BACKGROUND:The aggregation of α-synuclein (SNCA) in dopaminergic neurons of the substantia nigra is a key factor in the pathogenesis of Parkinson's disease (PD). Despite years of drug discovery efforts targeting SNCA aggregation, no disease-modifying drugs have been approved to date. The failure of numerous clinical trials can be attributed, at least in part, to the difficulty in identifying potent compounds during preclinical investigations. OBJECTIVE:Establish a screening approach based on molecular docking and autophagic flux detection to identify natural compounds from new perspectives of SNCA clearance and to explore its mechanism. METHODS:Molecular docking technique combined with autophagic flux detection was performed for preliminary screening of flavonoids in PubChem and CHEBI databases. Western blotting was utilized to detect the levels of SNCA, chaperone-mediated autophagy (CMA)-associated proteins, apoptosis-related proteins, and neuroinflammatory biomarkers, alongside the assessment of phosphorylation status of proteins implicated in signaling cascades. JC-1 staining was used to measure the mitochondrial transmembrane potential (MMP). RNA-sequencing and Kyoto encyclopedia of genes and genomes/gene ontology (KEGG/GO) analysis were optimized to detect gene expression. PD mouse motor function was assessed using rotarod, pole, open field, footprint, and gait analyses. Immunofluorescence staining was employed to detect the expression of Nuclear factor erythroid 2-related factor 2 (Nrf2), dopaminergic neuronal deficits, microglia activation, and production of inflammatory factors. LysoTracker Red staining and pSIN-PAmCherry-KFERQ-NE plasmid were used to evaluate the lysosomal activity. pHrodo™ Green E.coli BioParticles™ were employed to measure phagocytosis activity. RESULTS:By molecular docking and autophagic flux detection, we evaluated the efficacy of flavone derivatives and identified apigenin (AP) as a candidate that activates CMA to promote SNCA clearance and thereby inhibits SNCA-induced neurotoxicity. AP inhibited apoptosis by promoting SNCA degradation through Nrf2-mediated CMA activation. Moreover, AP could also inhibit apoptosis via the Nrf2/extracellular regulated protein kinases (ERK) feedback loop that operates independently of CMA activation. Additionally, AP enhanced the phagocytosis capabilities of BV2 cells and inhibited SNCA-induced neuroinflammation, both in vitro and in vivo. CONCLUSIONS:AP activates CMA to promote the clearance of SNCA, thereby inhibiting SNCA-induced neurotoxicity. Nrf2 and its role in AP-mediated neuroprotection may provide new insights that target degradation pathways to counteract SNCA pathology in PD.

BACKGROUND: Alzheimer’s disease (AD) and Parkinson’s disease (PD) share neuroinflammatory features, yet their common immune-related mechanisms remain unclear. METHODS: We integrated microarray datasets from AD/PD brain tissues to identify immune-related genes (IRGs). Hub genes were prioritized via protein-protein interaction (PPI) networks and validated using a Parkinson’s dementia (PDD) cohort and AD/PD mouse models. Functional enrichment, immune cell infiltration, and TF-miRNA networks were analyzed. RESULTS: Eleven hub IRGs (CXCR4, FLT1, SLIT1/2, SEMA3G/6D, etc.) were identified. CXCR4 and FLT1 exhibited significant upregulation in AD/PD patient brain tissues (AUC > 0.7, adjusted p-value of <0.05) and mouse model brain tissues (p < 0.05), correlating with cytokine signaling and axon guidance pathways. CXCR4 is uniquely associated with resting memory CD4+ T cells in both diseases, while FLT1 showed disease-specific immune interactions. A TF-miRNA network (39 TFs, 22 miRNAs) implicated CREB1 and STAT1/3 as key regulators. CONCLUSION: CXCR4 and FLT1 are pivotal shared immune hubs in AD/PD, linked to T-cell dysregulation and neuroinflammation. These findings highlight potential therapeutic targets and biomarkers for neurodegenerative comorbidity.

BACKGROUND:Serpin peptidase inhibitor clade H member 1 (SERPINH1) is implicated in collagen processing and tumor progression, yet its role in laryngeal squamous cell carcinoma (LSCC) remains unclear. This study aimed to elucidate the clinical significance and molecular mechanism of SERPINH1 in LSCC. METHODS:Multi-cohort bioinformatics analysis (TCGA, GEO) identified SERPINH1 as a prognostic marker. SERPINH1 expression was validated in LSCC tissues (IHC, immunofluorescence, Western blot). Functional assays (CCK-8, EdU, Transwell) and xenograft models assessed malignant behaviors. Transcriptomics and co-IP/LC-MS revealed downstream pathways and interactors. Wnt agonist (SKL2001) rescue experiments confirmed pathway dependency. RESULTS:SERPINH1 was overexpressed in LSCC tissues versus adjacent normal and predicted poor survival. SERPINH1 knockdown suppressed proliferation, migration/invasion, and tumor growth in vitro and in vivo. Mechanistically, SERPINH1 bound COL7A1 to stabilize the Wnt/β-catenin signaling complex, reducing β-catenin phosphorylation and enhancing nuclear translocation. Wnt activation via SKL2001 rescued SERPINH1-knockdown phenotypes. CONCLUSION:SERPINH1 drives LSCC progression via COL7A1-mediated Wnt/β-catenin signaling activation. Targeting this axis may offer novel therapeutic strategies for LSCC.

How to address the resistance of cisplatin (CDDP) has always been a clinical challenge. The resistance mechanism of platinum-based drugs is very complex, including nuclear DNA damage repair, apoptosis escape, and tumor metabolism reprogramming. Tumor cells can switch between mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis and develop resistance to chemotherapy drugs through metabolic variability. In addition, due to the lack of histone protection and a relatively weak damage repair ability, mitochondrial DNA (mtDNA) is more susceptible to damage, which in turn affects mitochondrial OXPHOS and can become a potential target for platinum-based drugs. Therefore, mitochondria, as targets of anticancer drugs, have become a hot topic in tumor resistance research. This study constructed a self-assembled nanotargeted drug delivery system LND-SS-Pt-TPP/HA-CD. β-Cyclodextrin-grafted hydronic acid (HA-CD)-encapsulated prodrug nanoparticles can target CD44 on the tumor surface and further deliver the prodrug to intracellular mitochondria through a triphenylphosphine group (TPP+). Disulfide bonds can be selectively degraded by glutathione (GSH) in mitochondria, releasing lonidamine (LND) and the cisplatin prodrug (Pt(IV)). Under the action of GSH and ascorbic acid, Pt(IV) is further reduced to cisplatin (Pt(II)). Cisplatin can cause mtDNA damage, induce mitochondrial dysfunction and mitophagy, and then affect mitochondrial OXPHOS. Meanwhile, LND can reduce the hexokinase II (HK II) level, induce destruction of mitochondria, and block energy supply by glycolysis inhibition. Ultimately, this self-assembled nano targeted delivery system can synergistically kill cisplatin-resistant lung cancer cells, which supplies an overcome cisplatin resistance choice via the disrupt mitochondria therapy.

The primary pathological change in Parkinson’s disease (PD) is the progressive degeneration of dopaminergic neurons in the substantia nigra. Additionally, excessive microglial activation and synaptic loss are also typical features observed in PD samples. Exercise trainings have been proven to improve PD symptoms, delay the disease progression as well as affect excessive microglial synaptic phagocytosis. In this study, we established a mouse model of PD by injecting mouse-derived α-synuclein preformed fibrils (M-α-syn PFFs) into the substantia nigra, and demonstrated that treadmill exercise inhibits microglial activation and synaptic phagocytosis in striatum. Using RNA-Seq and proteomics, we also found that PD involves excessive activation of the complement pathway which is closely related to over-activation of microglia and abnormal synaptic function. More importantly, exercise training can inhibit complement levels and complement-mediated microglial phagocytosis of synapses. It is probably triggered by CD55, as we observed that CD55 in the striatum significantly increased after exercise training and up-regulation of that molecule rescued motor deficits of PD mice, accompanied with reduced microglial synaptic phagocytosis in the striatum. This research elucidated the interplay among microglia, complement, and synapses, and analyzed the effects of exercise training on these factors. Our work also suggested CD55 as a complement-relevant candidate molecule for developing therapeutic strategies of PD.

Proteolysis targeting chimeras (PROTACs) can use the intrinsic protein degradation system in cells to degrade pathogenic target proteins, and are currently a revolutionary frontier of development strategy for tumor treatment with small molecules. However, the poor water solubility, low cellular permeability, and off-target side effects of most PROTACs have prevented them from passing the preclinical research stage of drug development. This requires the use of appropriate delivery systems to overcome these challenging hurdles and ensure precise delivery of PROTACs towards the tumor site. Therefore, the combination of PROTACs and multifunctional delivery systems will open up new research directions for targeted degradation of tumor proteins. In this review, we systematically reviewed the design principles and the most recent advances of various PROTACs delivery systems. Moreover, the constructive strategies for developing multifunctional PROTACs delivery systems were proposed comprehensively. This review aims to deepen the understanding of PROTACs drugs and promote the further development of PROTACs delivery system.

Purpose:This investigation sought to elucidate the genetic underpinnings that connect obesity indicators, circulating blood lipid levels, adipokines levels and obstructive sleep apnea syndrome (OSAS), employing a bidirectional two-sample Mendelian randomization (MR) analysis that utilizes data derived from extensive genome-wide association studies (GWAS).Methods:We harnessed genetic datasets of OSAS available from the FinnGen consortium and summary data of four obesity indices (including neck circumference), seven blood lipid (including triglycerides) and eleven adipokines (including leptin) from the IEU OpenGWAS database. We primarily utilized inverse variance weighted (IVW), weighted median, and MR-Egger methods, alongside MR-PRESSO and Cochran's Q tests, to validate and assess the diversity and heterogeneity of our findings.Results:After applying the Bonferroni correction, we identified significant correlations between OSAS and increased neck circumference (Odds Ratio [OR]: 3.472, 95% Confidence Interval [CI]: 1.954-6.169, P= 2.201E-05) and decreased high-density lipoprotein (HDL) cholesterol levels (OR: 0.904, 95% CI: 0.858-0.952, P= 1.251E-04). Concurrently, OSAS was linked to lower leptin levels (OR: 1.355, 95% CI: 1.069-1.718, P= 0.012) and leptin receptor levels (OR: 0.722, 95% CI: 0.530-0.996, P= 0.047). Sensitivity analyses revealed heterogeneity in HDL cholesterol and leptin indicators, but further multiplicative random effects IVW method analysis confirmed these correlations as significant (P< 0.05) without notable heterogeneity or horizontal pleiotropy in other instrumental variables.Conclusion:This investigation compellingly supports the hypothesis that OSAS could be a genetic predisposition for elevated neck circumference, dyslipidemia, and adipokine imbalance. These findings unveil potential genetic interactions between OSAS and metabolic syndrome, providing new pathways for research in this domain. Future investigations should aim to delineate the specific biological pathways by which OSAS impacts metabolic syndrome. Understanding these mechanisms is critical for developing targeted prevention and therapeutic strategies.

As an emerging anti-tumor strategy, chemodynamic therapy (CDT) utilizes a Fenton/Fenton-like reaction to generate highly toxic hydroxyl radicals to kill tumor cells. However, the efficiency of CDT is still hindered by the low Fenton/Fenton-like reaction rate. Herein, we report the combination of ion interference therapy (IIT) and chemodynamic therapy (CDT) via an amorphous iron oxide (AIO) nanomedicine with encapsulated EDTA-2Na (EDTA). Iron ions and EDTA are released from the nanomedicine in acidic tumors and chelate to form iron ion-EDTA, which improves the efficiency of CDT and promotes the generation of reactive oxygen species (ROS). In addition, EDTA can disrupt the homeostasis of Ca2+ in tumor cells by chelating with Ca2+ ions, which induces the separation of tumor cells and affects normal physiological activities. Both in vitro and in vivo experiments show that the nano chelating drugs exhibit significant improvement in Fenton reaction performance and excellent anti-tumor activity. This study based on chelation provides a new idea for designing efficient catalysts to enhance the Fenton reaction and provides more revelations on future research on CDT.

Background: The excessive activation of the microglia leads to the release of inflammatory factors that contribute to neuronal cell loss and neurodegeneration in Parkinson's Disease (PD). Mesencephalic astrocyte-derived neu-rotrophic factor (MANF) that belongs to a newly found neurotrophic factors (NTFs) family has been reported to promote neuronal survival in the PD models. However, the effects of the MANF on neuroinflammation in PD remain unclear.Methods: AAV8-MANF virus was constructed to determine whether the high expression of MANF can protect the neuroinflammation-induced dopaminergic neurodegeneration in rats with 6-OHDA-induced PD. Rotarod per-formance test, immunofluorescent staining and western bolt were employed to evaluate the behavioral dysfunction, dopaminergic neurodegeneration, microglia activation, and signal activation. 6-OHDA treated SH-SY5Y cells and LPS treated BV-2 cells were used as the in vitro model for MANF neuroprotective and neuro-inflammation mechanisms. Cell vitality and apoptosis were evaluated with MTT, CCK-8 and flow cytometric analysis. The AKT/GSK3 beta-Nrf2 signaling and the TNF-alpha/IL6 expression were measured by Western Blot.Results: Our findings indicated that the elevated MANF expression by the AAV8-MANF administration amelio-rated the motor dysfunction and protected the dopaminergic neurons in the 6-OHDA treated rats. The upregu-lated CD11b in the rat SN caused by the 6-OHDA administration was significantly attenuated by the pretreatment of the AAV8-MANF. Furthermore, the levels of p-AKT, p-GSK3 beta, BCL-2, and Nrf-2 were upregulated by the high expression of the MANF. Under the oxidative stress of the 6-OHDA, the MANF significantly reduced the apoptotic effect of the TNF-alpha on the SH-SY5Y cells. In the LPS treated BV-2 cells, the MANF reduced the production of the TNF-alpha and IL-6, via enhancing the Nrf-2, p-Akt, p-GSK3 beta, and p-NF-Kappa beta level.Conclusions: These results suggested that the MANF prevented the dopaminergic neurodegeneration caused by the microglia activation in PD via activation of the AKT/GSK3 beta-Nrf-2 signaling axis.

Obstructive sleep apnea (OSA), a state of sleep disruption, is characterized by recurrent apnea, chronic intermittent hypoxia (CIH) and hypercapnia. Previous studies have showed that CIH-induced neuroinflammatory plays a crucial role in cognitive deficits. Pseudoginsenoside GQ (PGQ) is a new oxytetracycline-type saponin formed by the oxidation and cyclization of the 20(S) Rg3 side chain. Rg3 has been found to afford anti-inflammatory effects, while whether PGQ plays a role of anti-neuroinflammatory remains unclear. The purpose of this study was to investigate whether PGQ attenuates CIH-induced neuroinflammatory and cognitive impairment and the possible mechanism it involves. We found that PGQ significantly ameliorated CIH-induced spatial learning deficits, and inhibited microglial activation, pro-inflammatory cytokine release, and neuronal apoptosis in the hippocampus of CIH mice. In addition, PGQ pretreatment promoted microglial M1 to M2 phenotypic transition in IH-induced BV-2 microglial, as well as indirectly inhibited IH-induced neuronal injury via modulation of microglia polarization. Furthermore, we noted that activation of HMGB1/TLR4/NF-κB signaling pathway induced by IH was inhibited by PGQ. Molecular docking results revealed that PGQ could bind to the active sites of HMGB1 and TLR4. Taken together, this work supports that PGQ inhibits M1 microglial polarization via the HMGB1/TLR4/NF-κB signaling pathway, and indirectly exerts neuroprotective effects, suggesting that PGQ may be a potential therapeutic strategy for cognitive impairment accompanied OSA.

Accurate assessments of exposure to urban air pollution with higher traffic emissions and its health risks still face several challenges, such as intensive computation of air pollution modeling and the limited availability of personal activity data. The macroscopic health effects can be transmitted to the whole population for personal prevention via air quality health index (AQHI), but the possibility risk index of the specific allergic diseases is still lacking. This interdisciplinary study aims at evaluating the forecasted results of high-resolution air quality with updated traffic emissions and accessing the potential impacts of outdoor pollution on morbidity of rhinitis for urban residents. A high-resolution modelling system (1 km × 1 km) containing the online traffic emission model (VEIN), meteorological and air quality model (WRF-CHIMERE) and the health impact module was developed. A new health index of Potential Morbidity Risk Index (PMRI) was further established using higher resolution health risk coefficients of major air pollutants on allergic rhinitis, and different methods (with/without considering population distributions) targeting different user groups (residents, hospitals and health administrations) were calculated and analyzed. Operational forecasted results of hourly PMRI can be further combined with online map services to serve as an effective tool for patients with allergic rhinitis to arrange their daily activities so as to avoid acute exacerbation. The forecasted PMRIs accessible to the public will also be beneficial for the public health administrations in planning the medical resource and improving the outpatient efficiency.

Chemodynamic therapy (CDT) is an antitumor strategy based on the Fenton response. However, the mild acidity in the tumor microenvironment (TME) limits the efficiency of the Fenton response. Lactic acid has the potential to regulate pH in TME by regulating its metabolism. & alpha;-cyano-4-hydroxycinnamic acid (CHCA) can block lactate transport and induce lactate accumulation in cells, thus enhancing intracellular acidity. Nevertheless, CHCA is insoluble in water and the existing nanodrug delivery systems have complex synthesis and low drug-loading. Herein, we use Fe3+ and CHCA to form ultrahigh drug-loading supramolecular nanoparticles (FC NPs) by an ultrafast self-assembly strategy at room temperature for only 5 min. Polyethylene glycol (PEG) modified FC (FCP) NPs undergo lactate metabolism regulation-enhanced CDT in tumor cells to generate toxic hydroxyl radicals to induce apoptosis. Besides, glutathione is consumed and glutathione peroxidase 4 is down-regulated to induce ferroptosis due to the oxidation of Fe3+. In vitro and in vivo experiments show FCP induced synergetic effect of CDT and ferroptosis as well as the excellent therapeutic effect compared with either CHCA or Fe3+ alone. We believe that the ideal design of the CHCA supramolecular nanosystem will provide more revelations on the future research about CDT and lactate metabolism therapy.

Charcot-Marie-Tooth type 4D (CMT4D) is an autosomal recessive demyelinating form of CMT characterized by progressive motor and sensory neuropathy. N-myc downstream regulated gene 1 (NDRG1) is the causative gene for CMT4D. Although more CMT4D cases have been reported, the comprehensive molecular mechanism underlying CMT4D remains elusive. Here, we generated a novel knockout mouse model in which the fourth and fifth exons of the Ndrg1 gene were removed. Ndrg1-deficient mice develop early progressive demyelinating neuropathy and limb muscle weakness. The expression pattern of myelination-related transcriptional factors, including SOX10, OCT6, and EGR2, was abnormal in Ndrg1-deficient mice. We further investigated the activation of the ErbB2/3 receptor tyrosine kinases in Ndrg1-deficient sciatic nerves, as these proteins play essential roles in Schwann cell myelination. In the absence of NDRG1, although the total ErbB2/3 receptors expressed by Schwann cells were significantly increased, levels of the phosphorylated forms of ErbB2/3 and their downstream signaling cascades were decreased. This change was not associated with the level of the neuregulin 1 ligand, which was increased in Ndrg1-deficient mice. In addition, the integrin β4 receptor, which interacts with ErbB2/3 and positively regulates neuregulin 1/ErbB signaling, was significantly reduced in the Ndrg1-deficient nerve. In conclusion, our data suggest that the demyelinating phenotype of CMT4D disease is at least in part a consequence of molecular defects in neuregulin 1/ErbB signaling.

Background:Exercise plays an essential role in improving motor symptoms in Parkinson's disease (PD), but the underlying mechanism in the central nervous system remains unclear.Methods:Motor ability was observed after 12-week treadmill exercise on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. RNA-sequencing on four brain regions (cerebellum, cortex, substantia nigra (SN), and striatum) from control animals, MPTP-induced PD, and MPTP-induced PD model treated with exercise for 12 weeks were performed. Transcriptional networks on the four regions were further identified by an integrative network biology approach.Results:The 12-week treadmill exercise significantly improved the motor ability of an MPTP-induced mouse model of PD. RNA-seq analysis showed SN and striatum were remarkably different among individual region's response to exercise in the PD model. Especially, synaptic regulation pathways about axon guidance, synapse assembly, neurogenesis, synaptogenesis, transmitter transport-related pathway, and synaptic regulation genes, including Neurod2, Rtn4rl2, and Cd5, were upregulated in SN and striatum. Lastly, immunofluorescence staining revealed that exercise rescued the loss of TH+ synapses in the striatal region in PD mice, which validates the key role of synaptic regulation pathways in exercise-induced protective effects in vivo.Conclusion:SN and striatum are important brain regions in which critical transcriptional changes, such as in synaptic regulation pathways, occur after the exercise intervention on the PD model.

Progressive accumulation of misfolded SNCA/α-synuclein is key to the pathology of Parkinson's disease (PD). Drugs aiming at degrading SNCA may be an efficient therapeutic strategy for PD. Our previous study showed that mesencephalic astrocyte-derived neurotrophic factor (MANF) facilitated the removal of misfolded SNCA and rescued dopaminergic (DA) neurons, but the underlying mechanisms remain unknown. In this study, we showed that AAV8-MANF relieved Parkinsonian behavior in rotenone-induced PD model and reduced SNCA accumulation in the substantia nigra. By establishing wildtype (WT) SNCA overexpression cellular model, we found that chaperone-mediated-autophagy (CMA) and macroautophagy were both participated in MANF-mediated degradation of SNCAWT. Nuclear factor erythroid 2-related factor (Nrf2) was activated to stimulating macroautophagy activity when CMA pathway was impaired. Using A53T mutant SNCA overexpression cellular model to mimic CMA dysfunction situation, we concluded that macroautophagy rather than CMA was responsible to the degradation of SNCAA53T, and this degradation was mediated by Nrf2 activation. Hence, our findings suggested that MANF has potential therapeutic value for PD. Nrf2 and its role in MANF-mediated degradation may provide new sights that target degradation pathways to counteract SNCA pathology in PD.

Despite remarkable progresses in nucleic acid-targeted tumor therapy, intracellular RNA and nuclear DNA-dual targeted cancer treatments via a single nano-delivery system have been little investigated. Herein, cis-platinum pro-drugs (DSP) and cytotoxic protein ribonuclease A (RNase A) dual-therapeutic agents-loaded large-pore mesoporous silica-coated beta-NaYF4:20%Yb,2%Er@beta-NaGdF4 upconversion nanoplatforms (UCSPtR) were prepared for chemo-protein combination therapy. The obtained upconversion nanoplatforms can not only transport cytotoxic protein molecules and DSP into tumor cells to induce intracellular RNA degradation-mediated and nuclear DNA-targeted killings of cancer cells, but also achieve upconversion luminescence (UCL) and magnetic resonance (MR) dual-mode bioimaging. We believe this RNA and DNA-dual-targeted nanosystem will provide more enlightenments for tumor therapy.

Basaloid squamous cell carcinoma and large cell neuroendocrine carcinoma are not common in head and neck, these tumors rarely occur in the larynx but both have highly aggressive clinical behavior and a high mortality rate. The diagnosis is complicated by these tumors’ atypical clinical and pathological features. This case details a coexistence of basaloid squamous cell carcinoma and large cell neuroendocrine carcinoma of a woman in the larynx. The patient underwent endoscopy- and coblation-assisted transoral microsurgery to achieve hyoid horizontal epiglottidectomy and has no recurrence after 12 months of follow-up.

Parkinson's disease (PD) is a common neurodegenerative disease with movement and balance impairments. Although studies have reported improvement of motor symptoms with physical exercise, the mechanisms by which exercise is beneficial remains poorly understood. Our study addresses the exercise-induced changes to peripheral immune cells by interrogating the transcriptome of blood-derived leukocytes in PD patients before and after exercise. Patients attended 1 h exercise classes twice a week for 12 weeks. Leukocytes were collected at the beginning and end of the study for gene expression analysis by RNA-seq or quantitative real-time PCR. We correlated differentially expressed genes after exercise with clinical measures and analyzed the potential functions of gene changes with Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analysis. Exercise improved measures of movement and balance when compared with scores before the exercise program. Among the gene changes, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis suggests that T-cell receptor signaling, T-cell activation, and T-cell migration pathways were downregulated, while the T-cell receptor signaling pathway was the most significantly correlated with clinical measures. To further investigate T-cell-related changes in PD leukocytes, we reanalyzed the differentially expressed genes from publicly available microarray data and found that genes in the T-cell activation, differentiation, and migration pathways were upregulated in PD samples compared to controls in a time-dependent manner. Together, our findings suggest that exercise rehabilitation may improve movement and balance in PD patients by reversing the upregulated T-cell activation pathways associated with PD. This study was registered with the Chinese Clinical Trial Registry under ChiCTR-TRC-14004707. Registered on May 27, 2014.

Abstract Early stage diagnosis of Parkinson’s disease (PD) is challenging without significant motor symptoms. The identification of effective molecular biomarkers as a hematological indication of PD may help improve the diagnostic timelines and accuracy. In the present paper, we analyzed and compared the blood samples of PD and control (CTR) patients to identify the disease-related changes and determine the putative biomarkers for PD diagnosis. Based on the RNA sequencing analysis, differentially expressed genes (DEGs) were identified, and the co-expression network of DEGs was constructed using the weighted gene correlation network analysis (WGCNA). The analysis leads to the identification of 87 genes that were exclusively regulated in the PD group, whereas 66 genes were significantly increased and 21 genes were significantly decreased in contrast with the control group. The results indicate that the core lncRNA–mRNA co-expression network greatly changes the immune response in PD patients. Specifically, the results showed that Prader Willi Angelman Region RNA6 (PWAR6), LINC00861, AC83843.1, IRF family, IFIT family and calcium/calmodulin-dependent protein kinase IV (CaMK4) may play important roles in the immune system of PD. Based on the findings from the present study, future research aims at identifying novel therapeutic strategies for PD.

: NUT carcinoma (NC) is a rare, highly invasive and fatal tumor and often misdiagnosed. It typically arises from the mediastinum and midline organs and has complicated pathogenesis and poor outcome. Genetically, its pathogenesis is related to a chromosomal rearrangement involving the NUTM1 gene. In most cases, the main oncoprotein is BRD4-NUT with a translocation between NUTM1 and BRD4 genes, but in a few cases, the oncoprotein is BRD3-NUT, or NSD3-NUT. Studies have shown that the histone hyperacetylation and BRD4 hyperphosphorylation may lead to the activation of cancer circuits. Abnormal production of microRNA, inactivation of tumor suppressor genes and abnormal activation of several signaling pathways are proposed as potential mechanisms underlying the pathogenesis of NC. Currently, there is no consensus on its standard treatment for NC. Extent of surgical resection with negative margins, initial radiotherapy and part of chemotherapy regimens may significantly associated with the improvement of progression-free survival (PFS) rate and overall survival (OS) rate. Some bromodomain and extraterminal inhibitors (BETis) have shown encouraging results in the clinical trials on NC, but delayed drug resistance is still an important issue that needs to be resolved. Histone deacetylase inhibitors are also found to possess the potential in the treatment of NC. Herein, we summarize recent advances in the pathogenesis and treatment of NC.