Function and Mechanism of Abscisic Acid on Microglia-Induced Neuroinflammation in Parkinson's Disease.

Parkinson's disease (PD), as a neurologically implemented disease with complex etiological factors, has a complex and variable pathogenesis. Accompanying further research, neuroinflammation has been found to be one of the possible factors in its pathogenesis. Microglia, as intrinsic immune cells in the brain, play an important role in maintaining microenvironmental homeostasis in the brain. However, over-activation of neurotoxic microglia in PD promotes neuroinflammation, which further increases dopaminergic (DA) neuronal damage and exacerbates the disease process. Therefore, targeting and regulating the functional state of microglia is expected to be a potential avenue for PD treatment. In addition, plant extracts have shown great potential in the treatment of neurodegenerative disorders due to their abundant resources, mild effects, and the presence of multiple active ingredients. However, it is worth noting that some natural products have certain toxic side effects, so it is necessary to pay attention to distinguish medicinal ingredients and usage and dosage when using to avoid aggravating the progression of diseases. In this review, the roles of microglia with different functional states in PD and the related pathways inducing microglia to transform into neuroprotective states are described. At the same time, it is discussed that abscisic acid (ABA) may regulate the polarization of microglia by targeting them, promote their transformation into neuroprotective state, reduce the neuroinflammatory response in PD, and provide a new idea for the treatment of PD and the selection of drugs.

Validation of a Novel Cuproptosis-Related Prognostic Gene Marker and Differential Expression Associated with Lung Adenocarcinoma.

BACKGROUND: Cuproptosis induction is seen as a promising alternative for immunotherapies and targeted therapies in breast cancer. The objective of this research was to examine the prognostic and biological importance of cuproptosis-related genes (CRGs) in lung adenocarcinoma (LUAD). METHODS: The following methods were used: GSE10072 dataset and TCGA database analysis, differential expression analysis of CRGs, and biological function (BP) and signaling pathway enrichment analysis, prognostic analysis and clinical analysis of CRGs, construction of the prognostic signature and RNA modified genes and miRNA analysis of CRGs in LUAD, immunoinfiltration analysis and immunohistochemical staining of DßH, UBE2D3, SOD1, UBE2D1 and LOXL2. RESULTS: AOC1, ATOX1, CCL8, CCS, COX11, CP, LOXL2, MAP2K2, PDK1, SCO2, SOD1, UBE2D1, UBE2D3 and VEGFA showed significantly higher expression, while ATP7B, DßH, PDE3B, SLC31A2, UBE2D2, UBE2D4 and ULK2 showed lower expression in LUAD tissues than normal tissues. We also found that ATP7B (4%), AOC1 (3%) PDE3B (2%), DßH (2%), CP (1%), ULK2 (1%), PDK1 (1%), LOXL2 (1%) and UBE2D3 (1%) showed higher mutation frequencies. The univariate Cox analysis was used to identify CRGs that have prognostic value. It identified 21 genes that showed significant prognostic value, containing DßH, UBE2D3, SOD1, UBE2D1 and LOXL2. Patients with DßH up-expression have a longer survival time and patients with UBE2D3, SOD1, UBE2D1 and LOXL2 down-expression also have a longer survival time. hsa-miR-29c-3p, hsa-miR-29a-3p, hsa-miR-181c-5p, hsa-miR-1245a, etc., play an important role in the miRNA regulatory network, and in LUAD, miR-29a, miR-29c and miR-181c high expression survival was longer, and miR-1245a low expression survival was longer. We also performed an analysis to examine the relationships between DßH, LOXL2, SOD1, UBE2D1 and UBE2D3 and immune infiltration in LUAD, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and DCs. CONCLUSION: DßH, UBE2D3, SOD1, UBE2D1, and LOXL2 are potential candidates implicated in LUAD and can be further explored for their application as diagnostic, prognostic, and therapeutic biomarkers for LUAD.

Integrative Analysis of the Role of TP53 in Human Pan-Cancer.

Tumor protein P53 (TP53) is an important tumor suppressor gene in humans. Under normal circumstances, TP53 can help repair mutated genes, or promote the death of cells with severe gene mutations (specifically, TP53 prevents cells from arrest in the G1/S phase when deoxyribonucleic acid (DNA) is damaged and promotes apoptosis if not repaired), and prevents normal cells from becoming malignant cells. TP53 mutations affect its tumor suppressor function, leading to the development of malignant tumors. In this study, using a public database, we explored the pan-cancer expression of TP53, its impact on patient survival and prognosis, the types of gene mutations, its correlation with immunity, and its regulation of other transcription factors and micro RNA (miRNA). The docking sites of therapeutic drugs and key amino acid sites of action provide a basis for future targeted therapies. TP53 has important biological functions in the human body. This study provides a theoretical basis for clinical TP53 gene therapy.

The reciprocal interactions between microglia and T cells in Parkinson's disease: a double-edged sword.

In Parkinson's disease (PD), neurotoxic microglia, Th1 cells, and Th17 cells are overactivated. Overactivation of these immune cells exacerbates the disease process and leads to the pathological development of pro-inflammatory cytokines, chemokines, and contact-killing compounds, causing the loss of dopaminergic neurons. So far, we have mainly focused on the role of the specific class of immune cells in PD while neglecting the impact of interactions among immune cells on the disease. Therefore, this review demonstrates the reciprocal interplays between microglia and T cells and the associated subpopulations through cytokine and chemokine production that impair and/or protect the pathological process of PD. Furthermore, potential targets and models of PD neuroinflammation are highlighted to provide the new ideas/directions for future research.

Parkinson's Disease as a Risk Factor for Prostate Adenocarcinoma: A Molecular Point of View.

INTRODUCTION: Cancer and neurodegeneration are two major leading causes of morbidity and death worldwide. Neurodegeneration results in excessive neuronal cell death, and cancer emerges from increased proliferation and resistance to cell death. Although most epidemiological studies support an inverse association between the risk for the development of neurodegenerative diseases and cancer, increasing evidence points to a positive correlation between specific types of cancer, like prostate adenocarcinoma (PRAD), and neurodegenerative diseases, like Parkinson's disease (PD). METHODS: PD and PRAD differential genes were screened through the GEO database, and the differential genes were analyzed using David, String, GEPIA, Kaplan-Meier plotter, TIMER2.0, proteinatlas, cBioPortal, and CTD databases to elucidate the biological function and molecular mechanism of PD and PRAD-related genes. RESULTS: Studies have shown that the hub gene and differentially expressed genes (DEGs) in PD were differentially expressed in PRAD, including CDC20, HSPA4L, ROBO1, DMKN, IFI27L2, LUZP2, PTN, PTGDS. In PRAD, the high expression of HSPA4L, ROBO1, DMKN, IFI27L2, PTN, and PTGDS genes was associated with longer survival, while the patients with low expression of CDC20 and LUZP2 genes had longer survival. The mRNA of CDC20 and LUZP2 were highly expressed, while the mRNAs of HSPA4L, ROBO1, DMKN, IFI27L2, and PTGDS were low expressed. Gene methylation did not affect the survival of patients. The high expression of miR-142, miR-186, miR-30a, miR-497, miR-590, miR-28, and miR-576 in microRNA (miRNA) might potentially be used as biomarkers for the progression of PD and PRAD and for the early diagnosis of PD and PRAD in the populations. The genes in this study were highly associated with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Somatic mutation mainly focused on missense mutation. Therapeutic drugs included acetaminophen and valproic acid (VPA). CONCLUSION: Bioinformatics was used to identify potential targets and novel molecular mechanisms that may serve as clinical markers for the diagnosis and treatment of PD and PRAD.

The Construction and Validation of a Novel Ferroptosis-Related Gene Signature in Parkinson's Disease.

As a newly discovered regulated cell death mode, ferroptosis is associated with the development of Parkinson's disease (PD) and has attracted much attention. Nonetheless, the relationship between ferroptosis and PD pathogenesis remains unclear. The GSE8397 dataset includes GPL96 and GPL97 platforms. The differential genes were analyzed by immune infiltration and Gene Set Enrichment Analysis (GSEA) (p < 0.05), and differential multiple |logFC| > 1 and weighted gene coexpression network analysis (WGCNA) were used to screen differential expression genes (DEGs). The intersection with 368 ferroptosis-related genes (FRGs) was conducted for gene ontology/Kyoto encyclopedia of gene and genome (GO/KEGG) enrichment analysis, gene expression analysis, correlation analysis, single-cell sequencing analysis, and prognosis analysis (area under the curve, AUC) and to predict relevant miRNAs and construct network diagrams using Cytoscape. The intersection genes of differentially expressed ferroptosis-related genes (DEFRGs) and mitochondrial dysfunction genes were validated in the substantia nigra of MPTP-induced PD mice models by Western blotting and immunohistochemistry, and the protein-binding pocket was predicted using the DoGSiteScorer database. According to the results, the estimated scores were positively correlated with the stromal scores or immune scores in the GPL96 and GPL97 platforms. In the GPL96 platform, the GSEA showed that differential genes were mainly involved in the GnRH signaling pathway, B cell receptor signaling pathway, inositol phosphate metabolism, etc. In the GPL97 platform, the GSEA showed that differential genes were mainly involved in the ubiquitin-mediated proteolysis, axon guidance, Wnt signaling pathway, MAPK signaling pathway, etc. We obtained 26 DEFRGs, including 12 up-regulated genes and 14 down-regulated genes, with good correlation. The area under the prognostic analysis curve (AUC > 0.700) showed a good prognostic ability. We found that they were enriched in different neuronal cells, oligodendrocytes, astrocytes, oligodendrocyte precursor cells, and microglial cells, and their expression scores were positively correlated, and selected genes with an AUC curve ≥0.9 were used to predict miRNA, including miR-214/761/3619-5p, miR-203, miR-204/204b/211, miR-128/128ab, miR-199ab-5p, etc. For the differentially expressed ferroptosis-mitochondrial dysfunction-related genes (DEF-MDRGs) (AR, ISCU, SNCA, and PDK4), in the substantia nigra of mice, compared with the Saline group, the expression of AR and ISCU was decreased (p < 0.05), and the expression of α-Syn and PDK4 was increased (p < 0.05) in the MPTP group. Therapeutic drugs that target SNCA include ABBV-0805, Prasinezumab, Cinpanemab, and Gardenin A. The results of this study suggest that cellular DEF-MDRGs might play an important role in PD. AR, ISCU, SNCA, and PDK4 have the potential to be specific biomarkers for the early diagnosis of PD.

The Role of Cellular Defense Systems of Ferroptosis in Parkinson's Disease and Alzheimer's Disease.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common rapidly developing neurodegenerative diseases that lead to serious health and socio-economic consequences. Ferroptosis is a non-apoptotic form of cell death; there is growing evidence to support the notion that ferroptosis is involved in a variety of pathophysiological contexts, and there is increasing interest in the role of ferroptosis in PD and AD. Simultaneously, cells may have evolved four defense systems to counteract the toxic effects of ferroptosis occasioned by lipid peroxidation. This review, which focuses on the analysis of ferroptosis in the PD and AD context, outlines four cellular defense systems against ferroptosis and how each of them is involved in PD and AD.

The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson's Disease.

Parkinson's disease (PD) is the second most common rapidly progressive neurodegenerative disease and has serious health and socio-economic consequences. Mitochondrial dysfunction is closely related to the onset and progression of PD, and the use of mitochondria as a target for PD therapy has been gaining traction in terms of both recognition and application. The disruption of mitochondrial proteostasis in the brain tissue of PD patients leads to mitochondrial dysfunction, which manifests as mitochondrial unfolded protein response, mitophagy, and mitochondrial oxidative phosphorylation. Physical exercise is important for the maintenance of human health, and has the great advantage of being a non-pharmacological therapy that is non-toxic, low-cost, and universally applicable. In this review, we investigate the relationships between exercise, mitochondrial proteostasis, and PD and explore the role and mechanisms of mitochondrial proteostasis in delaying PD through exercise.

Efficacy and evaluation of therapeutic exercises on adults with Parkinson's disease: a systematic review and network meta-analysis.

BACKGROUND: Exercises are an effective treatment in Parkinson's disease (PD), but there is still controversy over which types should be used. We aimed to compare and rank the types of exercise that improve PD symptoms by quantifying information from randomised controlled trials. METHODS: We performed a systematic review and network meta-analysis and searched PubMed, MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and China National Knowledge Infrastructure (CNKI) from their inception date to June 30, 2022. We included randomized controlled trials of 24 types of exercise for the interventional treatment of adults (≥ 50 years old) with PD. Effect size measures were standardized mean differences (SMDs) with 95% credible intervals (CrIs). The confidence of evidence was examined using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We identified 10 474 citations and included 250 studies involving 13 011 participants. Results of NMA showed that power training (PT) had the best benefits for motor symptoms compared with the control group (CON), with SMDs (95% CrI) (-1.46, [-2.18 to -0.74]). Body weight support treadmill training (BWS_TT) showed the best improvement in balance (1.55, [0.72 to 2.37]), gait velocity (1.15 [0.57 to 1.31]) and walking distance (1.96, [1.18 to 2.73]), and robotic assisted gait training (RA_GT) had the most benefits for freezing of gait (-1.09, [-1.80 to -0.38]). For non-motor symptoms, Dance showed the best benefits for depression (-1.71, [-2.79 to -0.73]). Only Yoga significantly reduced anxiety symptom compared with CON (-0.53, [0.96 to -0.11]). Only resistance training (RT) significantly enhanced sleep quality and cognition (-1.42, [-2.60 to -0.23]; 0.51, [0.09 to 0.94]). For muscle strength, PT showed the best advance (1.04, [0.64 to 1.44]). For concern of falling, five types of exercise were more effective than CON. CONCLUSIONS: There is low quality evidence that PT, Yoga, BWS_TT, Dance, and RT are the most effective treatments, pending outcome of interest, for adults with PD. TRIAL REGISTRATION: PROSPERO (CRD42021220052).

PEST-containing nuclear protein mediates the proliferation, migration, and invasion of human neuroblastoma cells through MAPK and PI3K/AKT/mTOR signaling pathways.

BACKGROUND: PEST-containing nuclear protein (PCNP), a novel nuclear protein, is involved in cell proliferation and tumorigenesis. However, the precise mechanism of action of PCNP in the process of tumor growth has not yet been fully elucidated. METHODS: ShRNA knockdown and overexpression of PCNP were performed in human neuroblastoma cells. Tumorigenic and metastatic effects of PCNP were examined by tumor growth, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo. RESULTS: PCNP over-expression decreased the proliferation, migration, and invasion of human neuroblastoma cells and down-regulation of PCNP showed reverse effects. PCNP over-expression increased protein expressions of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and cleaved poly adenosine diphosphate-ribose polymerase, as well as ratios of B-cell lymphoma-2 (Bcl-2)-associated X protein/Bcl-2 and Bcl-2-associated death promoter/B-cell lymphoma-extra large in human neuroblastoma cells, however PCNP knockdown exhibited reverse trends. PCNP over-expression increased phosphorylations of extracellular signal-regulated protein kinase 1/2, p38, c-Jun N-terminal kinase, as well as decreased phosphorylations of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), nevertheless PCNP knockdown exhibited opposite effects. Furthermore, PCNP over-expression significantly reduced the growth of human neuroblastoma xenograft tumors by down-regulating angiogenesis, whereas PCNP knockdown markedly promoted the growth of human neuroblastoma xenograft tumors through up-regulation of angiogenesis. CONCLUSIONS: PCNP mediates the proliferation, migration, and invasion of human neuroblastoma cells through mitogen-activated protein kinase and PI3K/AKT/mTOR signaling pathways, implying that PCNP is a therapeutic target for patients with neuroblastoma.

Cytoplasmic retention of protein phosphatase 2A inhibitor 2 (I2PP2A) induces Alzheimer-like abnormal hyperphosphorylation of Tau.

Abnormal hyperphosphorylation of Tau leads to the formation of neurofibrillary tangles, a hallmark of Alzheimer disease (AD), and related tauopathies. The phosphorylation of Tau is regulated by protein phosphatase 2A (PP2A), which in turn is modulated by endogenous inhibitor 2 (I2 (PP2A)). In AD brain, I2 (PP2A) is translocated from neuronal nucleus to cytoplasm, where it inhibits PP2A activity and promotes abnormal phosphorylation of Tau. Here we describe the identification of a potential nuclear localization signal (NLS) in the C-terminal region of I2 (PP2A) containing a conserved basic motif, (179)RKR(181), which is sufficient for directing its nuclear localization. The current study further presents an inducible cell model (Tet-Off system) of AD-type abnormal hyperphosphorylation of Tau by expressing I2 (PP2A) in which the NLS was inactivated by (179)RKR(181) → AAA along with (168)KR(169) → AA mutations. In this model, the mutant NLS (mNLS)-I2 (PP2A) (I2 (PP2A)AA-AAA) was retained in the cell cytoplasm, where it physically interacted with PP2A and inhibited its activity. Inhibition of PP2A was associated with the abnormal hyperphosphorylation of Tau, which resulted in microtubule network instability and neurite outgrowth impairment. Expression of mNLS-I2 (PP2A) activated CAMKII and GSK-3ß, which are Tau kinases regulated by PP2A. The immunoprecipitation experiments showed the direct interaction of I2 (PP2A) with PP2A and GSK-3ß but not with CAMKII. Thus, the cell model provides insights into the nature of the potential NLS and the mechanistic relationship between I2 (PP2A)-induced inhibition of PP2A and hyperphosphorylation of Tau that can be utilized to develop drugs preventing Tau pathology.

Gaucher-Associated Parkinsonism.

Gaucher disease is associated with Parkinson's disease (PD) by mutations in glucocerebrosidase (GCase). The gene encoding GCase, glucosidase beta acid (GBA), is an important risk factor for PD. Findings from large studies have shown that patients with PD have an increased frequency of mutations in GBA and that GBA mutation carriers exhibit diverse parkinsonian phenotypes and Lewy body pathology. Although the mechanism for this association remains elusive, some hypotheses have been proposed to explain it, including gain of function caused by GBA mutations, which increases α-synuclein (α-syn) aggregation, loss of function due to lysosomal enzyme deficiency, which affects α-syn clearance, and even a bidirectional feedback loop, but each of these hypotheses has its limitations. It is also worth noting that many findings have implicated the interaction between α-syn and GCase, indicating the essential role of the interaction in the pathogenesis of GBA-associated parkinsonism. Therefore, the current review focuses on α-syn and GCase, and it provides some new thoughts that may be helpful for understanding the α-syn-GCase interaction and unraveling the exact mechanism underlying GBA-associated parkinsonism.

Role of Inflammation in the Development of COVID-19 to Parkinson's Disease.

Background: The coronavirus disease 2019 (COVID-19) can lead to neurological symptoms such as headaches, confusion, seizures, hearing loss, and loss of smell. The link between COVID-19 and Parkinson's disease (PD) is being investigated, but more research is needed for a definitive connection. Methods: Datasets GSE22491 and GSE164805 were selected to screen differentially expressed gene (DEG), and immune infiltration and gene set enrichment analysis (GSEA) of the DEG were performed. WGCNA analyzed the DEG and selected the intersection genes. Potential biological functions and signaling pathways were determined, and diagnostic genes were further screened using gene expression and receiver operating characteristic (ROC) curves. Screening and molecular docking of ibuprofen as a therapeutic target. The effectiveness of ibuprofen was verified by constructing a PD model in vitro, and constructing "COVID19-PD" signaling pathway, and exploring the role of angiotensin-converting enzyme 2 (ACE2) in PD. Results: A total of 13 DEG were screened from the GSE36980 and GSE5281 datasets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that the DEG were mainly associated with the hypoxia-inducible factor (HIF-1), epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, etc. After analysis, it is found that ibuprofen alleviates PD symptoms by inhibiting the expression of nuclear factor kappa-B (NF-κB), interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α). Based on signal pathway construction, the importance of ACE2 in COVID-19-induced PD has been identified. ACE2 is found to have widespread distribution in the brain. In the 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced ACE2-null PD mice model, more severe motor and non-motor symptoms, increased NF-κB p65 and α-synuclein (α-syn) expression with significant aggregation, decreased tyrosine hydroxylase (TH), severe neuronal loss, and neurodegenerative disorders. Conclusion: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the risk of PD through an inflammatory environment and downregulation of ACE2, providing evidence for the molecular mechanism and targeted therapy associated with COVID-19 and PD.

The role of ACE2 in RAS axis on microglia activation in Parkinson's disease.

BACKGROUND: The classic renin-angiotensin system (RAS) induces organ damage, while the ACE2/Ang-(1-7)/MasR axis opposes it. However, the role of ACE2 in the brain is unclear. We studied ACE2's role in the brain. METHOD: We used male C57BL/6J (WT) mice, ACE2 knockout (KO) mice, and MPTP-induced mice. Behavioral tests confirmed successful modeling. We assessed the impact of ACE2 KO on the RAS axis and PD index, including ACE, ACE2, AT1, AT2, MasR, TH, α-syn, and Iba1. We investigated ACE2 and MasR's involvement in microglial activation via western blot and immunofluorescence. GSE10867 and GSE26532 datasets were used to analyze the effects of AT1 antagonists and in vitro PD models on microglia. RESULT: Behavioral tests revealed that MPTP mice displayed motor deficits, depression, anxiety, and increased inflammatory markers in the SN and CPU, with reduced antioxidant capacity. ACE2 KO worsened these symptoms and exacerbated inflammation and oxidative stress. LPS-induced ACE2/MasR activation in BV2 cells demonstrated anti-inflammatory and neuroprotective effects by modulating microglial polarization. Antagonists inhibited microglial activation via inflammation and ROS processes. CONCLUSION: The RAS axis regulates inflammation and oxidative stress to maintain CNS function, suggesting potential targets for neurologic disease treatment. Understanding microglial RAS activation can offer new therapeutic strategies.

A separation-free paper-based hydrogel device for one-step reactive oxygen species determination by a smartphone.

Paper-based analytical devices (PADs) are very convenient for determining biomarkers in point-of-care (POC) diagnosis while requiring sample pre-treatment or impurity separation. This study reports a novel hydrogel-coupled, paper-based analytical device (PAD) for separation-free H2O2 colorimetric detection in both aqueous solution and cell lysis with sample-to-answer analysis by directly loading into the sample test zone. By encapsulating an inorganic mimic enzyme and chromogenic substrate into the sodium alginate (SA) hydrogel, amplification of the color signal after catalyzing the substrate could be achieved. Taking advantage of the nanoscale porous structure of the hydrogel and the lateral flow channel of the PAD, large interference fragments or bio-macromolecules are prevented from diffusing into the chromogenic reaction, whereas the small target molecules enter the sensing region to trigger the catalytic reaction. This method demonstrated a rapid and accurate analysis with a limit of detection as low as 0.06 mM and detection selectivity. Our proposed device requires no enzyme and is separation-free, portable, easy-to-fabricate, and low-cost, and may offer a platform for quantitative or qualitative analysis of other analytes in body fluids for POC applications.

Innate neuroimmunity across aging and neurodegeneration: a perspective from amyloidogenic evolvability.

In Alzheimer's Disease (AD), amyloidogenic proteins (APs), such as ß-amyloid (Aß) and tau, may act as alarmins/damage-associated molecular patterns (DAMPs) to stimulate neuroinflammation and cell death. Indeed, recent evidence suggests that brain-specific type 2 immune networks may be important in modulating amyloidogenicity and brain homeostasis. Central to this, components of innate neuroimmune signaling, particularly type 2 components, assume distinctly specialized roles in regulating immune homeostasis and brain function. Whereas balanced immune surveillance stems from normal type 2 brain immune function, appropriate microglial clearance of aggregated misfolded proteins and neurotrophic and synaptotrophic signaling, aberrant pro-inflammatory activity triggered by alarmins might disrupt this normal immune homeostasis with reduced microglial amyloid clearance, synaptic loss, and ultimately neurodegeneration. Furthermore, since increased inflammation may in turn cause neurodegeneration, it is predicted that AP aggregation and neuroinflammation could synergistically promote even more damage. The reasons for maintaining such adverse biological conditions which have not been weeded out during evolution remain unclear. Here, we discuss these issues from a viewpoint of amyloidogenic evolvability, namely, aEVO, a hypothetic view of an adaptation to environmental stress by AP aggregates. Speculatively, the interaction of AP aggregation and neuroinflammation for aEVO in reproduction, which is evolutionally beneficial, might become a co-activating relationship which promotes AD pathogenesis through antagonistic pleiotropy. If validated, simultaneously suppressing both AP aggregation and specific innate neuroinflammation could greatly increase therapeutic efficacy in AD. Overall, combining a better understanding of innate neuroimmunity in aging and disease with the aEVO hypothesis may help uncover novel mechanism of pathogenesis of AD, leading to improved diagnostics and treatments.

ß-Synuclein Intermediates α-Synuclein Neurotoxicity in Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease in the world, and synuclein is closely related to the onset and progression of PD. Synuclein is considered a therapeutic target for PD. Recent studies have found that abnormal aggregation of α-synuclein (α-Syn) in the brains of PD patients leads to mitochondrial dysfunction and neuroinflammation. Research in the field of neuroscience has confirmed that ß-synuclein (ß-Syn) also plays a role in Parkinson's disease. However, there has been little research on the role mechanisms and interactions between ß-Syn and α-Syn in PD. Therefore, the purpose of this study is to clarify the relationship between α-Syn, ß-Syn, and PD and to explore the roles and interactions of ß-Syn and α-Syn in PD.

Clinical value and mechanistic analysis of HIIT on modulating risk and symptoms of depression: A systematic review.

Background: The exact causal mechanisms of depression remain unclear due to the complexity of the triggers, which has led to limitations in treating depression using modern drugs. High-intensity interval training (HIIT) is as effective as medication in treating depression without toxic side effects. Typically, HIIT requires less time commitment (i.e., shorter exercise duration) and exhibits pronounced benefits on depressive symptoms than other forms of physical exercise. This review summarizes the risk reduction and clinical effects of HIIT for depression and discusses the underlying mechanisms, providing a theoretical basis for utilizing HIIT in treating depression. Methods: A database search was conducted in PubMed, Embase, Web of Science, and Scopus from inception up to October 2022. The methodological quality of the included literature was evaluated by the physiotherapy evidence database (PEDro) scale criteria. The review focused on evaluating the changes in depression risk or symptoms of HIIT interventions in healthy individuals, patients with depression, and patients with other disorders co-morbid with depression. Consequently, the mechanisms associated with depression related HIIT were summarized. Results: A total of 586 participants (52 % female; mean age: 43.58±8.93 years) from 22 studies were included. Implementing HIIT using different exercise types alleviates depressive symptoms in individuals with depression and in individuals with depression who have exhibited comorbidities and reduced depression scale scores in subjects immediately after acute exercise. In addition, the long-interval HIIT and short-interval HIIT in the treatment of patients with cardiovascular or psychiatric disorders may reduce depressive symptoms via complex exercise-related changes on several levels, including by effecting the following measures: releasing monoamines, reducing neuronal death, inducing neurogenesis, modulating the functional homeostasis of the HPA axis, and enhancing the level of inflammation in the body. Conclusion: HIIT is a relatively safe and effective antidepressant, which may involve multiple neurobiological mechanisms (release of monoamines, reducing neuronal death, inducing neurogenesis, modulating the functional homeostasis of the HPA axis, and enhancing the level of inflammation in the body), thereby reducing the risk or symptoms of depression in participants.

Catalase immobilization: Current knowledge, key insights, applications, and future prospects - A review.

Catalase (CAT), a ubiquitous enzyme in all oxygen-exposed organisms, effectively decomposes hydrogen peroxide (H2O2), a harmful by-product, into water and oxygen, mitigating oxidative stress and cellular damage, safeguarding cellular organelles and tissues. Therefore, CAT plays a crucial role in maintaining cellular homeostasis and function. Owing to its pivotal role, CAT has garnered considerable interest. However, many challenges arise when used, especially in multiple practical processes. "Immobilization", a widely-used technique, can help improve enzyme properties. CAT immobilization offers numerous advantages, including enhanced stability, reusability, and facilitated downstream processing. This review presents a comprehensive overview of CAT immobilization. It starts with discussing various immobilization mechanisms, support materials, advantages, drawbacks, and factors influencing the performance of immobilized CAT. Moreover, the review explores the application of the immobilized CAT in various industries and its prospects, highlighting its essential role in diverse fields and stimulating further research and investigation. Furthermore, the review highlights some of the world's leading companies in the field of the CAT industry and their substantial potential for economic contribution. This review aims to serve as a discerning, source of information for researchers seeking a comprehensive cutting-edge overview of this rapidly evolving field and have been overwhelmed by the size of publications.

The potential bioactive ingredients and hub genes of five TCM prescriptions against lung adenocarcinoma were explored based on bioinformatics.

Analysis of the commonness of several prescriptions of traditional Chinese medicine (TCM) in the treatment of lung adenocarcinoma (LUAD) based on bioinformatics. Searched the TCM prescriptions for the treatment of LUAD in the literature published in the database, searched ingredients in the TCM through TCMSP and Swiss target prediction databases (OB ≥ 30%, DL > 0.18, Caco-2 > 0), and predicted the potential targets. GEO database retrieved LUAD gene chip data and screened (P < 0.05, | log2 (fold change) |> 1). The biological function, hub gene selection and survival period, immune infiltration, methylation, copy number variations (CNVs), and single-nucleotide variants (SNV) of hub genes were analyzed by DAVID, STRING, Kaplan-Meier plotter database, Cytoscape software, GSCALite database, and TIMER2.0. In this study, 5 TCM prescriptions were analyzed, and a total of 173 ingredients were obtained through database search, including 35 coincidence ingredients, a total of 603 potential targets, 621 LUAD-related genes, 16 up-regulated genes, and 31 down-regulated genes. A total of 61 terms of biological process (BP), 14 terms of cellular component (CC), and 14 terms of molecular function (MF) were obtained. Twenty core genes were obtained, including 15 genes with different survival periods, which were closely related to immune cells (B cell, CD8 + T cell, CD4 + T cell, macrophage, neutrophil, and dendritic cells). The low expression of ADRB2 and MAOA and the high expression of AUARK, CDK1, KIF11, MIF, TOP2A, and TTK were associated with the survival rate of LUAD patients (P < 0.05). Baicalein, Arachidonate, Hederagenin, and hub genes may become potential drugs and potential targets for LUAD treatment. Evaluated the efficacy of TCM in the treatment of LUAD from macro to micro, mined the hub genes, and predicted the mechanism of action, so as to lay the foundation for the development of new drugs of TCM, prescription optimization, or disease control.