Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort.

BACKGROUND AND OBJECTIVES: Inverse associations between caffeine intake and Parkinson disease (PD) have been frequently implicated in human studies. However, no studies have quantified biomarkers of caffeine intake years before PD onset and investigated whether and which caffeine metabolites are related to PD. METHODS: Associations between self-reported total coffee consumption and future PD risk were examined in the EPIC4PD study, a prospective population-based cohort including 6 European countries. Cases with PD were identified through medical records and reviewed by expert neurologists. Hazard ratios (HRs) and 95% CIs for coffee consumption and PD incidence were estimated using Cox proportional hazards models. A case-control study nested within the EPIC4PD was conducted, recruiting cases with incident PD and matching each case with a control by age, sex, study center, and fasting status at blood collection. Caffeine metabolites were quantified by high-resolution mass spectrometry in baseline collected plasma samples. Using conditional logistic regression models, odds ratios (ORs) and 95% CIs were estimated for caffeine metabolites and PD risk. RESULTS: In the EPIC4PD cohort (comprising 184,024 individuals), the multivariable-adjusted HR comparing the highest coffee intake with nonconsumers was 0.63 (95% CI 0.46-0.88, p = 0.006). In the nested case-control study, which included 351 cases with incident PD and 351 matched controls, prediagnostic caffeine and its primary metabolites, paraxanthine and theophylline, were inversely associated with PD risk. The ORs were 0.80 (95% CI 0.67-0.95, p = 0.009), 0.82 (95% CI 0.69-0.96, p = 0.015), and 0.78 (95% CI 0.65-0.93, p = 0.005), respectively. Adjusting for smoking and alcohol consumption did not substantially change these results. DISCUSSION: This study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine and its metabolites years before diagnosis.

Bimetal doped Cu-Fe-ZIF-8/g-C3N4 nanocomposites for the adsorption of tetracycline hydrochloride from water.

Bimetal doped Cu-Fe-zeolitic imidazole framework-8 (ZIF-8)/graphitic carbon nitride (GCN) (Cu-Fe-ZIF-8/GCN) nanocomposites were prepared via one-pot and ion-exchange methods. The main influencing factors, such as adsorbent concentration, TC concentration, initial pH, and coexisting ions, were evaluated in detail. Due to the suitable pore structures and the presence of multiple interactions on the surface, the nanocomposite showed a high adsorption capacity up to 932 mg g-1 for tetracycline hydrochloride (TC), outperforming ZIF-8 by 4.8 times. The adsorption kinetics and adsorption isotherm were depicted in good detail using pseudo-second-order kinetic and Langmuir models, respectively. Thermodynamic calculation revealed that the adsorption of the nanocomposite under experimental conditions was a spontaneous heat absorption process, and was primarily driven by chemisorption. After four cycles of use, the nanocomposite retained 87.2% of its initial adsorption capacity, confirming its high reusability and broad application prospects in removing tetracycline-type pollutants from wastewater.

The impact of the EU's Carbon Border Adjustment Mechanism on the global iron and steel trade and emission reduction.

The European Council completed the legislative procedure to establish the Carbon Border Adjustment Mechanism (CBAM) on April 25, 2023, which will be launched in 2027. The iron and steel sector is the main target of the forthcoming CBAM due to the industry's energy-intensive consumption with high carbon dioxide (CO2) emissions. However, minimal existing research has been conducted in this regard. This study employs GTAP-e 11.0 and TOPSIS models to estimate the effects of CBAM implementation on the major nations around the world from 2027 to 2030, examining countries' GDP, social welfare, iron and steel production, trade balance, and CO2 emissions to the global environment. This study concludes: (1) The GDP and social welfare of important iron and steel trade partners throughout the world will be significantly impacted by the application of CBAM. Most nations, including those in the EU, will experience negative GDP effects, with China undergoing the most pronounced social welfare declines followed by India. In contrast, the EU27 will benefit the most in terms of social welfare, followed by the US, Japan, and Russia. (2) Iron and steel production will decrease in all countries outside the EU, but it will have a positive impact on the trade balance of most countries. (3) The CO2 emissions of all countries except for the EU and Japan will decrease, with a positive impact on preventing carbon leakage in the international iron and steel trade. (4) Comprehensive analysis demonstrates that the EU will benefit the most, and China will suffer the most from CBAM application. Based on the above conclusions, this study proposes corresponding policy recommendations.

Alectinib continuation beyond progression in ALK-positive non-small cell lung cancer with alectinib-refractory.

Background: Alectinib, a next-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI), has demonstrated noteworthy efficacy in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, 53.3% of untreated patients receiving first-line treatment with alectinib developed resistance to alectinib. However, despite the widespread use of alectinib, studies on the efficacy and safety of continuing alectinib with other necessary therapies after progression of alectinib and possible population of benefit are still limited. Methods: This retrospective cohort study included fifteen patients with ALK-positive NSCLC from nine institutions in China who experienced disease progression after first- or second-line treatment and continued to receive alectinib treatment between 2019 and 2022. This study aimed to evaluate the median progression-free survival (mPFS), objective response rate (ORR), median overall survival (mOS), and adverse events (AEs) of continuing alectinib combined with other therapies after the emergence of drug resistance. Results: Among fifteen patients eligible for this study, all patients started continuing treatment with alectinib after oligoprogression or central nervous system (CNS) progression. The mPFS for the whole cohort receiving continuing alectinib with other necessary therapies was 8 months [95% confidence interval (CI): 4 to not applicable (NA)], with an ORR of 46.7%. The mOS was not reached. During continuing alectinib treatment, only one patient experienced grade 2 elevation of aspartate aminotransferase (AST) and serum glutamic-oxaloacetic transaminase (SGOT). Conclusions: The continuation of alectinib treatment combined with other necessary therapies demonstrates favorable response and safety in patients with ALK-positive NSCLC who experienced oligoprogression or CNS progression following alectinib in first- or second-line therapy. Instead of immediately switching to another ALK-TKI, continuing alectinib combined with other necessary therapies may offer greater survival benefits to the patients.

Shikonin reactivates TSGs GADD45B and PPP3CC to block NSCLC cell proliferation and migration through JNK/P38/MAPK signaling pathways.

BACKGROUND: Shikonin, a natural naphthoquinone compound extracted from the Chinese traditional herbal medicine "Lithospermum erythrorhizon", possesses antitumor activity against various cancer types. Tumor-suppressor genes (TSGs) negatively regulate cell growth, proliferation, and differentiation, thereby inhibiting tumor formation. However, the molecular mechanism of action of shikonin on TSGs in non-small-cell lung cancer (NSCLC) remains unclear. METHODS: The inhibitory effect of shikonin on the proliferation and migration abilities of lung cancer cells were measured by Cell Counting Kit 8 (CCK8) and wound healing assays. The alteration of genes by shikonin treatment was detected by mRNA high-throughput sequencing and further confirmed by qPCR and western blotting experiments. The dominant functions of the upregulated genes were analyzed by GO and KEGG profiling. RESULTS: Shikonin inhibited the proliferation and migration of A549 and H1299 NSCLC cells in a dose-dependent manner. mRNA high-throughput sequencing revealed a total of 1794 upregulated genes in shikonin-treated NSCLC cells. Moreover, bioinformatic analysis of GO and KEGG profiling revealed that the up-regulated genes were mostly involved in the JNK/P38/MAPK signaling pathway, among which the expression of GADD45B and PPP3CC was significantly enhanced. Finally, we confirmed that GADD45B and PPP3CC were indeed upregulated in JNK/P38/MAPK pathway. CONCLUSIONS: Taken together, these results suggested that shikonin might affect the expression of GADD45B and PPP3CC through the JNK/P38/MAPK pathway, therefore exerting an inhibitory effect on the proliferation and migration of cancer cells. To our knowledge, this is the first study reporting the role of shikonin in upregulating TSGs to activate the JNK/P38/MAPK signaling pathways in NSCLC.

Helicobacter pylori infection and Parkinson's Disease: etiology, pathogenesis and levodopa bioavailability.

Parkinson's disease (PD), a neurodegenerative disorder with an unknown etiology, is primarily characterized by the degeneration of dopamine (DA) neurons. The prevalence of PD has experienced a significant surge in recent years. The unidentified etiology poses limitations to the development of effective therapeutic interventions for this condition. Helicobacter pylori (H. pylori) infection has affected approximately half of the global population. Mounting evidences suggest that H. pylori infection plays an important role in PD through various mechanisms. The autotoxin produced by H. pylori induces pro-inflammatory cytokines release, thereby facilitating the occurrence of central inflammation that leads to neuronal damage. Simultaneously, H. pylori disrupts the equilibrium of gastrointestinal microbiota with an overgrowth of bacteria in the small intestinal known as small intestinal bacterial overgrowth (SIBO). This dysbiosis of the gut flora influences the central nervous system (CNS) through microbiome-gut-brain axis. Moreover, SIBO hampers levodopa absorption and affects its therapeutic efficacy in the treatment of PD. Also, H. pylori promotes the production of defensins to regulate the permeability of the blood-brain barrier, facilitating the entry of harmful factors into the CNS. In addition, H. pylori has been found to induce gastroparesis, resulting in a prolonged transit time for levodopa to reach the small intestine. H. pylori may exploit levodopa to facilitate its own growth and proliferation, or it can inflict damage to the gastrointestinal mucosa, leading to gastrointestinal ulcers and impeding levodopa absorption. Here, this review focused on the role of H. pylori infection in PD from etiology, pathogenesis to levodopa bioavailability.

HSP90AB1 is a host factor that promotes porcine deltacoronavirus replication.

Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus. It causes mortality in neonatal piglets and is of growing concern because of its broad host range, including humans. To date, the mechanism of PDCoV infection remains poorly understood. Here, based on a genome-wide CRISPR screen of PDCoV-infected cells, we found that HSP90AB1 (heat shock protein 90 alpha family class B1) promotes PDCoV infection. Knockdown or KO of HSP90AB1 in LLC-PK cells resulted in a significantly suppressed PDCoV infection. Infected cells treated with HSP90 inhibitors 17-AAG and VER-82576 also showed a significantly suppressed PDCoV infection, although KW-2478, which does not affect the ATPase activity of HSP90AB1, had no effect on PDCoV infection. We found that HSP90AB1 interacts with the N, NS7, and NSP10 proteins of PDCoV. We further evaluated the interaction between N and HSP90AB1 and found that the C-tail domain of the N protein is the HSP90AB1-interacting domain. Further studies showed that HSP90AB1 protects N protein from degradation via the proteasome pathway. In summary, our results reveal a key role for HSP90AB1 in the mechanism of PDCoV infection and contribute to provide new host targets for PDCoV antiviral research.

Dioxin(-like)-Related Biological Effects through Integrated Chemical-wide and Metabolome-wide Analyses.

Dioxin(-like) exposures are linked to adverse health effects, including cancer. However, metabolic alterations induced by these chemicals remain largely unknown. Beyond known dioxin(-like) compounds, we leveraged a chemical-wide approach to assess chlorinated co-exposures and parent compound products [termed dioxin(-like)-related compounds] among 137 occupational workers. Endogenous metabolites were profiled by untargeted metabolomics, namely, reversed-phase chromatography with negative electrospray ionization (C18-negative) and hydrophilic interaction liquid chromatography with positive electrospray ionization (HILIC-positive). We performed a metabolome-wide association study to select dioxin(-like) associated metabolic features using a 20% false discovery rate threshold. Metabolic features were then characterized by pathway enrichment analyses. There are no significant features associated with polychlorinated dibenzo-p-dioxins (PCDDs), a subgroup of known dioxin(-like) compounds. However, 3,110 C18-negative and 2,894 HILIC-positive features were associated with at least one of the PCDD-related compounds. Abundant metabolic changes were also observed for polychlorinated dibenzofuran-related and polychlorinated biphenyl-related compounds. These metabolic features were primarily enriched in pathways of amino acids, lipid and fatty acids, carbohydrates, cofactors, and nucleotides. Our study highlights the potential of chemical-wide analysis for comprehensive exposure assessment beyond targeted chemicals. Coupled with advanced endogenous metabolomics, this approach allows for an in-depth exploration of metabolic alterations induced by environmental chemicals.

Neurotropic virus infection and neurodegenerative diseases: Potential roles of autophagy pathway.

Neurodegenerative diseases (NDs) constitute a group of disorders characterized by the progressive deterioration of nervous system functionality. Currently, the precise etiological factors responsible for NDs remain incompletely elucidated, although it is probable that a combination of aging, genetic predisposition, and environmental stressors participate in this process. Accumulating evidence indicates that viral infections, especially neurotropic viruses, can contribute to the onset and progression of NDs. In this review, emerging evidence supporting the association between viral infection and NDs is summarized, and how the autophagy pathway mediated by viral infection can cause pathological aggregation of cellular proteins associated with various NDs is discussed. Furthermore, autophagy-related genes (ARGs) involved in Herpes simplex virus (HSV-1) infection and NDs are analyzed, and whether these genes could link HSV-1 infection to NDs is discussed. Elucidating the mechanisms underlying NDs is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of NDs.

HSP90AB1 Is a Host Factor Required for Transmissible Gastroenteritis Virus Infection.

Transmissible gastroenteritis virus (TGEV) is an important swine enteric coronavirus causing viral diarrhea in pigs of all ages. Currently, the development of antiviral agents targeting host proteins to combat viral infection has received great attention. The heat shock protein 90 (HSP90) is a critical host factor and has important regulatory effects on the infection of various viruses. However, its roles in porcine coronavirus infection remain unclear. In this study, the effect of HSP90 on TGEV infection was evaluated. In addition, the influence of its inhibitor VER-82576 on proinflammatory cytokine (IL-6, IL-12, TNF-α, CXCL10, and CXCL11) production induced by TGEV infection was further analyzed. The results showed that the knockdown of HSP90AB1 and HSP90 inhibitor VER-82576 treatment resulted in a reduction in TGEV M gene mRNA levels, the N protein level, and virus titers in a dose-dependent manner, while the knockdown of HSP90AA1 and KW-2478 treatment had no significant effect on TGEV infection. A time-of-addition assay indicated that the inhibitory effect of VER-82576 on TGEV infection mainly occurred at the early stage of viral replication. Moreover, the TGEV-induced upregulation of proinflammatory cytokine (IL-6, IL-12, TNF-α, CXCL10, and CXCL11) expression was significantly inhibited by VER-82576. In summary, these findings indicated that HSP90AB1 is a host factor enhancing TGEV infection, and the HSP90 inhibitor VER-82576 could reduce TGEV infection and proinflammatory cytokine production, providing a new perspective for TGEV antiviral drug target design.

Natural Shikonin Potentially Alters Intestinal Flora to Alleviate Acute Inflammation.

Shikonin, derived from the herb Lithospermum erythrorhizon (Purple Cromwell), is extensively utilized in traditional Chinese medicine as an anti-inflammatory agent; however, its effect on the intestinal flora is not yet known. Herein, we demonstrate that, compared to a blank control group, the intragastric administration of shikonin suppressed the swelling rate of ears in a mouse model of acute inflammation in a dose-dependent manner via animal experiments; furthermore, the 20 mg/kg shikonin treatment exhibited the highest inhibitory effect. In formal animal experimentation, we discovered that the inhibitory effect of shikonin with 20 mg/kg on inflammation was closely linked to the intestinal flora, whereby the microbiota phylum was altered in feces through a 16S rDNA sequencing analysis, implying that shikonin improves gut microbiota structures and compositions to counteract inflammation. Notably, using a real-time quantitative polymerase chain reaction (RT-qPCR), a Western blotting assay, and an immunohistochemistry (IHC) assay, we found that inflammatory cytokines such as TNF-α, IL-6, and IL-1ß reduced in both the shikonin-administration group and the positive control group than those in the blank control group, as expected. To the best of our knowledge, this is the first study to outline the underlying mechanism through which shikonin acts on gut microbes to alleviate acute inflammation, providing an alternative mechanism for shikonin to become a preventive agent in countering inflammation.

Quality Analysis and Correction of Sea Surface Temperature Data from China HY-1C Satellite in Southeast Asia Seas.

China's marine satellite infrared radiometer SST remote sensing observations began relatively late. Thus, it is essential to evaluate and correct the SST observation data of the Ocean Color and Temperature Scanner (COCTS) onboard the China HY-1C satellite in the Southeast Asia seas. We conducted a quality assessment and correction work on the SST of the China COCTS/HY-1C in Southeast Asian seas based on multisource satellite SST data and temperature data measured by Argo buoys. The accuracy evaluation results of the COCTS SST indicated that the bias, Std, and RMSE of the daytime SST data for HY-1C were -0.73 °C, 1.38 °C, and 1.56 °C, respectively, while the bias, Std, and RMSE of the nighttime SST data were -0.95 °C, 1.57 °C, and 1.83 °C, respectively. The COCTS SST accuracy was significantly lower than that of other infrared radiometers. The effect of the COCTS SST zonal correction was most significant, with the Std and RMSE approaching 1 °C. After correction, the RMSE of the daytime SST and nighttime SST data decreased by 32.52% and 42.04%, respectively.

Bioinformatics analysis and identification of upregulated tumor suppressor genes associated with suppressing colon cancer progression by curcumin treatment.

Tumor suppressor genes (TSGs) are commonly downregulated in colon cancer and play a negative role in tumorigenesis and cancer progression by affecting genomic integrity, the cell cycle, and cell proliferation. Curcumin (CUR), a Chinese herb-derived phytochemical, exerts antitumor effects on colon cancer. However, it remains unclear whether CUR exerts its antitumor effects by reactivating TSGs in colon cancer. Here, we demonstrated that CUR inhibited HT29 and HCT116 proliferation and migration by cell-counting kit-8, colony-formation, and wound-healing assays. Furthermore, the comprehensive bioinformatics analysis of mRNA sequencing revealed that 3,505 genes were significantly upregulated in response to CUR in HCT116 cells. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses showed that the most upregulated genes were enriched in cancer pathways containing 37 TSGs. Five (ARHGEF12, APAF1, VHL, CEBPA, and CASP8) of the 37 upregulated TSGs were randomly selected for real-time fluorescence polymerase chain reaction and the verification results showed that these five genes were significantly reactivated after CUR treatment, suggesting that TSGs are related to CUR-mediated colon cancer inhibition. ARHGEF12 is a newly identified TSG and a potential therapeutic target for colon cancer. Furthermore, molecular docking was performed to predict the binding sites of CUR and ARHGEF12, suggesting that CUR can prevent colon cancer cell invasion and metastasis by inhibiting ARHGEF12 and RhoA binding. In conclusion, the present study reveals that CUR inhibits colon cancer cell proliferation and migration by reactivating TSGs, revealing a new mechanism and potential target for colon cancer treatment.

Prediagnostic Blood Metal Levels and the Risk of Parkinson's Disease: A Large European Prospective Cohort.

BACKGROUND: Metals have been postulated as environmental concerns in the etiology of Parkinson's disease (PD), but metal levels are typically measured after diagnosis, which might be subject to reverse causality. OBJECTIVE: The aim of this study was to investigate the association between prediagnostic blood metal levels and PD risk. METHODS: A case-control study was nested in a prospective European cohort, using erythrocyte samples collected before PD diagnosis. RESULTS: Most assessed metals were not associated with PD risk. Cadmium has a suggestive negative association with PD (odds ratio [95% confidence interval] for the highest quartile, 0.70 [0.42-1.17]), which diminished among never smokers. Among current smokers only, lead was associated with decreased PD risk (0.06 [0.01-0.35]), whereas arsenic showed associations toward an increased PD risk (1.85 [0.45-7.93]). CONCLUSIONS: We observe no strong evidence to support a role of metals in the development of PD. In particular, smoking may confound the association with tobacco-derived metals. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Combining decellularized adipose tissue with decellularized adventitia extravascular matrix or small intestinal submucosa matrix for the construction of vascularized tissue-engineered adipose.

Adipose tissue is an endocrine organ. It serves many important functions, such as energy storage, hormones secretion, and providing insulation, cushioning and aesthetics to the body etc. Adipose tissue engineering offers a promising treatment for soft tissue defects. Early adipose tissue production and long-term survival are closely associated with angiogenesis. Decellularized matrix has a natural ECM (extracellular matrix) component, good biocompatibility, and low immunogenicity. Therefore, in this study, the injectable composite hydrogels were developed to construct vascularized tissue-engineered adipose by using the pro-angiogenic effects of aortic adventitia extravascular matrix (Adv) or small intestinal submucosa (SIS), and the pro-adipogenic effects of decellularized adipose tissue (DAT). The composite hydrogels were cross-linked by genipin. The adipogenic and angiogenic abilities of composite hydrogels were investigated in vitro, and in a rat dorsal subcutaneous implant model. The results showed that DAT and SIS or Adv 1:1 composite hydrogel promoted the migration and tube formation of endothelial cells. Furthermore, DAT and SIS or Adv 1:1 composite hydrogel enhanced adipogenic differentiation of adipose-derived mesenchymal stem cells (ASCs) through activation of PPARγ and C/EBPα. The in vivo studies further demonstrated that DAT with SIS or Adv in a 1:1 ratio also significantly promoted adipogenesis and angiogenesis. In addition, DAT with SIS or Adv in a 1:1 ratio hydrogel recruited macrophage population with enhanced M2-type macrophage polarization, suggesting a positive effect of inflammatory response on angiogenesis. In conclusion, these data suggest that the composite hydrogels of DAT with SIS or Adv in 1:1 ratio have apparent pro-adiogenic and angiogenic abilities, thus providing a promising cell-free tissue engineering biomaterial with broad clinical applications. STATEMENT OF SIGNIFICANCE: Decellularized adipose tissue (DAT) has emerged as an important biomaterial in adipose tissue regeneration. Early adipose tissue production and long-term survival is tightly related to the angiogenesis. The revascularization of the DAT is a key issue that needs to be solved in adipose regeneration. In this study, the injectable composite hydrogels were developed by using DAT with Adv (aortic adventitia extravascular matrix) or SIS (small intestinal submucosa) in different ratio. We demonstrated that the combination of DAT with SIS or Adv in 1:1 ratio effectively improved the proliferation of adipose stem cells and endothelial cells, and promoted greater adipose regeneration and tissue vascularization as compared to the DAT scaffold. This study provides the potential biomaterial for clinical soft tissue regeneration.

Lipopolysaccharide-binding protein and future Parkinson's disease risk: a European prospective cohort.

INTRODUCTION: Lipopolysaccharide (LPS) is the outer membrane component of Gram-negative bacteria. LPS-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS and has been used as a blood marker for LPS. LBP has recently been indicated to be associated with Parkinson's disease (PD) in small-scale retrospective case-control studies. We aimed to investigate the association between LBP blood levels with PD risk in a nested case-control study within a large European prospective cohort. METHODS: A total of 352 incident PD cases (55% males) were identified and one control per case was selected, matched by age at recruitment, sex and study center. LBP levels in plasma collected at recruitment, which was on average 7.8 years before diagnosis of the cases, were analyzed by enzyme linked immunosorbent assay. Odds ratios (ORs) were estimated for one unit increase of the natural log of LBP levels and PD incidence by conditional logistic regression. RESULTS: Plasma LBP levels were higher in prospective PD cases compared to controls (median (interquartile range) 26.9 (18.1-41.0) vs. 24.7 (16.6-38.4) µg/ml). The OR for PD incidence per one unit increase of log LBP was elevated (1.46, 95% CI 0.98-2.19). This association was more pronounced among women (OR 2.68, 95% CI 1.40-5.13) and overweight/obese subjects (OR 1.54, 95% CI 1.09-2.18). CONCLUSION: The findings suggest that higher plasma LBP levels may be associated with an increased risk of PD and may thus pinpoint to a potential role of endotoxemia in the pathogenesis of PD, particularly in women and overweight/obese individuals.

TRIM29 hypermethylation drives esophageal cancer progression via suppression of ZNF750.

Esophageal cancer (ESCA) is the seventh most frequent and deadly neoplasm. Due to the lack of early diagnosis and high invasion/metastasis, the prognosis of ESCA remains very poor. Herein, we identify skin-related signatures as the most deficient signatures in invasive ESCA, which are regulated by the transcription factor ZNF750. Of note, we find that TRIM29 level strongly correlated with the expression of many genes in the skin-related signatures, including ZNF750. TRIM29 is significantly down-regulated due to hypermethylation of its promoter in both ESCA and precancerous lesions compared to normal tissues. Low TRIM29 expression and high methylation levels of its promoter are associated with malignant progression and poor clinical outcomes in ESCA patients. Functionally, TRIM29 overexpression markedly hinders proliferation, migration, invasion, and epithelial-mesenchymal transition of esophageal cancer cells, whereas opposing results are observed when TRIM29 is silenced in vitro. In addition, TRIM29 inhibits metastasis in vivo. Mechanistically, TRIM29 downregulation suppresses the expression of the tumor suppressor ZNF750 by activating the STAT3 signaling pathway. Overall, our study demonstrates that TRIM29 expression and its promoter methylation status could be potential early diagnostic and prognostic markers. It highlights the role of the TRIM29-ZNF750 signaling axis in modulating tumorigenesis and metastasis of esophageal cancer.

Metal Exposure and Risk of Parkinson Disease: A Systematic Review and Meta-Analysis.

Metal exposure has been suggested as a possible environmental risk factor for Parkinson disease (PD). We searched the PubMed, EMBASE, and Cochrane databases to systematically review the literature on the relationship between metal exposure and PD risk and to examine the overall quality of each study and the exposure assessment method. A total of 83 case-control studies and 5 cohort studies published during the period 1963-July 2021 were included, of which 73 were graded as being of low or moderate overall quality. Investigators in 69 studies adopted self-reported exposure and biomonitoring after disease diagnosis for exposure assessment approaches. The meta-analyses showed that concentrations of copper and iron in serum and concentrations of zinc in either serum or plasma were lower, while concentrations of magnesium in CSF and zinc in hair were higher, among PD cases as compared with controls. Cumulative lead levels in bone were found to be associated with increased risk of PD. We did not find associations between other metals and PD. The current level of evidence for associations between metals and PD risk is limited, as biases from methodological limitations cannot be ruled out. High-quality studies assessing metal levels before disease onset are needed to improve our understanding of the role of metals in the etiology of PD.

Single-cell and bulk RNA sequencing identifies T cell marker genes score to predict the prognosis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the lethal malignancies, with limited biomarkers identified to predict its prognosis and treatment response of immune checkpoint blockade (ICB). This study aimed to explore the predictive ability of T cell marker genes score (TMGS) to predict their overall survival (OS) and treatment response to ICB by integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data. Multi-omics data of PDAC were applied in this study. The uniform manifold approximation and projection (UMAP) was utilized for dimensionality reduction and cluster identification. The non-negative matrix factorization (NMF) algorithm was applied to molecular subtypes clustering. The Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression was adopted for TMGS construction. The prognosis, biological characteristics, mutation profile, and immune function status between different groups were compared. Two molecular subtypes were identified via NMF: proliferative PDAC (C1) and immune PDAC (C2). Distinct prognoses and biological characteristics were observed between them. TMGS was developed based on 10 T cell marker genes (TMGs) through LASSO-Cox regression. TMGS is an independent prognostic factor of OS in PDAC. Enrichment analysis indicated that cell cycle and cell proliferation-related pathways are significantly enriched in the high-TMGS group. Besides, high-TMGS is related to more frequent KRAS, TP53, and CDKN2A germline mutations than the low-TMGS group. Furthermore, high-TMGS is significantly associated with attenuated antitumor immunity and reduced immune cell infiltration compared to the low-TMGS group. However, high TMGS is correlated to higher tumor mutation burden (TMB), a low expression level of inhibitory immune checkpoint molecules, and a low immune dysfunction score, thus having a higher ICB response rate. On the contrary, low TMGS is related to a favorable response rate to chemotherapeutic agents and targeted therapy. By combining scRNA-seq and bulk RNA-seq data, we identified a novel biomarker, TMGS, which has remarkable performance in predicting the prognosis and guiding the treatment pattern for patients with PDAC.

Methyl Ferulic Acid Alleviates Neuropathic Pain by Inhibiting Nox4-induced Ferroptosis in Dorsal Root Ganglia Neurons in Rats.

Neuropathic pain is a disease that has become one of the major public health problems and a global burden. Nox4-induced oxidative stress can lead to ferroptosis and neuropathic pain. Methyl ferulic acid (MFA) can inhibit the Nox4-induced oxidative stress. This study aimed to estimate whether methyl ferulic acid alleviates neuropathic pain by inhibiting the expression of Nox4 and its induction of ferroptosis. Adult male Sprague-Dawley rats were subjected to spared nerve injury (SNI) model to induce neuropathic pain. After the establishment of the model, methyl ferulic acid was given 14 days by gavage. Nox4 overexpression was induced by microinjection of the AAV-Nox4 vector. All groups measured paw mechanical withdrawal threshold (PMWT), paw thermal withdrawal latency (PTWL), and paw withdrawal cold duration (PWCD). The expression of Nox4, ACSL4, GPX4, and ROS was investigated by Western blot and immunofluorescence staining. The changes in iron content were detected by a tissue iron kit. The morphological changes in mitochondria were observed by transmission electron microscopy. In the SNI group, the paw mechanical withdrawal threshold, the paw withdrawal cold duration decreased, the paw thermal withdrawal latency did not change, the Nox4, ACSL4, ROS, and iron content increased, the GPX4 decreased, and the number of abnormal mitochondria increased. Methyl ferulic acid can increase PMWT and PWCD but does not affect PTWL. Methyl ferulic acid can inhibit Nox4 protein expression. Meanwhile, ferroptosis-related protein ACSL4 expression was decreased, GPX4 expression was increased, ROS, iron content and abnormal mitochondrial number were decreased. By overexpressing Nox4, the PMWT, PWCD, and ferroptosis of rats were more severe than those of the SNI group, but they could be reversed after treatment with methyl ferulic acid. In conclusion, methyl ferulic acid can alleviate neuropathic pain, which is related to Nox4-induced ferroptosis.