Causality between serum uric acid and diabetic microvascular complications - a mendelian randomization study.

BACKGROUND: The aim of this study was to investigate whether a causal relationship exists between serum uric acid (SUA) and diabetic microvascular complications using a two-sample Mendelian randomization (MR) method. METHODS: We used the MR approach, utilizing genome-wide association study (GWAS) summary statistics, to estimate the causal effect of SUA on diabetic microvascular complications in European individuals. The summary statistical data of SUA were obtained from the open database (IEU OPEN GWAS PROJECT) (p < 5 × 10- 8), and data on diabetic microvascular complications (diabetic nephropathy, diabetic neuropathy, diabetic retinopathy) were obtained from the FinnGen consortium. F-statistics were calculated to assess the correlation between instrumental variables (IVs) and SUA, and single nucleotide polymorphisms (SNPs) associated with confounders or outcomes were excluded by consulting the PhenoScanner database. Inverse variance weighting (IVW) was used for primary estimation, and MR‒Egger, weighted median (WM), and Mendelian randomization pleiotropy residuals sum and outliers (MR-PRESSO) were used for additional assessment. Heterogeneity was assessed using the Cochran's Q test, and polytropy was assessed using the MR‒Egger intercept. RESULTS: MR analysis revealed a causal relationship between a genetically predicted increase in SUA and diabetic nephropathy [OR = 1.32, 95%(CI) = 1.07-1.63, p = 0.008]. The results were consistent with those after MR-PRESSO [OR = 1.30, 95%(CI) = 1.07-1.58, p = 0.008]. There was a causal relationship between type 2 diabetes mellitus (T2DM) and renal complication IVW [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.049]. These results were consistent with those after MR-PRESSO [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.050]. There was no significant causal relationship between the genetically predicted increase in SUA and diabetic retinopathy [OR 1.09, 95%(CI) = 0.94-1.26, p = 0.249] or diabetic neuropathy [OR = 1.08, 95%(CI) = 0.84-1.40, p = 0.549]. CONCLUSIONS: This MR analysis suggests a causal relationship between genetically predicted uric acid increases and diabetic microvascular complications. A significant causal relationship exists between SUA and diabetic nephropathy but not between SUA and diabetic retinopathy or diabetic neuropathy.

Carrier-Free Self-Assembled Nanomedicines for Promoting Apoptosis and Inhibiting Proliferation in Hepatocellular Carcinoma.

In order to improve the effectiveness of tumor treatment and reduce the toxic side effects of drugs, we formed carrier-free multifunctional nanoparticles (BI NPs) by noncovalent interaction of berberine hydrochloride and IR780. BI NPs possessed the synergistic effects of promoting apoptosis, inhibiting proliferation and metastasis of tumors, and phototherapeutic treatment. Dispersive and passive targeting ability retention (EPR) effects of BI NPs on tumor sites in vivo could be monitored by fluorescence imaging. In addition, BI NPs exhibited effective reactive oxygen species (ROS) generation and photothermal conversion capabilities, photodynamic therapy (PDT), and photothermal therapy (PTT). Importantly, BI NPs inhibit tumor suppression through the AMPK/PI3K/AKT signaling pathway to inhibit tumor proliferation and metastasis. BI NPs not only have efficient in vivo multimodal therapeutic effects but also have good biosafety and potential clinical applications.

Ubiquitin specific peptidase 3: an emerging deubiquitinase that regulates physiology and diseases.

Proteins are the keystone for the execution of various life activities, and the maintenance of protein normalization is crucial for organisms. Ubiquitination, as a post-transcriptional modification, is widely present in organisms, and it relies on the sophisticated ubiquitin-proteasome (UPS) system that controls protein quality and modulates protein lifespan. Deubiquitinases (DUBs) counteract ubiquitination and are essential for the maintenance of homeostasis. Ubiquitin specific peptidase 3 (USP3) is a member of the DUBs that has received increasing attention in recent years. USP3 is a novel chromatin modifier that tightly regulates the DNA damage response (DDR) and maintains genome integrity. Meanwhile, USP3 acts as a key regulator of inflammatory vesicles and sustains the normal operation of the innate immune system. In addition, USP3 is aberrantly expressed in a wide range of cancers, such as gastric cancer, glioblastoma and neuroblastoma, implicating that USP3 could be an effective target for targeted therapies. In this review, we retrace all the current researches of USP3, describe the structure of USP3, elucidate its functions in DNA damage, immune and inflammatory responses and the cell cycle, and summarize the important role of USP3 in multiple cancers and diseases.

An injectable sequential dual-crosslinking catechol-functionalized hyaluronic acid hydrogel for enhanced regeneration of full-thickness burn injury.

Severe burn injuries with massive dermal loss are often underestimated despite their significant impact on morbidity and mortality. Resembling the natural extracellular matrix (ECM), hyaluronic acid (HA)-based dressings have been extensively explored as suitable candidates for burn wound treatment. However, native HA hydrogel's limitations, such as low mechanical strength, rapid degradation, and uncontrollable drug delivery, hinder its efficacy, especially for full-thickness burns requiring injectable hydrogels with robust antibacterial and angiogenic capabilities. Herein, we present a novel multifunctional sequential dual-curing hydrogel system, combining hyperbranched poly(DMA-DMAPMA-PEGDA) (DDP) polymer with thiolated hyaluronic acid (HA-SH). The DDP copolymer, featuring multi-vinyls and catechol functionalities, facilitates two curing reactions taking place sequentially with HA-SH under physiological conditions, balancing convenient injection with the mechanical strength essential for effective wound management. Furthermore, the resulting DDP/HA hydrogels demonstrate enhanced therapeutic attributes, including intrinsic angiogenic and antimicrobial effects, setting them as promising dressing options for deep burn wound therapy.

How CLSPN could demystify its prognostic value and potential molecular mechanism for hepatocellular carcinoma: A crosstalk study.

BACKGROUND & AIMS: CLSPN, a critical component of the S-phase checkpoint in response to DNA replication stress, has been implicated in the pathogenesis of multiple tumor types. The rising incidence of hepatocellular carcinoma (HCC) poses a significant challenge to global public health. Despite this, the specific functions of CLSPN in the development of HCC remain poorly understood. METHODS: We systematically evaluated the expression of CLSPN, prognosis and immune infiltration in patients with HCC and identified a competing endogenous RNA (ceRNA) network by using public database. The RT-qPCR, western blot, CCK8, transwell, flow cytometry, animal experiments, proteasome inhibition experiment, Co-IP assay and mass spectrometry were applied to explore its biological functions, post-transcriptional modifications and potential molecular mechanisms of CLSPN in HCC. RESULTS: We verified the expression of CLSPN, and its high expression is an independent prognostic factor in HCC. The expression of CLSPN is also associated with the immune microenvironment of HCC. CLSPN silencing inhibited the proliferation, migration, invasion and cell cycle progression of HCC cells. We established a PSMA3-AS1/hsa-miR-101-3p/CLSPN regulator axis in HCC. CLSPN was influenced by ubiquitination and was involved in the Wnt/ß-catenin pathway to regulate HCC progression. CONCLUSIONS: It was the first time to comprehensively discover and identify the expression, prognosis, immunotherapy, RNAs regulator, posttranscriptional modification, and molecular mechanisms of CLSPN in HCC. These novel insights have the potential to expedite the development of personalized treatment strategies and translational medicine approaches for HCC patients.

Tumor microenvironment responsive nano-platform for overcoming sorafenib resistance of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor, which seriously jeopardizes human health. The 5-year relative survival rate of HCC is only about 18%. Sorafenib, a small molecule multi-targeted tyrosine kinase inhibitor (MTKI), has been classified as the first-line treatment scheme for HCC and has significantly extended the median survival time for patients with advanced HCC. Nevertheless, the emergence of sorafenib resistance has substantially hampered its further clinical application. Herein, the nano-platform based on phototherapy and small molecular targeted therapy (SMTT) was devised to overcome the sorafenib resistance and reduce the adverse effects. Hollow mesoporous manganese dioxide (H-MnO2) was prepared by hard template method, and the prepared H-MnO2 was used to load sorafenib and Chlorin e6 (Ce6). Subsequently, the nanoparticle (NPs) were modified with dopamine to optimize biocompatibility. The final prepared NPs (MCS NPs) exhibit regular spherical shape with a hydrated particle size of approximately 97.02 nm. MCS NPs can not only possess tumor microenvironment (TME) stimuli-responsive drug release performance but also can enhance the efficacy of photodynamic therapy and reverse sorafenib resistance by alleviating tumor hypoxia. Under the action of phototherapy (Ce6) combined with molecular targeted therapy (sorafenib), MCS NPs manifest a satisfactory antitumor effect for sorafenib-sensitive or sorafenib-resistant HCC cells, and retain the antiangiogenic properties of sorafenib. In the nude mouse subcutaneous tumor model constructed with sorafenib-resistant cells, MCS NPs demonstrated superior tumor imaging ability and excellent biocompatibility. The tumor inhibition rate of the MCS NPs group without laser irradiation was 53.4 %, while the MCS NPs group with laser irradiation was as high as 100 %. The novel smart TME-responsive nano-platform shows great potential for overcoming sorafenib resistance and realizes multimodality imaging and therapy of HCC.

Spotlights on ubiquitin-specific protease 12 (USP12) in diseases: from multifaceted roles to pathophysiological mechanisms.

Ubiquitination is one of the most significant post-translational modifications that regulate almost all physiological processes like cell proliferation, autophagy, apoptosis, and cell cycle progression. Contrary to ubiquitination, deubiquitination removes ubiquitin from targeted protein to maintain its stability and thus regulate cellular homeostasis. Ubiquitin-Specific Protease 12 (USP12) belongs to the biggest family of deubiquitinases named ubiquitin-specific proteases and has been reported to be correlated with various pathophysiological processes. In this review, we initially introduce the structure and biological functions of USP12 briefly and summarize multiple substrates of USP12 as well as the underlying mechanisms. Moreover, we discuss the influence of USP12 on tumorigenesis, tumor immune microenvironment (TME), disease, and related signaling pathways. This study also provides updated information on the roles and functions of USP12 in different types of cancers and other diseases, including prostate cancer, breast cancer, lung cancer, liver cancer, cardiac hypertrophy, multiple myeloma, and Huntington's disease. Generally, this review sums up the research advances of USP12 and discusses its potential clinical application value which deserves more exploration in the future.

N6-methyladenosine with immune infiltration and PD-L1 in hepatocellular carcinoma: novel perspective to personalized diagnosis and treatment.

Background: Increasing evidence elucidated N6-methyladenosine (m6A) dysregulation participated in regulating RNA maturation, stability, and translation. This study aimed to demystify the crosstalk between m6A regulators and the immune microenvironment, providing a potential therapeutic target for patients with hepatocellular carcinoma (HCC). Methods: Totals of 371 HCC and 50 normal patients were included in this study. GSE121248 and GSE40367 datasets were used to validate the expression of HNRNPC. The R package "ConsensusClusterPlus" was performed to screen consensus clustering types based on the expression of m6A regulators in HCC. The R package "pheatmap", "immunedeconv", "survival", "survminer" and "RMS" were applied to investigate the expression, immunity, overall survival, and clinical application in different clusters and expression groups. Comprehensive analysis of HNRNPC in pan-cancer was conducted by TIMER2 database. Besides, HNRNPC mRNA and protein expression were verified by qRT-PCR and immunohistochemistry analysis. Results: Most of m6A regulators were over-expressed excerpt for ZC3H13 in HCC. Three independent clusters were screened based on m6A regulators expression, and the cluster 2 had a favorable prognosis in HCC. Then, the cluster 2 was positively expression in macrophage, hematopoietic stem cell, endothelial cell, and stroma score, while negatively in T cell CD4+ memory and mast cell. We identified HNRNPC was an independent prognostic factor in HCC, and nomogram performed superior application value for clinical decision making. Moreover, PD-L1 was significantly up-regulated in HCC tissues, cluster 1, and cluster 3, and we found PD-L1 expression was positively correlated with HNRNPC. Patients with HCC in high-expression groups was associated with tumor-promoting cells. Besides, HNRNPC was correlated with prognosis, TMB, and immune checkpoints in cancers. Particularly, the experiments confirmed that HNRNPC was positively expression in HCC cells and tissues. Conclusion: The m6A regulators play irreplaceable roles in prognosis and immune infiltration in HCC, and the relationship of HNRNPC and PD-L1 possesses a promising direction for therapeutic targets of immunotherapy response. Exploration of m6A regulators pattern could be build the prognostic stratification of individual patients and move toward to personalized treatment.

Crosstalk of ferroptosis regulators and tumor immunity in pancreatic adenocarcinoma: novel perspective to mRNA vaccines and personalized immunotherapy.

Pancreatic adenocarcinoma (PAAD) is the eighth leading cause of cancer-related mortality that causes serious physical and mental burden to human. Reactive oxygen species accumulation and iron overload might enable ferroptosis-mediated cancer therapies. This study was to elusive novel ferroptosis regulator and its association with immune microenvironment and PD-L1 in PAAD. RNA-seq data and relevant information were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression. The R packages "ggplot2" and "pheatmap" were used to the expression of 20 ferroptosis regulators between PAAD and normal tissues. The R package "ConsensusClusterPlus", "survival", "survminer", "immunedeconv", and TIDE algorithm performed consensus clustering, overall survival, progression-free survival, disease free survival, immune infiltration level, and immunotherapy responses between cluster 1 and cluster 2. The prognostic value was confirmed by the Kaplan-Meier curves, receiver operating characteristic curve, univariate and multivariate cox regression, and nomogram. Moreover, the relationship of FANCD2 and immunity, drug sensitivity was investigated by R package "ggstatsplot", "immunedeconv", "ggalluvial" and "pRRophetic". Besides, the qRT-PCR, immunohistochemistry and western blotting detected the expression of FANCD2 in PAAD cell lines. Most ferroptosis regulators were up-regulated in PAAD, while the expression of LPCAT3, MT1G, and GLS2 was down-regulated in PAAD (P < 0.05), indicting there was a positively correlation among ferroptosis regulators. Based on clustering parameter, we identified cluster 1 and cluster 2, and cluster 2 had a better prognosis for patients with PAAD. The immune infiltration level of cluster 1 was higher in macrophage M1, myeloid dendritic cell, T cell CD4 + Th2, B cell, T cell CD8 + central memory, immune score, and microenvironment score than cluster 2 in PAAD. Moreover, FANCD2 was up-regulated in PAAD by public databases, immunohistochemistry, qRT-PCR and Western blotting, which had closely related to overall survival, immune microenvironment, and drug sensitivity. A novel crosstalk of ferroptosis exhibits a favourable prognostic performance and builds a robust theoretical foundation for mRNA vaccine and personalized immunotherapy. FANCD2 could be an effective for prognostic recognition, immune efficacy evaluation, and mRNA vaccine for patients with PAAD, providing a vital guidance for further study of regulating tumor immunity and vaccine development.

Glycosylation-related molecular subtypes and risk score of hepatocellular carcinoma: Novel insights to clinical decision-making.

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer deaths worldwide, seriously affecting human community health and care. Emerging evidence has shown that aberrant glycosylation is associated with tumor progression and metastasis. However, the role of glycosylation-related genes in HCC has notbeen reported. Methods: Weighted gene coexpression network analysis and non-negative matrix factorization analysis were applied to identify functional modules and molecularm subtypes in HCC. The least absolute shrinkage and selection operator Cox regression was used to construct the glycosylation-related signature. The independent prognostic value of the risk model was confirmed and validated by systematic techniques, including principal component analysis, T-distributed random neighbor embedding analysis, Kaplan-Meier survival analysis, the ROC curve, multivariate Cox regression, the nomogram, and the calibration curve. The single-sample gene set enrichment analysis, gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were evaluated by the immune microenvironment and potential biological processes. The quantitative real-time polymerase chain reaction and immunohistochemistry analysis were used to verify the expression of five genes. Results: We identified the glycosylation-related genes with bioinformatics analysis to construct and validate a five-gene signature for the prognosis of HCC patients. Patients with HCC in the high-risk group had a worse prognosis. The risk score could be an independent factor and was associated with clinical features, such as the grade and stage. The nomogram exhibited an accurate score that included the risk score and clinical parameters. The infiltration levels of antitumor cells were upregulated in the low-risk group, including B_cells, Mast_cells, neutrophils, NK_cells, and T_helper_cells. Moreover, glycosylation was more sensitive to immunotherapy, and may play a critical role in the metabolic processes of HCC, such as bile acid metabolism and fatty acid metabolism. In addition, the five-gene messenger RNA (mRNA) and protein expression were overexpressed in HCC cells and tissues. Conclusions: The glycosylation-related signature is effective for prognostic recognition, immune efficacy evaluation, and substance metabolism in HCC, providing a novel insight for therapeutic target prediction and clinical decision-making.

A synergy between dopamine and electrostatically bound bactericide in a poly (vinyl alcohol) hybrid hydrogel for treating infected wounds.

Antibacterial hydrogels have emerged as viable options for battling infections associated with impaired wound healing. It is challenging in developing antibacterial hydrogels that have sustained and stable bactericidal activity while avoiding the use of any agents that may adversely affect safety. In view of this concern, a multi-functional polyvinyl alcohol (PVA)/sodium alginate-dopamine (SA-DA) hydrogel matrix-based wound dressing embedding with bis-quaternary triphenyl-phosphonium salt (BTPP+), that would present long-term intrinsic antimicrobial properties was developed using freeze-thawing (F-T) method herein. DA endows the hydrogel with efficient bacteria capture ability and subsequently the captured bacterial pathogens were in situ killed by electrostatically bound BTPP+, and hence significantly augmented the antibacterial efficacy. Furthermore, DA, co-operating with BTPP+ could promote erythrocyte and platelet aggregation on hydrogels, which ensures hydrogels with improved hemostasis capacity. Thus, this investigation provides a feasible simple avenue for development of long-term intrinsic antimicrobial hydrogel dressings with efficient hemostasis efficacy for infected wounds.

Gender-Based Deep Learning Firefly Optimization Method for Test Data Generation.

Software testing is a widespread validation means of software quality assurance in industry. Intelligent optimization algorithms have been proved to be an effective way of automatic test data generation. Firefly algorithm has received extensive attention and been widely used to solve optimization problems because of less parameters and simple implement. To overcome slow convergence rate and low accuracy of the firefly algorithm, a novel firefly algorithm with deep learning is proposed to generate structural test data. Initially, the population is divided into male subgroup and female subgroup. Following the randomly attracted model, each male firefly will be attracted by another randomly selected female firefly to focus on global search in whole space. Each female firefly implements local search under the leadership of the general center firefly, constructed based on historical experience with deep learning. At the final period of searching, chaos search is conducted near the best firefly to improve search accuracy. Simulation results show that the proposed algorithm can achieve better performance in terms of success coverage rate, coverage time, and diversity of solutions.

PEGylated Bis-Quaternary Triphenyl-Phosphonium Tosylate Allows for Balanced Antibacterial Activity and Cytotoxicity.

Quaternary triphenylphosphonium compounds (TPP+) have been widely recognized as an important antimicrobial because of their fast antimicrobial speed and broad antimicrobial spectrum. However, small-molecule TPP+ compounds have the defects of toxicity, which is the key factor that limits their practical applications. Here, two mono- and one bis-quaternary phosphonium tosylate compounds with different lengths of oligo(ethylene glycol) (OEG) chains and TPP+ as the active moiety were synthesized. Bis-TPP+ have a short OEG chain coupling two TPP+ at both ends, while mono-TPP+ attaches the OEG chain at one end in one molecule. In vitro antibacterial activities were evaluated against both Gram-positive as well as Gram-negative bacteria in terms of the inhibition zone (ZOI) and minimum inhibitory concentration (MIC). To investigate the antibacterial mechanism, ß-galactosidase activity was monitored for measuring the degree of membrane permeability correlated to the abilities to disrupt the membranes of bacteria. Moreover, their structure-antibacterial activity and structure-cytotoxicity relationships were further analyzed. The results indicated that bis-TPP+ synthesized can reach the sterilization rate 90% or more against Escherichia coli and Staphylococcus aureus at MICs of 3.1 and 1.5 mg/mL, respectively, and meanwhile, the cell proliferation can reach more than 80%. This paper represents an excellent approach for development of bis-TPP+ bactericidal molecules that would achieve an optimal balance between antimicrobial activity and cytotoxicity.