Unveiling the pathological functions of SOCS in colorectal cancer: Current concepts and future perspectives.

Colorectal cancer (CRC) remains a significant global health challenge, marked by increasing incidence and mortality rates in recent years. The pathogenesis of CRC is complex, involving chronic inflammation of the intestinal mucosa, heightened immunoinflammatory responses, and resistance to apoptosis. The suppressor of cytokine signaling (SOCS) family, comprised of key negative regulators within cytokine signaling pathways, plays a crucial role in cell proliferation, growth, and metabolic regulation. Deficiencies in various SOCS proteins can trigger the activation of the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathways, following the binding of cytokines and growth factors to their receptors. Mounting evidence indicates that SOCS proteins are integral to the development and progression of CRC, positioning them as promising targets for novel anticancer therapies. This review delves into the structure, function, and molecular mechanisms of SOCS family members, examining their roles in cell proliferation, apoptosis, migration, epithelial-mesenchymal transition (EMT), and immune modulation. Additionally, it explores their potential impact on the regulation of CRC immunotherapy, offering new insights and perspectives that may inform the development of innovative therapeutic strategies for CRC.

The Toxoplasma Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti-T. Gondii Immunity and Tumor Immunotherapy.

Toxoplasma gondii (T. gondii)-associated polymorphic effector proteins are crucial in parasite development and regulating host anti-T. gondii immune responses. However, the mechanism remains obscure. Here, it is shown that Toxoplasma effector dense granules 4 (GRA4) restricts host IFN-I activation. Infection with Δgra4 mutant T. gondii strain induces stronger IFN-I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27-catalyzed K48-ubiquitination at Lys251/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent Δgra4 strain (ME49Δompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN-I production. Earlier vaccination with ME49Δompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49Δompdc treatment. Notably, ME49Δompdc/gra4 vaccination induces a specific CD64+MAR-1+CD11b+ dendritic cell subset, thereby enhancing T cell anti-tumor responses. Overall, these findings identify the negative role of T. gondii GRA4 in modulating host IFN-I signaling and suggest that GRA4 can be a potential target for the development of T. gondii vaccines and tumor immunotherapy.

Chemoprophylaxis Effect of EGCG on the Recurrence of Colorectal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: The recurrence rate of Colorectal Cancer (CRC) after cure is always high. The purpose of this study was to investigate whether green tea extract (-)-Epigallocatechin gallate (EGCG) has an effective preventive effect on the recurrence of CRC. METHODS: We conducted a systematic literature review and meta-analysis of the effects of taking EGCG or placebo on disease recurrence in patients after colon polyp removal. RESULTS: Five Randomized Controlled Trials (RCTs) were included in this review. A double-blind drug trial involving 1389 participants involved EGCG and placebo. The results showed no significant publication bias or heterogeneity in the five studies (I2 = 38%; p = 0.17). Patients taking EGCG had a lower recurrence rate of CRC than those in the placebo group. The results were statistically significant (Z=2.83, p < 0.05). CONCLUSION: This study demonstrated that long-term EGCG can prevent CRC recurrence to a certain extent.

Identification of diagnose related therapeutic targets of Danggui buxue decoction in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological disease. Currently, there is no disease-modifying therapy to slow the progression of the disease. Danggui buxue decoction (DBD) is widely used in the clinic because of its therapeutic effect. However, little is known about the molecular mechanism of DBD against PD. This study intends to explore the possible molecular mechanisms involved in DBD treatment of PD based on network pharmacology, and provide potential research directions for future research. METHODS: Firstly, the active components and target genes of DBD were screened from the traditional Chinese medicine systems pharmacology (TCMSP), DrugBank and UniProt database. Secondly, target genes of PD were identified from the (GEO) dataset, followed by identification of common target genes of DBD and PD. Thirdly, analysis of protein-protein interaction (PPI), functional enrichment and diagnosis was performed on common target genes, followed by correlation analysis between core target genes, immune cell, miRNAs, and transcription factors (TFs). Finally, molecular docking between core target genes and active components, and real-time PCR were performed. RESULTS: A total of 72 common target genes were identified between target genes of DBD and target genes of PD. Among which, 11 target genes with potential diagnostic value were further identified, including TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2. The combinations with the best docking binding were identified, including kaempferol-AKT1/HMOX1/NOS2/NOS3, quercetin-AKT1/ERBB2/IL1B/HMOX1/MMP9/TP53/NOS3/TGFB1. Moreover, IL1B and NOS2 respectively positively and negatively correlated with neutrophil and Type 1 T helper cell. Some miRNA-core target gene regulatory pairs were identified, such as hsa-miR-185-5p-TP53/TGFB1/RELA/MAPK14/IL1B/ERBB2/AKT1 and hsa-miR-214-3p-NOS3. These core target genes were significantly enriched in focal adhesion, TNF, HIF-1, and ErbB signaling pathway. CONCLUSION: Diagnostic TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2 may be considered as potential therapeutic targets of DBD in the treatment of PD.

Nordihydroguaiaretic Acid-Cross-Linked Phenylboronic Acid-Functionalized Polyplex Micelles for Anti-angiogenic Gene Therapy of Orthotopic and Metastatic Tumors.

Polyplexes are required to be equipped with multiple functionalities to accomplish adequate structure stability and gene transfection efficacy for gene therapy. Herein, a 4-carboxy-3-fluorophenylboronic acid (FPBA)-functionalized block copolymer of PEG-b-PAsp(DET/FBA) and PAsp(DET/FBA) (abbreviated as PB and HB) was synthesized and applied for engineering functional polyplex micelles (PMs) through ionic complexation with pDNA followed by strategic cross-linking with nordihydroguaiaretic acid (NDGA) in respect to the potential linkage of polyphenol and FPBA moieties. In relation to polyplex micelles void of cross-linking, the engineered multifunctional polyplex micelles (PBHBN-PMs) were determined to possess improved structural tolerability against the exchange reaction with charged species. Besides, the FPBA/NDGA cross-linking appeared to be selectively cleaved in the acidic endosomal compartments but not the neutral milieu. Furthermore, the PBHB-PMs with the optimal FPBA/NDGA cross-linking degree were identified to possess appreciable cellular uptake and endosomal escape activities, eliciting a significantly high level of gene expression relative to P-PMs and PB-PMs. Eventually, in vivo antitumor therapy by our proposed multifunctional PMs appeared to be capable of facilitating expression of the antiangiogenic genomic payloads (sFlt-1 pDNA) via systemic administration. The enriched antiangiogenic sFlt-1 in the tumors could silence the activities of angiogenic cytokines for the inhibited neo-vasculature and the suppressed growth of orthotopic 4T1 tumors. Of note, the persistent expression of the antiangiogenic sFlt-1 is also presumed to migrate into the blood circulation, thereby accounting for an overall antiangiogenic environment in preventing the potential pulmonary metastasis. Hence, our elaborated multifaceted PMs inspired fascinating potential as an intriguing gene delivery system for the treatment of clinical solid tumors and metastasis.

Microbiome-Metabolome Analysis Insight into the Effects of the Extract of Phyllanthus emblica L. on High-Fat Diet-Induced Hyperlipidemia.

The fruit of Phyllanthus emblica L. (FEPE) has a long history of use in Asian folk medicine. The main bioactive compounds in FEPE are polyphenols, known for their potent antioxidant, anti-inflammatory, and hypolipidemic activities. The present study aimed to investigate the intervention effect of FEPE (100 and 200 mg/kg) on hyperlipidemia for 8 weeks and preliminarily explored the potential mechanism by microbiome-metabolome analysis. The results showed that a high-dose FEPE (200 mg/kg) effectively alleviated dyslipidaemic symptoms and body weight gain in hyperlipidemic mice induced by a high-fat diet (HFD). Microbiome analysis showed that FEPE altered the structure of the intestinal microbiota, which included an increase in specific probiotics (such as Akkermansia, Anaerovorax, and Bacteroides) and a decrease in harmful bacteria (including A2, Acetitomaculum, Candidatus_Arthromitus, Lachnospiraceae_NK4A136_group, Lachnospiraceae_NK4B4_group, Rikenella, and Streptococcus), as well as a reduction in the level of short-chain fatty acids (SCFAs). In addition, significant changes in the hepatic metabolome were observed, and eight key metabolites associated with betaine metabolism, lysine degradation, methionine metabolism, and fatty acid metabolism pathways were primarily filtered. The correlated analysis identified several key "microbiota-metabolite" axes in the treatment of hyperlipidemia by FEPE extract. In conclusion, the present study is expected to provide a basis for treating hyperlipidemia with FEPE from the perspective of the microbiome-liver metabolome axis.

Comparison of the biomechanical properties of grafts in three anterior cruciate ligament reconstruction techniques based on three-dimensional finite element analysis.

OBJECTIVE: To evaluate the biomechanical characteristics of grafts from three different anterior cruciate ligament (ACL) reconstructive surgeries and to determine which method is better at restoring knee joint stability. METHODS: A 31-year-old female volunteer was enrolled in the study. According to the magnetic resonance imaging of her left knee, a three-dimensional model consisting of the distal femur, proximal tibia and fibula, ACL, posterior cruciate ligament, medial collateral ligament and lateral collateral ligament was established. Then, the ACL was removed from the original model to simulate the knee joint after ACL rupture. Based on the knee joint model without the ACL, single-bundle ACL reconstruction, double-bundle ACL reconstruction, and flat-tunnel ACL reconstruction were performed. The cross-sectional diameters of the grafts were equally set as 6 mm in the three groups. The bone tissues had a Young's modulus of 17 GPa and a Poisson's ratio of 0.36. The ligaments and grafts had a Young's modulus of 390 MPa and a Poisson's ratio of 0.4. Six probes were placed in an ACL or a graft to obtain the values of the equivalent stress, maximum principal stress, and maximum shear stress. After pulling the proximal tibia with a forward force of 134 N, the distance that the tibia moved and the stress distribution in the ACL or the graft, reflected by 30 mechanical values, were measured. RESULTS: The anterior tibial translation values were similar among the three groups, with the double-bundle ACL reconstruction group performing the best, followed closely by the patellar tendon ACL reconstruction group. In terms of stress distribution, 13 out of 30 mechanical values indicated that the grafts reconstructed by flat bone tunnels had better performance than the grafts in the other groups, while 12 out of 30 showed comparable outcomes, and 5 out of 30 had worse outcomes. CONCLUSION: Compared with traditional single-bundle and double-bundle ACL reconstructions, flat-tunnel ACL reconstruction has advantages in terms of stress dispersion. Additionally, flat-tunnel ACL reconstruction falls between traditional double-bundle and single-bundle ACL reconstructions in terms of restoring knee joint stability and is superior to single-bundle ACL reconstruction.

OsLCD3 interacts with OsSAMS1 to regulate grain size via ethylene/polyamine homeostasis control.

A fundamental question in developmental biology is how to regulate grain size to improve crop yields. Despite this, little is still known about the genetics and molecular mechanisms regulating grain size in crops. Here, we provide evidence that a putative protein kinase-like (OsLCD3) interacts with the S-adenosyl-L-methionine synthetase 1 (OsSAMS1) and determines the size and weight of grains. OsLCD3 mutation (lcd3) significantly increased grain size and weight by promoting cell expansion in spikelet hull, whereas its overexpression caused negative effects, suggesting that grain size was negatively regulated by OsLCD3. Importantly, lcd3 and OsSAMS1 overexpression (SAM1OE) led to large and heavy grains, with increased ethylene and decreased polyamines production. Based on genetic analyses, it appears that OsLCD3 and OsSAMS1 control rice grain size in part by ethylene/polyamine homeostasis. The results of this study provide a genetic and molecular understanding of how the OsLCD3-OsSAMS1 regulatory module regulates grain size, suggesting that ethylene/polyamine homeostasis is an appropriate target for improving grain size and weight.

Evaluation of the consistency of the MRI- based AI segmentation cartilage model using the natural tibial plateau cartilage.

OBJECTIVE: The study aims to evaluate the accuracy of an MRI-based artificial intelligence (AI) segmentation cartilage model by comparing it to the natural tibial plateau cartilage. METHODS: This study included 33 patients (41 knees) with severe knee osteoarthritis scheduled to undergo total knee arthroplasty (TKA). All patients had a thin-section MRI before TKA. Our study is mainly divided into two parts: (i) In order to evaluate the MRI-based AI segmentation cartilage model's 2D accuracy, the natural tibial plateau was used as gold standard. The MRI-based AI segmentation cartilage model and the natural tibial plateau were represented in binary visualization (black and white) simulated photographed images by the application of Simulation Photography Technology. Both simulated photographed images were compared to evaluate the 2D Dice similarity coefficients (DSC). (ii) In order to evaluate the MRI-based AI segmentation cartilage model's 3D accuracy. Hand-crafted cartilage model based on knee CT was established. We used these hand-crafted CT-based knee cartilage model as gold standard to evaluate 2D and 3D consistency of between the MRI-based AI segmentation cartilage model and hand-crafted CT-based cartilage model. 3D registration technology was used for both models. Correlations between the MRI-based AI knee cartilage model and CT-based knee cartilage model were also assessed with the Pearson correlation coefficient. RESULTS: The AI segmentation cartilage model produced reasonably high two-dimensional DSC. The average 2D DSC between MRI-based AI cartilage model and the tibial plateau cartilage is 0.83. The average 2D DSC between the AI segmentation cartilage model and the CT-based cartilage model is 0.82. As for 3D consistency, the average 3D DSC between MRI-based AI cartilage model and CT-based cartilage model is 0.52. However, the quantification of cartilage segmentation with the AI and CT-based models showed excellent correlation (r = 0.725; P values < 0.05). CONCLUSION: Our study demonstrated that our MRI-based AI cartilage model can reliably extract morphologic features such as cartilage shape and defect location of the tibial plateau cartilage. This approach could potentially benefit clinical practices such as diagnosing osteoarthritis. However, in terms of cartilage thickness and three-dimensional accuracy, MRI-based AI cartilage model underestimate the actual cartilage volume. The previous AI verification methods may not be completely accurate and should be verified with natural cartilage images. Combining multiple verification methods will improve the accuracy of the AI model.

[Mechanism of astragaloside â £ combined with Panax notoginseng saponins in regulating angiogenesis to treat cerebral ischemia based on network pharmacology and experimental verification].

Network pharmacology and animal and cell experiments were employed to explore the mechanism of astragaloside Ⅳ(AST Ⅳ) combined with Panax notoginseng saponins(PNS) in regulating angiogenesis to treat cerebral ischemia. The method of network pharmacology was used to predict the possible mechanisms of AST Ⅳ and PNS in treating cerebral ischemia by mediating angiogenesis. In vivo experiment: SD rats were randomized into sham, model, and AST Ⅳ(10 mg·kg~(-1)) + PNS(25 mg·kg~(-1)) groups, and the model of cerebral ischemia was established with middle cerebral artery occlusion(MCAO) method. AST Ⅳ and PNS were administered by gavage twice a day. the Longa method was employed to measure the neurological deficits. The brain tissue was stained with hematoxylin-eosin(HE) to reveal the pathological damage. Immunohistochemical assay was employed to measure the expression of von Willebrand factor(vWF), and immunofluorescence assay to measure the expression of vascular endothelial growth factor A(VEGFA). Western blot was employed to determine the protein levels of vascular endothelial growth factor receptor 2(VEGFR2), VEGFA, phosphorylated phosphatidylinositol 3-kinase(p-PI3K), and phosphorylated protein kinase B(p-AKT) in the brain tissue. In vitro experiment: the primary generation of rat brain microvascular endothelial cells(rBEMCs) was cultured and identified. The third-generation rBMECs were assigned into control, model, AST Ⅳ(50 µmol·L~(-1)) + PNS(30 µmol·L~(-1)), LY294002(PI3K/AKT signaling pathway inhibitor), 740Y-P(PI3K/AKT signaling pathway agonist), AST Ⅳ + PNS + LY294002, and AST Ⅳ + PNS + 740Y-P groups. Oxygen glucose deprivation/re-oxygenation(OGD/R) was employed to establish the cell model of cerebral ischemia-reperfusion injury. The cell counting kit-8(CCK-8) and scratch assay were employed to examine the survival and migration of rBEMCs, respectively. Matrigel was used to evaluate the tube formation from rBEMCs. The Transwell assay was employed to examine endothelial cell permeability. Western blot was employed to determine the expression of VEGFR2, VEGFA, p-PI3K, and p-AKT in rBEMCs. The results of network pharmacology analysis showed that AST Ⅳ and PNS regulated 21 targets including VEGFA and AKT1 of angiogenesis in cerebral infarction. Most of these 21 targets were involved in the PI3K/AKT signaling pathway. The in vivo experiments showed that compared with the model group, AST Ⅳ + PNS reduced the neurological deficit score(P<0.05) and the cell damage rate in the brain tissue(P<0.05), promoted the expression of vWF and VEGFA(P<0.01) and angiogenesis, and up-regulated the expression of proteins in the PI3K/AKT pathway(P<0.05, P<0.01). The in vitro experiments showed that compared with the model group, the AST Ⅳ + PNS, 740Y-P, AST Ⅳ + PNS + LY294002, and AST Ⅳ + PNS + 740Y-P improved the survival of rBEMCs after OGD/R, enhanced the migration of rBEMCs, increased the tubes formed by rBEMCs, up-regulated the expression of proteins in the PI3K/AKT pathway, and reduced endothelial cell permeability(P<0.05, P<0.01). Compared with the LY294002 group, the AST Ⅳ + PNS + LY294002 group showed increased survival rate, migration rate, and number of tubes, up-regulated expression of proteins in the PI3K/AKT pathway, and decreased endothelial cell permeability(P<0.05,P<0.01). Compared with the AST Ⅳ + PNS and 740Y-P groups, the AST Ⅳ + PNS + 740Y-P group presented increased survival rate, migration rate, and number of tubes and up-regulated expression of proteins in the PI3K/AKT pathway, and reduced endothelial cell permeability(P<0.01). This study indicates that AST Ⅳ and PNS can promote angiogenesis after cerebral ischemia by activating the PI3K/AKT signaling pathway.

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma.

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γc) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

Atovaquone enhances antitumor efficacy of TCR-T therapy by augmentation of ROS-induced ferroptosis in hepatocellular carcinoma.

T-cell receptor (TCR) engineered T-cell therapy has recently emerged as a promising adoptive immunotherapy approach for tumor treatment, yet hindered by tumor immune evasion resulting in poor therapeutic efficacy. The introduction of ferroptosis-targeted inducers offers a potential solution, as they empower T cells to induce ferroptosis and exert influence over the tumor microenvironment. Atovaquone (ATO) stands as a prospective pharmaceutical candidate with the potential to target ferroptosis, effectively provoking an excessive generation and accumulation of reactive oxygen species (ROS). In this study, we evaluated the effectiveness of a combination therapy comprising ATO and TCR-T cells against hepatocellular carcinoma (HCC), both in vitro and in vivo. The results of lactate dehydrogenase and cytokine assays demonstrated that ATO enhanced cytotoxicity mediated by AFP-specific TCR-T cells and promoted the release of IFN-γ in vitro. Additionally, in an established HCC xenograft mouse model, the combined therapy with low-dose ATO and TCR-T cells exhibited heightened efficacy in suppressing tumor growth, with no apparent adverse effects, comparable to the results achieved through monotherapy. The RNA-seq data unveiled a significant activation of the ferroptosis-related pathway in the combination therapy group in comparison to the TCR-T cells group. Mechanistically, the synergy between ATO and TCR-T cells augmented the release of IFN-γ by TCR-T cells, while concurrently elevating the intracellular and mitochondrial levels of ROS, expanding the labile iron pool, and impairing the integrity of the mitochondrial membrane in HepG2 cells. This multifaceted interaction culminated in the potentiation of ferroptosis within the tumor, primarily induced by an excess of ROS. In summary, the co-administration of ATO and TCR-T cells in HCC exhibited heightened vulnerability to ferroptosis. This heightened susceptibility led to the inhibition of tumor growth and the stimulation of an anti-tumor immune response. These findings suggest that repurposing atovaquone for adoptive cell therapy combination therapy holds the potential to enhance treatment outcomes in HCC.

Performance of 99mTc-PYP scintigraphy in the diagnosis of hereditary transthyretin cardiac amyloidosis.

OBJECTIVE: Most reported research has primarily investigated wild-type transthyretin cardiac amyloidosis (ATTRwt-CA). However, the application of bone scintigraphy for hereditary transthyretin cardiac amyloidosis (ATTRv-CA) has not been systematically investigated. Therefore, in this study, we aimed to evaluate the diagnostic value of 99mTc-PYP scintigraphy in ATTRv-CA. METHODS: Fifty-four patients were enrolled in a highly suspected cardiac amyloidosis cohort. Transthyretin (TTR) gene characteristics were summarized in the ATTRv-CA group. In 99mTc-PYP scintigraphy, the diagnostic efficiency of the visual score (VGS) and heart-to-contralateral chest (H/CL) ratio were evaluated. Furthermore, the interobserver consistency among the diagnosticians was investigated. RESULTS: Twenty-eight patients were diagnosed with ATTRv-CA with eight genotypes. The Ala97Ser genotype accounts for 46% (n = 13) with a mean age of disease onset, definite diagnosis, and interval of 61.6 ± 1.9, 66.5 ± 1.3, and 4.0 (3.0, 6.2) years, respectively. Their VGS is Grade 3, and their H/CL ratio is higher than that of the non-Ala97Ser group, but no statistical significance exists (mean H/CL: 1.95 ± 0.06 vs. 1.87 ± 0.02, p = 0.844). Additionally, ATTRv-CA patients showed VGS ≥ 2, and mean H/CL ratio of 2.09 ± 0.06. The sensitivity and specificity of VGS were 100% and 65%, respectively. And the interobserver consistency analysis of VGS showed the intraclass correlation coefficient is 0.522. The best cutoff value of H/CL ratio was 1.51 (AUC = 0.996), and the diagnostic consistency of H/CL (bias: 0.018) was high. CONCLUSIONS: Ala97Ser is the most common genotype in ATTRv-CA in our cohort, with characteristics of later onset and rapid progression, but delayed diagnosis and extensive 99mTc-PYP uptake. Overall, ATTRv-CA patients showed moderate-to-extensive myocardial 99mTc-PYP uptake. Additionally, VGS carries subjectivity, low specialty and interobserver consistency. But H/CL exhibit high diagnostic efficacy and interobserver consistency. The H/CL ratio is more useful than VGS.

The underlying mechanisms of DNA methylation in high salt memory in hypertensive vascular disease.

This study demonstrates the effect and DNA methylation-related mechanisms of a high-salt diet and salt memory-induced hypertension and vasculopathy. Thirty Sprague Dawley rats were randomly divided into a control (CON) group (n = 6) and a modeling group (n = 24). A 12% NaCl solution (1 mL/100 g) was intragastrically administered for 60 consecutive days for modeling. An increase in blood pressure up to 140 mmHg was considered successful modeling. Twelve of fifteen successfully modeled rats were randomly selected and divided into a High Salt Diet (HSD) group and a High Salt Memory (HSM) group (n = 6). Rats in HSD group were intragastrically administered a 12% NaCl solution, while rats in HSM group were administered a 3% NaCl solution twice a day for 30 days. At the end of the intervention, blood pressure and the serum levels of ET-1, NO, TNF-α and IL-1ß were measured. RRBS-heavy sulfite sequencing technology was selected for DNA methylation analysis. The systolic blood pressure of rats in the HSD group and HSM group was significantly higher than that in the CON group. Compared with those in the CON group, the serum levels of ET-1 in the HSM group and the serum levels of NO in the HSD group and HSM group were significantly increased. The methylation level of the CON group was lower than that of the HSD group and the HSM group, and there was no significant difference between the HSD group and the HSM group. The methylation level of Myoz3 was downregulated in the HSD group and HSM group. The methylation level of Fgd3 were upregulated in HSD group and downregulated in the HSM group. The methylation levels of AC095693.1, Adamts3, PDGFA and PDGFRα were downregulated in the HSD group and upregulated in the HSM group. According to the GO database, the differentially methylated genes were significantly enriched in the coordination of cell function, genetic development, and RNA transcription. There were three main metabolic pathways that were enriched in the differentially expressed genes between the groups: the PI3K-Akt signaling pathway, MAPK signaling pathway, and Hippo signaling pathway. Excessive salt intake may cause hypertension and vascular damage, and this damage may continue after the reduction of salt intake. Therefore, salt memory phenomenon exists, and this memory effect may be correlated with the levels of DNA methylation.

Strategies and rules for tuning TCR-derived therapy.

Manipulation of T cells has revolutionized cancer immunotherapy. Notably, the use of T cells carrying engineered T cell receptors (TCR-T) offers a favourable therapeutic pathway, particularly in the treatment of solid tumours. However, major challenges such as limited clinical response efficacy, off-target effects and tumour immunosuppressive microenvironment have hindered the clinical translation of this approach. In this review, we mainly want to guide TCR-T investigators on several major issues they face in the treatment of solid tumours after obtaining specific TCR sequences: (1) whether we have to undergo affinity maturation or not, and what parameter we should use as a criterion for being more effective. (2) What modifications can be added to counteract the tumour inhibitory microenvironment to make our specific T cells to be more effective and what is the safety profile of such modifications? (3) What are the new forms and possibilities for TCR-T cell therapy in the future?

Serum soluble TREM2 is an independent biomarker associated with coronary heart disease.

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a unique receptor expressed by macrophages in atherosclerotic plaque and is involved in the progression of atherosclerosis. Whether serum soluble TREM2 (sTREM2) levels has a relationship with coronary heart disease (CHD) remains unclear. METHODS: The cross-sectional study included 86 patients with CHD and 86 controls matched with age and sex. Demographic information, medication history, and laboratory data were collected. sTREM2 concentrations were detected by enzyme-linked immunosorbent assay. We compared the sTREM2 levels in two groups and constructed stepwise linear regression analysis for factors related to the sTREM2 level in patients with CHD; we further used the logistic regression model to evaluate the relationship between sTREM2 and CHD. The diagnostic value of sTREM2 and other biomarkers in CHD was evaluated by the receiver operating characteristic curve (ROC). RESULTS: The serum level of sTREM2 in CHD patients is higher than that in controls. In CHD patients, the stepwise linear regression analysis found that sTREM2 levels were correlated with triglyceride (TG), high-density lipoprotein cholesterols (HDL-C), apolipoprotein B (ApoB) and smoking status. Logistic regression models showed that sTREM2 was associated independently with CHD after adjusted confounders. The ROC curve showed a sensitivity of 59.3% and specificity of 81.4% with an area under the curve of 0.781 (95% CI: 0.711-0.852) for the diagnosis of CHD with serum sTREM2 at a cut-off value of > 1104.894 pg/ml, indicating a higher diagnostic value than high sensitivity C reaction protein (hs-CRP) and apolipoprotein B (ApoB). CONCLUSION: In this study, we provide evidence that sTREM2 levels are elevated in CHD patients and are associated with various cardiovascular risk factors. Additionally, sTREM2 demonstrates better diagnostic performance compared to traditional indicators in identifying CHD. These findings suggest that sTREM2 may serve as a potential biomarker for coronary heart disease.

Recent Progress of Supramolecular Chemotherapy Based on Host-Guest Interactions.

Chemotherapy is widely recognized as an effective approach for treating cancer due to its ability to eliminate cancer cells using chemotherapeutic drugs. However, traditional chemotherapy suffers from various drawbacks, including limited solubility and stability of drugs, severe side effects, low bioavailability, drug resistance, and challenges in tracking treatment efficacy. These limitations greatly hinder its widespread clinical application. In contrast, supramolecular chemotherapy, which relies on host-guest interactions, presents a promising alternative by offering highly efficient and minimally toxic anticancer drug delivery. In this review, an overview of recent advancements in supramolecular chemotherapy based on host-guest interactions is provided. The significant role it plays in guiding cancer therapy is emphasized. Drawing on a wealth of cutting-edge research, herein, a timely and valuable resource for individuals interested in the field of supramolecular chemotherapy or cancer therapy, is presented. Furthermore, this review contributes to the progression of the field of supramolecular chemotherapy toward clinical application.

Tumor subtypes and signature model construction based on chromatin regulators for better prediction of prognosis in uveal melanoma.

Background: Uveal Melanoma (UM) is the most prevalent primary intraocular malignancy in adults. This study assessed the importance of chromatin regulators (CRs) in UM and developed a model to predict UM prognosis. Methods: Gene expression data and clinical information for UM were obtained from public databases. Samples were typed according to the gene expression of CRs associated with UM prognosis. The prognostic key genes were further screened by the protein interaction network, and the risk model was to predict UM prognosis using the least absolute shrinkage and selection operator (LASSO) regression analysis and performed a test of the risk mode. In addition, we performed gene set variation analysis, tumor microenvironment, and tumor immune analysis between subtypes and risk groups to explore the mechanisms influencing the development of UM. Results: We constructed a signature model consisting of three CRs (RUVBL1, SIRT3, and SMARCD3), which was shown to be accurate, and valid for predicting prognostic outcomes in UM. Higher immune cell infiltration in poor prognostic subtypes and risk groups. The Tumor immune analysis and Tumor Immune Dysfunction and Exclusion (TIDE) score provided a basis for clinical immunotherapy in UM. Conclusion: The risk model has prognostic value for UM survival and provides new insights into the treatment of UM.

AtSAMS regulates floral organ development by DNA methylation and ethylene signaling pathway.

S-adenosylmethionine synthase is the key enzyme involved in the biosynthesis of S-adenosylmethionine, which serves as the universal methyl group donor and a common precursor for the biosynthesis of ethylene and polyamines. However, little is known about how SAMS controls plant development. Here, we report that the abnormal floral organ development in the AtSAMS-overexpressing plants is caused by DNA demethylation and ethylene signaling. The whole-genome DNA methylation level decreased, and ethylene content increased in SAMOE. Wild-type plants treated with DNA methylation inhibitor mimicked the phenotypes and the ethylene levels in SAMOE, suggesting that DNA demethylation enhanced ethylene biosynthesis, which led to abnormal floral organ development. DNA demethylation and elevated ethylene resulted in changes in the expression of ABCE genes, which is essential for floral organ development. Furthermore, the transcript levels of ACE genes were highly correlated to their methylation levels, except for the down-regulation of the B gene, which might have resulted from demethylation-independent ethylene signaling. SAMS-mediated methylation and ethylene signaling might create crosstalk in the process of floral organ development. Together, we provide evidence that AtSAMS regulates floral organ development by DNA methylation and ethylene signaling pathway.