Identifying biomarkers that reflect disease progression in Parkinson’s disease (PD) is of substantial clinical relevance. Accumulating evidence suggests a potential link between orthostatic hypotension and disease progression in PD. However, prior studies have largely relied on single baseline assessments, thereby overlooking longitudinal fluctuations in orthostatic blood pressure changes. This study aimed to identify distinct longitudinal trajectories of orthostatic systolic blood pressure change (∆SBP) and to investigate their associations with disease progression in PD. A total of 1,081 PD patients were included from two independent cohorts. Latent class trajectory model was applied to delineate longitudinal ∆SBP trajectories. Cox proportional hazards models and linear mixed-effects models were used to evaluate the associations between ∆SBP trajectories and clinical progression. Two latent class of ∆SBP trajectories were identified: a low-stable trajectory and an increasing trajectory. Compared with the low-stable class, patients in the increasing ∆SBP trajectory exhibited a higher risk of developing cognitive impairment, along with faster decline in visuospatial, attentional, and executive functions. They also showed more severe motor symptoms and rapid eye movement sleep behavior disorder, as well as accelerated progression of autonomic dysfunction and impairment in activities of daily living. An increasing ∆SBP trajectory was associated with a more pronounced progression across multiple clinical domains in PD, suggesting that longitudinal orthostatic blood pressure patterns may represent a clinically relevant dimension of disease heterogeneity.

Polyethylene terephthalate microplastics (PET-MPs) pose significant environmental and health concerns due to their persistence and potential toxicity, yet their impact on intervertebral disc degeneration (IDD) remains poorly understood. This study integrated network toxicology, machine learning, molecular docking, single-cell transcriptomics, and in vitro experiments to systematically explore the potential mechanisms through which PET-MPs may contribute to IDD. Through combined multi-database screening, WGCNA, and machine learning-based SHAP analysis, five core targets were identified: ANGPTL4, CDC42, CTSK, VKORC1, and FN1. GO and KEGG pathway analyses, complemented by molecular docking and dynamics simulations, revealed significant enrichment in AGE-RAGE, Toll-like receptor, and ECM-related pathways and suggested stable binding of PET with ANGPTL4 and VKORC1. Single-cell transcriptomics demonstrated specific upregulation of these genes in degenerative nucleus pulposus cells, accompanied by enhanced immune–stromal communication. In vitro, PET-MPs dose-dependently induced cytotoxicity, reactive oxygen species overproduction, ECM degradation, and upregulation of Angptl4 and Vkorc1, collectively suggesting a potential pro-degenerative effect on nucleus pulposus cells.

To investigate the core targets and immunomodulatory mechanisms of Huoluo Xiaoling Pellet (HLXLP) for promoting tissue repair. Network pharmacology and protein-protein interaction network were used to screen active components in HLXLP, the disease-related targets and the core targets, followed by GO and KEGG enrichment analyses and molecular docking to predict the pharmacological mechanisms. The toxicity of HLXLP was evaluated in zebrafish, and in a tissue regeneration model established in 3 dpf zebrafish larvae by amputating 95% of the tail fin, the effects of a formulated zebrafish embryo culture medium and 10, 20, and 40 μg/mL of aqueous extract of HLXLP on tissue regeneration was evaluated; RT-qPCR was performed to detect mRNA expressions of tissue regeneration marker genes and the core target genes. Transgenic zebrafish with fluorescently labeled macrophages and neutrophils were used to observe immune cell migration during tissue regeneration, and macrophage polarization at different stages was assessed with RT-qPCR. We identified a total of 149 intersected targets between HLXLP active components and tissue repair and 5 core targets (AKT1, IL-6, TNF-α, EGFR and STAT3). GO and KEGG analyses suggested that the effects of HLXLP were mediated primarily through the JAK-STAT pathway, adhesion junctions and positive regulation of cell migration. HLXLP was minimally toxic below 40 μg/mL and lethal at 320 μg/mL in zebrafish, and caused renal and pericardial edema and vascular defects above 80 μg/mL. In zebrafish with tail fin amputation, HLXLP significantly promoted tissue regeneration, reduced IL-6 and TNF-α and enhanced AKT1, EGFR and STAT3 mRNA expressions, modulated neutrophil and macrophage recruitment to the injury sites, and regulated M1/M2 macrophage polarization during tissue regeneration. HLXLP promotes zebrafish tail fin regeneration through multiple active components, targets and pathways for immunomodulation of immune cell migration and macrophage polarization to suppress inflammation and accelerate healing.

BACKGROUND:Kidney function abnormalities is a common complication following ischemic stroke. Lipocalin 2 (LCN2) is currently a well-recognized specific biomarker of tubular injury. However, the role of LCN2 in kidney function abnormalities following stroke remains elusive. The sympathetic nervous system plays a crucial role in linking the brain and kidney. However, whether the kidney sympathetic nervous system regulates the expression of LCN2 following ischemic stroke has not been identified. METHODS:In this study, we established a middle cerebral artery occlusion (MCAO) model to induce ischemic stroke in mice. Renal function was assessed 24 h after cerebral ischemia-reperfusion injury. Transcriptomic sequencing of kidney tissue was performed to identify potential pathological mechanisms. The role of LCN2 in post-stroke renal injury was investigated using renal tubule-specific LCN2 knockout mice and a combination of qPCR, western blotting, immunofluorescence, and transmission electron microscopy. In addition, renal denervation (RDN) was used to explore the relationship between sympathetic nerves and the expression of renal LCN2. RESULTS:Ischemic stroke significantly exhibits renal functional impairment 24 h after reperfusion. Notably, RNA sequencing and Western blotting revealed a markedly increased expression of renal LCN2 following ischemic stroke. Renal tubular Lcn2-specific knockout significantly ameliorated the occurrence of kidney function abnormalities after stroke. Subsequently, we observed that the activation of renal sympathetic nerves upregulates LCN2 and induces kidney function abnormalities after stroke. CONCLUSIONS:These findings reveal a neural pathway in which the sympathetic nervous system upregulates LCN2, providing potential therapeutic strategies for renal protection following ischemic stroke.

OBJECTIVES:To investigate the core targets and immunomodulatory mechanisms of Huoluo Xiaoling Pellet (HLXLP) for promoting tissue repair. METHODS:Network pharmacology and protein-protein interaction network were used to screen active components in HLXLP, the disease-related targets and the core targets, followed by GO and KEGG enrichment analyses and molecular docking to predict the pharmacological mechanisms. The toxicity of HLXLP was evaluated in zebrafish, and in a tissue regeneration model established in 3 dpf zebrafish larvae by amputating 95% of the tail fin, the effects of a formulated zebrafish embryo culture medium and 10, 20, and 40 μg/mL of aqueous extract of HLXLP on tissue regeneration was evaluated; RT-qPCR was performed to detect mRNA expressions of tissue regeneration marker genes and the core target genes. Transgenic zebrafish with fluorescently labeled macrophages and neutrophils were used to observe immune cell migration during tissue regeneration, and macrophage polarization at different stages was assessed with RT-qPCR. RESULTS:We identified a total of 149 intersected targets between HLXLP active components and tissue repair and 5 core targets (AKT1, IL-6, TNF-α, EGFR and STAT3). GO and KEGG analyses suggested that the effects of HLXLP were mediated primarily through the JAK-STAT pathway, adhesion junctions and positive regulation of cell migration. HLXLP was minimally toxic below 40 μg/mL and lethal at 320 μg/mL in zebrafish, and caused renal and pericardial edema and vascular defects above 80 μg/mL. In zebrafish with tail fin amputation, HLXLP significantly promoted tissue regeneration, reduced IL-6 and TNF-α and enhanced AKT1, EGFR and STAT3 mRNA expressions, modulated neutrophil and macrophage recruitment to the injury sites, and regulated M1/M2 macrophage polarization during tissue regeneration. CONCLUSIONS:HLXLP promotes zebrafish tail fin regeneration through multiple active components, targets and pathways for immunomodulation of immune cell migration and macrophage polarization to suppress inflammation and accelerate healing.

Background Sphingolipid dysregulation in Parkinson's disease (PD) may affect the release and uptake of striatal dopamine. However, the longitudinal relationship between sphingolipids, striatal dopaminergic degeneration, and clinical correlates in idiopathic PD (iPD) remain unclear. Objective To investigate the relationship between plasma sphingolipids, striatal dopamine transporter specific binding ratio (DAT-SBR) and clinical symptoms in iPD. Methods We included 283 iPD patients and 121 healthy controls (HC) from the Parkinson's Progression Markers Initiative (PPMI), utilizing available data on plasma sphingolipids (sphingomyelin [SM] and ceramide [CER]), striatal DAT-SBR and clinical assessments. Linear mixed models and mediation analyses were used to examine the relationship between sphingolipids, DAT-SBR, and clinical progression in iPD. Results Lower baseline SM levels were significantly associated with a faster decline in DAT-SBR in both the caudate (p = 0.015) and putamen (p = 0.002), with the putamen association remaining significant after Bonferroni correction (p = 0.015). No significant association was found for CER. Patients in the lowest quartile of baseline SM showed faster progression in MDS-UPDRS I (p = 0.013) and II (p = 0.011), while those in the lowest quartile of baseline CER showed faster progression in MDS-UPDRS II (p = 0.013) and III (p = 0.033). The progression rate of caudate DAT-SBR partially mediated the relationships between SM and progression in MDS-UPDRS I and II (p < 0.01). Conclusion Sphingolipids are associated with worse dopaminergic degeneration and potentially linked to faster progression in iPD, holding the promise for identifying individuals with faster progression in iPD.

The dichotomized brain system is a concept that was generalized from the 'dual syndrome hypothesis' to explain the heterogeneity of cognitive impairment, in which anterior and posterior brain systems are independent but partially overlap. The dopaminergic system acts on the anterior brain and is responsible for executive function, working memory, and planning. In contrast, the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function. Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson's disease. Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections. However, whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated. Furthermore, the precise role of the cerebellum in patients with Parkinson's disease and cognitive impairment remains unclear. Therefore, in this review, we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition, as reported by previous studies, and investigated the role of the cerebellum in patients with Parkinson's disease and cognitive impairment, as determined by functional neuroimaging. Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson's disease.

Background Encephalitis caused by dengue virus (DENV) is considered a manifestation of severe dengue. Tanreqing injection (TRQ) is a well-known Chinese patented medicine, which has been used to treat brain-related disorders by inhibiting inflammation. Nevertheless, the effects of TRQ on DENV encephalitis have not been studied. The aim of this study was to evaluate the effects of TRQ on DENV encephalitis and to explore its potential mechanisms. Methods The cytotoxicity of TRQ was examined by MTT assay, and the anti-DENV activities of TRQ in BHK-21 baby hamster kidney fibroblast were evaluated through CCK-8 and plaque assays. The expression levels of NO, IL1B/IL-1β, TNFα and IL6 were measured by qRT‒PCR and ELISA in the BV2 murine microglial cell line. The inhibitory effects of TRQ on NLRP3 inflammasome activation in BV2 cells were examined by Western blotting, qRT‒PCR and ELISA. The effects of TRQ on HT22 mouse hippocampal neuronal cells were examined by CCK-8 assay, morphology observation and flow cytometry. Moreover, a DENV-infected ICR suckling mouse model was developed to investigate the protective role of TRQ in vivo. Results TRQ decreased the release of NO, IL6, TNFα and IL1B from BV2 cells and inhibited the activation of NLRP3. The presence of the NLRP3 agonist nigericin reversed the anti-inflammatory activities of TRQ. Furthermore, TRQ inhibited the death of HT22 cells by decreasing IL1B in DENV-infected BV2 cells. In addition, TRQ significantly attenuated weight loss, reduced clinical scores and extended the survival in DENV-infected ICR suckling mice. Critically, TRQ ameliorated pathological changes in ICR suckling mice brain by inhibiting microglia and NLRP3 activation and decreasing the production of inflammatory factors and the number of dead neurons. Conclusion TRQ exerts potent inhibitory effects on dengue encephalitis in vitro and in vivo by reducing DENV-2-induced microglial activation and subsequently decreasing the inflammatory response, thereby protecting neurons. These findings demonstrate the potential of TRQ in the treatment of dengue encephalitis.

Parkinson's disease (PD) is a neurodegenerative condition that results in dyskinesia, with oxidative stress playing a pivotal role in its progression. Antioxidant peptides may thus present therapeutic potential for PD. In this study, a novel cathelicidin peptide (Cath-KP; GCSGRFCNLFNNRRPGRLTLIHRPGGDKRTSTGLIYV) was identified from the skin of the Asiatic painted frog ( Kaloula pulchra). Structural analysis using circular dichroism and homology modeling revealed a unique αββ conformation for Cath-KP. In vitro experiments, including free radical scavenging and ferric-reducing antioxidant analyses, confirmed its antioxidant properties. Using the 1-methyl-4-phenylpyridinium ion (MPP +)-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, Cath-KP was found to penetrate cells and reach deep brain tissues, resulting in improved MPP +-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1 (Sirt1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation. Both focal adhesion kinase (FAK) and p38 were also identified as regulatory elements. In the MPTP-induced PD mice, Cath-KP administration increased the number of tyrosine hydroxylase (TH)-positive neurons, restored TH content, and ameliorated dyskinesia. To the best of our knowledge, this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress. These findings expand the known functions of cathelicidins, and hold promise for the development of therapeutic agents for PD.

Stroke, a major neurological disorder and a leading cause of disability and death, often inflicts damage upon other organs, particularly the kidneys. While chronic kidney disease (CKD) has long been established as a significant risk factor for cerebrovascular disease, stroke can induce renal dysfunction, manifesting as acute kidney injury (AKI) or CKD. Mounting clinical and basic research evidence supports the existence of a bidirectional brain-kidney crosstalk following stroke, implicating specific mechanisms and pathways in stroke-related renal dysfunction. This review analyzes pertinent experimental studies, elucidating the underlying mechanisms of this cerebro-renal interaction following stroke. Additionally, we summarize the current landscape of clinical research investigating brain-kidney interplay and discuss potential challenges in the future. By enhancing our understanding of the scientific underpinnings of brain-kidney crosstalk, this review paves the way for improved treatment strategies and outcomes for stroke patients. Recognizing the intricate interplay between the brain and kidneys after stroke holds profound clinical implications.

BackgroundTanreqing injection (TRQ) has been employed in clinical practice as a treatment for dengue fever (DF). Nevertheless, the precise pharmacological mechanism underlying its efficacy remains elusive.MethodNetwork pharmacology, molecular docking, transcriptome sequencing, and experimental evaluation were employed to analyze and study the inhibitory potential of TRQ against dengue virus (DENV).ResultWe found that TRQ inhibited the replication of DENV in human umbilical vein endothelial cells, Huh-7 cells, and Hep3B cells. In addition, TRQ prolonged the survival duration of AG129 mice infected with DF, decreased the viral load in serum and organs, and alleviated organ damage. Subsequently, ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of TRQ was performed to identify 314 targets associated with 36 active compounds present in TRQ. Integration of multiple databases yielded 47 DF-related genes. Then, 15 hub targets of TRQ in DF were determined by calculating the network topology parameters (Degree). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these pathways were primarily enriched in the processes of cytokine activation and leukocyte cross-endothelial migration, with significant enrichment of cell adhesion molecules. Molecular docking revealed favorable binding affinity between TRQ's key active compounds and the predicted hub targets. Transcriptome sequencing results showed TRQ's ability to restore the expression of vascular cell adhesion molecule-1 (VCAM-1) post-DENV infection. Finally, TRQ was found to modulate the immune status by regulating the nuclear factor kappa-B (NF-κB)- intercellular cell adhesion molecule-1 (ICAM-1)/VCAM-1 axis, as well as reduce immune cell alterations, inflammatory factor secretion, vascular permeability, and bleeding tendencies induced by DENV infection.ConclusionOur research suggests that TRQ exerts therapeutic effects on DF by regulating the NF-κB-ICAM-1/VCAM-1 axis.

Background: Previous research revealed differences in cerebellar white matter integrity by disease stages, indicating a compensatory role in Parkinson's disease (PD). However, the temporal evolution of cerebellar white matter microstructure in patients with PD (PwPD) remains unclear. Objective: To unravel temporal evolution of cerebellar white matter and its dopaminergic correlates in PD. Methods: We recruited 124 PwPD from the PPMI study. The participants were divided into two subsets: Subset 1 (n = 41) had three MRI scans (baseline, 2 years, and 4 years), and Subset 2 (n = 106) had at least two MRI scans at baseline, 1 year, and/or 2 years. Free water-corrected diffusion metrics were used to measure the microstructural integrity in cerebellar peduncles (CP), the main white matter tracts connecting to and from the cerebellum. The ACAPULCO processing pipeline was used to assess cerebellar lobules volumes. Linear mixed-effect models were used to study longitudinal changes. We also examined the relationships between microstructural integrity in CP, striatal dopamine transporter specific binding ratio (SBR), and clinical symptoms. Results: Microstructural changes in CP showed a non-linear pattern in PwPD. Free water-corrected fractional anisotropy (FAt) increased in the first two years but declined from 2 to 4 years, while free water-corrected mean diffusivity exhibited the opposite trend. The initial increased FAt in CP correlated with cerebellar regional volume atrophy, striatal dopaminergic SBR decline, and worsening clinical symptoms, but this correlation varied across disease stages. Conclusions: Our findings suggest a non-linear evolution of microstructural integrity in CP throughout the course of PD, indicating the adaptive structural reorganization of the cerebellum simultaneously with progressive striatal dopaminergic degeneration in PD.

Objective: The involvement of the cerebellum in Parkinson's disease (PD) is increasingly recognized. Previous research revealed differences in cerebellar white matter integrity by disease stages, indicating a potential early compensatory increase. However, the temporal evolution of cerebellar white matter microstructure in people with PD (PwPD) remains unclear.Methods: Two cohorts were used in the study: Cohort 1 (PPMI) with 124 PwPD over a 4-year follow-up, and a local cross-sectional cohort of 173 PwPD to complement temporal patterns. Free water corrected diffusion metrics were used to quantify the microstructural integrity in cerebellar peduncles (CP), the primary white matter tracts to and from the cerebellum. Linear mixed-effect models were employed to examine their longitudinal evolution. Additionally, we explored the relationship between microstructural integrity in CP and clinical symptoms, as well as dopaminergic degeneration.Results: The mean age in Cohort 1 and 2 was 61.0 ± 9.5 and 62.4 ± 9.3 years, respectively. In Cohort 1, microstructural changes in CP showed a non-linear pattern, increasing in the first two years but declining from 2 to 4 years. The initial increase microstructural integrity in CP was corroborated cross-sectionally from Cohort 2. The initial increased microstructural integrity in CP correlated with cerebellar regional volume atrophy, striatal dopaminergic degeneration, and worsening clinical symptoms, but this correlation varied across disease stages.Interpretation: Our findings suggest a non-linear evolution of microstructural integrity in CP throughout the course of PD, indicating an early-stage adaptive structural reorganization of the cerebellum with progressive basal ganglia dysfunction in PD.Funding: This work was supported by National Natural Science Foundation of China (No.82071419, No.82301663, No.82301420); Key Research and Development Program of Guangzhou (No.202206010086); Science and Technology Planning Project of Guangzhou (No.202201000005); China Postdoctoral Science Foundation under Grant Number 2023M730742; Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (No. 2022B1212010011).Declaration of Interest: The authors report no competing interests.Ethical Approval: Cohort 1: Ethical approval for the PPMI study was obtained from the Institutional Review Board of all participating sites, and written informed consent was obtained from all participants. Corhort 2: All participants provided written informed consent to participate in this study, approved by the Medical Ethics Committee of Guangdong Provincial People's Hospital [No. KY-Z-2022-132-02].

AIMS:Rare studies have investigated the association between heterogeneity of motor progression and risk of early cognitive impairment in Parkinson's disease (PD). In this study, we aim to identify distinct trajectories of motor progression longitudinally and investigate their impact on predicting mild cognitive impairment (MCI). METHODS:A 5-year cohort including 415 PD patients at baseline was collected from the Parkinson's Progression Markers Initiative. The severity of motor symptoms was evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III. The latent class trajectory model and nonlinear mixed-effects model were used to analyze and delineate the longitudinal changes in motor symptoms. Propensity score matching (PSM) was used to minimize the impact of potential confounders. Cox proportional hazard models were applied to calculate hazard ratios for MCI, and a Kaplan-Meier curve was generated using the occurrence of MCI during the follow-up as the time-to-event. RESULTS:Two latent trajectories were identified: a mild and remitting motor symptoms class (Class 1, 33.01%) and a severe and progressive motor symptom class (Class 2, 66.99%). Patients in Class 2 initially exhibited severe motor symptoms that worsened progressively despite receiving anti-PD medications. In comparison, patients in Class 1 exhibited milder symptoms that improved following drug therapy and a slower progression. During a 5-year follow-up, patients in Class 2 showed a higher risk of developing MCI compared to those in Class 1 before PSM (Log-Rank 28.58, p < 0.001) and after PSM (Log-Rank 8.20, p = 0.004). CONCLUSIONS:PD patients with severe and progressive motor symptoms are more likely to develop MCI than those with mild and stable motor symptoms.

Fenpropathrin (Fen), a volatile pyrethroid insecticide, is used widely for agricultural applications and has been reported to increase the risk of Parkinson’s disease (PD). However, the molecular basis, underlying mechanisms, and pathophysiology of Fen-exposed Parkinsonism remain unknown. Recent studies have revealed epigenetic mechanisms underlying PD-related pathway regulation, including DNA methylation. Epigenetic mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases. After whole-genome bisulfite sequencing (WGBS) of midbrain tissues from a Fen-exposed PD-like mouse model, we performed an association analysis of DNA methylation and gene expression. Then we successfully screened for the DNA methylation differential gene Ambra1, which is closely related to PD. The hypermethylation-low expression Ambra1 gene aggravated DA neuron damage in vitro and in vivo through the Ambra1/Parkin/LC3B-mediated mitophagy pathway. We administered 5-aza-2′-deoxycytidine (5-Aza-dC) to upregulate Ambra1 expression, thereby reducing Ambra1-mediated mitophagy and protecting DA neurons against Fen-induced damage. In conclusion, these findings elucidate the potential function of Ambra1 under the regulation of DNA methylation, suggesting that the inhibition of DNA methylation may alleviate Fen-exposed neuron damage.

BACKGROUND:The microbiota plays a significant role in the tumor microenvironment, and its impact on tumor development and treatment outcome cannot be overlooked. Thus, it is essential to comprehend the interactions between the microbiota and the tumor microenvironment. RECENT FINDINGS:With the advent of next-generation sequencing, microbiota research has advanced significantly in recent years. The interaction between the intratumoral microbiota and the tumor microenvironment is an emerging area of research that holds great promise for understanding and treating solid tumor progression. This crosstalk between the intratumoral microbiota and the tumor microenvironment is a complex process that involves a multitude of factors, including the immune system, cellular signaling pathways, and metabolic processes. The origin of the intratumoral microbiota differs between various solid tumor, and the quantity and diversity of intratumoral microbiota also fluctuate significantly within each solid tumor. CONCLUSION:The aim of this review is to provide a detailed summary of the intratumoral microbiota in various types of solid tumors. This will include an analysis of their origins, differences, and how they impact the progression of solid tumors. Furthermore, we will emphasize the significant potential that the intratumoral microbiota holds for the diagnosis and treatment of solid tumors.

The relationship between the composite dietary antioxidant index (CDAI), a comprehensive measure of individual dietary antioxidants, and the prevalence and mortality of metabolic syndrome (MetS) remains unknown. We aimed to explore these relationships in the National Health and Nutrition Examination Survey (NHANES). We explored these relationships using two independent cohorts. First, we addressed CDAI and the prevalence of MetS in the general population; second, we explored the association between CDAI and mortality in patients with MetS by following NHANES 2001–2018 participants through December 31, 2019. In addition, restricted cubic spline (RCS), stratified analysis, and sensitivity analysis were used for further interpretation. We included 24,514 participants aged 20–85 years, in which the prevalence of MetS was 27.61 %. CDAI was negatively and dose-responsively associated with the prevalence of MetS, however it was not associated with mortality in patients with MetS. In addition, CDAI was associated with a reduced prevalence of certain components of MetS, including dyslipidemia and central obesity. RCS showed a linear correlation between CDAI and MetS and the above components. Stratified analyses indicated that alcohol consumption was a significant influence of CDAI-MetS and that socioeconomic status and lifestyle specificity existed. Sensitivity analysis confirmed the stability of the results. CDAI was protective against the development of MetS in the general population, but not against mortality in patients with MetS. Clinicians need to develop individualized prevention strategies to reduce the development of MetS by modifying CDAI.

Ethnopharmacological relevance: Dengue virus (DENV) infection is a global public health issue without effective therapeutic interventions. Chinese medicine with heat-clearing and detoxifying properties has been frequently used in the treatment of viral infection. Ampelopsis Radix (AR) is a traditional Chinese medicine for clearing heat and detoxification that has been widely used in the prevention and treatment of infectious diseases. However, no studies on the effects of AR against viral infection have been reported, thus far. Aim of the study: To explore the anti-DENV activities of the fraction (AR-1) obtained from AR both in vitro and in vivo. Materials and methods: The chemical composition of AR-1 was identified by liquid chromatography-tandem MS (LC-MS/MS). The antiviral activities of AR-1 were studied in baby hamster kidney fibroblast BHK-21 cells, ICR suckling mice and induction of interferon alpha/beta (IFN-alpha/beta) and IFN-gamma R / (AG129) mice. Results: Based on LC-MS/MS analysis, 60 compounds (including flavonoids, phenols, anthraquinones, alkaloids and other types) were tentatively characterized from AR-1. AR-1 inhibited the cytopathic effect, the production of progeny virus and the synthesis of viral RNA and proteins by blocking DENV-2 binding to BHK-21 cells. Moreover, AR-1 significantly attenuated weight loss, decreased clinical scores and prolonged the survival of DENV-infected ICR suckling mice. Critically, the viral load in blood, brain and kidney tissues and the patho-logical changes in brain were remarkably alleviated after AR-1 treatment. Further study on AG129 mice showed that AR-1 obviously improved the clinical manifestations and survival rate, reduced viremia, attenuated gastric distension and relieved the pathological lesions caused by DENV. Conclusions: In summary, this is the first report that AR-1 exhibits anti-DENV effects both in vitro and in vivo, which suggests that AR-1 may be developed as a therapeutic candidate against DENV infection.

Abstract Background Chorea-acanthocytosis (ChAc) is a rare hereditary autosomal recessive neurodegenerative disorder caused by pathogenic variants of the Vacuolar Protein Sorting 13 homolog A (VPS13A) gene. The variant spectrum of VPS13A has not been completely elucidated. This study reports two novel heterozygous VPS13A pathogenic variants in ChAc that expand the variant spectrum of VPS13A. Case presentation We described a case of a 29-year-old man with typical clinical manifestations of ChAc, including chorea, orofacial lingual dyskinesia, vocal tics, elevated serum biochemical indicators, increased acanthocytes in peripheral blood, and caudate nucleus atrophy. Next-generation sequencing revealed two heterozygous variants of VPS13A: a nonsense variant (NM_033305.2: c.8215G > T, p. Glu2739Ter) and a deletion variant in the exons 25–31. Conclusion The identified nonsense variant gives rise to premature translation termination, while the deletion variant is expected to cause a significant in-frame deletion of amino acid residues in the encoded protein. Both variants are considered to be pathogenic and result in loss-of-function proteins. These findings have implications for the genetic counseling of patients with VPS13A variants.

Cerebellar dysfunction may substantially contribute to the clinical symptoms of Parkinson's disease (PD). The role of cerebellar subregions in tremors and gait disturbances in PD remains unknown. To investigate alterations in cerebellar subregion volumes and functional connectivity (FC), as well as FC between the dentate nucleus (DN) and ventral lateral posterior nucleus (VLp) of the thalamus, which are potentially involved in different PD motor subtypes. We conducted morphometric and resting-state functional connectivity analyses in various cerebellar subregions in 22 tremor-dominant (TD)-PD and 35 postural instability gait difficulty dominant (PIGD)-PD patients and 38 sex- and age-matched healthy controls (HCs). The volume and FC alterations in various cerebellar subregions and the neural correlates of these changes with the clinical severity scores were investigated. The PIGD-PD group showed greater FC between the right motor cerebellum (CBMm) and left postcentral gyrus than the HC group, and a higher FC was associated with less severe PIGD symptoms. In contrast, the TD-PD group had decreased FC between the right DN and left VLp compared with the PIGD-PD and HC groups, and lower FC was associated with worse TD symptoms. Furthermore, the PIGD-PD group had higher FC between the left DN and left inferior temporal gyrus than the TD-PD group. Morphometric analysis revealed that the TD-PD group showed a significantly higher volume of left CBMm than the HC group. Our findings point to differential alteration patterns in cerebellar subregions and offer a new perspective on the pathophysiology of motor subtypes of PD.