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BMC Medical Genomics Jun 2024Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to...
BACKGROUND
Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to produce/use adequate renal dopamine may contribute to the development of hypertension and renal dysfunction. The heterodimeric amino acid transporter LAT2/4F2hc (SLC7A8/SLC3A2 genes) promotes the uptake of L-DOPA, the natural precursor of dopamine. We examined the plausibility that SLC7A8/SLC3A2 gene polymorphisms may contribute to hypertensive CKD by affecting the L-DOPA uptake.
METHODS
421 subjects (203 men and 218 women, mean age of 78.9 ± 9.6 years) were recruited and divided in four groups according to presence/absence of CKD, defined as reduced estimated glomerular filtration rate (eGFR < 60 ml/min/m) calculated using the creatinine-based Berlin Initiative Study-1 (BIS1) equation, and to presence/absence of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg). Subjects were analysed for selected SNPs spanning the SLC7A8 and SLC3A2 loci by Sequenom MassARRAY iPLEX platform.
RESULTS
The most significant SNP at the SLC3A2 (4F2hc) locus was rs2282477-T/C, with carriers of the C-allele having a lower chance to develop hypertension among CKD affected individuals [OR = 0.33 (CI 0.14-0.82); p = 0.016]. A similar association with hypertensive CKD was found for the SLC7A8 (LAT2) rs3783436-T/C, whose C-allele resulted associated with decreased risk of hypertension among subjects affected by CKD [OR = 0.56 (95% CI 0.35-0.90; p = 0.017]. The two variants were predicted to be potentially functional.
CONCLUSIONS
The association between SLC3A2 and SLC7A8 variants to hypertension development in patients with renal failure could be linked to changes in L-DOPA uptake and consequently dopamine synthesis. Although the associations do not survive correction for Bonferroni multiple testing, and additional research is needed, our study opens new avenues for future basic and translational research in the field of hypertensive CKD.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Fusion Regulatory Protein 1, Heavy Chain; Genetic Predisposition to Disease; Hypertension; Levodopa; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Risk Factors; Adaptor Proteins, Signal Transducing
PubMed: 38890684
DOI: 10.1186/s12920-024-01935-2 -
Chirality Jun 2024Chirality plays a fundamental role in natural phenomena, yet its manifestation on solid surfaces remains relatively unexplored. In this study, we investigate the...
Chirality plays a fundamental role in natural phenomena, yet its manifestation on solid surfaces remains relatively unexplored. In this study, we investigate the formation of chiroptical melanin-based self-assembled films on quartz substrates, leveraging mussel-inspired surface chemistry. Water-soluble porphyrins serve as molecular synthons, facilitating the spontaneous formation of hetero-aggregates in phosphate-buffered saline containing L- or D-DOPA. Spectroscopic analysis reveals chiral transfer from DOPA enantiomers to porphyrin hetero-aggregates, followed by the disruption of these latter and subsequent generation of chiral melanin structures in solution. Quartz substrates inserted into these solutions spontaneously accumulate homogeneous melanin-like films over days, demonstrating the feasibility of self-assembly. The resulting films exhibit characteristic UV/Vis and CD spectra, with distinct signals indicating successful chiral induction. Interestingly, the AFM characterizations reveal a distinct surface morphology, and in addition, some thermal and mechanical properties have been taken into account. Overall, this study sheds light on the formation, stability, and chiroptical properties of melanin-based films, paving the way for their application in various fields.
PubMed: 38890151
DOI: 10.1002/chir.23695 -
Neuropharmacology Jun 2024Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that...
Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that sub-anesthetic ketamine produces acute anti-parkinsonian, and acute anti-dyskinetic effects in preclinical models of Parkinson's disease (PD). Ketamine is a multifunctional drug and exerts effects through blockade of N-methyl-d-aspartate receptors but also through interaction with the opioid system. In this report, we provide detailed pharmacokinetic rodent data on ketamine and its main metabolites following an intraperitoneal injection, and second, we explore the pharmacodynamic properties of ketamine in a rodent PD model with respect to the opioid system, using naloxone, a pan-opioid receptor antagonist, in unilateral 6-hydroxydopamine-lesioned male rats, treated with 6 mg/kg levodopa (l-DOPA) to establish a model of l-DOPA-induced dyskinesia (LID). As previously reported, we showed that ketamine (20 mg/kg) is highly efficacious in reducing LID and now report that the magnitude of this effect is resistant to naloxone (3 and 5 mg/kg). The higher naloxone dose of 5 mg/kg, however, led to an extension of the time-course of the LID, indicating that opioid receptor activation, while not a prerequisite for the anti-dyskinetic effects of ketamine, still exerts an acute modulatory effect. In contrast to the mild modulatory effect on LID, we found that naloxone added to the anti-parkinsonian activity of ketamine, further reducing the akinetic phenotype. In conclusion, our data show opioid receptor blockade differentially modulates the acute anti-parkinsonian and anti-dyskinetic actions of ketamine, providing novel mechanistic information to support repurposing ketamine for individuals with LID.
PubMed: 38889877
DOI: 10.1016/j.neuropharm.2024.110047 -
Chemical Communications (Cambridge,... Jun 2024An electrochemical sensor based on porous aromatic cages was reported, which can achieve chiral sensing of DOPA enantiomers. The prepared sensor can achieve a...
An electrochemical sensor based on porous aromatic cages was reported, which can achieve chiral sensing of DOPA enantiomers. The prepared sensor can achieve a recognition efficiency of up to 2.6 for DOPA enantiomers. The enhanced recognition efficiency could be attributed to the cooperation of intermolecular interactions, and the efficient charge transfer process.
PubMed: 38887804
DOI: 10.1039/d4cc02622e -
Microbiome Jun 2024Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic...
BACKGROUND
Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic and preventative approaches is highly desirable. Accumulating evidence in the past several years has established associations between the gut microbiome and microbial metabolites with drinking behavior, but druggable targets and their underlying mechanism of action are understudied.
RESULTS
Here, using a drink-in-the-dark mouse model, we identified a microbiome metabolite-based novel treatment (sodium valerate) that can reduce excessive alcohol drinking. Sodium valerate is a sodium salt of valeric acid short-chain fatty acid with a similar structure as γ-aminobutyric acid (GABA). Ten days of oral sodium valerate supplementation attenuates excessive alcohol drinking by 40%, reduces blood ethanol concentration by 53%, and improves anxiety-like or approach-avoidance behavior in male mice, without affecting overall food and water intake. Mechanistically, sodium valerate supplementation increases GABA levels across stool, blood, and amygdala. It also significantly increases H4 acetylation in the amygdala of mice. Transcriptomics analysis of the amygdala revealed that sodium valerate supplementation led to changes in gene expression associated with functional pathways including potassium voltage-gated channels, inflammation, glutamate degradation, L-DOPA degradation, and psychological behaviors. 16S microbiome profiling showed that sodium valerate supplementation shifts the gut microbiome composition and decreases microbiome-derived neuroactive compounds through GABA degradation in the gut microbiome.
CONCLUSION
Our findings suggest that sodium valerate holds promise as an innovative therapeutic avenue for the reduction of habitual binge drinking, potentially through multifaceted mechanisms. Video Abstract.
Topics: Animals; Male; Mice; Gastrointestinal Microbiome; gamma-Aminobutyric Acid; Fatty Acids, Volatile; Alcohol Drinking; Amygdala; Ethanol; Mice, Inbred C57BL; Disease Models, Animal; Binge Drinking; Pentanoic Acids
PubMed: 38886761
DOI: 10.1186/s40168-024-01829-6 -
Frontiers in Aging Neuroscience 2024This meta-analysis aims to assess the effectiveness and safety of robot-assisted deep brain stimulation (DBS) surgery for Parkinson's disease(PD).
OBJECTIVE
This meta-analysis aims to assess the effectiveness and safety of robot-assisted deep brain stimulation (DBS) surgery for Parkinson's disease(PD).
METHODS
Four databases (Medline, Embase, Web of Science and CENTRAL) were searched from establishment of database to 23 March 2024, for articles studying robot-assisted DBS in patients diagnosed with PD. Meta-analyses of vector error, complication rate, levodopa-equivalent daily dose (LEDD), Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS II, UPDRS III, and UPDRS IV were performed.
RESULTS
A total of 15 studies were included in this meta-analysis, comprising 732 patients with PD who received robot-assisted DBS. The pooled results revealed that the vector error was measured at 1.09 mm (95% CI: 0.87 to 1.30) in patients with Parkinson's disease who received robot-assisted DBS. The complication rate was 0.12 (95% CI, 0.03 to 0.24). The reduction in LEDD was 422.31 mg (95% CI: 68.69 to 775.94). The improvement in UPDRS, UPDRS III, and UPDRS IV was 27.36 (95% CI: 8.57 to 46.15), 14.09 (95% CI: 4.67 to 23.52), and 3.54 (95% CI: -2.35 to 9.43), respectively.
CONCLUSION
Robot-assisted DBS is a reliable and safe approach for treating PD. Robot-assisted DBS provides enhanced accuracy in contrast to conventional frame-based stereotactic techniques. Nevertheless, further investigation is necessary to validate the advantages of robot-assisted DBS in terms of enhancing motor function and decreasing the need for antiparkinsonian medications, in comparison to traditional frame-based stereotactic techniques.: PROSPERO(CRD42024529976).
PubMed: 38882524
DOI: 10.3389/fnagi.2024.1419152 -
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 -
Movement Disorders Clinical Practice Jun 2024Heterozygous mutations in GBA1 gene are known as most common genetic risk factor for Parkinson's disease (PD). However, role of GBA1 mutations in non-α-synuclein...
BACKGROUND
Heterozygous mutations in GBA1 gene are known as most common genetic risk factor for Parkinson's disease (PD). However, role of GBA1 mutations in non-α-synuclein disorders is unclear.
CASES
Case index, 76 year-old woman referred to our movement disorders outpatient clinic for 2-year history of gait impairment, falls and motor slowness, with partial response to levodopa. Clinical and instrumental examinations were consistent with Progressive Supranuclear Palsy-Corticobasal Syndrome (PSP-CBS). Case 2 is older sister reporting depressive symptoms; however, she had dementia (MMSE 18/30), gait apraxia and vertical supranuclear gaze palsy (VSNGP). Case 3 is her deceased older sister who had been diagnosed with Corticobasal Syndrome (CBS). Case 4, older brother had been diagnosed with Parkinson's disease-dementia (PDD) with good response to levodopa. Two affected living siblings harboring same genetic variant.
CONCLUSIONS
To our knowledge, this is the first family showing such intrafamilial variability ranging from CBS to PDD to dementia.
PubMed: 38881158
DOI: 10.1002/mdc3.14146 -
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 -
Neurology and Therapy Jun 2024The management of Parkinson's disease (PD) continues to evolve with advancements in non-oral levodopa-based therapies aiming to provide continuous drug delivery (CDD).... (Review)
Review
The management of Parkinson's disease (PD) continues to evolve with advancements in non-oral levodopa-based therapies aiming to provide continuous drug delivery (CDD). Such therapies address the challenges posed by the emergence of motor fluctuations, dyskinesias, and non-motor fluctuations (NMF) associated with oral levodopa administration and contributing to define the advanced stage of PD. The key focus of this review is placed on subcutaneous foslevodopa/foscarbidopa (Foslevodopa/foscarbidopa) infusion, showcasing its recent clinical availability and efficacy in providing continuous levodopa delivery. While providing an overview of the other non-oral levodopa-based CDD systems, such as intrajejunal levodopa-carbidopa infusion and levodopa-entacapone-carbidopa infusion, we highlight the current promising evidence for Foslevodopa/foscarbidopa to improve, for example, "on time" without troublesome dyskinesia and reducing "off time" in people with advanced PD. Additionally, Foslevodopa/foscarbidopa demonstrates potential in managing early morning off periods, sleep quality and other motor and non-motor symptoms. Moreover, other non-oral CDD options such as ND0612 and DIZ102/DIZ101 are discussed, with focus on their pharmacokinetics/pharmacodynamics, efficacy, and safety profiles. While these advancements present new therapeutic avenues, long-term observational studies are warranted to elucidate their impact on existing PD therapies. Overall, this review provides insights into the evolving landscape of non-oral CDD therapies and offers a pragmatic approach for their integration into clinical practice.
PubMed: 38874708
DOI: 10.1007/s40120-024-00635-4