👤 Kejian Shi

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with KRAS mutations in ~ 95% of cases. While KRAS inhibitors have shown promise, therapeutic resistance necessitates combination approaches. In particular, it is important to understand how downstream signaling of KRAS supports PDAC growth. For example, DUSP6 has emerged as an important dual-specificity phosphatase regulating KRAS-MAPK signaling. DUSP6 is markedly overexpressed in PDAC tumors compared to normal pancreatic tissue, with transcriptomic and single-cell RNA-seq analyses revealing its enrichment in epithelial tumor cells, especially in metastatic lesions. High DUSP6 expression correlates with the quasi-mesenchymal/squamous molecular subtype and poorer survival outcomes. Gene set enrichment analyses linked DUSP6 to pathways involved in cell migration and metabolism in metastatic samples. Functionally, DUSP6 knockdown in PDAC cells increases ERK/MAPK activation and alters migration. Metabolic profiling revealed enhanced basal glycolysis upon DUSP6 suppression. However, combined glycolysis inhibition and DUSP6 knockdown did not affect migration, suggesting that glycolytic changes are not the driver of altered migratory behavior. These findings reveal that DUSP6 independently regulates migration and metabolism in PDAC, emphasizing its dual role in disease progression. This study underscores the significance of DUSP6 as a potential therapeutic target and provides new insights into its contributions to PDAC progression. Show less

Long-term space missions are of growing research interest because of the space exploration. However, plenty of works focused on the impaired immune response, less attention has been paid to the activation of immunosuppressive or anti-inflammatory function. The molecular mechanism of immune disorder induced by microgravity still needs investigation. Here, we used a random positioning machine to generate a simulated microgravity environment and evaluated its effects on mouse RAW 264.7 macrophage cell line. We used ATAC-seq and RNA-seq for revealing the mechanism at chromatin level and gene level. From ATAC-seq, we obtained an average of 75,700,675 paired-end clean reads for each library and the mapping rates averaged at 96.8 %. The number of differential accessible regions were 510 for increased peaks, 638 for decreased peaks. From RNA-seq, we obtained 278 differentially expressed genes, of which 104 were down-regulated and 174 were up-regulated genes. Through ATAC-seq and RNA-seq multi-omics analysis, we identified a group of 17 genes. Then we chose 6 up-regulated genes (CD83, CEBPD, CXCR5, DUSP6, SEMA4B, TNFRSF22) that related to immunosuppressive function for further confirmation. The qRT-PCR results were consistent with sequencing results, which indicated that simulated microgravity leads to the up-regulated expression of immunosuppressive genes of macrophages. Taken together, our results offered novel insights for understanding the brief principles and mechanisms of simulated microgravity induced immune dysfunction to macrophage. Show less

Atherosclerosis is characterized by persistent inflammatory condition, leading to various cardiovascular complications. Foam cell formation, resulting from macrophage uptake of oxidized low-density lipoprotein (ox-LDL), contributes significantly to atherosclerosis progression. This study was designed to investigate the involvement of bispecific phosphatase-6 (DUSP6) and its potential regulatory mechanisms in foam cell formation and atherosclerosis. We employed THP-1 cells to induce foam cell formation. The lipid droplet accumulation, cholesterol content, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were evaluated using Oil Red O staining, cholesterol assay, ELISA, and qRT-PCR techniques. We investigated DUSP6 ubiquitination via immunoprecipitation and western blot (WB) analysis. A bioinformatics approach identified FBXL14 as a potential E3 ligase involved in DUSP6 ubiquitination, further confirmed by siRNA and overexpression experiments. The impact of FBXL14 on the NRF2 signaling pathway was assessed using WB analysis. DUSP6 interference suppressed foam cell formation and inflammatory factor secretion. Upon ox-LDL treatment, DUSP6 underwent deubiquitylation, with FBXL14 emerging as the candidate E3 ligase. FBXL14 overexpression induced DUSP6 ubiquitination, leading to the NRF2 signaling pathway activation. It counteracted with DUSP6 overexpression on foam cell formation and inflammation. In ApoE-/- mice, sh-DUSP6 adenovirus injection mitigated atherosclerotic lesion progression and improved the lipid profile, with increased the proteins expression of NQO1, HO-1, and NRF2 in aortic tissue. DUSP6 and FBXL14 play vital roles in modulating foam cell formation and inflammatory responses in atherosclerosis. Targeting these molecules could offer therapeutic potential in attenuating atherosclerosis-related complications. Not applicable. Show less

A chimeric protein of heparanase and Ig-Fc was designed as a novel tool to expand the detection of structurally heterogeneous heparan sulfate (HS) and related glycosaminoglycans. The whole mouse heparanase gene was combined with the gene segment encoding the mouse IgG1 hinge-Fc domain. A point mutation E335A was inserted to disable putative HS degradation activity. Chimeric proteins consisted of the latent form of the enzyme devoid of HS degradation activity. The chimeric proteins bound to heparin, Show less

SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV Show less

Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known as Mendelian randomization (MR), we sought to determine the causal impact of PUFAs on the likelihood of developing skin diseases among individuals of European ancestry. We integrated GWAS data from the CHARGE consortium and UK Biobank to identify genetic instruments for omega-3 PUFAs and desaturase activity, using two-sample MR to assess their associations with six skin diseases. Elevated levels of omega-3 fatty acids were found to substantially lower the probability of experiencing atopic dermatitis (0.92, [0.85,0.98]), while increased DPA levels correlated with a substantial increase in the probability of squamous cell carcinoma occurrence (2.25, [1.29,3.92]). Increased DHA levels were also associated with a reduced risk of atopic dermatitis (0.90, [0.84,0.96]) but increased the risk of solar dermatitis (1.38, [1.09,1.73]). In addition, tissue-type specific MR analysis revealed that elevated FADS1 expression in fibroblasts significantly inhibited atopic dermatitis development (β = -0.181, [-0.276,-0.0853]), while elevated FADS2 expression in non-sun-exposed skin tissues was associated with a reduced risk of squamous cell carcinoma (β = -0.562, [-0.833,-0.029]). Conversely, heightened FADS2 expression was strongly linked to a greater likelihood of developing atopic dermatitis in both sun-exposed and sun-protected skin areas (β = 0.107, [0.0348,0.179]; β = 0.192, [0.114,0.0270], respectively). This study reveals the causal role of omega-3 PUFAs and FADS expression in specific tissues and blood in skin diseases. These findings underscore the potential of PUFA biosynthesis pathways as therapeutic targets for skin disease interventions. Show less

With the sharp increase in the incidence of papillary thyroid carcinoma (PTC), the disease-specific survival rate has not improved significantly. Cholesterol metabolism plays a crucial role in tumor proliferation, regulation of tumor immune escape, and tumor drug resistance. However, there are few studies on the role of cholesterol metabolism in the occurrence and development of thyroid cancer (THCA). This study aimed to investigate the predictive value of cholesterol metabolism-related genes (CMRGs) in THCA and the relationship between immune invasion and drug sensitivity. Cholesterol metabolism-related genes we identified from the molecular signatures database, and univariate Cox regression and least absolute shrinkage and selection operator(LASSO) were used to construct a predictive model of cholesterol metabolism-related genes based on the TCGA-THCA dataset. The TCGA dataset was randomly divided into a training group and a validation group to verify the model's predictive value and independent prognostic effect. We then constructed a nomogram and performed enrichment analysis, immune cell infiltration, and drug sensitivity analysis. Finally, TCGA-THCA and GSE33630 datasets were used to detect the expression of signature genes, which was further verified by the HPA database. Six CMRGs (FADS1, NPC2, HSD17B7, ACSL4, APOE, HMGCS2) we identified by univariate Cox and LASSO regression to construct a prognostic model for 155 genes related to cholesterol metabolism. Their prognostic value was confirmed in the validation set, and a highly accurate nomogram was constructed combined with clinical features. We found that the mortality rate of high-risk patients increased by 11.41 times, and the infiltration of immune cells in the high-risk group was significantly reduced. Moreover, through drug sensitivity analysis, we obtained sensitive drugs for different risk groups. The GSE33630 dataset verified the expression of six CMRGs, and the HPA database verified the protein expression of the NPC2 gene. Cholesterol metabolism-related features are a promising biomarker for predicting THCA prognosis and can potentially guide personalized immunization and targeted therapy. Show less

Age-related Macular Degeneration (AMD) is widely acknowledged as a principal cause of vision loss in the elderly. Currently, the therapeutic interventions available in clinical practice fail to achieve satisfactory outcomes. Therefore, it is imperative that we approach the progress of AMD from novel perspectives in order to explore new therapeutic strategies. We obtained transcriptomic data from the macular and the peripheral retina from patients with AMD and a control group from the Gene Expression Omnibus (GEO) database. Through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we identified differentially expressed genes (DEGs) that were significantly enriched in functions associated with ferroptosis. Subsequent application of machine learning techniques enabled the identification of key hub genes, whose diagnostic potential was further validated. Additionally, the expression of these hub genes was corroborated in both animal and cellular models. Finally, we performed a functional enrichment analysis of these hub genes. In the macula of patients with AMD, 452 DEGs were identified, while in the peripheral retina, 222 DEGs were discovered. Within the macula, 19 genes were associated with ferroptosis, compared to 3 in the peripheral retina. Consequently, the macular was selected as the primary focus of the study. Subsequent screening of these 19 genes using LASSO regression, Support Vector Machine (SVM), and Random Forest algorithms identified four hub genes: FADS1, TFAP2A, AKR1C3, and TTPA. Consequently, we utilized cigarette smoke extract (CSE) to either stimulate retinal pigment epithelial (RPE) cells in vitro or administer it via intravitreal injection, thereby establishing in vitro and in vivo models of AMD. Results from RT-PCR and Western blot analyses revealed an upregulation of FADS1, AKR1C3, and TTPA, while TFAP2A exhibited decreased expression. Finally, we investigated the infiltration of immune cells within the macular and performed a functional enrichment analysis of the hub genes. We identified four key ferroptosis-related genes (FRGs)-FADS1, AKR1C3, TFAP2A, and TTPA-that possess diagnostic relevance for AMD and correlate with immune cell infiltration. Moreover, significant changes in both mRNA and protein expression levels of these genes have been observed in in vitro experiments and mice models. Show less

This study aims to investigate associations between omega-3 polyunsaturated fatty acids (PUFAs) and myopia. Two-sample Mendelian randomization (MR) was conducted to estimate the associations between plasma levels of omega-3 PUFAs and three traits of myopia, including myopia, high myopia (HM), and refractive spherical equivalent (RSE). Summary data-based Mendelian randomization (SMR) and colocalization analysis were conducted to examine the associations between the FADS1 and FADS2 genes and three traits of myopia in European populations. The cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNHANES) was performed to explore the relationship in East Asian adolescents. In the Two-sample MR study, plasma levels of total omega-3 PUFAs (0.993[0.990, 0.996]), Docosahexaenoic acid (DHA) (0.992[0.989, 0.996]), and Eicosapentaenoic Acid (EPA) (0.969[0.955, 0.983]) were found to be significantly and inversely associated with myopia in European populations, and similar results were shown in HM and RSE. SMR ( Show less

This study aims to comprehensively analyze the intricate relationship between unsaturated fatty acids (UFAs, particularly omega-3 and omega-6 UFAs) and acne, from their clinical therapeutic effects to their underlying genetic regulatory mechanisms, to elucidate the role of UFAs in acne pathogenesis. Clinical evidence synthesis: we systematically reviewed randomized controlled trials (RCTs) to evaluate the impact of UFA supplementation on acne treatment outcomes. Genetic analysis: two-sample Mendelian randomization (MR) analysis we used to investigate causal relationships between serum UFA metabolites and acne, identifying potential key regulatory enzymes. The synthesis of these RCT studies confirmed that UFA supplementation improved acne conditions. MR analysis revealed causal links between three serum UFA metabolites and acne, with dihomo-gamma-linolenic acid (DGLA) (OR = 8.457; 95% CI: 2.367-30.214; P-value = 0.001) as a risk factor and arachidonic acid (AA) (OR = 0.209; 95% CI: 0.071-0.618; P-value = 0.005) and eicosapentaenoic acid (EPA) (OR = 0.318; 95% CI: 0.102-0.991; P-value = 0.048) as protective factors. Functional annotation suggested enzymes such as Δ5 desaturase (FADS1) and Δ6 desaturase (FADS2) may play a role in acne regulation. This study offers evidence that supports a connection between UFAs and acne, examining this relationship from both clinical and genetic angles. These findings highlight the role of specific UFAs and their associated metabolic enzymes in the development of acne. Omega-3 UFAs seem to have a protective effect against acne, whereas certain types and ratios of omega-6 UFAs might contribute to acne formation. The varied impacts of UFAs on acne could be attributed to disease processes mediated by specific enzymes. However, the study's limitations include its genetic analysis being primarily based on European populations, which limits the applicability of the findings to other groups. Future research should aim to include a more diverse range of participants to improve the generalizability of the results. Show less

Epilepsy is a prevalent neurological disorder that affects over 70 million individuals worldwide and is often associated with cognitive impairments. Despite the widespread impact of epilepsy and cognitive impairments, the genetic basis and causal relationships underlying these conditions remain uncertain, prompting us to conduct a comprehensive investigation into the molecular mechanisms involved. In this study, we utilized statistical data from the third National Health and Nutrition Examination Survey (NHANES III) to evaluate correlation and large-scale pan-phenotype genome-wide association study (GWAS) data to establish genetic correlation and causality. Leveraging multi-omics datasets, we performed a comprehensive post-analysis that included variant prioritization, gene analysis, tissue and cell type enrichment, and pathway annotation. An integrated strategy-multi-trait analysis of GWAS (MTAG), transcriptome-wide association study (TWAS), summary-data-based Mendelian Randomization (SMR), and protein quantitative trait locus (pQTL)-MR-was performed to investigate the shared genetic architecture. Based on multiple orthogonal lines of evidence, we thereby identified 40 single nucleotide polymorphisms (SNPs) and 85 genes common to both conditions. Additionally, we optimized candidate genes such as GNAQ, FADS1, and PTK2 by single-cell expression analysis and molecular pathway mechanisms, thereby highlighting potential shared genetic pathways. These findings elucidate the genetic interplay and co-occurring mechanisms between epilepsy and cognitive impairments, providing crucial insights for future research and therapeutic strategies. Show less

Essential fatty acids could regulate inflammation, especially n-3 PUFA (n-3 polyunsaturated fatty acids), which are considered to have a protective effect to inhibit neuroinflammation. Peony seed oil is one of the most abundant n-3 PUFAs in oils. but the mechanism of peony seed oil affecting inflammation in mice brains is still lacking convincing evidence. Sixty male C57BL/6J mice were randomly allocated into four groups: D-gal (D-galactose) induced model group, FO (D-gal + fish oil), PSO (D-gal + peony seed oil). After 10 weeks, the fatty acid composition in liver and brain tissues and potentially related genes were examined. Docosahexaenoic acid (DHA) was significantly higher, while arachidonic acid (AA) was significantly lower in both in the PSO and FO groups than that in the model group in the brain and liver. In the PSO and FO groups, the relative mRNA levels of Show less

Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we identified a novel super-enhancer-associated long noncoding RNA (SE-lncRNA), Zinc Finger MIZ-Type Containing 1 Antisense RNA 1 (ZMIZ1-AS1), which is highly expressed in osteosarcoma and promoted tumor cell proliferation, migration, and invasion. Mechanistically, the m⁶A demethylase ALKBH5 post-transcriptionally stabilized ZMIZ1-AS1 through m⁶A demethylation. Furthermore, ZMIZ1-AS1 directly bound to the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1), facilitating the translocation of PTBP1 from the nucleus to the cytoplasm. The relocalized PTBP1 then bound to and stabilized fibroblast growth factor receptor 1 (FGFR1) mRNA. In nude mouse models, ZMIZ1-AS1 overexpression promoted tumor growth and lung metastasis. Notably, combined inhibition of ALKBH5 (using ALKBH5-IN-5) and FGFR1 (using BGJ398/infigratinib) synergistically suppressed ZMIZ1-AS1-driven oncogenesis in vivo. Our study establishes the ALKBH5/ZMIZ1-AS1/PTBP1/FGFR1 signaling axis as a key driver of osteosarcoma progression and a promising target for therapeutic intervention. Show less

The development of FGFR1-driven stem cell leukemia and lymphoma syndrome (SCLL) in mouse models is accompanied by an increase in highly heterogenous myeloid derived suppressor cells (MDSCs), which promote immune evasion. To dissect this heterogeneity, we used a combination of CyTOF and scRNA-Seq to define the phenotypes and genotypes of these MDSCs. CyTOF demonstrated increased levels of circulating macrophages in the peripheral blood of leukemic mice, and flow cytometry demonstrated that these macrophages were derived from Ly6C Show less

Protein arginine methyltransferase 5 (PRMT5) complexes with methylosome protein 50 (MEP50) play crucial roles in tumor progress. However, the regulatory mechanism of governing the PRMT5-MEP50 hetero-octameric complex remains unclear. Here, we demonstrate that C6orf223, to our knowledge an uncharacterized protein, facilitates PRMT5-MEP50 multiprotein complex assembling, thereby promoting colorectal cancer (CRC) growth and metastasis. C6orf223 forms dimers through disulfide bonds, with its N-terminal arginine-enriched region binding to the C-terminal negatively charged groove of PRMT5, thus stabilizing PRMT5-MEP50 multiprotein and enhancing PRMT5 methyltransferase activity. Consequently, PRMT5-mediated H4R3me2s substantially decreases the expression of the tumor suppressor GATA5, leading to the upregulation of multiple oncogenic target genes including WWTR1, FGFR1, and CLU. Targeting C6orf223 using siRNAs encapsulated in ferritin protein shells effectively suppresses CRC tumor growth and metastasis. Collectively, our findings characterize the role of C6orf223 in facilitating PRMT5-MEP50 hetero-octameric complex assembling and suggest that C6orf223 could serve as a potential therapeutic target for CRC. Show less

SANET-ep (NCT02588170) and SANET-p (NCT02589821) demonstrated the efficacy and safety of surufatinib versus placebo in patients with advanced extra-pancreatic and pancreatic neuroendocrine tumours (NETs). Here, we present a pooled analysis of final overall survival (OS) from two randomised phase 3 studies. The SANET studies were randomised, placebo-controlled, double-blind, phase 3 studies in China, comparing the efficacy and safety of oral 300-mg surufatinib (n = 265) versus placebo (n = 133) in patients with unresectable/metastatic, well-differentiated NETs (grade 1/2). After progression of disease or study unblinding, patients receiving placebo crossed over/switched to open-label surufatinib. By pooling the data from the two studies, OS analysis was completed using Kaplan-Meier methodology and a Cox proportional hazards model in the intention-to-treat population. Exploratory analyses were performed using different models to correct the confounding effect introduced by crossover. Long-term safety was assessed. At study termination, 69 % of the placebo group had crossed over/switched to surufatinib. Median OS was 50.1 versus 46.8 months for patients initially on surufatinib versus those initially on placebo (stratified hazard ratio [HR] 0.935, 95 % confidence interval [CI] 0.684-1.278; p = 0.6727). After correcting the confounding effect introduced by crossover/switching, the HR ranged from 0.558 to 0.825. Commonly (≥10 %) reported treatment-related adverse events (grade 3/4) included hypertension and proteinuria. OS of patients initially on surufatinib was not significantly longer versus patients initially on placebo, likely due to the high amount of crossover from placebo to surufatinib. No new safety signals were observed. SANET-ep (NCT02588170) and SANET-p (NCT02589821). Show less

Dysregulation of the fibroblast growth factor receptor 1 (FGFR1) signaling has prompted efforts to develop therapeutic agents, which is a carcinogenic driver of many cancers, including breast, prostate, bladder, and chronic myeloid leukemia. Despite significant progress in the development of potent and selective FGFR inhibitors, the long-term efficacy of these drugs in cancer therapy has been hampered by the rapid onset of acquired resistance. Therefore, more drug discovery strategies are needed to promote the development of FGFR-targeted drugs. Here, we discovered compound S2h, a compound that selectively and effectively degrades FGFR1 at nanomolar concentrations in KG1a cells (IC Show less

A distinctive subset of uterine mesenchymal tumors display recurrent genetic fusions involving receptor tyrosine kinases, including NTRK, PDGFB, FGFR1, and RET, presumably leading to aberrant pathway activation. A pair of recent studies have highlighted the existence of a genetic fusion-negative uterine sarcoma that is characterized by activating mutations in ERBB2/ERBB3, CDKN2A deletion, inactivating ATRX mutation, and a S100 + /SOX10 + immunohistochemical profile. This report describes another case of this emerging entity that was diagnosed in a 57-year-old woman. The 8-cm tumor was centered in the uterine cervix and was comprised mostly of spindle cells configured in fascicles. The tumor was diffusely immunoreactive for SOX10 and S100, with more localized staining for CD68, CD56, MITF, and PRAME. HMB-45, ER, PR, HER2, Melan-A/MART1, STAT6, pan-TRK, ALK, CD34, desmin, CD10, myogenin, and pancytokeratins were all negative, and there was retained expression of H3K27me3. The following molecular alterations were found: ERBB2 p.Val777Leu, ATRX p.F2113Sfs*, CDKN2A deep deletion, NF1 p.W2317*, SMARCA4 p691Sfs*. The authors review the sparse literature on molecular-genetic aberrations involving the epidermal growth factor receptor family of receptor tyrosine kinases (ERBB1/EGFR, ERBB2, ERBB3, and ERBB4) in uterine mesenchymal tumors, a review that suggests that such tumors may be pathologically heterogeneous. The potential clinical significance of demonstrating a targetable ERBB2/ERBB3 tyrosine kinase mutation or other EGFR family aberrations, as well as its distinctive pathologic profile, supports the segregation of the tumor reported herein as a distinct and emerging entity. Show less

The global decline in sperm quality in men is closely associated with environmental exposure to the plasticizer Di-(2-ethylhexyl) phthalate (DEHP), but the molecular mechanisms underlying its induction of asthenozoospermia (AZS) remain incompletely understood. By integrating the toxicological targets of DEHP and differential genes in AZS patients, and combining machine learning, molecular docking, and dynamics simulations, this study successfully identified hub genes and signaling pathways induced by DEHP in AZS, aiming to provide new strategies for the prevention and treatment of this disease. A total of 26 toxicological targets were identified, with FGFR1, MMP7, and ST14 clearly defined as playing crucial regulatory roles in DEHP-induced AZS. This study also reveals that DEHP may induce reproductive system inflammation, affecting the proliferation and survival of reproductive cells, and subsequently impacting sperm vitality, possibly through regulating the mTORC1 pathway, TNF-α signaling via the NF-κB pathway, and MYC targets v1 pathway. Furthermore, changes in the immune microenvironment revealed the significant impact of immune status on testicular function. In conclusion, this study provides important scientific evidence for understanding the molecular mechanisms of AZS and developing prevention and treatment strategies based on toxicological targets. Show less

Single nucleotide polymorphisms (SNPs) located in the genes participating in the steroid hormone metabolism pathway may influence the outcomes of androgen deprivation therapy (ADT) in prostate cancer (PCa) patients, but findings on the Chinese population remain limited. A multicentric cohort of 301 Chinese PCa patients receiving first-line ADT was enrolled. Germline SNPs located in 62 steroid hormone metabolism-related genes were analyzed for associations with time to ADT failure using multivariate Cox regression. Important expression quantitative trait loci (eQTLs) were discovered. Four SNPs were significantly associated with time to ADT failure: rs36119043 in AKR1D1 (hazard ratio, HR = 2.02, 95% confidence interval, 95% CI: 1.44-2.85, p = 5.72 × 10 SNPs in the steroid hormone metabolism pathway can predict time to ADT failure in Chinese PCa patients, supporting their potential role for drug response and pharmacogenomic stratification. Show less

Mutations in LRRK2, a leading genetic cause of Parkinson's disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples (n = 651) and matched CSF samples (n = 129) from LRRK2 mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, LRRK2 mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of LRRK2 status, PD was associated with nominally lower levels of inflammatory analytes in CSF, with minimal changes observed in serum. Correlation analyses revealed distinct immune profiles between serum and CSF, suggesting compartmentalized immune responses. These findings highlight immune alterations in LRRK2 mutation carriers and PD, providing potential serum markers for monitoring immune responses and avenues for mechanistic studies. Show less

Altering inflammation can impact the recovering heart's structure and function following myocardial infarction (MI). MAP kinase-activated protein kinase 2 (MK2) regulates the stability of several pro-inflammatory cytokines. Hence, this study was to determine if MK2 deficiency impaired the inflammatory phase of post-MI wound repair. Myocardial infarctions were induced by permanent ligation of the left anterior descending coronary artery in 12-week-old male MK2 Show less

Lupus nephritis is recognized as a common and severe complication of systemic lupus erythematosus, without an optimal therapeutic strategy currently available. While mesenchymal stem cells (MSCs) hold therapeutic promise, their efficacy varies substantially, likely due to their plasticity and capacity to adopt pro-inflammatory (MSC1) or anti-inflammatory (MSC2) functional states in response to different microenvironments. Here, we report for the first time that IL-27, via JAK1-STAT1 signaling, up-regulates indoleamine 2,3-dioxygenase (IDO) in MSCs, driving MSC differentiation toward an IDO-positive MSC2 phenotype with low immunogenicity. These IDO-positive MSC2 cells produce kynurenine and kynurenic acid, the metabolites of tryptophan, which bind to the intracellular aryl hydrocarbon receptor. This interaction stimulates an increase in the anti-inflammatory factor TSG-6 and induces the differentiation of regulatory T cells. Notably, IL-27-conditioned MSC2 demonstrated superior therapeutic efficacy compared to conventional MSCs in a murine lupus nephritis model. In conclusion, this study revealed that IL-27 is a critical modulator of MSC immune plasticity and presented a novel therapeutic strategy utilizing IL-27-enhanced MSC2 for autoimmune diseases. Show less

Ionizable lipids are critical for determining the potency of mRNA lipid nanoparticles (LNPs). Various mRNA therapies require LNPs that achieve efficient delivery while maintaining appropriate immunogenicity in vivo. While research has largely focused on screening the amine headgroups, linkers and hydrophobic tails of ionizable lipids, the role of tail unsaturation in influencing mRNA delivery and immunogenicity of LNPs has received less attention. Here, we utilized a four-component Ugi reaction (Ugi-4CR) system to synthesize a small library of 17 ionizable lipids with identical backbones but varying in degrees, positions, and types of unsaturation in hydrophobic tails. We systemically investigated structure-activity relationships and elucidated the influence of tail unsaturation on physicochemical properties, endosomal escape, mRNA delivery efficiency and immunogenicity of LNPs. The findings indicate that optimization of tail unsaturation could serve as a promising strategy to improve mRNA encapsulation and delivery efficacy while modulating LNP immunogenicity in vivo. Using interleukin-27 (IL-27)-encoded mRNA as a model, we demonstrated the potential of selected LNPs for protein supplementation therapies. These insights provide a foundation for the rational design of ionizable lipids, advancing the development of more efficient and safer mRNA delivery systems. Show less

Mutations in the Leucine-rich repeat kinase 2 ( We investigated the levels of soluble immune regulators in the serum (n=651) and cerebrospinal fluid (CSF, n=129) of In this extensive discovery cohort, we identified several elevated serum immune regulatory factors associated with This study highlights distinct immune profiles associated with LRRK2 mutations and PD in the periphery and CNS. Serum levels of SDF-1alpha and TNF-RII were elevated in LRRK2 mutation carriers, while CSF immune markers were reduced. In PD, irrespective of LRRK2 status, reduced CSF inflammatory analytes and weak serum signals were observed. These results provide insight into immune dysregulation linked to LRRK2 mutations. If replicable in independent datasets, they offer potential avenues for biomarker and therapeutic exploration. Show less

Sjögren's Syndrome (SS) and Type 1 Diabetes (T1D) are autoimmune disorders that can co-occur in patients, leading to complex clinical presentations. Despite observational evidence of their co-occurrence, the underlying genetic mechanisms remain poorly understood. To investigate the shared genetic factors and pathways between SS and T1D, we conducted a comprehensive analysis using multiomic approaches. Conditional and conjunctional false discovery rate analyses were performed to identify genetic polygenicity and overlap between the two diseases. Functional annotation and pathway analysis identified SNPs with regulatory potential. Furthermore, Mendelian Randomization (MR) analyses were employed to investigate causal associations between gene expression and disease risk. Single-cell differential gene expression analysis was also employed to validate the associations of risk genes with T1D and SS. Our analysis identified 36 shared loci, revealing common genetic enrichment between SS and T1D. Functional annotation and pathway analysis revealed 52 credible genes involved in cysteine-related processes, apoptotic signalling and immune responses. MR analyses revealed that AC007283.5 was positively linked with both SS and T1D, while PLEKHM1 and CRHR1-T1 were negatively associated. Additionally, CERS2 was positively associated with SS, DEF6 was positively associated with T1D, and KANSL1-AS1 was negatively associated with T1D, indicating the presence of complex regulatory mechanisms. Moreover, Single-cell differential gene expression analysis confirmed the dysregulation of risk genes in SS and T1D. This study identified shared genetic factors and pathways underlying SS and T1D, highlighting cysteine-related processes and apoptotic signalling. The findings underscore the complex interplay of autoimmunity and the need for targeted treatments addressing their common mechanisms. Show less

Gastroesophageal reflux disease (GERD) is a chronic inflammatory gastrointestinal disease, which has no thoroughly effective or safe treatment. Elevated oxidative stress is a common consequence of chronic inflammatory conditions. We employed Summary-data based MR (SMR) analysis to assess the associations between gene molecular characteristics and GERD. Exposure data were the summary-level data on the levels of DNA methylation, gene expression, and protein expression, which obtained from related methylation, expression, and protein quantitative trait loci investigations (mQTL, eQTL, and pQTL). Outcome data, Genome-wide association study (GWAS) summary statistics of GERD, were extracted from the Ong's study (discovery), the Dönertaş's study (replication), and the FinnGen study (replication). Colocalization analysis was performed to determine if the detected signal pairs shared a causative genetic mutation. Oxidative stress related genes and druggable genes were imported to explore oxidative stress mechanism underlying GERD and therapeutic targets of GERD. The Drugbank database was utilized to conduct druggability evaluation. After multi-omics SMR analysis and colocalization analysis, we identified seven key genes for GERD, which were SUOX and SERPING1, DUSP13, SULT1A1, LMOD1, UBE2L6, and PSCA. SUOX was screened out to be the mediator, which suggest that GERD is related to oxidative stress. SERPING1, SULT1A1, and PSCA were selected to be the druggable genes. These findings offered strong support for the identification of GERD treatment targets in the future as well as for the study of the oxidative stress mechanism underlying GERD. Show less