RESUMEN
Aortic aneurysm is a life-threatening disease with limited interventions that is closely related to vascular smooth muscle cell (VSMC) phenotypic switching. SLC44A2, a member of the solute carrier series 44 (SLC44) family, remains undercharacterized in the context of cardiovascular diseases. Venn diagram analysis based on microarray and single-cell RNA sequencing identified SLC44A2 as a major regulator of VSMC phenotypic switching in aortic aneurysm. Screening for Slc44a2 among aortic cell lineages demonstrated its predominant location in VSMCs. Elevated levels of SLC44A2 were evident in the aorta of both patients with abdominal aortic aneurysm and angiotensin II-infused (Ang II-infused) Apoe-/- mice. In vitro, SLC44A2 silencing promoted VSMCs toward a synthetic phenotype, while SLC44A2 overexpression attenuated VSMC phenotypic switching. VSMC-specific SLC44A2-knockout mice were more susceptible to aortic aneurysm under Ang II infusion, while SLC44A2 overexpression showed protective effects. Mechanistically, SLC44A2's interaction with NRP1 and ITGB3 activates TGF-ß/SMAD signaling, thereby promoting contractile gene expression. Elevated SLC44A2 in aortic aneurysm is associated with upregulated runt-related transcription factor 1 (RUNX1). Furthermore, low-dose lenalidomide (LEN; 20 mg/kg/day) suppressed aortic aneurysm progression by enhancing SLC44A2 expression. These findings reveal that the SLC44A2-NRP1-ITGB3 complex is a major regulator of VSMC phenotypic switching and provide a potential therapeutic approach (LEN) for aortic aneurysm treatment.
Asunto(s)
Aneurisma de la Aorta Abdominal , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Músculo Liso Vascular , Miocitos del Músculo Liso , Animales , Humanos , Masculino , Ratones , Angiotensina II/farmacología , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/patología , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/genética , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones Noqueados , Ratones Noqueados para ApoE , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Fenotipo , Transducción de Señal , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismoRESUMEN
BACKGROUND: Iguratimod (IGU) is widely used in clinical practice due to its stable anti-inflammatory effects. Our previous studies have confirmed that the proportion of Th17/Treg balance in patients taking IGU altered significantly. This study aims to explore the role of IGU in antibody-mediated rejection (ABMR) and its potential mechanisms. METHODS: We conducted bioinformatics analysis of sequencing data from the GEO database to analyze the abundance of immune cell infiltration in transplanted kidney tissues. In vivo, IGU was intervened in a mice secondary skin transplantation model and a mice kidney transplantation ABMR model, and histological morphology of the grafts were examined by pathological staining, while relevant indicators were determined through qRT-PCR, immunohistochemistry, and enzyme-linked immunosorbent assay, observed T cell differentiation by flow cytometry, and preliminarily assessed the immunosuppressive effect of IGU. In vitro, we established Th17 and Treg cell induction and stimulation differentiation culture systems and added IGU for intervention to explore its effects on their differentiation. RESULTS: Through bioinformatics analysis, we found that Th17 and Treg may play important roles in the occurrence and development of ABMR. In vivo, we found that IGU could effectively reduce the damage caused by ABMR to the grafts, alleviate the infiltration of inflammatory cells in the graft tissues, and reduce the deposition of C4d in the grafts. Moreover, it is also found that IGU regulated the differentiation of Th17 and Treg cells in the spleen and peripheral blood and reduced the expression of IL-17A in the grafts and serum. In addition, same changes were observed in the induction and differentiation culture system of Th17 and Treg cells in vitro after the addition of IGU. CONCLUSION: IGU can inhibit the progression of ABMR by regulating the differentiation of Th17 and Treg cells, providing novel insights for optimizing clinical immunosuppressive treatment regimens.
Asunto(s)
Cromonas , Rechazo de Injerto , Trasplante de Riñón , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Células Th17 , Animales , Células Th17/inmunología , Linfocitos T Reguladores/inmunología , Rechazo de Injerto/inmunología , Ratones , Cromonas/farmacología , Masculino , Inmunosupresores/uso terapéutico , Humanos , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Células Cultivadas , SulfonamidasRESUMEN
Chronic allograft dysfunction (CAD) poses a significant challenge in kidney transplantation, with renal vascular endothelial-to-mesenchymal transition (EndMT) playing a vital role. While renal vascular EndMT has been verified as an important contributing factor to renal allograft interstitial fibrosis/tubular atrophy in CAD patients, its underlying mechanisms remain obscure. Currently, Src activation is closely linked to organ fibrosis development. Single-cell transcriptomic analysis in clinical patients revealed that Src is a potential pivotal mediator in CAD progression. Our findings revealed a significant upregulation of Src which closely associated with EndMT in CAD patients, allogeneic kidney transplanted rats and endothelial cells lines. In vivo, Src inhibition remarkably alleviate EndMT and renal allograft interstitial fibrosis in allogeneic kidney transplanted rats. It also had a similar antifibrotic effect in two endothelial cell lines. Mechanistically, the knockout of Src resulted in an augmented AMBRA1-mediated mitophagy in endothelial cells. We demonstrate that Src knockdown upregulates AMBRA1 level and activates mitophagy by stabilizing Parkin's ubiquitination levels and mitochondrial translocation. Subsequent experiments demonstrated that the knockdown of the Parkin gene inhibited mitophagy in endothelial cells, leading to increased production of Interleukin-6, thereby inducing EndMT. Consequently, our study underscores Src as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis, exerting its impact through the regulation of AMBRA1/Parkin-mediated mitophagy.
RESUMEN
Harmine is a naturally occurring ß-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy.
RESUMEN
BACKGROUND: BK virus (BKV) infection is an opportunistic infectious complication and constitutes a risk factor for premature graft failure in kidney transplantation. Our research aimed to identify associations and assess the impact of single-nucleotide polymorphisms (SNPs) on metabolism-related genes in patients who have undergone kidney transplantation with BKV infection.
Material/Methods: The DNA samples of 200 eligible kidney transplant recipients from our center, meeting the inclusion criteria, have been collected and extracted. Next-generation sequencing was used to genotype SNPs on metabolism-associated genes (CYP3A4/5/7, UGT1A4/7/8/9, UGT2B7). A general linear model (GLM) was used to identify and eliminate confounding factors that may influence the outcome events. Multiple inheritance models and haplotype analyses were utilized to identify variation loci associated with infection caused by BKV and ascertain haplotypes, respectively.
Results: A total of 141 SNPs located on metabolism-related genes were identified. After Hardy-Weinberg equilibrium (HWE) and minor allele frequency (MAF) analysis, 21 tagger SNPs were selected for further association analysis. Based on GLM results, no confounding factor was significant in predicting the incidence of BK polyomavirus-associated infection. Then, multiple inheritance model analyses revealed that the risk of BKV infection was significantly associated with rs3732218 and rs4556969. Finally, we detect significant associations between haplotype T-A-C of block 2 (rs4556969, rs3732218, rs12468274) and infection caused by BKV (P = 0.0004).
Conclusions: We found that genetic variants in the UGT1A gene confer BKV infection susceptibility after kidney transplantation.
RESUMEN
Objective: To investigate the role of Interleukin-34 (IL-34) in acute T cell-mediated rejection (TCMR) following renal transplantation. Methods: The mice acute TCMR model of renal transplantation was established and identified by hematoxylin and eosin (HE) and immunohistochemistry (IHC) staining. Then, IHC staining of IL-34 was also performed to determine the expression of IL-34 in allografts. Recipients were infected with IL-34 overexpression adeno-associated virus, infection efficiency of which was estimated by enzyme linked immunosorbent assay (ELISA), Western blot, and immunofluorescence. HE and IHC staining were used to estimate the grades of TCMR. Flow cytometry was performed on lymphocytes in spleens of recipients including regulatory T cells (Tregs) and M2 macrophages. The expression of cytokines in vivo was analyzed by Mouse Cytokine Grp I Panel. Finally, Tregs and M2 macrophages were cultured in vitro and treated with IL-34 to observe the effects of IL-34 on the differentiation of the cells. Results: The mouse TCMR model was successfully established by HE, periodic acid shiff (PAS), CD4 and CD8 IHC staining. The expression of IL-34 was significantly decreased in allografts with TCMR. BALB/c mice were successfully infected with IL-34 overexpression adeno-associated virus. Subsequently, the grade of rejection in mice TCMR model was evaluated by HE and IHC staining according to Banff criteria. It is suggested that the grade of TCMR in IL-34 overexpressed mice was significantly decreased. IHC staining and Flow cytometry showed that the proportion of Tregs and M2 macrophages in the spleens and allografts were significantly increased in IL-34 overexpressed mice. Serum levels of interferon-gamma (IFN-γ), IL-17 and tumor necrosis factor-alpha (TNF-α) were downregulated in IL-34 overexpressed mice. Moreover, IL-34 could promote macrophage M2 polarization, while failed to promote differentiation of naïve T cells into Tregs in vitro. Conclusion: Overexpression of IL-34 may attenuate the progression of TCMR episodes in allografts by increasing the polarization of M2 macrophages in the spleens and allografts, which may become a potential therapeutic strategy for TCMR.
RESUMEN
BACKGROUND: The assessment of left ventricular (LV) remodeling and its association with mineral and bone disorder (MBD) in kidney transplant recipients (KTRs) have not been systematically studied. We aimed to evaluate LV remodeling changes one year after kidney transplantation (KT) and identify their influencing factors. METHODS: Ninety-five KTRs (68 males; ages 40.2 ± 10.8 years) were followed before and one year after KT. Traditional risk factors and bone metabolism indicators were assessed. Left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF) and left ventricular diastolic dysfunction (LVDD) were measured using two-dimensional transthoracic echocardiography. The relationship between MBD and LV remodeling and the factors influencing LV remodeling were analyzed. RESULTS: One year after KT, MBD was partially improved, mainly characterized by hypercalcemia, hypophosphatemia, hyperparathyroidism, 25-(OH) vitamin D deficiency, elevated bone turnover markers, and bone loss. LVMI, the prevalence of left ventricular hypertrophy (LVH), and the prevalence of LVDD decreased, while LVEF increased. LVH was positively associated with postoperative intact parathyroid hormone (iPTH) and iPTH nonnormalization. â³LVMI was positively associated with preoperative type-I collagen N-terminal peptide and postoperative iPTH. LVEF was negatively associated with postoperative phosphorous. â³LVEF was negatively associated with postoperative iPTH. LVDD was positively associated with postoperative lumbar spine osteoporosis. Preoperative LVMI was negatively associated with â³LVMI and positively associated with â³LVEF. Advanced age, increased BMI, diabetes, longer dialysis time, lower albumin level, and higher total cholesterol and low-density lipoprotein levels were associated with LV remodeling. CONCLUSIONS: LV remodeling partially improved after KT, showing a close relationship with MBD.
Asunto(s)
Trasplante de Riñón , Masculino , Humanos , Volumen Sistólico , Función Ventricular Izquierda , Remodelación Ventricular , Minerales , Hipertrofia Ventricular IzquierdaRESUMEN
BACKGROUND: The status of mineral and bone disorder (MBD) after kidney transplantation is not fully understood, and the assessment of abnormal mineral and bone metabolism in kidney transplant recipients (KTRs) has not been standardized. MATERIALS AND METHODS: We performed a retrospective analysis of 292 KTRs in our center. The levels of biochemical markers of bone metabolism and bone mineral density (BMD) were assessed. We evaluated the influencing factors of BMD using linear regression analysis. And correlation test was used for the correlation analysis between bone metabolism indicators and other indicators. RESULTS: Postoperative MBD mainly manifested as hypercalcemia (8.9%), hypophosphatemia (27.1%), low levels of 25-hydroxyvitamin D(25(OH)vitD) (67.0%), hyperparathyroidism (50.6%), and high levels of bone turnover markers (BTMs). The prevalence of osteopenia/osteoporosis in the femoral neck (FN) and lumbar spine (LS) was 20.1%/2.8% and 26.1%/3.6%, respectively. Multivariate analysis indicated that FN BMD was positively associated with body mass index (BMI) and negatively associated with acute rejection history (p < 0.05); while LS BMD was positively associated with BMI, and negatively associated with intact parathyroid hormone (iPTH) (p < 0.05). Biochemical markers of bone metabolism were affected by age, sex, preoperative dialysis mode and time, postoperative time, transplanted kidney function, and iPTH levels. LS BMD was negatively correlated with iPTH and BTMs (p < 0.05). CONCLUSION: MBD persisted after kidney transplantation. Decreased bone mass was associated with persistent hyperparathyroidism, acute rejection history, low BMI, advanced age, and menopause. Dynamic monitoring of bone metabolism index and BMD helps to assess MBD after kidney transplantation.
Asunto(s)
Hiperparatiroidismo , Trasplante de Riñón , Femenino , Humanos , Estudios Retrospectivos , Trasplante de Riñón/efectos adversos , Diálisis Renal , Densidad Ósea , Hormona Paratiroidea , Biomarcadores , Hiperparatiroidismo/epidemiología , Hiperparatiroidismo/etiologíaRESUMEN
BACKGROUND: The assessment and prevention of vascular calcification (VC) in kidney transplant recipients (KTRs) have not been systematically studied. We aimed to evaluate VC change one year after kidney transplantation (KT) and identify their influencing factors. METHODS: 95 KTRs (68 males; ages 40.2 ± 10.8 years) were followed one year after KT. Changes in bone mineral density (BMD) and bone metabolism biomarkers were assessed. Coronary artery calcification (CAC) and thoracic aortic calcification (TAC) were measured using 192-slice third-generation dual-source CT. The relationship between bone metabolism indicators and VC and the factors influencing VC were analyzed. RESULTS: Postoperative estimated glomerular filtration rate was 79.96 ± 24.18 mL/min*1.73 m2. One year after KT, serum phosphorus, intact parathyroid hormone (iPTH), osteocalcin, type I collagen N-terminal peptide (NTx), type I collagen C-terminal peptide, and BMD decreased, 25-hydroxyvitamin D remained low, and VC increased. Post-CAC and TAC were negatively correlated with pre-femoral neck BMD, and TAC was positively correlated with post-calcium. CAC and TAC change were positively correlated with post-calcium and 25-hydroxyvitamin D. Increased CAC was positively associated with hemodialysis and pre-femoral neck osteopenia. CAC change was positively associated with prediabetes, post-calcium, and pre-CAC and negatively associated with preoperative and postoperative femoral neck BMD, and NTx change. Increased TAC was positively associated with age, prediabetes, preoperative parathyroid hyperplasia/nodule, post-calcium, and post-femoral neck osteopenia. TAC change was positively associated with age, diabetes, pre-triglyceride, pre-TAC, dialysis time, post-calcium and post-iPTH, and negatively associated with post-femoral neck BMD. CONCLUSIONS: Mineral and bone disorders persisted, and VC progressed after KT, showing a close relationship.
Asunto(s)
Enfermedades Óseas Metabólicas , Trasplante de Riñón , Estado Prediabético , Calcificación Vascular , Masculino , Humanos , Trasplante de Riñón/efectos adversos , Calcio , Colágeno Tipo I , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/etiología , Calcificación Vascular/metabolismo , Densidad Ósea , Minerales , PéptidosRESUMEN
Background: Interstitial fibrosis and tubular atrophy (IFTA) are the histopathological manifestations of chronic kidney disease (CKD) and one of the causes of long-term renal loss in transplanted kidneys. Necroptosis as a type of programmed death plays an important role in the development of IFTA, and in the late functional decline and even loss of grafts. In this study, 13 machine learning algorithms were used to construct IFTA diagnostic models based on necroptosis-related genes. Methods: We screened all 162 "kidney transplant"-related cohorts in the GEO database and obtained five data sets (training sets: GSE98320 and GSE76882, validation sets: GSE22459 and GSE53605, and survival set: GSE21374). The training set was constructed after removing batch effects of GSE98320 and GSE76882 by using the SVA package. The differentially expressed gene (DEG) analysis was used to identify necroptosis-related DEGs. A total of 13 machine learning algorithms-LASSO, Ridge, Enet, Stepglm, SVM, glmboost, LDA, plsRglm, random forest, GBM, XGBoost, Naive Bayes, and ANNs-were used to construct 114 IFTA diagnostic models, and the optimal models were screened by the AUC values. Post-transplantation patients were then grouped using consensus clustering, and the different subgroups were further explored using PCA, Kaplan-Meier (KM) survival analysis, functional enrichment analysis, CIBERSOFT, and single-sample Gene Set Enrichment Analysis. Results: A total of 55 necroptosis-related DEGs were identified by taking the intersection of the DEGs and necroptosis-related gene sets. Stepglm[both]+RF is the optimal model with an average AUC of 0.822. A total of four molecular subgroups of renal transplantation patients were obtained by clustering, and significant upregulation of fibrosis-related pathways and upregulation of immune response-related pathways were found in the C4 group, which had poor prognosis. Conclusion: Based on the combination of the 13 machine learning algorithms, we developed 114 IFTA classification models. Furthermore, we tested the top model using two independent data sets from GEO.
RESUMEN
BACKGROUND: Iguratimod has been shown to promote bone formation and inhibit bone resorption in rheumatoid arthritis patients. We aimed to explore its effect on bone metabolism and vascular calcification (VC) in kidney transplant recipients (KTRs). METHODS: A post hoc analysis was conducted among the subjects in our previous randomized clinical trial (NCT02839941). Forty-three KTRs completing bone metabolism 52 weeks after enrollment were selected for this analysis, among whom 27 patients received VC examinations. In the iguratimod group, iguratimod (25 mg twice daily) was added adjuvant to the traditional triple regimen. At the 52-week follow-up, the following parameters were assessed: serum calcium, phosphorus, 25-hydroxyvitamin D, intact parathyroid hormone (iPTH), bone alkaline phosphatase (BALP), osteocalcin, type I collagen N-terminal peptide (NTx), type I collagen C-terminal peptide (CTx), bone mineral density (BMD) of the femoral neck and lumbar spine, coronary artery calcification (CAC) and thoracic aortic calcification (TAC). Bone metabolic and VC indices were compared between the two groups using the independent samples t test and Wilcoxon nonparametric test. RESULTS: At 52 weeks after enrollment, the iguratimod group had lower osteocalcin (p = 0.010), BALP (p = 0.015), NTx (p = 0.007), CTx (p = 0.012), CAC (p = 0.080) and TAC scores (p = 0.036) than the control group. There was no significant difference in serum calcium, phosphorus, 25-hydroxyvitamin D, iPTH and BMD between the groups. Iguratimod could reduce bone turnover markers (BTMs) at both high and low iPTH levels. The adverse effect of iguratimod was mild and tolerable. CONCLUSION: Iguratimod is safe, can reduce BTMs and may could attenuate VC in the first year after KT.
Asunto(s)
Colágeno Tipo I , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Calcio , Osteocalcina , Densidad Ósea , Péptidos , Hormona Paratiroidea , Biomarcadores , Minerales , Fósforo , Remodelación ÓseaRESUMEN
BACKGROUND: The assessment and prevention of mineral and bone disorder (MBD) in kidney transplant recipients (KTRs) have not been standardized. This study aimed to evaluate MBD one year after kidney transplantation (KT) and identify the influencing factors of MBD. METHODS: A total of 95 KTRs in our center were enrolled. The changes in bone mineral density (BMD) and bone metabolism biochemical markers, including serum calcium (Ca), phosphorus(P), 25-hydroxyvitamin D(25(OH)vitD), intact parathyroid hormone (iPTH), bone alkaline phosphatase, osteocalcin (OC), type I collagen N-terminal peptide and type I collagen C-terminal peptide (CTx), over one year after KT were assessed. The possible influencing factors of BMD were analyzed. The relationships between bone metabolism biochemical markers were evaluated. The indicators between groups with or without iPTH normalization were also compared. RESULTS: MBD after KT was manifested as an increased prevalence of hypophosphatemia and bone loss, persistent 25(OH)vitD deficiency, and partially decreased PTH and bone turnover markers (BTMs). Femoral neck BMD was positively correlated with body mass index (BMI) and postoperative 25(OH)vitD, and negatively correlated with postoperative PTH. Lumbar spine BMD was positively correlated with BMI and preoperative TG, and negatively correlated with preoperative OC and CTx. BMD loss was positively associated with glucocorticoid accumulation. Preoperative and postoperative iPTH was negatively correlated with postoperative serum P and 25(OH)vitD, and positively correlated with postoperative Ca and BTMs. The recipients without iPTH normalization, who accounted for 41.0% of all KTRs, presented with higher Ca, lower P, higher BTMs, advanced age, and a higher prevalence of preoperative parathyroid hyperplasia. CONCLUSIONS: MBD persisted after KT, showing a close relationship with hyperparathyroidism, high bone turnover, and glucocorticoid accumulation.
Asunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica , Hiperparatiroidismo , Trasplante de Riñón , Humanos , Biomarcadores , Densidad Ósea , Remodelación Ósea , Estudios de Cohortes , Colágeno Tipo I , Glucocorticoides , Trasplante de Riñón/efectos adversos , Hormona Paratiroidea , Péptidos , OsteoporosisRESUMEN
Background: Further research needs to be conducted on the role of genetic variables in kidney transplantation fibrosis. In this study, we used next-generation sequencing (NGS) to examine the relationship between matrix metalloproteinase (MMP) genes and single-nucleotide polymorphisms (SNPs) in renal allograft fibrosis. Methods: This study comprised 200 patients, whose complete DNA samples were taken. The SNPs in MMP genes were identified using targeted NGS. Hardy-Weinberg equilibrium (HWE) and minor allele frequency (MAF) tests were conducted, followed by a linkage disequilibrium (LD) analysis. Finally, the SNPs and severity of kidney allograft fibrosis were evaluated using different inheritance models. Results: In total, 41 MMP gene-related SNPs were identified using targeted sequencing, and 20 tagger SNPs were retained for further study. The general linear models (GLMs) revealed that sirolimus treatment had a substantial effect on kidney graft fibrosis. The multiple inheritance model analyses revealed that SNP rs9059 of the MMP9 gene was strongly associated with kidney graft fibrosis. The in-vitro experiments showed the MMP9 rs9509 mutation promotes the process of epithelial-mesenchymal transition (EMT) in the human kidney 2 (HK2) cells. Conclusions: The SNP rs9059 is associated with significant kidney allograft pathological changes by promoting EMT progression. Our findings provide insights into the etiology of renal allograft interstitial fibrosis and the MMP9 could be used as a potential treatment target in the future.
RESUMEN
Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.
Asunto(s)
Glioma , Inhibidores de Puntos de Control Inmunológico , Interleucina-8 , Animales , Ratones , Linfocitos T CD8-positivos , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Glioma/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Interleucina-8/metabolismo , Linfocitos T , Microambiente TumoralRESUMEN
OBJECTIVE: This study was designed to analyze the correlation between single nucleotide polymorphisms (SNP) related to drug metabolism and pharmacokinetics of mycophenolic acid (MPA) during long-term follow-up. MATERIALS AND METHOD: A retrospective cohort study involving 71 renal transplant recipients was designed. Blood samples were collected to extract total DNAs, followed by target sequencing based on next-generation sequencing technology. The MPA area under the curve (AUC) was calculated according to the formula established in our center. The general linear model and linear regression model were used to analyze the association between SNPs and MPA AUC. RESULTS: A total of 689 SNPs were detected in our study, and 90 tagger SNPs were selected after quality control and linkage disequilibrium analysis. The general linear model analysis showed that 9 SNPs significantly influenced MPA AUC. A forward linear regression was conducted, and the model with the highest identical degree (r2=0.55) included 4 SNPs (SLCO1B1: rs4149036 [P < 0.0001], ABCC2: rs3824610 [P = 0.005], POR: rs4732514 [P = 0.006], ABCC2: rs4148395 [P = 0.007]) and 6 clinical factors (age [P < 0.0001], gender [P < 0.0001], the incident of acute rejection (AR) [P = 0.001], albumin [P < 0.0001], duration after renal transplantation [P = 0.01], lymphocyte numbers [P = 0.026]). The most relevant SNP to MPA AUC in this model was rs4149036. The subgroup analysis showed that rs4149036 had a significant influence on MPA AUC in the older group (P = 0.02), high-albumin group (P = 0.01), male group (P = 0.046), and both within-36-month group (P = 0.029) and after-36-month group (P = 0.041). The systematic review included 4 studies, and 2 of them showed that the mutation in SLCO1B1 resulted in lower MPA AUC, which was contrary to our study. CONCLUSION: A total of 4 SNPs (rs4149036, rs3824610, rs4148395, and rs4732514) were identified to be significantly correlated with MPA AUC. Rs4149036, located in SLCO1B1, was suggested to be the most relevant SNP to MPA AUC, which had a stronger influence on recipients who were elder, male, or with high serum albumin. Furthermore, 6 clinical factors, including age, gender, occurrence of acute rejection, serum albumin, time from kidney transplantation, and blood lymphocyte numbers, were found to affect the concentration of MPA.
Asunto(s)
Trasplante de Riñón , Ácido Micofenólico , Masculino , Humanos , Anciano , Ácido Micofenólico/uso terapéutico , Trasplante de Riñón/métodos , Estudios Retrospectivos , Polimorfismo de Nucleótido Simple , Área Bajo la Curva , Albúmina Sérica/metabolismo , Inmunosupresores/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismoRESUMEN
Background: Chronic kidney disease (CKD) is often accompanied by alterations in the metabolic profile of the body, yet the causative role of these metabolic changes in the onset of CKD remains a subject of ongoing debate. This study investigates the causative links between metabolites and CKD by leveraging the results of genomewide association study (GWAS) from 486 blood metabolites, employing bulk two-sample Mendelian randomization (MR) analyses. Building on the metabolites that exhibit a causal relationship with CKD, we delve deeper using enrichment analysis to identify the metabolic pathways that may contribute to the development and progression of CKD. Methods: In conducting the Mendelian randomization analysis, we treated the GWAS data for 486 metabolic traits as exposure variables while using GWAS data for estimated glomerular filtration rate based on serum creatinine (eGFRcrea), microalbuminuria, and the urinary albumin-to-creatinine ratio (UACR) sourced from the CKDGen consortium as the outcome variables. Inverse-variance weighting (IVW) analysis was used to identify metabolites with a causal relationship to outcome. Using Bonferroni correction, metabolites with more robust causal relationships are screened. Additionally, the IVW-positive results were supplemented with the weighted median, MR-Egger, weighted mode, and simple mode. Furthermore, we performed sensitivity analyses using the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out (LOO) test. Pathway enrichment analysis was conducted using two databases, KEGG and SMPDB, for eligible metabolites. Results: During the batch Mendelian randomization (MR) analyses, upon completion of the inverse-variance weighted (IVW) approach, sensitivity analysis, and directional consistency checks, 78 metabolites were found to meet the criteria. The following four metabolites satisfy Bonferroni correction: mannose, N-acetylornithine, glycine, and bilirubin (Z, Z), and mannose is causally related to all outcomes of CKD. By pathway enrichment analysis, we identified eight metabolic pathways that contribute to CKD occurrence and progression. Conclusion: Based on the present analysis, mannose met Bonferroni correction and had causal associations with CKD, eGFRcrea, microalbuminuria, and UACR. As a potential target for CKD diagnosis and treatment, mannose is believed to play an important role in the occurrence and development of CKD.
RESUMEN
Pyrano[4,3-c]pyridine-diones, which are the key skeleton of bioactive compounds and functional materials, are usually prepared via a multistep synthesis using expensive substrates. This work demonstrates that Rh(III)-catalyzed dual C(sp2)-H functionalization and C-O/C-N annulation of monoamide fumarates can produce pyrano[4,3-c]pyridine-1,5(6H)-diones in high yield (up to 82%) in a single step. The substrates of monoamide fumarates and acetylenes are structurally simple, readily available, and inexpensive. The additive AgSbF6 effectively raised the yields. On account of easier dehydrogenation of OH in the COOH group than NH in the amide group in the reaction, the process first undergoes C-O annulation and then is succeeded by C-N annulation.
Asunto(s)
Rodio , Rodio/química , Estructura Molecular , Catálisis , Fumaratos , Piridinas/químicaRESUMEN
Background: This study aimed to explore the effect and mechanism of iguratimod (IGT) on M1 macrophage polarization and antibody-mediated rejection (ABMR) after renal transplant. Methods: Bioinformatics analysis was performed using three public databases derived from the GEO database. Sprague-Dawley (SD) rats were pre-sensitized with donors of Wistar rats in skin transplantation and a rat renal transplant ABMR model was established from the donors to skin pre-sensitized recipients. Subsequently, IGT was treated on the ABMR model. Routine staining and immunofluorescence (IF) staining were performed to observe the pathological changes in each group and flow cytometry was performed to detect the changes of DSA titers in peripheral blood. In addition, bone-marrow-derived macrophage (BMDM) was extracted and interfered with IGT to explore the effect of IGT in vivo. PCR, IF staining, and Western blot were used to detect the expression of related genes and proteins. Results: Bioinformatics analysis revealed that several immune cells were significantly infiltrated in the ABMR allograft, while M1 macrophage was noticed with the most significance. Results of IF staining and PCR proved the findings of the bioinformatics analysis. Based on this, IGT was observed to significantly attenuate the degree of peritubular capillary vasculitis and arteriolitis in the rat renal transplant ABMR model, whereas it decreases the expression of C4d and reduces the titer of DSA. Results in vitro suggested that M1 macrophage-related transcripts and proteins were significantly reduced by the treatment of IGT in a dose- and time-dependent manner. Furthermore, IGT intervention could remarkably decrease the expression of KLF4. Conclusion: Polarization of M1 macrophages may aggravate ABMR after renal transplant by promoting DSA-mediated endothelial cell injury, and IGT may attenuate the pathogenesis of ABMR by targeting KLF4.