysis demonstrated that quercetin supplementation significantly reduced total-cholesterol, LDL-cholesterol, and CRP levels, yet did not affect triglycerides, HDL-cholesterol, IL-6 and TNF-α among patients with MetS and related disorders.

The effects of resveratrol intake on weight loss: a systematic review and meta-analysis of randomized controlled trials.

This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of resveratrol intake on weight loss. We searched the following databases until July 2018: MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Out of 831 reports, 36 RCTs were eligible for including to our meta-analysis. The pooled results, using random-effects model showed that resveratrol supplementation significantly decreased body weight (SMD = -0.17; 95% CI, -0.33, -0.01; P = 0.03; I2: 62.6), body mass index (BMI) (SMD = -0.20; 95% CI, -0.35, -0.05; P = 0.01; I2: 60.6), fat mass (SMD = -0.32; 95% CI, -0.62, -0.03; P = 0.03; I2: 77.9) and waist circumference (WC) (SMD = -0.42; 95% CI, -0.68, -0.16; P = 0.001; I2: 75.2), and significantly increased lean mass (SMD = 1.21; 95% CI, 0.75, 1.67; P < 0.001; I2: 87.6). We found no significant effect of resveratrol administration on leptin (SMD = -0.20; 95% CI, -0.68, 0.27; P = 0.40; I2: 85.3) and adiponectin levels (SMD = 0.08; 95% CI, -0.39, 0.55; P = 0.74; I2: 91.0). Resveratrol supplementation significantly decreased body weight in obese patients (SMD -0.43; 95% CI, -0.60, -0.26) compared with other diseases (SMD 0.02; 95% CI, -0.29, 0.33), and type 2 diabetes mellitus (SMD -0.17; 95% CI, -0.37, 0.02). Overall, the current meta-analysis demonstrated that resveratrol intake significantly reduced weight, BMI, WC and fat mass, and significantly increased lean mass, but did not affect leptin and adiponectin levels.

The effects of resveratrol on lipid profiles and liver enzymes in patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There are current trials investigating the effect of resveratrol supplementation on lipid profiles and liver enzymes among patients with metabolic syndrome (MetS) and related disorders; however, their findings are controversial. This systematic review and meta-analysis were aimed to determine the effects of resveratrol supplementation on lipid profiles and liver enzymes among patients with MetS and related disorders. METHODS: We performed a comprehensive search of the following online databases up to November 2018: Cochrane Library, PubMed, Embase, and Web of Science. The relevant articles were assessed for quality of studies using the Cochrane risk of bias tool. RESULTS: Out of 2459 citations, 31 articles were appropriate for including to the current meta-analysis. The pooled results indicated that resveratrol use significantly decreased total cholesterol [weighted mean difference (WMD) = - 7.65 mg/dL; 95% CI, - 12.93, - 2.37; P < 0.01; I2: 83.4%] and increased gamma-glutamyl transferase (GGT) concentrations (WMD = 1.76 U/l; 95% CI, 0.58, 2.94; P < 0.01; I2: 20.1%). We found no significant effect of resveratrol supplementation on triglycerides (WMD = - 5.84 mg/dL; 95% CI, - 12.68, 1.00; P = 0.09; I2: 66.8%), LDL- (WMD = -2.90 mg/dL; 95% CI, - 10.88, 5.09; P = 0.47; I2: 96.0%), HDL-cholesterol (WMD = 0.49 mg/dL; 95% CI, - 0.80, 1.78; P = 0.45; I2: 74.0%), alanine aminotransferase (ALT) (WMD = -0.14 U/l; 95% CI, - 3.69, 3.41; P = 0.93; I2: 79.6%), and aspartate aminotransferase (AST) (WMD = -0.34 U/l; 95% CI, - 2.94, 2.27; P = 0.80; I2: 88.0%) concentrations. CONCLUSIONS: This meta-analysis demonstrated that resveratrol supplementation among patients with MetS and related disorders significantly reduced total cholesterol and increased GGT concentrations, but did not affect triglycerides, LDL-, HDL-cholesterol, ALT, and AST concentrations. This data suggests that resveratrol may have a potential cardio-protective effect in patients with MetS and related disorders.

The effects of statin use on inflammatory markers among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials.

Current evidence suggests that statin use decreases the incidence of cardiovascular diseases (CVD) through reducing LDL cholesterol and decreasing inflammation. Metabolic syndrome (MetS) is usually associated with increased inflammatory markers and increased risk of CVD. We conducted a systematic review and meta-analysis to determine the effect of statin use on inflammatory markers including C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1 (IL-1) among patients with MetS and related disorders. PubMed, EMBASE, Web of Science databases, and Cochrane Library were searched for randomized controlled trials (RCTs) through April 2018. Three independent investigators evaluated study eligibilities, extracted data, and assessed study quality using the Cochrane Collaboration risk of bias tool and Jadad's quality scales. Heterogeneity was determined using Cochran's Q statistic and I-square (I2) test. Based on the heterogeneity results, we pooled data using random-effect or fixed effect models presented as standardized mean differences (SMD) and corresponding 95% confidence intervals (CI). One hundred thirteen RCTs (19,644 patients) were included in our meta-analysis. The pooled results using random effects model showed that statin use statistically significantly decreased CRP level (SMD= -0.97; 95% CI, -1.10, -0.85; P < 0.001; I2: 95.1%), TNF-α (SMD= -1.88; 95% CI, -2.40, -1.38; P < 0.001; I2: 97.2%), IL-6 (SMD= -1.67; 95% CI, -1.98, -1.34; P < 0.001; I2: 96.5%), and IL-1 concentrations (SMD= -8.35; 95% CI, -10.49, -6.22; P < 0.001; I2: 98.4%) among patients with MetS and related disorders. Our meta-analysis showed beneficial effects of statin use on reducing inflammatory markers in patients with MetS and related disorders.

Correlation of serum levels and gene expression of tumor necrosis factor-α-induced protein-8 like-2 with Parkinson disease severity.

Different immune-mediated mechanisms involved in the pathogenesis of Parkinson disease (PD) as a neurodegenerative and inflammatory disease. According to our knowledge, there is no report evaluating Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2), a cytokine maintaining immune homeostasis, in PD. We analyzed the correlation of the serum levels and circulatory gene expression of TIPE2 with severity of PD. In this case-control study, 43 patients with PD and 40 healthy subjects were enrolled. The diagnosis of PD was performed byclinical diagnostic criteria of the UK Parkinson's Disease Society Brain Bank. The severity of PD was evaluated by modified Hoehn and Yahr (H and Y) scale. Serum levels and gene expression of TIPE2 were assessed by Elisa and real time PCR, respectively. The mean serum levels and gene expression of TIPE2 in patients with PD did not have significant difference compared to healthy subjects. Linear multiple regression analysis showed that increased serum levels of TIPE2 are positively related to age and severity of PD (P ≤ 0.0001). In addition, the gene expression of TIPE2 was found to be associated with age (P < 0.0001). Our study showed that the serum levels of TIPE2 and its gene expression might be important prognostic biomarkers of PD.

Predicting role of Myc-induced nuclear antigen 53 in determining the development and severity of systemic lupus erythematosus.

Introduction: Systemic lupus erythematosus (SLE) as an autoimmune disease can relate to an imbalance between regulatory T cells (Tregs) and Th17 cells. Previous reports have shown that Myc-induced nuclear antigen (Mina) 53 protein is involved in the developments of Tregs and Th17 cells. Therefore, the current study focused on determining whether Mina53 level is correlated to the severity of SLE. Methods: The blood samples were collected from 60 patients with SLE (30 cases with mild SLE and 30 cases with severe SLE) and 30 healthy subjects. The serum concentration of Mina53 was measured using enzyme-linked immunosorbent assay (ELISA). The expression of Mina53 gene was assessed using real-time PCR method after extracting RNA from isolated peripheral blood mononuclear cells and synthesizing cDNA. Results: Patients with SLE showed significant increases in the serum level and gene expression of Mina53 compared to healthy subjects (P<0.001). Furthermore, serum level and gene expression of Mina53 showed significant effects on SLE disease and its severity (P<0.01). There was the highest sensitivity and maximum specificity in the cut-off point of Mina53 serum level equal to 125.4 (area under the curve (AUC)=0.951) and Mina53 expression level equal to 8.5 (AUC=0.88) for SLE diagnosis. The cut-off point of Mina53 serum level equal to 139.5 (AUC=0.854) and the cut-off point of Mina53 expression level equal to 8.5 (AUC=0.788) had the highest sensitivity and maximum specificity determining severe forms of SLE. Discussion: Our results showed that the changes in serum and expression levels of Mina53 have significant effects on SLE disease and its severity. These levels may be considered as diagnostic and predictive markers for SLE.

Non-Coding RNAs and Neurodegenerative Diseases: Information of their Roles in Apoptosis.

Apoptosis can be known as a key factor in the pathogenesis of neurodegenerative disorders. In disease conditions, the rate of apoptosis expands and tissue damage may become apparent. Recently, the scientific studies of the non-coding RNAs (ncRNAs) has provided new information of the molecular mechanisms that contribute to neurodegenerative disorders. Numerous reports have documented that ncRNAs have important contributions to several biological processes associated with the increase of neurodegenerative disorders. In addition, microRNAs (miRNAs), circular RNAs (circRNAs), as well as, long ncRNAs (lncRNAs) represent ncRNAs subtypes with the usual dysregulation in neurodegenerative disorders. Dysregulating ncRNAs has been associated with inhibiting or stimulating apoptosis in neurodegenerative disorders. Therefore, this review highlighted several ncRNAs linked to apoptosis in neurodegenerative disorders. CircRNAs, lncRNAs, and miRNAs were also illustrated completely regarding the respective signaling pathways of apoptosis.

Correlations between single nucleotide polymorphisms in obsessive-compulsive disorder with the clinical features or response to therapy.

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder, in which the patient endures intrusive thoughts or is compelled to perform repetitive or ritualized actions. Many cases of OCD are considered to be familial or heritable in nature. It has been shown that a variety of internal and external risk factors are involved in the pathogenesis of OCD. Among the internal factors, genetic modifications play a critical role in the pathophysiological process. Despite many investigations performed to determine the candidate genes, the precise genetic factors involved in the disease remain largely undetermined. The present review summarizes the single nucleotide polymorphisms that have been proposed to be associated with OCD symptoms, early onset disease, neuroimaging results, and response to therapy. This information could help us to draw connections between genetics and OCD symptoms, better characterize OCD in individual patients, understand OCD prognosis, and design more targeted personalized treatment approaches.

Can Berberine Serve as a New Therapy for Parkinson's Disease?

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurodegeneration and deposition of alpha-synuclein. Mechanisms associated with PD etiology include oxidative stress, apoptosis, autophagy, and abnormalities in neurotransmission, to name a few. Drugs used to treat PD have shown significant limitations in their efficacy. Therefore, recent focus has been placed on the potential of active plant ingredients as alternative, complementary, and efficient treatments. Berberine is an isoquinoline alkaloid that has shown promise as a pharmacological treatment in PD, given its ability to modulate several molecular pathway associated with the disease. Here, we review contemporary knowledge supporting the need to further characterize berberine as a potential treatment for PD.

Aquaporin 4 and brain-related disorders: Insights into its apoptosis roles.

Brain-related disorders are leading global health problems. Various internal and external factors are involved in the progression of brain-related disorders. Inflammatory pathways, oxidative stresses, apoptosis, and deregulations of various channels are critical players in brain-related disorder pathogenesis. Among these players, aquaporins (AQP) have critical roles in various physiological and pathological conditions. AQPs are water channel molecules that permit water to cross the hydrophobic lipid bilayers of cellular membranes. AQP4 is one of the important members of AQP family. AQPs are involved in controlling apoptosis pathways in brain-related disorders. In this regard, several reports have evaluated the pathological effects of AQP4 by targeting the apoptosis-related processes in brain-related disorders. Here, for the first time, we highlight the impact of AQP4 on apoptosis-related processes in brain-related disorders.

Therapeutic Potential of Resveratrol in the Treatment of Glioma: Insights into its Regulatory Mechanisms.

Glioma is a prevalent primary tumor of the brain and spinal cord. Several biological pathways play an important role in the pathogenesis of glioma, including apoptosis, autophagy, cell cycle arrest, migration, and invasion. The low efficacy of chemotherapy and radiation therapy has forced researchers to evaluate alternative treatments for glioma. In this regard, flavonoids have been studied. Resveratrol is a flavonoid with distinct pharmacological activities that has been used in the treatment of various diseases. Several recent studies have also focused on its therapeutic efficacy against glioma. Resveratrol exerts its pharmacological attributes by regulating various molecular and cellular pathways. Here, we review contemporary knowledge in support of the use of resveratrol in the treatment of glioma and its effects on various molecular and cellular mechanisms.

The correlation of helios and neuropilin-1 frequencies with parkinson disease severity.

OBJECTIVES: Parkinson disease (PD), a neurodegenerative disease, has also some immunologic basis in which several regulatory factors, like Helios and Neuropilin-1 (NRP-1) may show some roles in its pathogenesis. We aimed to evaluate the circulatory frequency of T regulatory cells (Tregs) expressing Helios and NRP-1 in PD. PATIENTS AND METHODS: In this case-control study, 83 patients with PD and 83 healthy controls were enrolled. The diagnosis of PD was accomplished in accordance with clinical diagnostic criteria of the UK Parkinson Disease Society Brain Bank. The modified Hoehn and Yahr (H and Y) were used to measure the severity of PD. Flow cytometry was used to evaluate the circulatory frequency of CD4+CD25+Foxp3+Tregs expressing and Helios and NRP-1 in all participants. Also, correlation of H and Y with such frequencies was evaluated. RESULTS: Our findings showed that frequency of CD4+CD25+Foxp3+Tregs expressing NRP-1 (P = 0.04) and Helios (P = 0.01) in patients with PD was significantly higher than those in healthy subjects. The frequency of Tregs expressing Helios and NRP-1 showed a negative correlation with H and Y criteria and disease duration. Multiple linear regression analysis indicated that the severity of PD is the only effective factor on the frequency of CD4+CD25+Foxp3+NRP-1+Tregs (P = 0.012) and CD4+CD25+FoxP3+ Helios + Tregs (P = 0.038). CONCLUSION: Our study showed that the increased frequency of Tregs expressing Helios and NRP-1 is associated with the severity of PD.