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Heliyon Jun 2024We developed novel and optimal Q10-NLC/SLN formulations as antioxidant and anti-tyrosinase agents. The formulations were analyzed for particle size, morphology,...
Preparation and characterization of novel nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN) containing coenzyme Q10 as potent antioxidants and antityrosinase agents.
We developed novel and optimal Q10-NLC/SLN formulations as antioxidant and anti-tyrosinase agents. The formulations were analyzed for particle size, morphology, entrapment efficiency (EE %), and long-term stability. The drug release and skin penetration were evaluated using dialysis bag diffusion and Sprague Dawley (SD) rats, respectively. Cytotoxicity and protecting effects were assessed by AlamarBlue® assay, ROS level by DCFH-DA, and tyrosinase activity by l-DOPA assay, measuring the absorbance at 470 nm. The selected formulations had optimal surface characterizations, including Z-average size, PDI, and Zeta potential ranging from 125 to 207 nm, 0.09-0.22, and -7 to -24, respectively. They also exhibited physiochemical stability for up to 6 months and EE% above 80 %. The lipids ratio and co-Q10 amount as variable factors significantly affected particle size and zeta potential but were insignificant on PDI. The release diagram showed that Q10-NLC/SLN revealed a fast release during the first 8 h and prolonged release afterward. The skin permeation revealed a higher accumulative uptake of co-Q10 in the skin for Q10-NLC/SLN compared to Q10 emulsions. Both selected Q10-NLC and Q10-SLN could reduce intracellular ROS after exposure to HO. The Q10-NLC was found to be more potent for inhibiting the tyrosinase activity compared to O10-SLN. The results suggest that the new formulations are promising carriers for topical delivery of co-Q10 as an anti-aging and skin-whitening agent.
PubMed: 38882272
DOI: 10.1016/j.heliyon.2024.e31429 -
Chinese Medicine Jun 2024Shaoyao Decoction (SYD) is a widely recognized herbal formula utilized in traditional Chinese medicine for the treatment of diarrhea. Although it has demonstrated...
BACKGROUND
Shaoyao Decoction (SYD) is a widely recognized herbal formula utilized in traditional Chinese medicine for the treatment of diarrhea. Although it has demonstrated significant effectiveness in clinical practice for treating ulcerative colitis, the precise mechanisms by which it operates remain largely elusive.
METHODS
The active ingredients of SYD were obtained by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), which were used to explore the potential pharmacological mechanism based on TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) and PANTHER (Protein Analysis Through Evolutionary Relationships) classification system. In a mouse model of dextran sulfate sodium (DSS)-induced colitis, mRNA sequencing, 16S rDNA sequencing and targeted metabolomics techniques were used to elucidate the mechanisms of SYD, and immunohistochemistry, immunofluorescence, enzyme linked immunosorbent assay, real time quantitative polymerase chain reaction and western blot were used to test the key targets. In addition, QGP-1 and H9 cells were performed to validate the discoveries from the animal experiments.
RESULTS
In the mouse model of DSS-induced colitis, SYD effectively alleviated symptoms such as bloody stool, tissue damage, inflammation, intestinal flora dysbiosis and abnormal gene expression. Analyses of both differential expressed genes in colonic tissue and predicted 16S rDNA genes, as well as the analyses of targeted genes from TCMSP based on the active ingredients in UPLC-MS/MS of SYD, uncovered the enrichment of pathways involved in the biosynthesis and degredation of 5-hydroxytryptamine (5-HT). Interestingly, SYD suppressed the relative abundance of key genes in 5-HT synthesis, Tph1(Tryptophan hydroxylase 1) and Ddc (Dopa decarboxylase), in faeces from DSS-induced mice, leading to a reduction in the concentration of fecal 5-HT. Moreover, SYD augmented the production of butyric acid. Subsequently, increasing butyric acid influenced the metabolism of 5-HT in the organism through G protein-coupled receptor 43 by impeding its synthesis, facilitating its transport and degredation. These findings were additionally corroborated in a model utilizing enterochromaffin cell (QGP-1 cells). Furthermore, reduced levels of 5-HT hindered the activation of T lymphocytes (H9 cells) via the PKC (Protein kinase C) and NF-κB (Nuclear factor kappa-B) signaling pathways, by means of HTR1A (5-HT receptor 1A) and HTR3 (5-HT receptor 3). Additionally, diminished secretion of 5-HT resulted in reduced secretion of associated cytokines, thereby alleviating inflammation in the colon.
CONCLUSION
Through modulation of T lymphocyte activation mediated by 5-HT metabolism in the local colon via the intestinal flora and its metabolite, SYD effectively mitigated colonic inflammation in DSS-induced mice.
PubMed: 38879471
DOI: 10.1186/s13020-024-00958-2 -
Turkish Neurosurgery Aug 2023Apathy is a newly recognized non-motor symptom and has a high impact on the quality of life in Parkinson's Disease (PD). The effect of subthalamic deep brain stimulation...
AIM
Apathy is a newly recognized non-motor symptom and has a high impact on the quality of life in Parkinson's Disease (PD). The effect of subthalamic deep brain stimulation (STN DBS) on apathy is controversial. This study aimed to investigate the impact of STN DBS on apathy and the possible relationship between apathy, depression, and levodopa equivalent dosage (LED) in PD patients.
MATERIAL AND METHODS
A total of 26 patients have been evaluated via the Unified Parkinson Disease Rating Scale (UPDRS), Beck Depression Inventory (Beck D), and Beck Anxiety Inventory (Beck A), Montreal Cognitive Assessment (MoCA), Parkinson Disease Questionnaire (PDQ-39) just before and 6 months after DBS.
RESULTS
Apathy scores (AES) showed a slight decrease from 54.00±10.30 to 52.69±8.88 without any statistical significance (p= 0.502) after DBS therapy. No correlation was detected between the post-treatment changes in apathy and UPDRS scores, Beck D, Beck A. Although the direction of the correlation between changes in AES scores and LED values was negative, the results did not reach statistical significance.
CONCLUSION
STN DBS therapy does not have a negative effect on apathy in PD Patients. Despite the satisfactory motor improvement, conservative dopaminergic dose reduction after surgery seems to be the main point to prevent apathy increase in PD patients after STN DBS.
PubMed: 38874248
DOI: 10.5137/1019-5149.JTN.43415-23.3 -
Frontiers in Aging Neuroscience 2024Levodopa (L-dopa) therapy is the principal pharmacological treatment for Parkinson's disease (PD). Nevertheless, prolonged use of this drug may result in different...
OBJECTIVE
Levodopa (L-dopa) therapy is the principal pharmacological treatment for Parkinson's disease (PD). Nevertheless, prolonged use of this drug may result in different involuntary movement symptoms caused by the medication, referred to as levodopa-induced dyskinesia (LID). LID is associated with changes in synaptic plasticity of the D1 medium spiny neurons (MSNs) located in the dorsal striatum (dStr). Within the striatum, the amount of Dopamine D3 receptor (D3R) is notably increased in LID, demonstrating colocalization with D1R expression in neurons, and the level of D3R expression is directly related to the intensity of LID. IRL 790, as a D3R antagonist, can ameliorate LID. This study aims to explore if IRL 790 improves LID by regulating the synaptic plasticity of D1+ MSNs in dStr.
METHODS
The electrophysiology and synaptic spine density of D1+ MSNs in dStr were recorded for sham mice, LID mice, and LID mice treated with IRL 790. The regulation of synaptic plasticity in LID D1+ MSNs by IRL 790 was analyzed. Behavioral tests were conducted to confirm the treatment effect of IRL 790 on LID.
RESULTS
In LID D1+ MSNs, there was persistent abnormal LTP, absence of LTD, and an increase in spontaneous excitatory postsynaptic currents (sEPSCs). IRL 790 treatment restored normal LTP, LTD, and sEPSCs. Treatment with IRL 790 also restored the reduced dendritic spine density in D1+ MSNs of LID mice. IRL790 improved dyskinetic manifestations in LID mice.
CONCLUSION
IRL790 ameliorates LID by regulating the synaptic structure and functional plasticity of striatal D1+ MSNs.
PubMed: 38872625
DOI: 10.3389/fnagi.2024.1401991 -
Noro Psikiyatri Arsivi 2024As a neurologist who has followed up countless Parkinson's patients over the last 32 years of my fifty-year career; I denied diagnosing myself with Parkinson's disease... (Review)
Review
As a neurologist who has followed up countless Parkinson's patients over the last 32 years of my fifty-year career; I denied diagnosing myself with Parkinson's disease (PD), although the seldom mild involuntary "twitches" that occurred in the thumb of my right hand over a two-year period, resembled Parkinson's disease tremor. However, when these involuntary contractions became persistent; considering its similarity to characteristic resting tremor in typical PD, the positive effect of dopaminergic medications, the development of levodopa-induced dyskinesias and other non-motor symptoms, it was clear that the PD diagnosis was accurate. This situation naturally caused me anxiety, and for a year and a half, I kept my diagnosis hidden from everyone except a few close relatives. However, with the encouragement of a psychiatrist friend, when I was able to share my condition with my loved ones, I felt a relative reduction in the burden I was carrying and consequently experienced emotional relief. I am still able to carry out my daily activities independently with a rather low dose of medication, and my PD symptoms do not attract noticeable attention.
PubMed: 38868853
DOI: 10.29399/npa.28634 -
DOPA-decarboxylase is elevated in CSF, but not plasma, in prodromal and de novo Parkinson's disease.Translational Neurodegeneration Jun 2024
Topics: Parkinson Disease; Humans; Female; Prodromal Symptoms; Male; Middle Aged; Aged; Dopa Decarboxylase; Biomarkers
PubMed: 38863007
DOI: 10.1186/s40035-024-00421-0 -
Proceedings of the National Academy of... Jun 2024In bacteria, attenuation of protein-tyrosine phosphorylation occurs during oxidative stress. The main described mechanism behind this effect is the HO-triggered...
In bacteria, attenuation of protein-tyrosine phosphorylation occurs during oxidative stress. The main described mechanism behind this effect is the HO-triggered conversion of bacterial phospho-tyrosines to protein-bound 3,4-dihydroxyphenylalanine. This disrupts the bacterial tyrosine phosphorylation-based signaling network, which alters the bacterial polysaccharide biosynthesis. Herein, we report an alternative mechanism, in which oxidative stress leads to a direct inhibition of bacterial protein-tyrosine kinases (BY-kinases). We show that DefA, a minor peptide deformylase, inhibits the activity of BY-kinase PtkA when is exposed to oxidative stress. High levels of PtkA activity are known to destabilize pellicle formation, which leads to higher sensitivity to oxidative stress. Interaction with DefA inhibits both PtkA autophosphorylation and phosphorylation of its substrate Ugd, which is involved in exopolysaccharide formation. Inactivation of drastically reduces the capacity of to cope with oxidative stress, but it does not affect the major oxidative stress regulons PerR, OhrR, and Spx, indicating that PtkA inhibition is the main pathway for DefA involvement in this stress response. Structural analysis identified DefA residues Asn95, Tyr150, and Glu152 as essential for interaction with PtkA. Inhibition of PtkA depends also on the presence of a C-terminal α-helix of DefA, which resembles PtkA-interacting motifs from known PtkA activators, TkmA, SalA, and MinD. Loss of either the key interacting residues or the inhibitory helix of DefA abolishes inhibition of PtkA in vitro and impairs postoxidative stress recovery in vivo, confirming the involvement of these structural features in the proposed mechanism.
Topics: Bacillus subtilis; Oxidative Stress; Phosphorylation; Bacterial Proteins; Protein-Tyrosine Kinases; Hydrogen Peroxide; Amidohydrolases
PubMed: 38857388
DOI: 10.1073/pnas.2321890121 -
European Stroke Journal Jun 2024Novel therapeutic approaches are needed in stroke recovery. Whether pharmacological therapies are beneficial for enhancing stroke recovery is unclear. Dopamine is a...
RATIONALE
Novel therapeutic approaches are needed in stroke recovery. Whether pharmacological therapies are beneficial for enhancing stroke recovery is unclear. Dopamine is a neurotransmitter involved in motor learning, reward, and brain plasticity. Its prodrug levodopa is a promising agent for stroke recovery.
AIM AND HYPOTHESIS
To investigate the hypothesis that levodopa, in addition to standardized rehabilitation therapy based on active task training, results in an enhancement of functional recovery in acute ischemic or hemorrhagic stroke patients compared to placebo.
DESIGN
ESTREL (nhancement of troke habilitation with ) is a randomized (ratio 1:1), multicenter, placebo-controlled, double-blind, parallel-group superiority trial.
PARTICIPANTS
610 participants (according to sample size calculation) with a clinically meaningful hemiparesis will be enrolled ⩽7 days after stroke onset. Key eligibility criteria include (i) in-hospital-rehabilitation required, (ii) capability to participate in rehabilitation, (iii) previous independence in daily living.
INTERVENTION
Levodopa 100 mg/carbidopa 25 mg three times daily, administered for 5 weeks in addition to standardized rehabilitation. The study intervention will be initiated within 7 days after stroke onset.
COMPARISON
Matching placebo plus standardized rehabilitation.
OUTCOMES
The primary outcome is the between-group difference of the Fugl-Meyer-Motor Assessment (FMMA) total score measured 3 months after randomization. Secondary outcomes include patient-reported health and wellbeing (PROMIS 10 and 29), patient-reported assessment of improvement, Rivermead Mobility Index, modified Rankin Scale, National Institutes of Health Stroke Scale (NIHSS), and as measures of harm: mortality, recurrent stroke, and serious adverse events.
CONCLUSION
The ESTREL trial will provide evidence of whether the use of Levodopa in addition to standardized rehabilitation in stroke patients leads to better functional recovery compared to rehabilitation alone.
PubMed: 38853524
DOI: 10.1177/23969873241255867 -
Insights Into Imaging Jun 2024The efficacy of levodopa, the most crucial metric for Parkinson's disease diagnosis and treatment, is traditionally gauged through the levodopa challenge test, which...
BACKGROUND
The efficacy of levodopa, the most crucial metric for Parkinson's disease diagnosis and treatment, is traditionally gauged through the levodopa challenge test, which lacks a predictive model. This study aims to probe the predictive power of T1-weighted MRI, the most accessible modality for levodopa response.
METHODS
This retrospective study used two datasets: from the Parkinson's Progression Markers Initiative (219 records) and the external clinical dataset from Ruijin Hospital (217 records). A novel feature extraction method using MedicalNet, a pre-trained deep learning network, along with three previous approaches was applied. Three machine learning models were trained and tested on the PPMI dataset and included clinical features, imaging features, and their union set, using the area under the curve (AUC) as the metric. The most significant brain regions were visualized. The external clinical dataset was further evaluated using trained models. A paired one-tailed t-test was performed between the two sets; statistical significance was set at p < 0.001.
RESULTS
For 46 test set records (mean age, 62 ± 9 years, 28 men), MedicalNet-extracted features demonstrated a consistent improvement in all three machine learning models (SVM 0.83 ± 0.01 versus 0.73 ± 0.01, XgBoost 0.80 ± 0.04 versus 0.74 ± 0.02, MLP 0.80 ± 0.03 versus 0.70 ± 0.07, p < 0.001). Both feature sets were validated on the clinical dataset using SVM, where MedicalNet features alone achieved an AUC of 0.64 ± 0.03. Key responsible brain regions were visualized.
CONCLUSION
The T1-weighed MRI features were more robust and generalizable than the clinical features in prediction; their combination provided the best results. T1-weighed MRI provided insights on specific regions responsible for levodopa response prediction.
CRITICAL RELEVANCE STATEMENT
This study demonstrated that T1w MRI features extracted by a deep learning model have the potential to predict the levodopa response of PD patients and are more robust than widely used clinical information, which might help in determining treatment strategy.
KEY POINTS
This study investigated the predictive value of T1w features for levodopa response. MedicalNet extractor outperformed all other previously published methods with key region visualization. T1w features are more effective than clinical information in levodopa response prediction.
PubMed: 38853208
DOI: 10.1186/s13244-024-01690-z -
Neurobiology of Disease Aug 2024Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal...
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
Topics: Animals; Dyskinesia, Drug-Induced; Levodopa; Oxidopamine; Mice; Male; Mice, Inbred C57BL; Serotonin 5-HT4 Receptor Agonists; Antiparkinson Agents; Corpus Striatum; Receptors, Serotonin, 5-HT4; Parkinsonian Disorders; Pyridines; Neurons; Piperidines; Pyrimidines
PubMed: 38852753
DOI: 10.1016/j.nbd.2024.106559