Meta-analysis of iron metabolism markers levels of Parkinson’s disease patients determined by fluid and MRI measurements

BackgroundParkinson’ s disease (PD) is a progressive neurodegenerative disease featured neuropathologically by the loss of dopaminergic neurons of the substantia nigra (SN). Iron overload in the SN is mainly relative to the pathology and pathogenesis of PD. Postmortem samples of PD has indicated the increased levels of brain iron. However, there is no consensus on iron content through iron-sensitive magnetic resonance imaging (MRI) techniques and the alteration of iron and iron related metabolism markers levels in blood and cerebrospinal fluids (CSF) are still unclear based on the current studies. In this study, we performed a meta-analysis to explore the iron concentration and iron metabolism markers levels through iron-sensitive MRI quantification and body fluid.MethodsA comprehensive literature search was performed in PubMed, EMBASE and Cochrane Library databases for relevant published studies that analyzed iron load in the SN of PD patients using quantitative susceptibility mapping (QSM) or susceptibility weighting imaging (SWI), and iron metabolism markers, iron, ferritin, transferrin, total iron-binding capacity（TIBC）in CSF sample or serum/plasma sample (from Jan 2010 to Sep 2022 to filter these inaccurate researches attributed to unadvanced equipment, inaccurate analytical methods). Standardized mean differences (SMD) or mean differences (MD) and 95% confidence intervals (CI) with random or fixed effect model was used to estimate the results.ResultsForty-two articles fulfilled the inclusion criteria including 19 for QSM, 6 for SWI, and 17 for serum/plasma/CSF sample including 2874 PD patients and 2821 healthy controls (HCs). Our meta-analysis results founded a notable difference for QSM values increase (19.67, 95% CI=18.69–20.64) and for SWI measurements (−1.99, 95% CI= −3.52 to −0.46) in the SN in PD patients. However, the serum/plasma/CSF iron levels and serum/plasma ferritin, transferrin, total iron-binding capacity (TIBC) did not differ significantly between PD patients and HCs.ConclusionsOur meta-analysis showed the consistent increase in the SN in PD patients using QSM and SWI techniques of iron-sensitive MRI measures while no significant differences were observed in other iron metabolism markers levels.     

A Chronobiological Approach to Circulating Levels of Renin, Angiotensin-Converting Enzyme, Aldosterone, ACTH, and Cortisol in Addison's Disease

This study deals with a chronobiological approach to the circadian rhythm of the renin-angiotensin-aldosterone system (RAAS) and the ACTH-cor-tisol axis (ACA) in patients with Addison's disease (PAD). The aim is to explore the mechanism(s) for which the circadian rhythmicity of the RAAS and ACA takes place. The study has shown that both the RAAS and ACA are devoid of a circadian rhythm in PAD. The lack of rhythmicity for renin and ACTH provides indirect evidence that their rhythmic secretion is in some way related to the circadian oscillation of aldosterone and cortisol. This implies a new concept: a positive feedback may be included among the mechanisms which chronoregulate the RAAS and ACA.     

Shelter selection in the kissing bugs Triatoma infestans and Rhodnius prolixus: Intra- and inter-specific interactions and quality evaluation

Triatomines display most of their activities during the night. Before sunrise, they search, select and occupy adequate shelters to stay during the photophase, avoiding exposure to diurnal predators. In this work, we first explored the interactions between individuals of the same or different species in the shelter selection process of Triatoma infestans (Klug 1834) and Rhodnius prolixus (Stål 1859). When two groups of insects (either of different nutritional status, nymphal instar or species) were released together over an experimental arena containing two identical shelters, all nymphs were distributed randomly, suggesting the absence of intra- and inters-pecific interactions. Secondly, we analysed their preferences for particular features of shelters by releasing one group of insects (either T. infestans or R. prolixus) over an arena containing two different refuges. Nymphs exhibited preferences for darker shelters with a vertical orientation of its substrate and elevated from the ground, highlighting the importance of such features in a shelter selection context. We conclude that these species disregard the presence of other individuals but evaluate certain characteristics of the shelters to choose them. This information may contribute to understanding the colonization/recolonization dynamic processes of these Chagas disease vectors.     

Insights into circular RNAs: Biogenesis,function and their regulatory roles in cardiovascular disease

As a distinctive member of the noncoding RNA family, circular RNAs (circRNAs) are generated from single-stranded, covalently closed structures and are ubiquitous in mammalian cells and tissues. Due to its atypical circular architecture, it was conventionally deemed insignificant dark matter for a prolonged duration. Nevertheless, studies conducted over the last decade have demonstrated that this abundant, structurally stable and tissue-specific RNA has been increasingly relevant in diverse diseases, including cancer, neurological disorders, diabetes mellitus and cardiovascular diseases (CVDs). Therefore, regulatory pathways controlled by circRNAs are widely involved in the occurrence and pathological processes of CVDs through their function as miRNA sponges, protein sponges and protein scaffolds. To better understand the role of circRNAs and their complex regulatory networks in CVDs, we summarize current knowledge of their biogenesis and function and the latest research on circRNAs in CVDs, with the hope of paving the way for the identification of promising biomarkers and therapeutic strategies for CVDs.     

COVID-19 plasma proteome reveals novel temporal and cell-specific signatures for disease severity and high-precision disease management

Coronavirus disease 2019 (COVID-19) is a systemic inflammatory condition with high mortality that may benefit from personalized medicine and high-precision approaches. COVID-19 patient plasma was analysed with targeted proteomics of 1161 proteins. Patients were monitored from Days 1 to 10 of their intensive care unit (ICU) stay. Age- and gender-matched COVID-19-negative sepsis ICU patients and healthy subjects were examined as controls. Proteomic data were resolved using both cell-specific annotation and deep-analysis for functional enrichment. COVID-19 caused extensive remodelling of the plasma microenvironment associated with a relative immunosuppressive milieu between ICU Days 3–7, and characterized by extensive organ damage. COVID-19 resulted in (1) reduced antigen presentation and B/T-cell function, (2) increased repurposed neutrophils and M1-type macrophages, (3) relatively immature or disrupted endothelia and fibroblasts with a defined secretome, and (4) reactive myeloid lines. Extracellular matrix changes identified in COVID-19 plasma could represent impaired immune cell homing and programmed cell death. The major functional modules disrupted in COVID-19 were exaggerated in patients with fatal outcome. Taken together, these findings provide systems-level insight into the mechanisms of COVID-19 inflammation and identify potential prognostic biomarkers. Therapeutic strategies could be tailored to the immune response of severely ill patients.     

Design,Synthesis, and Biological Evaluation of Novel Indanone Derivatives as Cholinesterase Inhibitors for Potential Use in Alzheimer's Disease

Indanone derivatives containing meta/para-substituted aminopropoxy benzyl/benzylidene moieties were designed based on the structures of donepezil and ebselen analogs as the cholinesterase inhibitors. The designed compounds were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were measured. Inhibitory potencies (IC₅₀ values) for the synthesized compounds ranged from 0.12 to 11.92 μM and 0.04 to 24.36 μM against AChE and BChE, respectively. Compound 5 c showed the highest AChE inhibitory potency with IC₅₀ value of 0.12 μM, whereas the highest BChE inhibition was achieved by structure 7 b (IC₅₀=0.04 μM). Structure-activity relationship (SAR) analysis revealed that there is no significant difference between meta and para-substituted derivatives in AChE and BChE inhibition. However, the most potent AChE inhibitor 5 c belongs to meta-substituted compounds, while the most active BChE inhibitor is para-substituted derivative 7 b . The order of enzyme inhibition potency based on the substituted amine group is dimethyl amine>piperidine>morpholine. Compounds containing C=C linkage are more potent AChE inhibitors than the corresponding saturated structures. Molecular docking studies indicated that 5 c interacts with AChE in a very similar way to that observed experimentally for donepezil. The introduced indanone-aminopropoxy benzylidenes could be used in drug-discovery against Alzheimer's disease.     

Isolation of anti-fungal phenolic compounds from petioles of two Hevea brasiliensis (rubber) genotypes and their effect on Phytophthora meadii

Phenolic compounds were present in greater amounts in non‐infected petioles of genotypes of Hevea brasiliensis that are resistant to Phytophthora leaf disease than in genotypes that are susceptible. Phenolic compounds extracted from petioles of either susceptible (PB86) or resistant (RRIC100) genotypes, before or after infection with Phytophthora meadii, had anti‐fungal properties. Artificially infected petioles of PB86 had phenolic acids, triterpenoids or flavonoids, whereas healthy petioles contained only triterpenoids or flavonoids. However, healthy or infected petioles of RRIC100 contained only trace amounts of the above compounds and of vanillin (3‐methoxy‐4‐hydroxybenzaldehyde). Vanillin and umbelliferone (7‐hydroxycoumarin) were shown to suppress zoospore germination of P. meadii on glass slides and to inhibit its growth in pea broth and V‐8 juice agar. Vanillin was slightly more active than umbelliferone. Resistance of RRIC100 to Phytophthora was suspected as being related to the polymerisation of phenolic compounds to form lignin, which may suppress further spread of the pathogen's mycelium into healthy tissues. Formation of lignin from phenolic aldehydes as a barrier to disease spread may be a critical factor in resistance.     

Chemical speciation of arsenic in urine of patients with blackfoot disease

Blackfoot disease is a peripheral vascular disease resulting in gangrene of the lower extremities. Although extensive epidemiological study has implicated high arsenic content in artesian well water of the endemic area bears some important connection with the disease, the etiology of the disease is still not clarified. In this study, attention is paid to chemical speciation of arsenic in order to find out whether the concentrations of arsenic species in urine of Blackfoot disease patients are different from those of controls. Experimental results indicate that the total arsenic, inorganic arsenic, monomethylarsonic acid, and other forms of arsenic in the urine of patients are significantly higher than those of the contols. The possible connection of those arsenic species with the etiology of the disease is discussed.     

Prostaglandin H Synthetase-Mediated Metabolism of Dopamine: Implication for Parkinson's Disease

Abstract: Differences in prostaglandin H synthetase (PHS) activity in the substantia nigra of age- and post-mortem interval-matched parkinsonian, Alzheimer's, and normal control brain tissue were assessed. Prostaglandin E₂ (PGE₂, an index of PHS activity) was higher in substantia nigra of parkinsonian brain tissue than Alzheimer's or control tissue. Incubation of substantia nigra slices with arachidonic acid (AA) increased PGE₂ synthesis. Dopamine stimulated PHS synthesis of PGE₂. [³H]Dopamine was activated by PHS to electrophilic intermediate(s) that covalently bound to DNA, microtubulin protein, bovine serum albumin, and sulfhydryl reagents. When AA was replaced by hydrogen peroxide, PHS/H₂O₂-supported binding proceeded at rates similar to those observed with PHS/AA. Indomethacin and aspirin inhibited AA-mediated cooxidation of dopamine but not H₂O₂-mediated metabolism. PHS-mediated metabolism of dopamine was not affected by monoamine oxidase inhibitors. Substrate requirements and effects of specific inhibitors suggest cooxidation of dopamine is mediated by the hydroperoxidase activity of PHS. ³²P-postlabeling was used to detect dopamine-DNA adducts. PHS/AA activation of dopamine in the presence of DNA resulted in the formation of five dopamine-DNA adducts, i.e., 23, 43, 114, 70, and 270 amol/µg DNA. DNA adduct formation was PHS, AA, and dopamine dependent. PHS catalyzed cooxidation of dopamine in dopaminergic neuronal degeneration is discussed.     

In vitro neurotoxicity of amyloid β-peptide cross-linked by transglutaminase

Transglutaminase catalyzes the intermolecular cross-linking of peptides between Gln and Lys residues, forming an -(-glutamyl) lysine bond. Amyloid -peptide, a major constituent of the deposits in Alzheimer disease, contains Lys16, Lys28, and Gln15 which may act as substrates of transglutaminase. Transglutaminase treatment of amyloid -peptide (1–28) and amyloid -peptide (1–40) yielded cross-linked oligomers. Transglutaminase-treated A retarded neurite extension of PC12 cells, and rat cultured neurons of hippocampus and septum, brain areas severely affected by Alzheimer disease, and subsequently caused cell death, whereas the transglutaminase-untreated counterparts did not show harmful effects. The transglutaminase-catalyzed oligomers of amyloid -peptide and their neurotoxicity may be involved in two characteristics in Alzheimer disease, neuronal degeneration and formation of the insoluble deposits.Abbreviations: AD – Alzheimer disease, A – amyloid -peptide, DMEM – Dulbecco's modified Eagle's medium, DMEM/F–12–1:1 mixture of DMEM and Ham's F–12 medium, FCS – fetal calf serum, HS – horse serum, PAGE – polyacrylamide gel electrophoresis, MTT – 3-(4,5-dimethylthiazol–2-yl)–2,5-diphenyltetrazolium bromide, NGF – nerve growth factor, TGase – transglutaminase.