查看更多>>摘要：Obesity-related glomerulopathy(ORG)is an independent risk factor for chronic kid-ney disease and even progression to end-stage renal disease.Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG,but relatively little is known about cell-specific changes in gene expression.To define the transcriptomic landscape at single-cell resolution,we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing.We report for the first time that immune cells,including T cells and B cells,are decreased in ORG patients.Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells.This gene is related to inflammation and cell proliferation.Analysis of differential gene expression in glomerular cells(endothelial cells,mesangial cells,and podocytes)showed that these cell types were mainly enriched in genes related to oxidative phosphorylation,cell adhesion,thermogenesis,and inflammatory pathways(PI3K-Akt signaling,MAPK signaling).Furthermore,we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway.Moreover,an evaluation of cell-cell communications revealed that there were interactions between glomer-ular parietal epithelial cells and other cells in ORG patients,with major interactions between parietal epithelial cells and podocytes.Altogether,our identification of molecular events,cell types,and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.
查看更多>>摘要：The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARS-CoV-2 vaccines in containing coronavirus disease 2019(COVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient protection.Intranasal immunization can improve mucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA vaccine.After intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-CoV-2 pseudoviruses were markedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 receptors.Furthermore,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and spleen.Collectively,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locally and systemically.
查看更多>>摘要：Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program.Phosphoenolpyruvate carboxylase 1(PCK1),a gluconeogenic metabolic enzyme,is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis.The onco-genesis and progression of tumors are closely related to cancer stem cells.It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma.Herein,the results showed that PCK1 inhibited the self-renewal property of hepatoma cells,reduced the mRNA level of cancer stem cell markers,and inhibited tumorigenesis.Moreover,PCK1 increased the sensitivity of hepatocellular carci-noma cells to sorafenib.Furthermore,we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation.Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib.Thus,combined treatment with verteporfin and sorafenib may be a potential anti-tumor strat-egy in hepatocellular carcinoma.
查看更多>>摘要：Pyruvate dehydrogenase kinase 1(PDK1)phosphorylates the pyruvate dehydroge-nase complex,which inhibits its activity.Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis,which plays an important role in tumor progression.This study aims to elucidate how PDK1 pro-motes breast cancer progression.We found that PDK1 was highly expressed in breast cancer tissues,and PDK1 knockdown reduced the proliferation,migration,and tumorigenicity of breast cancer cells and inhibited the HIF-1α(hypoxia-inducible factor 1α)pathway.Further investigation showed that PDK1 promoted the protein stability of HIF-1α by reducing the level of ubiquitination of HIF-1α.The HIF-1 α protein levels were dependent on PDK1 kinase activity.Furthermore,HIF-1 α phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells.The phosphorylation of HIF-1 α at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1α with von Hippel-Lindau and prolyl hydroxylase domain.We also found that PDK1 enhanced HIF-1 α transcriptional ac-tivity.In summary,PDK1 enhances HIF-1 α protein stability by phosphorylating HIF-1 α at Ser451 and promotes HIF-1 α transcriptional activity by enhancing the binding of HIF-1 α to P300.PDK1 and HIF-1 α form a positive feedback loop to promote breast cancer progression.
查看更多>>摘要：The tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense mutant.However,there are currently no approved targeted therapies or immunotherapies against mutant p53.Here,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in vitro.We then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic effects.Our results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type p53.In cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity.We made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles.In vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice.The administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 antibody.These results indicate that targeting specific mutant epitopes us-ing DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.
查看更多>>摘要：CYP3A5 is a cytochrome P450(CYP)enzyme that metabolizes drugs and contributes to drug resistance in cancer.However,it remains unclear whether CYP3A5 directly influences cancer progression.In this report,we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal adenocarcinoma.Multi-omics analysis showed that CYP3A5 knockdown re-sults in a decrease in various glucose-related metabolites through its effect on glucose trans-port.A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP,a negative regulator of GLUT1.Notably,CYP3A5-generated reactive oxygen species were proved to be responsible for atten-uating the AKT-4EBP1-TXNIP signaling pathway.CYP3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic cancer.Taken together,our results,for the first time,reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.
查看更多>>摘要：Dissecting the genetic components that contribute to the two main subphenotypes of steroid-sensitive nephrotic syndrome(SSNS)using genome-wide association studies(GWAS)strategy is important for understanding the disease.We conducted a multicenter cohort study(360 patients and 1835 controls)combined with a GWAS strategy to identify susceptibility var-iants associated with the following two subphenotypes of SSNS:steroid-sensitive nephrotic syn-drome without relapse(SSNSWR,181 patients)and steroid-dependent/frequent relapse nephrotic syndrome(SDNS/FRNS,179 patients).The distribution of two single-nucleotide poly-morphisms(SNPs)in ANKRD36 and ALPG was significant between SSNSWR and healthy controls,and that of two SNPs in GAD1 and HLA-DQA1 was significant between SDNS/FRNS and healthy controls.Interestingly,rs1047989 in HLA-DQA1 was a candidate locus for SDNS/FRNS but not for SSNSWR.No significant SNPs were observed between SSNSWR and SDNS/FRNS.Meanwhile,chromosome 2:171713702 in GAD1 was associated with a greater steroid dose(＞0.75 mg/kg/d)upon relapse to first remission in patients with SDNS/FRNS(odds ratio=3.14;95％confidence interval,0.97-9.87;P=0.034).rs117014418 in APOL4 was significantly associated with a decrease in eGFR of greater than 20％compared with the baseline in SDNS/FRNS patients(P=0.0001).Protein-protein intersection network construction suggested that HLA-DQA1 and HLA-DQB1 function together through GSDMA.Thus,SSNSWR belongs to non-HLA region-dependent nephropathy,and the HLA-DQA/DQB region is likely strongly associated with dis-ease relapse,especially in SDNS/FRNS.The study provides a novel approach for the GWAS strategy of SSNS and contributes to our understanding of the pathological mechanisms of SSNSWR and SDNS/FRNS.
查看更多>>摘要：Gastric cancer is highly prevalent among digestive tract tumors.Due to the intri-cate nature of the gastric cancer immune microenvironment,there is currently no effective treatment available for advanced gastnc cancer.However,there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4(EP4)in gastric cancer.In our previous study,we identified a novel small molecule EP4 receptor antagonist called YY001.Treatment with YY001 alone demonstrated a signihcant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model.Furthermore,adminis-tration of YY001 stimulated a robust immune response within the tumor microenvironment,characterized by increased infiltration of antigen-presenting cells,T cells,and M1 macro-phages.Additionally,our research revealed that YY001 exhibited remarkable synergistic ef-fects when combined with the PD-1 antibody and the clinically targeted drug apatinib,rather than fluorouracil.These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer,whether used as a standalone treatment or in combi-nation with other drugs.
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