Peritoneal fibrosis is the leading cause of ultrafiltration failure and treatment discontinuation in long-term peritoneal dialysis, but there are currently no effective tools for its early diagnosis. The pathophysiological mechanisms involved include mesothelial–mesenchymal transition, chronic inflammation, pathological angiogenesis, hypoxia, metabolic disturbances, oxidative stress/ferroptosis, and activation of the renin–angiotensin–aldosterone system. A positive feedback loop forms between the TGF-β1/Smad and inflammatory NF-κB pathways; hypoxia-driven HIF-1α/VEGF links angiogenesis with fibrosis; and metabolic dysregulation introduces epigenetics as a novel driving factor. Emerging non-invasive biomarkers in peritoneal dialysis effluent, such as CCL18, IL-17A, AQP1, MMP-2, eDcR2, XBP1s, and exosomal ILK, show great promise for early diagnosis. By examining the cross-regulatory interactions among these mechanisms from a pathological network perspective, rather than focusing on isolated molecules, we can accelerate the translation of biomarker discoveries into clinical practice and improve long-term outcomes for patients undergoing peritoneal dialysis.

Objective:To compare the analgesic efficacy and safety of deep, superficial and combined deep-superficial erector spinae plane block (ESPB) combined with subanesthetic-dose esketamine in patients undergoing percutaneous kyphoplasty (PKP). Patients and Methods:A total of 120 elderly patients with osteoporotic vertebral compression fractures and undergoing elective PKP were randomly divided into three groups (n=40 each): a deep ESPB group (D), a superficial ESPB group (S) and a combined deep-superficial ESPB group (C). All patients received intravenous esketamine (0.125 mg/kg) preoperatively. We recorded intraoperative and postoperative Visual Analogue Scale (VAS) scores, hemodynamic parameters, the onset time for sensory block, rescue analgesia requirements and adverse reactions. Results:The combined group exhibited significantly lower cumulative intraoperative pain (AUC: 0-4), fewer administrations of rescue analgesia, and more stable hemodynamics than the two single-depth groups (P<0.01 for all). Differences in postoperative analgesia were only observed at 6 hours, with no significant differences at 12 and 24 hours. No significant difference was found between the three groups in terms of the incidence of adverse reactions. Conclusion:Combined deep and superficial ESPB combined with subanesthetic-dose esketamine provides superior intraoperative analgesia and hemodynamic stability for patients with PKP, with a safety profile that is similar to single-depth blocks.

Background To compare the clinical efficacy and safety of rituximab (RTX) monotherapy versus the combination of RTX and glucocorticoids (GC) in the treatment of primary membranous nephropathy (PMN). Methods This retrospective, single-center cohort study enrolled 128 patients diagnosed with PMN between January 2021 and November 2024. 51 patients received RTX monotherapy and 77 patients received RTX + GC therapy, who were all followed up for 12 months. Primary outcomes were defined as the complete remission and partial remission. Secondary outcomes included the changes in proteinuria, serum albumin, serum creatinine, eGFR and adverse events during the follow-up time. Results Within 12 months of follow-up time, the complete remission rates in RTX + GC and RTX groups were 55.84% and 43.14%, and the composite remission rates were 88.31% and 86.27%, respectively, which were no significant difference by Kaplan–Meier survival analysis. No statistically significant difference was observed in proteinuria, serum albumin, serum creatinine and eGFR between the two groups during the 12 months. Compared with RTX group, the RTX + GC group exhibited a significantly higher incidence of adverse events. Moreover, the results of the logistic regression identified RTX + GC as an independent risk factor and eGFR as an independent protective factor for infection. Conclusion Compared with RTX monotherapy, RTX + GC therapy did not significantly improve the clinical remission rate of patients with PMN, but was associated with a substantially increased risk of infections. These findings warrant validation in large-scale, prospective, randomized controlled trials in the future.

Fucoidan, a sulfated polysaccharide, demonstrates many biological activities. It has found extensive applications across medicine, food, cosmetics, and other industries. Recent investigations have highlighted that low molecular weight fucoidan (LMWF) possesses enhanced bioavailability and greater biological efficacy than its high molecular weight counterpart. The reduced molecular size facilitates improved absorption and augments several physiological activities, particularly its antioxidant, anti-tumor, and hypoglycemic properties. As a result, strategies for fucoidan degradation hold significant scientific and practical relevance. This review provides an overview of the primary strategy for fucoidan degradation, encompassing physical, chemical, and biological methods, and evaluates the strengths and limitations of each approach. Among these, biodegradation emerges as a promising technique, offering advantages such as environmental sustainability, high specificity, product uniformity, and gentle reaction conditions. The LMWF shows considerable potential for use in medical and food-related applications, and its production through biodegradation supports broader goals of environmental conservation and sustainable development.

Serine metabolism plays a pivotal role in cancer progression by supporting essential biosynthetic pathways and energy production. Exploring the intricacies of serine metabolism in cancer may uncover novel therapeutic opportunities. This study presents a comprehensive pan-cancer analysis of serine metabolism-related genes (SMGs), with a particular emphasis on colorectal cancer (CRC), to elucidate their expression patterns, genetic alterations and clinical significance. We performed a pan-cancer analysis of SMGs using integrating transcriptomic, genomic and epigenetic data from TCGA and GTEx databases. For CRC, we performed in-depth analyses comparing expression patterns between tumour and normal tissues, examining prognostic significance and exploring associations with the tumour microenvironment (TME). The distribution patterns of SMGs within the TME were further investigated using single-cell RNA sequencing and immunohistochemistry. Key SMGs, including PHGDH, SLC1A5 and SLC38A2, were validated in two independent real-world cohorts of CRC. Pan-cancer analysis revealed that SMGs are differentially expressed across tumour types, with their dysregulation associated with copy number alterations and epigenetic modifications. In CRC, aberrant SMG expression is significantly associated with clinical outcomes, key signalling pathways and the TME. Notably, PHGDH was consistently upregulated in CRC and associated with poor prognosis, while SLC1A5 emerged as a potential biomarker for liver metastasis. This study underscores the importance of SMGs, particularly PHGDH, SLC1A5 and SLC38A2, in CRC progression and prognosis. Our findings offer valuable insights into SMGs as a potential therapeutic target and provide a foundation for developing personalised metabolic interventions in CRC.

Pharmacological research has showed that multi-targeted drug therapies offer superior efficacy and reduced side effects compared to single-target drug therapies. In this study, we designed and characterized four novel chimeric peptides G(1-5)-EM2, EM2-G(1-5), G(1-9)-EM2 and EM2-G(1-9) which incorporate endomorphin-2 (EM-2) and the active fragments of ghrelin. Calcium mobilization assays revealed that these four chimeric peptides acted as weak mixed agonists for the μ-opioid receptor (MOR), κ-opioid receptor (KOR), and growth hormone secretagogue receptor 1α (GHS-R1α). The results of fluorescence imaging experiments indicated that G(1-5)-EM2 and G(1-9)-EM2 could penetrate the blood-brain barrier (BBB) following intravenous (i.v.) injection. All chimeric peptides induced almost equal antinociceptive effects compared with EM-2 or better antinociceptive effects than EM-2 after intracerebroventricular (i.c.v.) injection in the acute pain in mice. Among them, G(1-5)-EM2 could cross the BBB and enter the brain to induce antinociceptive effect through central opioid receptors after i.v. injection. Our findings demonstrated that the chimeric peptides produced significant antinociception mainly via MOR, DOR and GHS-R1α without inducing antinociceptive tolerance, or with a lower tendency for antinociceptive tolerance after i.c.v. injection in the acute pain in mice. Furthermore, the chimeric peptides mitigated or eliminated the digestive side effects associated with EM-2. The collective results highlight G(1-5)-EM2 as the most promising candidate among the chimeric peptides. The chimeric peptides represent a promising class of potential analgesics for clinical pain management. However, further optimization is necessary to maximize their therapeutic potential.

Objective:This study aims to investigate and discuss the effect of pericapsular nerve group (PENG) block with liposomal bupivacaine (LB) on postoperative rebound pain following hip fracture in older adults. Patients and Methods:Ninety patients scheduled for hip fracture surgery were randomized into three groups: LB (liposomal bupivacaine, 30 mL), R (0.375% ropivacaine, 30 mL), and C (saline, 30 mL). MAP and HR were recorded at T1 (pre-induction), T2 (post-intervention), and T3 (skin incision). NRS scores were evaluated at 12-72 h postoperatively, along with rebound pain, quadriceps function, analgesic consumption, and adverse reactions. Results:The incidence of rebound pain was significantly lower in the LB and R groups than in the C group (p < 0.05). The AUC of NRS scores over 72 hours was significantly lower in the LB group (2.053 ± 1.258) than in the R (3.600 ± 2.087) and C (4.880 ± 2.739) groups (p < 0.0001). Hemodynamic analysis revealed significant differences in HR between T2 and T3 in all groups (LB: 77.10 ± 11.28 vs 73.77 ± 8.47; R: 79.57 ± 8.05 vs 74.00 ± 8.13; C: 80.50 ± 8.71 vs 84.13 ± 8.07; p < 0.05). MAP in the LB group differed significantly from Group C across the three time points (p < 0.05). There were no significant differences between the groups in adverse events. Conclusion:LB PENG blockade reduces rebound pain incidence post-nerve block in elderly hip fracture patients, decreases PCA demand, preserves quadriceps function, and enhances satisfaction.

Rnd3 is a small Rho-GTPase that has been implicated in various cardiovascular diseases. Yet, its role in diabetes-induced cardiomyocyte senescence remains unknown. Here we tested the role of Rnd3 in cardiomyocyte senescence and diabetic cardiomyopathy (DCM). The expression of Rnd3 was found to be reduced in peripheral blood mononuclear cells from diabetic patients and correlated negatively with age but positively with cardiac function. In 96-week-old Sprague Dawley (SD) rats, cardiac function was impaired, accompanied by an increased number of SA-β-gal-positive cells and elevated levels of the senescence-associated secretory phenotype (SASP) related factors, compared to those of 12-week-old rats. Diabetes and high glucose (HG, 35 mmol/L D-glucose) suppressed Rnd3 expression in cardiomyocytes and induced cardiomyocyte senescence. The deficiency of Rnd3 exacerbated cardiomyocyte senescence in vitro and in vivo. MicroRNA sequencing in AC16 cells identified a conserved miR-103a-3p (present in humans and rats) as a key HG-upregulated microRNA that bound to the Rnd3 3'-UTR. In cultured cardiomyocytes, miR-103a-3p inhibitors antagonized HG-induced cardiomyocyte senescence dependent on Rnd3 expression. Treatment with AAV9 vectors carrying miR-103a-3p sponges and Rnd3-overexpressing plasmids alleviated cardiomyocyte senescence and restored cardiac function in diabetic SD rats. HG stimulation increased STAT3 (Tyr705) phosphorylation and promoted its nuclear translocation in H9C2 cells, an effect exacerbated by Rnd3 knockout. Mechanistically, Rnd3 interacted with p-STAT3 in the cytoplasm, facilitating proteasome-mediated ubiquitination and p-STAT3 degradation. The STAT3 inhibitor S3I-201 blocked HG-induced STAT3 activation and mitigated cardiomyocyte senescence. These findings suggest that diabetes induces cardiomyocyte senescence via the miR-103a-3p/Rnd3/STAT3 signaling pathway, highlighting a potential therapeutic target for DCM.

To explore the association between solid fuels and mild cognitive impairment (MCI) and the role of the healthy lifestyle score (HLS) in the association between solid fuels and MCI. Data were obtained from CHARLS from 2011 to 2020. A logistic regression model which assessed the impact of solid fuel use on MCI was applied. A full HLS was constructed to evaluate the interaction and joint effects of HLS with solid fuels. 11054 people were enclosed in this study and the proportion of the population using solid fuels is as high as 74.05 % for heating fuels and 56.53 % for cooking fuels. Results showed that solid fuel use was positively associated with the risk of MCI during cooking and heating, with 95 % confidence intervals (95 % CI) of 1.11 (1.00, 1.23) for cooking and 1.14 (1.00, 1.31) for heating. Further, a healthy BMI was beneficial in reducing the harmful effects of solid fuels. Solid fuel use was significantly associated with MCI among middle-aged and older Chinese adults. Our results also suggested that higher HLS is beneficial in reducing the risk of MCI from solid fuels. In this study, we are prompted to use cleaner fuels and ventilation equipment along with the need to develop effective HLS measures for interventions.

Bisphenol A bis(diphenyl phosphate) (BDP), a widely used oligomeric organophosphorus flame retardant, is widespread in environments and organisms. However, the toxicity of BDP remains largely unexplored. The intestine is an immune organ and is subjected to injury caused by contaminants. Here zebrafish were exposed to 0, 10 and 100 μg/L BDP for 21d, followed by another 21d of recovery, to investigate its intestinal toxicity. BDP altered the gut microbiota compositions with obvious changes in the abundance of phyla Proteobacteria and Fusobacteria, and genera Cetobacterium, Hydrogenophaga and Aeromonas, leading to intestinal dysbiosis. Consequently, distinct intestinal histopathological alteration was observed in the BDP-exposed zebrafish. The expressions of Claudin-1 and Mucin 2 decreased dose-dependently, whose disruption was persistent, indicating that BDP destroyed the barrier integrity and function of intestine. In addition, superoxide dismutase (SOD) and malondialdehyde (MDA), as well as the expressions of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) increased, magnifying the occurrence of oxidative damage and inflammation. Significant correlation was found between the microbiota alteration and intestinal disruptions, suggesting that BDP-induced gut microbiota dysbiosis participates in the progression of intestinal injury. This study reveals the intestinal toxicity of BDP, and provides insights into its potential risks in organisms.

Human adenovirus (HAdV) infection causes acute respiratory diseases in immunocompetent individuals worldwide. Infections by HAdV-55, one of the important pathogens leading to respiratory tract infections, often develop into pneumonia and are frequently associated with outbreaks in military camps and schools. We studied 186 HAdV-55-positive nasopharyngeal swab samples that were collected from patients with respiratory infection in Wuhan, China, from 2018 to 2019. Fifteen samples with high viral loads were selected for viral isolation and cultured with MRC-5 cells. These strains were then whole-genome sequenced to investigate their genetic characteristics by phylogenetic analyses. We then selected three HAdV-55 strains to quantify viral replication and further assessed the pathogenic characteristics of one strain in Syrian hamsters and BALB/c nude mice. HAdV-55-174 exhibited the highest replication ability in cultured cells compared to other strains, so this strain was selected for further investigation. Although the hamsters and mice were not so susceptible to HAdV-55-174 infection, viral loads were detected in the lungs and tracheas of the animal models, and persistent HAdV-55-174 replication was only observed in BALB/c nude mice. Histopathological lesions, including a widened alveolar septum and inflammatory cell infiltration, were observed in the lungs and tracheas of HAdV-55-174 infected animals. We isolated and characterized the HAdV-55 strains circulating in Wuhan from 2018 to 2019, which may be meaningful for further studies on HAdV-55 infection and pathogenesis.

Background: Marginal zone lymphomas (MZLs) comprise a diverse group of indolent lymphoproliferative disorders; however, some patients develop histologic transformation (HT) with rapid progression to aggressive lymphoma.Methods: Forty-three MZLs with HT (HT-MZLs), 535 MZLs, and 174 de novo diffuse large B-cell lymphomas (DLBCLs) without rearrangements of MYC, BCL2, and BCL6 were collected. Among these, 22 HT-MZLs, 39 MZLs, and 174 DLBCLs were subjected to 148-gene targeted exome sequencing. The clinicopathologic features of patients who had HT-MZL and their genetic alterations were compared with those of patients who had MZLs and DLBCLs.Results: All 43 HT-MZLs corresponded to DLBCLs. No HT-MZLs harbored BCL2 and MYC and/or BCL6 rearrangements. Bone marrow involvement and higher levels of lactate dehydrogenase were significantly more common in HT-MZLs than in MZLs. Furthermore, upregulated BCL6, MUM1, C-MYC, and Ki-67 expression was observed more frequently in HT-MZLs than in MZLs. TBL1XR1 was the most frequently altered gene (63.6%) in HT-MZLs, followed by CCND3 (31.8%), CARD11, ID3, and TP53 (22.7%). A trend toward worse progression-free survival in patients with TBL1XR1 mutations was observed. Compared with MZLs and non-germinal center B-cell (GCB) type DLBCLs, significantly higher frequencies of TBL1XR1 and ID3 mutations were identified in HT-MZLs. PIM1 mutations frequently occurred in DLBCLs and were significantly associated with TBL1XR1 mutations but were mutated less in HT-MZLs that had TBL1XR1 mutations.Conclusions: The current findings reveal the clinicopathologic and genetic features of HT-MZLs, suggesting that these tumors might constitute a group distinct from MZL and de novo non-GCB type DLBCL. TBL1XR1 mutations may be considered a predictor of HT in MZL.

Lipopolysaccharide (LPS), a unique component of the outer membrane of Gram-negative bacteria, possesses immune-activating properties. It induces an immune response by stimulating host cells to produce a lot of inflammatory cytokines with a thermogenic effect, which may cause an inflammatory response. In the past few decades, the structure and function of LPS and its mechanism leading to inflammation have been extensively analyzed. Since LPS can cause inflammation, it is often used to establish inflammation models. These models are crucial in the study of inflammatory diseases that pose a serious threat to human health. In addition, the non-pro-inflammatory effects of LPS under certain circumstances are also being studied widely. This review summarizes the methods by which LPS has been used to establish inflammatory models at the cellular and animal levels to study related diseases. It also introduces in detail the evaluation indicators necessary for the successful establishment of these models, providing a reference for future research.

Burn induced-pain (BIP) is one of the most common pain symptoms, which seriously affects the quality of sufferer life. Researches show that multi-targeted drug therapies offer superior efficacy and fewer side effects compared to single-target drug therapies. Consequently, in this study, we developed G(1-5)-EM2, a multi-targeted peptide designed to target μ-opioid receptor and the growth hormone secretagogue receptor 1α (GHS-R1α), and explored its antinociceptive effects on burn injury pain. Calcium mobilization experiments revealed that G(1-5)-EM2 demonstrated weak multi-agonist activities to μ-opioid receptor and κ-opioid receptor as well as GHS-R1α in vitro. Near-infrared fluorescence imaging experiments demonstrated that G(1-5)-EM2 could penetrate the blood-brain barrier (BBB) and access the brain following intravenous injection. The enzymatic stability of G(1-5)-EM2 was significantly enhanced compared to EM2. Our results indicated that intrathecal administration of G(1-5)-EM2 mitigated mechanical allodynia and thermal hyperalgesia in BIP. These antinociceptive effects of G(1-5)-EM2 were partially mediated through μ-opioid receptor and GHS-R1α. Moreover, intrathecal administration of G(1-5)-EM2 significantly decreased burn-induced up-regulation of phosphorylated p38 MAPK, phosphorylated NF-κBp65 and TRPV1 in the ipsilateral spinal cord, reduced the levels of IL-1β, IL-6 and TNF-α in serum, and enhanced wound healing in burned skin. Repeated intrathecal administration of G(1-5)-EM2 produced a non-tolerance-forming antinociception in BIP. These results suggest that the multi-targeted peptide G(1-5)-EM2 exhibits a novel role in alleviating BIP with fewer side effects and may represent a promising strategy for developing new analgesic drugs.

AbstractThis study aims to investigate the effects of the Galectin‐3 (Gal‐3) inhibitor TD139 on inflammation and the extracellular signal‐regulated kinase (ERK)/c‐Jun N‐terminal kinase (JNK)/p38 pathway in gestational diabetes mellitus (GDM). Human placental tissues were treated with TD139 and TNF‐α, assessing Gal‐3, ERK/JNK/p38 activation, and inflammatory cytokines. GDM was induced in mice via subcutaneous injections of streptozotocin (STZ). After confirming GDM, mice were treated with 15 mg/kg TD139 on GD 10.5 12.5, 14.5, 16.5, and 18.5. Serum inflammatory cytokines were measured on GD 20.5, and post‐delivery placental tissues were analyzed. Data were analyzed using one‐way or two‐way repeated measures ANOVA with post hoc tests. TD139 suppressed TNF‐α‐induced increases in Gal‐3, IL‐1β, IL‐6, MCP‐1, and ERK/JNK/p38 activation in placental tissues. In STZ‐induced GDM mice, TD139 reduced glucose levels, weight loss, and food and water intake. TD139 significantly lowered TNF‐α, IL‐1β, IL‐6, and MCP‐1 in serum and placental tissues and inhibited the ERK/JNK/p38 pathway. TD139 improved pup numbers in GDM mice compared to untreated ones. TD139 reduces inflammation and inhibits the ERK/JNK/p38 pathway in TNF‐α stimulated placental tissues and STZ‐induced GDM mice, suggesting its therapeutic potential for managing GDM‐related placental inflammation and improving pregnancy outcomes. The study used TNF‐α to mimic GDM in placental tissues and an STZ‐induced GDM mouse model, which may not fully represent human GDM complexity. Future research should explore alternative models, and broader signaling pathways, and thoroughly evaluate TD139's safety in pregnancy.

Objective: Despite its involvement in regulating various cellular functions, the expression and role of WD repeatcontaining protein 77 (WDR77) in cancer remain elusive. This study aims to explore the expression and potential roles of WDR77 across multiple cancers, with a particular focus on its relevance in colorectal cancer (CRC). Methods: We obtained WDR77 RNA-seq data, mutations, CNVs, and DNA methylation data from the TCGA, GTEx, and GEO databases to investigate its expression patterns and prognostic value. Additionally, we examined the correlation between WDR77 expression and somatic mutations, copy number variations, DNA methylation, and mRNA modifications. We utilized GSVA, GSEA algorithms, and CRISPR KO data from the Dependency Map database to explore WDR77 ' s potential biological functions. The association between WDR77 and the tumor immune microenvironment was investigated using ESTIMATE and IOBR algorithms. Finally, we assessed WDR77 expression in CRC and its impact on cell proliferation through qRT-PCR, Western blotting, immunohistochemistry, CCK8, colony formation, and EdU assays. Results: WDR77 was upregulated in various tumors and correlated with poor patient prognosis. Its high expression positively correlated with pathways related to cell proliferation and negatively correlated with immune-related pathways. In CRC, WDR77 expression was associated with specific clinical features, genomic alterations, and immune microenvironment characteristics. Experimental validation confirmed upregulated WDR77 expression in CRC tissues and cells, with WDR77 knockdown significantly inhibiting CRC cell proliferation. Conclusion: WDR77 holds potential as an oncogene and biological marker in various cancers, particularly CRC.

Depression is a mental disease that involves a variety of complex physiological mechanisms. A wide range of methods have therefore been used to establish mouse models of depression, and there are currently many ways to develop such mouse models. The present study aimed to compare the effects of various model induction methods and assesses their different effects. To this end, C57BL/6J mice were divided into three experimental groups: the chronic restraint stress (CRS) group received 6 hours of daily confinement within restraint tubes over a 3-week period; the chronic lipopolysaccharide (C-LPS) administration group received daily intraperitoneal injections of 0.5 mg/kg LPS for 1 week; and the acute LPS (A-LPS) administration group received a singular intraperitoneal injection of 0.83 mg/kg LPS. A corresponding control group was established for each experimental condition. Following mouse model establishment, depression-like behaviors were assessed through the forced swimming and tail suspension tests; anxiety-related behaviors were evaluated using the open field test and elevated plus maze. Furthermore, the expression of the immediate early gene c-Fos, ionized calcium-binding adapter molecule 1 (IBA1), and glial fibrillary acidic protein (GFAP) was examined via immunofluorescence. Longer immobility durations during the forced swimming and tail suspension tests were observed across all model groups (p < 0.05), indicating depression-like behaviors. Furthermore, the CRS and C-LPS group, but not the A-LPS group, showed significant anxiety-like behaviors in the elevated plus maze (p < 0.05). All model groups also exhibited significant increases in both time and distance explored within the central area of the open field test (p < 0.05). The activation of GFAP- and IBA1-positive cells in the cerebral cortex and hippocampus was also markedly pronounced in all experimental groups, suggesting the association of neuroinflammatory responses with induced depressive states. The present findings contribute to our understanding of the pathophysiology of stress-induced and neuroinflammatory-associated depression, and will help researchers to choose suitable depression models for their investigations.

Introduction: Lung cancer (LC) remains a leading cause of cancer mortality worldwide, underscoring the urgent need for novel therapeutic targets. The integration of Mendelian randomization (MR) with proteomic data presents a novel approach to identifying potential targets for LC treatment.Methods: This study utilized a proteome-wide MR analysis, leveraging publicly available data from genome-wide association studies (GWAS) and protein quantitative trait loci (pQTL) studies. We analyzed genetic association data for LC from the TRICL-ILCCO Consortium and proteomic data from the Decode cohort. The MR framework was employed to estimate the causal effects of specific proteins on LC risk, supplemented by external validation, co-localization analyses, and exploration of protein-protein interaction (PPI) networks.Results: Our analysis identified five proteins (TFPI, ICAM5, SFTPB, COL6A3, EPHB1) with significant associations to LC risk. External validation confirmed the potential therapeutic relevance of ICAM5 and SFTPB. Co-localization analyses and PPI network exploration provided further insights into the biological pathways involved and their potential mechanistic roles in LC pathogenesis.Conclusion: The study highlights the power of integrating genomic and proteomic data through MR analysis to uncover novel therapeutic targets for lung cancer. The identified proteins, particularly ICAM5 and SFTPB, offer promising directions for future research and development of targeted therapies, demonstrating the potential to advance personalized medicine in lung cancer treatment.

Atherosclerosis (AS) is the common basis for the onset of cardiovascular events. The lipid metabolism theory considers foam cell formation as an important marker for the initiation of AS. Fucoidan is an acidic polysaccharide that can reduce lipid accumulation in foam cells. Studies show that tea polysaccharides can be transported to lysosomes via the tubulin pathway. However, the specific mechanism of action of fucoidan on foam cells has not been extensively studied. Therefore, we further explored the mechanism of action of fucoidan and evaluated whether it could reduce lipid accumulation in foam cells by affecting the expression of lysosomal pathway-related genes and proteins. In this study, three inhibitors, CPZ, EIPA, and colchicine, were used to inhibit endocytosis, macropinocytosis, and the tubulin pathway, respectively, to study the pathways of action. Transcriptomics and proteomics analysis, as well as western blotting and qRT-PCR were used to determine the effects of fucoidan and the inhibitors on lysosomal genes and proteins. Fucoidan could enter foam cells through both endocytosis and via macropinocytosis, and then further undergo intracellular transport via the tubulin pathway. After fucoidan treatment, the expression of lysosomal pathway-related genes and proteins including LAMP2, AP3, AP4, MCOLN1, and TFEB in foam cells increased significantly (P < 0.01). However, the expression of lysosomal genes and proteins after colchicine intervention was comparable with that in the model group. Therefore, the tubulin pathway inhibited by colchicine is an important pathway for the transport and distribution of fucoidan within cells. In summary, fucoidan may be transported to lysosomes via the tubulin pathway and may enhance the expression of lysosomal genes, promoting autophagy, thereby accelerating lipid clearance in foam cells. Due to its significant lipid-lowering effect, it can be used in the clinical treatment of AS.

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic joint inflammation and cartilage damage. Current therapeutic strategies often result in side effects, necessitating the development of targeted and safer treatment options. This study introduces a novel nanotherapeutic system, 2-APB@DGP-MM, which utilizes macrophage membrane (MM)-encapsulated nanoparticles (NPs) for the targeted delivery of 2-Aminoethyl diphenylborinate (2-APB) to inflamed joints more effectively. The NPs are designed with a matrix metalloproteinase (MMP)-cleavable peptide, allowing for MMP-responsive drug release within RA microenvironment. Comprehensive in vitro and in vivo assays confirmed the successful synthesis and loading of 2-APB into the DSPE-GPLGVRGC-PEG (DGP) NPs, as well as their ability to repolarize macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype. The NPs demonstrated high biocompatibility, low cytotoxicity, and enhanced cellular uptake. In a collagen-induced arthritis (CIA) mouse model, intra-articular injection of 2-APB@DGP-MM significantly reduced synovial inflammation and cartilage destruction. Histological analysis corroborated these findings, demonstrating marked improvements in joint structure and delayed disease progression. Above all, the 2-APB@DGP-MM nanotherapeutic system offers a promising and safe approach for RA treatment by modulating macrophage polarization and delivering effective agents to inflamed joints.