Glutaraldehyde crosslinked ternary carboxymethylcellulose/polyvinyl alcohol/polyethyleneimine film with enhanced mechanical properties, water resistance, antibacterial activity, and UV-shielding ability without any UV absorbents.

Despite the plethora of methods reported for fabricating ultraviolet (UV) shielding films using various UV absorbers to date, it remains a major challenge for the development of novel UV shielding films that simultaneously exhibit excellent transparency. In this work, a novel composite film (GA-x-CMC/PVA/PEI) is fabricated by integrating anionic carboxymethylcellulose (CMC), cationic polyethyleneimine (PEI), and polyvinyl alcohol (PVA) via electrostatic and hydrogen bond interactions and further cross-linking with glutaraldehyde (GA). Herein, PVA expands hydrogen bonding networks, reduces film haze, and enhances its mechanical strength. GA acts as a crosslinker in producing Schiff bases with PEI and acetals with CMC and PVA. The synthesized GA-x-CMC/PVA/PEI composite film possesses a notable amount of unsaturated -CH=N- bonds of Schiff base, resulting from the condensation of PEI and GA, which exhibit superior shielding efficiency against both UV-A and UV-B rays while maintaining exceptional transparency, visibility, and simultaneously enhancing mechanical properties and thermal stability. Notably, increasing the content of PEI leads to almost complete shielding of the entire UV spectrum (<400 nm) due to the increasing of the number of -CH=N- unsaturated bonds. Furthermore, the obtained film without any UV-shielding additives has exceptional mechanical properties, hydrophobicity, and antibacterial properties, rendering it a wide application prospect.

TET3-overexpressing macrophages promote endometriosis.

Endometriosis is a debilitating, chronic inflammatory disease affecting ~10% of reproductive age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we reported identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We showed that factors from the disease microenvironment upregulated TET3 expression transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated pro-inflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival, hence vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation both in human and mouse macrophages. This degradation was dependent on a VHL E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.

Bidirectional effects of the tryptophan metabolite indole-3-acetaldehyde on colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) has a high incidence and mortality. Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis, progression, and metastasis of CRC. AIM: To investigate the effect of indole-3-acetaldehyde (IAAD) on CRC. METHODS: The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines (HCT116 and DLD-1). Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests. Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide. Invasiveness was investigated using the transwell assay. Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor (AhR) downstream genes. The PharmMapper, SEA, and SWISS databases were used to screen for potential target proteins of IAAD, and the core proteins were identified through the String database. RESULTS: IAAD reduced tumorigenesis in a syngeneic mouse model. In CRC cell lines HCT116 and DLD1, IAAD exhibited cytotoxicity starting at 24 h of treatment, while it reduced Ki67 expression in the nucleus. The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells, which may be related to the activation of AhR. IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells. At low concentrations (< 12.5 µmol/L), IAAD only exhibited cytotoxic effects without promoting cell invasion. In addition, predictions based on online databases, protein-protein interaction analysis, and molecular docking showed that IAAD can bind to matrix metalloproteinase-9 (MMP9), angiotensin converting enzyme (ACE), poly(ADP-ribose) polymerase-1 (PARP1), matrix metalloproteinase-2 (MMP2), and myeloperoxidase (MPO). CONCLUSION: Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC; however, at high concentrations (≥ 25 µmol/L), it can also promote epithelial-mesenchymal transition and invasion in CRC cells. IAAD activates AhR and directly binds MMP9, ACE, PARP1, MMP2, and MPO, which partly reveals why it has a bidirectional effect.

Prognostic implication and immunotherapy response prediction of a novel ubiquitination-related gene signature in liver cancer.

HCC, also known as hepatocellular carcinoma, is a frequently occurring form of cancer with an unfavorable prognosis. This research constructed a prognostic signature related to ubiquitination and investigated its correlation with the response to immunotherapy in HCC. The Molecular Signatures Database provided a compilation of genes associated with ubiquitination. A gene signature related to ubiquitination was obtained through Cox regression using the Least Absolute Shrinkage and Selection Operator method. The genetic factors CPY26B1, MCM10, SPINK4, and TRIM54 notably impacted the outcomes of HCC. The patients were divided into two groups: one group had a high risk of poor survival while the other had a low risk but a greater chance of controlling HCC progression. Both univariate and multivariate analyses using Cox regression found the risk score to be an independent predictor of HCC prognosis. Gene set enrichment analysis (GSEA) indicated enrichment in cell cycle and cancer-related microRNAs in high-risk groups. The tumor microenvironment (TME), response to immunotherapy, and effectiveness of chemotherapy medications positively correlated with the risk score. In the high-risk group, erlotinib showed higher IC50 values compared to the low-risk group which exhibited higher IC50 values for VX-11e, AKT inhibitor VIII, AT-7519, BMS345541, Bortezomib, CP466722, FMK, and JNK-9L. The results of RT-qPCR revealed that the expression of four UEGs was higher in tumor tissue as compared to normal tissue. Based on the genes that were expressed differently and associated with ubiquitination-related tumor categorization, we have developed a pattern of four genes and a strong nomogram that can predict the prognosis of HCC, which could be useful in identifying and managing HCC.

Expression and clinical significance of short-chain fatty acids in patients with intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver condition that typically arises in the middle and late stages of pregnancy. Short-chain fatty acids (SCFAs), prominent metabolites of the gut microbiota, have significant connections with various pregnancy complications, and some SCFAs hold potential for treating such complications. However, the metabolic profile of SCFAs in patients with ICP remains unclear. AIM: To investigate the metabolic profiles and differences in SCFAs present in the maternal and cord blood of patients with ICP and determine the clinical significance of these findings. METHODS: Maternal serum and cord blood samples were collected from both patients with ICP (ICP group) and normal pregnant women (NP group). Targeted metabolomics was used to assess the SCFA levels in these samples. RESULTS: Significant differences in maternal SCFAs were observed between the ICP and NP groups. Most SCFAs exhibited a consistent declining trend in cord blood samples from the ICP group, mirroring the pattern seen in maternal serum. Correlation analysis revealed a positive correlation between maternal serum SCFAs and cord blood SCFAs [r (Pearson) = 0.88, P = 7.93e-95]. In both maternal serum and cord blood, acetic and caproic acids were identified as key metabolites contributing to the differences in SCFAs between the two groups (variable importance for the projection > 1). Receiver operating characteristic analysis demonstrated that multiple SCFAs in maternal blood have excellent diagnostic capabilities for ICP, with caproic acid exhibiting the highest diagnostic efficacy (area under the curve = 0.97). CONCLUSION: Compared with the NP group, significant alterations were observed in the SCFAs of maternal serum and cord blood in the ICP group, although they displayed distinct patterns of change. Furthermore, the SCFA levels in maternal serum and cord blood were significantly positively correlated. Notably, certain maternal serum SCFAs, specifically caproic and acetic acids, demonstrated excellent diagnostic efficiency for ICP.

Bone marrow mesenchymal stem cell-derived exosomes shuttle microRNAs to endometrial stromal fibroblasts that promote tissue proliferation /regeneration/ and inhibit differentiation.

BACKGROUND: Human bone marrow-derived stem cells (hBMDSCs) are well characterized mediators of tissue repair and regeneration. An increasing body of evidence indicates that these cells exert their therapeutic effects largely through their paracrine actions rather than clonal expansion and differentiation. Here we studied the role of microRNAs (miRNAs) present in extracellular vesicles (EVs) from hBMDSCs in tissue regeneration and cell differentiation targeting endometrial stromal fibroblasts (eSF). METHODS: Extracellular vesicles (EVs) are isolated from hBMDSCs, characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) techniques. Extracted total RNA from EVs was subjected to RNA seq analysis. Transfection and decidualization studies were carried out in endometrial stromal fibroblasts (eSF). Gene expression was analyzed by qRTPCR. Unpaired t-test with Welch's correction was used for data analysis between two groups. RESULTS: We identified several microRNAs (miRNAs) that were highly expressed, including miR-21-5p, miR-100-5p, miR-143-3p and let7. MiR-21 is associated with several signaling pathways involved in tissue regeneration, quiescence, cellular senescence, and fibrosis. Both miR-100-5p and miR-143-3p promoted cell proliferation. MiR-100-5p specifically promoted regenerative processes by upregulating TGF-ß3, VEGFA, MMP7, and HGF. MiR-100-5p blocked differentiation or decidualization as evidenced by morphologic changes and downregulation of decidualization mediators including HOXA10, IGFBP1, PRL, PR-B, and PR. CONCLUSION: EVs delivered to tissues by hBMDSCs contain specific miRNAs that prevent terminal differentiation and drive repair and regeneration. Delivery of microRNAs is a novel treatment paradigm with the potential to replace BMDSCs in cell-free regenerative therapies.

Study of the impurity profile of photodegradation in lomefloxacin hydrochloride ear drops using liquid chromatography combined with ion trap/time-of-flight mass spectrometry.

RATIONALE: Lomefloxacin hydrochloride ear drops are highly unstable to light and prone to produce photodegradation impurities. These impurities might be related to the phototoxicity of lomefloxacin, which could seriously threaten the health of patients. In this article, the photodegradation impurity profile in lomefloxacin hydrochloride ear drops was studied for further improvement of quality control of the drug. METHODS: By studying the chromatographic behavior of photodegradation impurities, the photodegradation impurities in lomefloxacin hydrochloride ear drops were separated and detected effectively. Liquid chromatography combined with ion trap/time-of-flight mass spectrometry was applied to characterize the structures of the photodegradation impurities in lomefloxacin hydrochloride ear drops. RESULTS: The structures of 17 impurities in lomefloxacin hydrochloride ear drops were elucidated based on high-resolution MSn data in positive ion mode, 12 of them being unknown impurities. CONCLUSIONS: The structural characteristics and fragmentation patterns of the photodegradation impurities were also studied. The study of the photodegradation impurity profile in lomefloxacin hydrochloride ear drops provides a scientific basis for quality control of these ear drops and ensures the safety of drug use by the public.

Examination of the adoption intention of new energy vehicles from the perspective of functional attributes and media richness.

Drawing on the theory of media richness, this paper aims to explore the impact of media richness on consumers' adoption intention through their perception of new energy vehicle (NEV) function attributes, and assess the moderation roles of brand familiarity and locus of control. A structural equation model is applied to analyze the data collected from 427 respondents. Empirical results demonstrate that consumers' perception of an electric attribute (i.e., charging efficiency) and two intelligent attributes (i.e., car networking and self-driving) are determinants of their adoption intention of NEVs. The other electric attribute (range) is trivial in consumers' perception. We also find that low, medium, and high-richness media significantly affect consumers' perception of NEVs' functional attributes. Compared to the high-richness, medium-richness correlates significantly with two types of NEV functional attributes. Regarding moderating effects, consumer familiarity with NEV's brand negatively impacts the relationship between media richness and adoption intention. Furthermore, low and medium-richness media effectively stimulate individuals with external control to adopt NEV, while high-richness media adversely influence individuals with internal control.

Microplastic-mediated new mechanism of liver damage: From the perspective of the gut-liver axis.

Microplastics (MPs) are environmental contaminants that are present in all environments and can enter the human body, accumulate in various organs, and cause harm through the ingestion of food, inhalation, and dermal contact. The connection between bowel and liver disease and the interplay between gut, liver, and flora has been conceptualized as the "gut-liver axis". Microplastics can alter the structure of microbial communities in the gut and the liver can also be a target for microplastic invasion. Numerous studies have found that when MPs impair human health, they not only promote dysbiosis of the gut microbiota and disruption of the gut barrier but also cause liver damage. For this reason, the gut-liver axis provides a new perspective in understanding this toxic response. The cross-talk between MPs and the gut-liver axis has attracted the attention of the scientific community, but knowledge about whether MPs cause gut-liver interactions through the gut-liver axis is still very limited, and the effect of MPs on liver injury is not well understood. MPs can directly induce microbiota disorders and gut barrier dysfunction. As a result, harmful bacteria and metabolites in the gut enter the blood through the weak intestinal barrier (portal vein channel along the gut-liver axis) and reach the liver, causing liver damage (inflammatory damage, metabolic disorders, oxidative stress, etc.). This review provides an integrated perspective of the gut-liver axis to help conceptualize the mechanisms by which MP exposure induces gut microbiota dysbiosis and hepatic injury and highlights the connection between MPs and the gut-liver axis. Therefore, from the perspective of the gut-liver axis, targeting intestinal flora is an important way to eliminate microplastic liver damage.

Gut microbiota-derived trimethylamine N-Oxide: a novel target for the treatment of preeclampsia.

Pre-eclampsia (PE) is the most common complication of pregnancy and seriously threatens the health and safety of the mother and child. Studies have shown that an imbalance in gut microbiota can affect the progression of PE. Trimethylamine N-oxide (TMAO) is an intestinal microbiota-derived metabolite that is thought to be involved in the occurrence of PE; however, its causal relationship and mechanism remain unclear. In this clinical cohort study, including 28 patients with eclampsia and 39 matched healthy controls, fecal samples were collected for 16S rRNA gene sequencing, and serum was collected for targeted metabolomics research. The results showed that the level of TMAO and the abundance of its source bacteria had significantly increased in patients with PE, and were positively correlated with the clinical progression of PE. Fecal microbiota transplantation (FMT) was applied to an antibiotic-depleted-treated mouse model and targeted inhibition of TMAO. The results of the FMT experiment revealed that mice that received fecal microbiota transplantation from patients with PE developed typical PE symptoms and increased oxidative stress and inflammatory damage, both of which were reversed by 3,3-Dimethyl-1-butanol (DMB), a TMAO inhibitor, which also improved pregnancy outcomes in the model mice. Similar results were obtained in the classical NG-Nitroarginine methyl ester (L-NAME) induced PE mouse model. Mechanistically, TMAO promotes the progression of PE by regulating inflammatory and oxidative stress-related signaling pathways, affecting the migration and angiogenesis of vascular endothelial cells, as well as the migration and invasion of trophoblast cells. Our results reveal the role and mechanism of gut microbiota and TMAO in the progression of PE, provides new ideas for exploring the pathogenesis and therapeutic targets of PE, and determines the potential application value of TMAO as a target for PE intervention.

Chemo-photothermal nanoplatform with diselenide as the key for ferroptosis in colorectal cancer.

Colorectal cancer (CRC) is a prevalent clinical malignancy of the gastrointestinal system, and its clinical drug resistance is the leading cause of poor prognosis. Mechanistically, CRC cells possess a specific oxidative stress defense mechanism composed of a significant number of endogenous antioxidants, such as glutathione, to combat the damage produced by drug-induced excessive reactive oxygen species (ROS). We report on a new anti-CRC nanoplatform, a multifunctional chemo-photothermal nanoplatform based on Camptothecin (CPT) and IR820, an indocyanine dye. The implementation of a GSH-triggered ferroptosis-integrated tumor chemo-photothermal nanoplatform successfully addressed the poor targeting ability of CPT and IR820 while exhibiting significant growth inhibitory effects on CRC cells. Mechanistically, to offset the oxidative stress created by the broken SeSe bonds, endogenous GSH was continuously depleted, which inactivated GPX4 to accumulate lipid peroxides and induce ferroptosis. Concurrently, exogenously administered linoleic acid was oxidized under photothermal conditions, resulting in an increase in LPO accumulation. With the breakdown of the oxidative stress defense system, chemotherapeutic efficacy could be effectively enhanced. In combination with photoacoustic imaging, the nanoplatform could eradicate solid tumors by means of ferroptosis-sensitized chemotherapy. This study indicates that chemotherapy involving a ferroptosis mechanism is a viable method for the treatment of CRC.

Copper ions reinforced flexible carboxymethylcellulose/polyethyleneimine composite films with enhanced mechanical properties, UV-shielding performance, thermal stability, solvent resistance, and antibacterial activity.

A composite film (CMC/PEI) consisting of anionic carboxymethylcellulose (CMC) and cationic polyethyleneimine (PEI) can be easily produced through the solution casting method using self-assembly based on electrostatic interaction and hydrogen bonding. Subsequently, the resulting CMC/PEI polyelectrolyte composite film with a network structure was crosslinked with divalent Cu2+ ions through ionic and coordination bonds, resulting in a strengthened Cu(II)@CMC/PEI film. The composite film was characterized based on its structural, surface, thermal, UV protection, antibacterial, and degradation aspects. The results demonstrated this film has impressive mechanical properties, remarkable solvent resistance, good antibacterial properties, and excellent UV-shielding performance by completely blocking ultraviolet light with wavelengths below 360 nm. These properties can be attributed to the presence of Cu2+ ions and PEI in the film. This work is valuable for the development of novel UV-shielding materials and should contribute to the design of carboxymethylcellulose composite films with desirable properties and exceptional performance.

Logistic regression analysis of risk factors for hematoma after autologous arteriovenous fistula in hemodialysis patients.

To determine the risk factors and nursing countermeasures for post-operative hematoma in hemodialysis patients with autogenous arteriovenous fistula by logistic regression analysis. A retrospective analysis of 240 chronic hemodialysis patients admitted to our hospital from January 2019 to October 2022 was performed. Physical and vascular examinations of the patients were performed by surgeons. Continuous care measures were implemented for all patients. The patient serum creatinine (Scr) and blood urea nitrogen (BUN) were measured on the day of inclusion and after the implementation of care measures. Self-management scales were used to analyze patients' self-management. Fatigue symptoms were assessed using the Fatigue Scale 14. The WHO Quality of Life Scale (WHOQOL-BREF score) was used to assess patients' quality of life. Self-Rating Depression Scale and Self-Rating Anxiety Scale (SAS) were used to assess negative affect. Treatment compliance was assessed according to 3 levels: complete compliance, compliance, and noncompliance. In all, 240 patients underwent 240 initial and 48 repeat procedures; 18 of the 240 patients experienced fistula failure, with an overall success rate of 92.5% (222/240). There were no significant differences in renal function, self-management, General Self-Efficacy Scale, fatigue symptom scores, and WHOQOL-BREF scores between the postoperative hematoma group and no-hematoma group before the continuous care. After continuous care, renal function, self-management, General Self-Efficacy Scale, fatigue symptom scores, and WHOQOL-BREF scores were better in the postoperative no-hematoma group than in the hematoma group, and the difference was statistically significant (P < .05). Logistic regression analysis of risk factors for postoperative hematoma showed that elevated Scr and BUN levels, decreased self-management and SAS scores and poor treatment compliance were independent risk factors for postoperative hematoma in hemodialysis patients with autologous arteriovenous fistulas (P < .05). Elevated Scr levels, elevated BUN levels, decreased self-management scores, decreased SAS scores, and poor treatment compliance were independent risk factors for postoperative hematoma in hemodialysis patients with autogenous arteriovenous fistulas. By providing continuous care to hemodialysis patients based on timing theory, the negative emotions can be alleviated and the self-efficacy, quality of life, and treatment compliance of the patients can be improved.

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study.

BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear. METHODS: Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined. RESULTS: In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A, TET2, RUNX1, and ASXL1. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (P<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1ß and interleukin-6 and lower interleukin-4 and IgG galactosylation levels. CONCLUSIONS: This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.