⍺-Synuclein levels in Parkinson's disease - Cell types and forms that contribute to pathogenesis.

Parkinson's disease (PD) has two main pathological hallmarks, the loss of nigral dopamine neurons and the proteinaceous aggregations of ⍺-synuclein (⍺Syn) in neuronal Lewy pathology. These two co-existing features suggest a causative association between ⍺Syn aggregation and the underpinning mechanism of neuronal degeneration in PD. Both increased levels and post-translational modifications of ⍺Syn can contribute to the formation of pathological aggregations of ⍺Syn in neurons. Recent studies have shown that the protein is also expressed by multiple types of non-neuronal cells in the brain and peripheral tissues, suggesting additional roles of the protein and potential diversity in non-neuronal pathogenic triggers. It is important to determine (1) the threshold levels triggering ⍺Syn to convert from a biological to a pathologic form in different brain cells in PD; (2) the dominant form of pathologic ⍺Syn and the associated post-translational modification of the protein in each cell type involved in PD; and (3) the cell type associated biological processes impacted by pathologic ⍺Syn in PD. This review integrates these aspects and speculates on potential pathological mechanisms and their impact on neuronal and non-neuronal ⍺Syn in the brains of patients with PD.

Human Endogenous Retroviruses in Neurodegenerative Diseases.

Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by the fact that they comprise approximately 8% of the human genome. HERVs have been implicated in the pathogenesis of neurodegenerative diseases, a group of CNS diseases characterized by a progressive loss of structure and function of neurons, resulting in cell death and multiple physiological dysfunctions. Much evidence indicates that HERVs are initiators or drivers of neurodegenerative processes in multiple sclerosis and amyotrophic lateral sclerosis, and clinical trials have been designed to target HERVs. In recent years, the role of HERVs has been explored in other major neurodegenerative diseases, including frontotemporal dementia, Alzheimer's disease and Parkinson's disease, with some interesting discoveries. This review summarizes and evaluates the past and current research on HERVs in neurodegenerative diseases. It discusses the potential role of HERVs in disease manifestation and neurodegeneration. It critically reviews antiretroviral strategies used in the therapeutic intervention of neurodegenerative diseases.

Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration.

Parkinson's disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. The activity of DA neurons is likely altered in PD, but we understand little about if or how chronic changes in activity may contribute to degeneration. To address this question, we developed a chemogenetic (DREADD) mouse model to chronically increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology. Chronic hyperactivation of DA neurons resulted in prolonged increases in locomotor activity during the light cycle and decreases during the dark cycle, consistent with chronic changes in DA release and circadian disturbances. We also observed early, preferential degeneration of SNc projections, recapitulating the PD hallmarks of selective vulnerability of SNc axons and the comparative resilience of ventral tegmental area axons. This was followed by eventual loss of midbrain DA neurons. Continuous DREADD activation resulted in a sustained increase in baseline calcium levels, supporting an important role for increased calcium in the neurodegeneration process. Finally, spatial transcriptomics from DREADD mice examining midbrain DA neurons and striatal targets, and cross-validation with human patient samples, provided insights into potential mechanisms of hyperactivity-induced toxicity and PD. Our results thus reveal the preferential vulnerability of SNc DA neurons to increased neural activity, and support a potential role for increased neural activity in driving degeneration in PD.

RAAS in diabetic retinopathy: mechanisms and therapies.

Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.

Association between serum uric acid and deep venous thrombosis in European populations: A two-sample Mendelian randomization study.

BACKGROUND AND AIM: Previous experimental and observational studies showed that serum uric acid (SUA) was associated with deep venous thrombosis (DVT), but the causal relationship is unclear. This study aimed to explore the potential causal association between SUA and DVT. METHODS AND RESULTS: We designed a two-sample Mendelian randomization (MR) analysis by using summary-level data from large genome-wide association studies performed in European individuals. A total of 14 SUA-related single-nucleotide polymorphisms (SNPs) (P value < 5 × 10-8) were identified as instrumental variables. The inverse variance weighted method was used as the primary method to compute the odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for per standard deviation increase in SUA. MR Egger, weighted median, weighted mode, and simple mode were also applied to test the robustness of the results. We found no significant causal effects of serum uric acid on deep venous thrombosis (odds ratio [OR]: 1.000, 95 % confidence interval [CI]: 0.998-1.002, p = 0.78) by using inverse variance weighted. MR analyses based on other methods showed similar results. CONCLUSIONS: There was no potential causal associations between higher genetically predicted SUA levels and increased risk of deep venous thrombosis. Further, MR studies with more valid SNPs and more DVT cases are needed. Validation of the findings is also recommended.

A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder that affects the motor system. Increasing evidence indicates that lysosomal dysfunction is pivotal in the pathogenesis of PD, typically characterized by dysregulation of sphingolipids in lysosomes. ATP-binding cassette subfamily A member 5 (ABCA5) is a lysosomal transporter that mediates the removal of excess sphingomyelin from lysosomes. We therefore investigated whether the expression levels of ABCA5 are associated with sphingomyelin levels and α-synuclein pathology in PD. Firstly, we undertook a comprehensive assessment of the six sphingolipid classes that are part of the lysosomal salvage pathway in the disease-affected amygdala and disease-unaffected visual cortex using liquid chromatography-mass spectrometry. We found that sphingomyelin levels were significantly increased in PD compared to controls and correlated with disease duration only in the amygdala, whereas, the five other sphingolipid classes were slightly altered or unaltered. Concomitantly, the expression of ABCA5 was upregulated in the PD amygdala compared to controls and correlated strongly with sphingomyelin levels. Using neuronal cells, we further verified that the expression of ABCA5 was dependent on cellular levels of sphingomyelin. Interestingly, sphingomyelin levels were strongly associated with α-synuclein in the amygdala and were related to α-synuclein expression. Finally, we revealed that sphingomyelin levels were also increased in PD plasma compared to controls, and that five identical sphingomyelin species were increased in both the brain and the plasma. When put together, these results suggest that in regions accumulating α-synuclein in PD, ABCA5 is upregulated to reduce lysosomal sphingomyelin levels potentially as a protective measure. This process may provide new targets for therapeutic intervention and biomarker development for PD.

Performance of SHOX2 and RASSF1A methylation assay in supernatants and matched cell pellets for the diagnosis of malignant pleural effusion.

BACKGROUND: It is difficult to distinguish between malignant pleural effusion (MPE) and benign pleural effusion (BPE). The purpose of this study was to determine the best specimen type by evaluating the DNA methylation status of SHOX2 and RASSF1A in 3 matched PE components. METHODS: In total, 94 patients were enrolled, including 45 MPE, 35 BPE, and 14 undefined PE (UPE) with malignancies. PE samples were processed into supernatants, fresh-cell pellets, and formalin-fixed and paraffin-embedded (FFPE) cell blocks, respectively. A quantitative real-time PCR was used to detect the methylation status of SHOX2 and RASSF1A. RESULTS: SHOX2 and RASSF1A methylation levels were significantly higher in the 3 MPE sample types than those of BPE (P < 0.05). The area under the curve using cell-free DNA (cf-DNA) was the highest. The detection sensitivity of SHOX2 and RASSF1A in fresh-cell DNA, cf-DNA and FFPE cell-block were 71.1% (32/45), 97.8% (44/45) and 66.7% (28/42), respectively, with specificities of 97.1% (34/35), 94.3% (33/35), and 96.9% (31/32). Notably, a combination of the cytological analysis and cf-DNA methylation assay showed an increase in positivity rate from 75.6% to 100%. CONCLUSIONS: The SHOX2 and RASSF1A methylation assay using cf-DNA, the primary recommended specimen type, can excellently increase the diagnostic sensitivity of MPE. A combination of methylation assay with cytological analysis can be used for auxiliary diagnosis of PE.

RAAS in diabetic retinopathy: mechanisms and therapies

ABSTRACT Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.

Understanding the Role of CDH4 in Multiple System Atrophy Brain.

BACKGROUND: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. A major pathological feature of MSA is the presence of α-synuclein aggregates in oligodendrocytes, the myelinating cells of the central nervous system. A genome-wide association study revealed that the CDH4 gene is associated with MSA. However, virtually nothing is known about the role of CDH4 in the context of MSA. OBJECTIVE: Our aim was to compare the expression of CDH4 between MSA and control brains, and to investigate its relationship with α-synuclein in oligodendrocytes. METHODS: RNA and protein were prepared from putamen, motor cortex white matter, cerebellum, and superior occipital cortex tissues collected from MSA (N = 11) and control (N = 13) brains. The expression of CDH4 was measured at mRNA and protein levels by qPCR and western blotting. Oligodendrocyte cells were cultured on plates and transfected with CDH4 cDNA and its impact on α-synuclein was analyzed. RESULTS: Firstly, we found that CDH4 in MSA brain was significantly elevated in the disease-affected motor cortex white matter in MSA (N = 11) compared to controls (N = 13) and unaltered in the disease-unaffected superior occipital cortex. Secondly, we determined that increases in CDH4 expression caused changes in the cellular levels of α-synuclein in oligodendrocytes. CONCLUSIONS: When put together, these results provide evidence that support the GWAS association of CDH4 with MSA.

Elevated GRO-α and IL-18 in serum and brain implicate the NLRP3 inflammasome in frontotemporal dementia.

Neuroinflammation is a hallmark of frontotemporal dementia (FTD), a heterogeneous group of proteinopathies characterized by the progressive degeneration of the frontal and temporal lobes. It is marked by microglial activation and subsequent cytokine release. Although cytokine levels in FTD brain and CSF have been examined, the number of cytokines measured in each study is limited and knowledge on cytokine concentrations in FTD serum is scarce. Here, we assessed 48 cytokines in FTD serum and brain. The aim was to determine common cytokine dysregulation pathways in serum and brain in FTD. Blood samples and brain tissue samples from the superior frontal cortex (SFC) were collected from individuals diagnosed with behavioral variant FTD (bvFTD) and healthy controls, and 48 cytokines were measured using a multiplex immunological assay. The data were evaluated by principal component factor analysis to determine the contribution from different components of the variance in the cohort. Levels of a number of cytokines were altered in serum and SFC in bvFTD compared to controls, with increases in GRO-α and IL-18 in both serum and SFC. These changes could be associated with NLRP3 inflammasome activation or the NFκB pathway, which activates NLRP3. The results suggest the possible importance of the NLRP3 inflammasome in FTD. An improved understanding of the role of inflammasomes in FTD could provide valuable insights into the pathogenesis, diagnosis and treatment of FTD.

Systematic review and meta-analysis of the efficacy of olprinone and MEFV gene in treating heart failure.

Cardiovascular failure is the main cause of death in industrialized societies. The results of recent studies have shown that some mutations in the MEFV gene are common in heart failure patients. For this reason, the study of mutations and genetic factors has been of great help in the treatment of this disease, but despite this, due to the heterogeneity of clinical symptoms, multiple pathophysiological processes, and environmental genetic factors, the complete understanding of the genetic causes of this disease is very complicated. As the new generation of phosphodiesterase (PDE) III inhibitor, olprinone, the inhibition of human heart PDE III by olprinone is highly selective. It is suitable for the treatment of acute heart failure (HF) and acute cardiac insufficiency after cardiac surgery. In this study Olprinone, milrinone, PDE inhibitors, cardiac failure, and HF were selected as the search terms to retrieve articles published between January 1999 and March 2022. RevMan5.3 and Stata were employed to analyze and evaluate the risk bias of the included articles. Besides, the Q test and heterogeneity were utilized to evaluate the heterogeneity between articles. The results of this research showed No heterogeneity was found between each research group. The sensitivity (Sen) and specificity (Spe) of the two methods were compared. Olprinone showed more significant therapeutic effects than other PDE inhibitors. Besides, the therapeutic effect on the patients with HF in the two groups was obvious. The incidence of postoperative adverse reactions among the patients without relieving HF was low. The influences on urine flow of the two group's demonstrated heterogeneity, and its effect revealed no statistical meaning. The meta-analysis confirmed that the Spe and Sen of olprinone treatment were higher than those of other PDE inhibitors. In terms of hemodynamics, there was little difference between various treatment methods.

Progress in the applications of atomic force microscope (AFM) for mineralogical research.

Mineral surface properties and mineral-aqueous interfacial reactions are essential factors affecting the geochemical cycle, related environmental impacts, and bioavailability of chemical elements. Compared to macroscopic analytical instruments, an atomic force microscope (AFM) provides necessary and vital information for analyzing mineral structure, especially the mineral-aqueous interfaces, and has excellent application prospects in mineralogical research. This paper presents recent advances in the study of properties of minerals such as surface roughness, crystal structure and adhesion by atomic force microscopy, as well as the progress of application and main contributions in mineral-aqueous interfaces analysis, such as mineral dissolution, redox and adsorption processes. It describes the principles, range of applications, strengths and weaknesses of using AFM in combination with IR and Raman spectroscopy instruments to characterization of minerals. Finally, according to the limitations of the AFM structure and function, this research proposes some ideas and suggestions for developing and designing AFM techniques.

Role of Oligodendrocyte Lineage Cells in Multiple System Atrophy.

Multiple system atrophy (MSA) is a debilitating movement disorder with unknown etiology. Patients present characteristic parkinsonism and/or cerebellar dysfunction in the clinical phase, resulting from progressive deterioration in the nigrostriatal and olivopontocerebellar regions. MSA patients have a prodromal phase subsequent to the insidious onset of neuropathology. Therefore, understanding the early pathological events is important in determining the pathogenesis, which will assist with developing disease-modifying therapy. Although the definite diagnosis of MSA relies on the positive post-mortem finding of oligodendroglial inclusions composed of α-synuclein, only recently has MSA been verified as an oligodendrogliopathy with secondary neuronal degeneration. We review up-to-date knowledge of human oligodendrocyte lineage cells and their association with α-synuclein, and discuss the postulated mechanisms of how oligodendrogliopathy develops, oligodendrocyte progenitor cells as the potential origins of the toxic seeds of α-synuclein, and the possible networks through which oligodendrogliopathy induces neuronal loss. Our insights will shed new light on the research directions for future MSA studies.

Preserving cognitive function in patients with Alzheimer's disease: The Alzheimer's disease neuroprotection research initiative (ADNRI).

The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease (AD) and associated socioeconomic burdens. Abnormal metabolism of amyloid-ß (Aß) has been proposed as a significant pathomechanism in AD, supported by results of recent clinical trials using anti-Aß antibodies. Nonetheless, the cognitive benefits of the current treatments are limited. The etiology of AD is multifactorial, encompassing Aß and tau accumulation, neuroinflammation, demyelination, vascular dysfunction, and comorbidities, which collectively lead to widespread neurodegeneration in the brain and cognitive impairment. Hence, solely removing Aß from the brain may be insufficient to combat neurodegeneration and preserve cognition. To attain effective treatment for AD, it is necessary to (1) conduct extensive research on various mechanisms that cause neurodegeneration, including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level; (2) identify neuroprotective intervention targets against different neurodegeneration mechanisms; and (3) discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients. The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated, multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD. The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD, with the goal of halting or even reversing cognitive decline.

Carbon sequestration characteristics of two plantation forest ecosystems with different lithologies of karst.

In karst regions, the majority of studies have focused on ecosystem carbon sequestration in the same lithology, but no studies in different lithologies. In this study, actual measurements were used to reveal carbon sequestration characteristics of two plantation forest ecosystems (Bodinieri cinnamon and Cupressus funebris) with different lithologies of karst. The results showed that the tree layer showed the highest vegetation biomass, carbon content, carbon density, and ratio of aboveground biomass to belowground biomass. The carbon density of B. cinnamon plantation and C. funebris plantation was high in dolomite and in limestone respectively. The soil quality and carbon density of bare ground and plantation varied across different lithologies. The carbon density of various ecosystem components was in the order of vegetation>soil>litterfall. The carbon density and net carbon density of plantation varied across different lithologies. In B. cinnamon plantation, the carbon sequestration rate of vegetation and ecosystem was high in dolomite, moderate in limestone, and low in dolomitic sandstone. In Cupressus funebris plantation, the carbon sequestration rate was in the order of limestone>dolomite>dolomitic sandstone. These findings revealed that lithology is an important factor affecting ecosystem carbon pools, and plantation ecosystems have low biomass and low carbon density in karst areas.

Increased unsaturated lipids underlie lipid peroxidation in synucleinopathy brain.

Lipid peroxidation is a process of oxidative degradation of cellular lipids that is increasingly recognized as an important factor in the pathogenesis of neurodegenerative diseases. We were therefore interested in the manifestation of lipid peroxidation in synucleinopathies, a group of neurodegenerative diseases characterized by the central pathology of α-synuclein aggregates, including Parkinson's disease, multiple system atrophy, dementia with Lewy bodies and Alzheimer's disease with Lewy bodies. We assessed lipid peroxidation products, lipid aldehydes, in the amygdala, a common disease-affected region in synucleinopathies, and in the visual cortex, a disease-unaffected region. We found that the levels of lipid aldehydes were significantly increased in the amygdala, but not in the visual cortex. We hypothesized that these increases are due to increases in the abundance of unsaturated lipids, since lipid aldehydes are formed from unsaturated lipids. We undertook a comprehensive analysis of membrane lipids using liquid chromatography-mass spectrometry and found that unsaturated phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and sphingomyelin were specifically elevated in the amygdala and correlated with increases in lipid aldehydes. Furthermore, unsaturated phosphatidylethanolamine levels were associated with soluble α-synuclein. Put together, these results suggest that manifestation of lipid peroxidation is prevalent in synucleinopathies and is likely to be due to increases in unsaturated membrane lipids. Our findings underscore the importance of lipid peroxidation in α-synuclein pathology and in membrane structure maintenance.

ATP-binding cassette transporter expression is widely dysregulated in frontotemporal dementia with TDP-43 inclusions.

The human brain is highly enriched in lipids and increasing evidence indicates that dysregulation of lipids in the brain is associated with neurodegeneration. ATP-binding cassette subfamily A (ABCA) transporters control the movement of lipids across cellular membranes and are implicated in a number of neurodegenerative diseases. However, very little is known about the role of ABCA transporters in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), which is a common form of younger-onset dementia. We therefore undertook a comprehensive analysis of the expression of ABCA transporters (ABCA1-13) in five key brain regions (amygdala, inferior temporal cortex, superior frontal cortex, cerebellum and parietal cortex) in FTLD-TDP and controls. We found that the expression of ABCA2, ABCA3, ABCA4, ABCA7, ABCA9, ABCA10 and ABCA13 was significantly altered in FTLD-TDP in a region-specific manner. In addition, the expression of ABCA transporters correlated specifically to different neural markers and TARDBP. These results suggest substantial dysregulation of ABCA transporters and lipid metabolism in FTLD-TDP and these changes are associated with neuroinflammation.

Adaptive structural changes in the motor cortex and white matter in Parkinson's disease.

Parkinson's disease (PD) is a movement disorder characterized by the early loss of nigrostriatal dopaminergic pathways producing significant network changes impacting motor coordination. Recently three motor stages of PD have been proposed (a silent period when nigrostriatal loss begins, a prodromal motor period with subtle focal manifestations, and clinical PD) with evidence that motor cortex abnormalities occur to produce clinical PD[8]. We directly assess structural changes in the primary motor cortex and corticospinal tract using parallel analyses of longitudinal clinical and cross-sectional pathological cohorts thought to represent different stages of PD. 18F-FP-CIT positron emission tomography and subtle motor features identified patients with idiopathic rapid-eye-movement sleep behaviour disorder (n = 8) that developed prodromal motor signs of PD. Longitudinal diffusion tensor imaging before and after the development of prodromal motor PD showed higher fractional anisotropy in motor cortex and corticospinal tract compared to controls, indicating adaptive structural changes in motor networks in concert with nigrostriatal dopamine loss. Histological analyses of the white matter underlying the motor cortex showed progressive disorientation of axons with segmental replacement of neurofilaments with α-synuclein, enlargement of myelinating oligodendrocytes and increased density of their precursors. There was no loss of neurons in the motor cortex in early or late pathologically confirmed motor PD compared to controls, although there were early cortical increases in neuronal neurofilament light chain and myelin proteins in association with α-synuclein accumulation. Our results collectively provide evidence of a direct impact of PD on primary motor cortex and its output pathways that begins in the prodromal motor stage of PD with structural changes confirmed in early PD. These adaptive structural changes become considerable as the disease advances potentially contributing to motor PD.

Chemically Modified Bovine ß-Lactoglobulin as a Broad-Spectrum Influenza Virus Entry Inhibitor with the Potential to Combat Influenza Outbreaks.

Frequent outbreaks of the highly pathogenic influenza A virus (AIV) infection, together with the lack of broad-spectrum influenza vaccines, call for the development of broad-spectrum prophylactic agents. Previously, 3-hydroxyphthalic anhydride-modified bovine ß-lactoglobulin (3HP-ß-LG) was proven to be effective against human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it has also been used in the clinical control of cervical human papillomavirus (HPV) infections. Here, we show its efficacy in potently inhibiting infection by divergent influenza A and B viruses. Mechanistic studies suggest that 3HP-ß-LG binds, possibly through its negatively charged residues, to the receptor-binding domain in the hemagglutinin 1 (HA1) subunit in the HA of the influenza virus, thus inhibiting the attachment of the HA to sialic acid on host cells. The intranasal administration of 3HP-ß-LG led to the protection of mice against challenges by influenza A(H1N1)/PR8, A(H3N2), and A(H7N9) viruses. Furthermore, 3HP-ß-LG is highly stable when stored at 50 °C for 30 days and it shows excellent safety in vitro and in vivo. Collectively, our findings suggest that 3HP-ß-LG could be successfully repurposed as an intranasal prophylactic agent to prevent influenza virus infections during influenza outbreaks.