Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

The purpose of this study was to investigate the regulatory effects of biofilm associated non-coding small RNA(sRNA)00085 on the survival and environmental fitness of Listeria monocytogenes.Homologous recombination technology was used to construct a deletion mutant strain(△sRNA 00085)and a complementary strain(C △sRNA 00085)of the sRNA00085 target gene.The differences in biological characteristics were compared among the standard strain,△sRNA 00085,and C△sRNA 00085.The deletion of sRNA00085 led to a significant decrease in biofilm formation capacity and sensitivity to several antibiotics,including penicillin,piperacillin,doxycycline,tetracycline,vancomycin,and cotrimoxazole.However,only the minimum inhibitory concentration(MIC)of tetracycline exhibited a significant decrease in △sRNA00085.Meanwhile,the decreased biofilm formation and antibiotic resistance of the sRNA00085 mutant were restored in the C△sRNA00085 strain.Furthermore,we investigated the transcription levels of tetracycline resistance-related genes in L.monocytogenes.Down-regu-lated transcription of the tetS gene but no significant difference in transcription of the tetA gene were observed in △sRNA 00085 compared with the standard strain and C△sRNA00085.Moreover,the elimination of sRNA00085 did not affect bacterial growth ability or sensitivity to disinfectants.These findings highlight that sRNA00085 plays an important role in the environ-mental adaptability of L.monocytogenes by affecting bacterial biofilm formation and resistance.

Urticaria is an immune-mediated allergic disease. This study explored the effect of Jingfang Mixture on spleen T lymphocyte subsets of urticaria mice. A total of 50 Kunming mice were randomized into normal group(C), model group(V), and low-(JF-L, 0.5 g·kg~(-1)), medium-(JF-M, 1 g·kg~(-1)) and high-dose(JF-H, 2 g·kg~(-1)) Jingfang Mixture groups, with 10 mice in each group. The mixture of ovalbumin and aluminum hydroxide(0.1 mg + 0.1 mL) was used(intraperitoneal injection) to induce urticaria in mice. The administration began 6 days after the first immunization, and the second immunization was carried out 10 days after the first immunization. The pruritus index was detected within 30 min after the second immunization. The administration lasted 21 days. After 21 days, the serum was taken to detect the total IgE level. Based on hematoxylin and eosin(HE) staining, the pathological changes of skin tissue were observed, and Western blot was used to detect the levels of p-Janus kinase 2(JAK2)/JAK2 and p-signal transducer and activator of transcription 3(STAT3)/STAT3 in skin tissue. The spleen was taken to detect the spleen index, and flow cytometry was employed to determine the expression of lymphocyte subsets. The results showed that group V had obvious pathological changes in skin tissue compared with group C. Moreover, group V showed more scratches, higher spleen index, and higher level of total serum IgE than group C. In addition, higher levels of p-JAK2 and p-STAT3, lower proportions of CD4~+T, Th1, and Treg, higher proportions of CD8~+T, Th2, and Th17, and lower ratios of CD4~+/CD8~+, Th1/Th2, and Terg/Th17 were observed in group V than in group C. Compared with group V, each administration group showed alleviation of the pathological morphology of skin tissue, obvious epidermal thickening, relatively intact collagen fiber structure of dermal reticular layer, alleviated edema, and relief of vasodilation and peripheral inflammatory cell infiltration. Moreover, less scratching, lower spleen index, lower p-JAK2/JAK2 and p-STAT3/STAT3 were observed in the administration groups than in group V. JF-M group and JF-H group demonstrated lower levels of total IgE, larger proportions of CD4~+T, Th1, and Treg, smaller proportions of CD8~+ T, Th2, and Th17, and higher ratios of CD4~+/CD8~+, Th1/Th2, and Terg/Th17. In conclusion, Jingfang Mixture may improve the symptoms of urticaria mice by regulating the balance of spleen T lymphocyte subsets through JAK2-STAT3 signaling pathway.
Mice ; Animals ; Janus Kinase 2/pharmacology* ; Spleen ; T-Lymphocyte Subsets/metabolism* ; Signal Transduction ; Urticaria ; Immunoglobulin E

To observe the effect of Xinfeng Capsules on rheumatoid arthritis (RA) B lymphocytes,inflammatory mediators,FAK/CAPN/PI3K pathway,in order to explore the mechanism of Xinfeng Capsules in improving clinical symptoms of RA.Joint and systemic symptoms of RA patients were observed,and laboratory indicators[hemoglobin (HGB),platelet count (PLT),erythrocyte sedimentation (ESR),immunoglobulin (Ig) G,Ig A,Ig M,rheumatoid factor (RF),anti-cyclic citrulline antibody (CCP-AB),C-reactive protein (CRP)]were detected.ELISA was used to detect serum interleukin (IL)-1β，IL-10,IL-33,chemokine 5 (CCL5),and vascular endothelial growth factor (VEGF).CD3~-CD19~+B cells were measured by flow cytometry.Western blot was used to detect FAK,p-FAK,CAPN,PI3K protein.The results showed that Xinfeng Capsules could significantly alleviate RA joint and systemic symptoms and improve clinical efficacy.And Xinfeng Capsules could increase HGB,decrease PLT,CCP-AB,CRP,ESR index,upregulate IL-10 expression,and down-regulate IL-1β，IL-33,CCL5,VEGF,CD3~-CD19~+B cells,FAK,p-FAK,CAPN,PI3K expressions (P<0.01).Based on the above results,Xinfeng Capsules may reduce the expression of CD3~-CD19~+,regulate the balance of inflammatory cytokines and chemokines,inhibit abnormal activation of FAK/CAPN/PI3K pathway,and improve clinical symptoms of RA.
Arthritis, Rheumatoid/drug therapy* ; B-Lymphocytes ; Capsules ; Drugs, Chinese Herbal ; Humans ; Phosphatidylinositol 3-Kinases ; Vascular Endothelial Growth Factor A

China ; Humans ; Otolaryngology

OBJECTIVE: To investigate the effect of atractylenolide I on proliferation and apoptosis of U266 cells, and anti-multiple myeloma effect of bortezomib. METHODS: Bortezomib, bortezomib combined atractylenolide I and atractylenolide I at different concentrations were added into U266 cells respectively, cellular proliferation toxicity was evaluated by CCK-8 assay, apoptosis and cell cycle were detected by using flow cytometry with Annexin V-FITC/PI staining. RT-PCR and Western blot analysis were used to detect the mRNA and protein levels of targeting gene Caspase-3,Caspase-9,BCL-2,BAX,JAK2,STAT3 and IL-6, respectively. RESULTS: The proliferation of U266 cells could inhibited by atractylenolide I, and the apoptosis of U266 cells could be promoted by atractylenolide I, also, which showed a dose-dependent manner(P<0.00; r=0.99). Moreover, the atractylenolide I could regulat the mitochondrial pathway(P<0.01). The combination of 2 drugs could strengther the inhibition of U266 cell proliferation significantly, and the expression level of IL-6,JAK2,STAT3 and BCL-2 mRNA and protein could be decreased by single drug and 2 drugs both(P<0.01). CONCLUSION Atractylenolide I significantly inhibits the proliferation of U266 cells and promotes their apoptosis. At the same time, it acts synergistically with bortezomib, which may be related to mitochondrial pathway, and probably related to the regulating of IL-6, JAK2 and STAT3 gene expression in signal pathway of JAK2/STAT3.

OBJECTIVE: To investigate the prognostic factors of esophageal cancer with multiple organ metastases and establish a prognostic prediction model. METHODS: Patients data were extracted from the SEER database. The clinical data of 388 patients with esophageal cancer with multiple organ metastases were retrospectively analyzed. Risk factors were analyzed by log-rank method and survival curves were drawn by K-M method. Multivariate analysis was performed by Cox proportional hazard model to obtain independent prognostic factors for multi-organ metastasis of esophageal cancer. A prediction nomogram was further established.RESULTS: The mean survival time of patients in this study was 7.3 months, and the survival rates for 1-, 3-, and 5-year were 15.5%,1.2%, and 0, respectively. Age was an independent prognostic factor. The value of C-index was 0.618. CONCLUSION: The prognosis of esophageal cancer with multiple organ metastases is poor. Age at the diagnosis and patterns of multiple organ metastases are related to the survival time of patients. The prediction nomogram provided a good prognosis prediction.

OBJECTIVE: To analyze the prognostic factors related to liver metastasis of esophageal cancer and establish an effective prediction model. METHODS: The data of 464 cases of esophageal cancer with liver metastasis from 2010 to 2015 was collected from the National Cancer Institute SEER database by SEER stat 8.3.5 software. SPSS(v25.0) was used to analyze the prognostic factors of esophageal cancer liver metastasis and Kaplan-Meier curve was used for survival analysis. We introduced the meaningful variables of single factor analysis in Cox proportional hazard model and multivariate analysis and obtained the independent influencing factors of prognosis.Independent factors were then included in the accelerated failure time model to construct the nomogram. RESULTS: The mean survival time of patients in this study was 11.6 months(95%CI: 10.075-13.209), and their 1-, 3-, and 5-year survival rates were 29.4%, 5.5%, and 0,respectively. Age(HR=1.452, 95% CI: 1.175-1.795), marriage(HR=0.753, 95%CI: 0.611-0.927) and surgery(HR=0.428, 95% CI: 0.227-0.807) were independent prognostic factors for patients. We constructed the nomogram with risk factors of prognosis, and the C-index value was 0.614. CONCLUSION: The prognosis of esophageal cancer liver metastasis is poor. being young, Being married, and surgery are associated with better survival, and the nomogram we have constructed is proved to have good predictive ability.

OBJECTIVE: To investigate the prognostic factors of esophageal cancer with brain metastasis. METHODS: SEER Stat 8.3.5 was used to collect 39 cases of esophageal cancer with brain metastasis from 2010 to 2015 in the Surveillance, Epidemiology and End RESULTS:(SEER) database. X-tile software was used to determine the best cut-off value of the age. Prognostic factors were analyzed with log-rank and Cox proportional hazard model by SPSS(v25.0). RESULTS: The median survival time of patients with esophageal cancer with brain metastasis was 7.0 months, the 6-month survival rate was 53.3%, and the 1-year survival rate was 16.3%. Only age(χ~2=4.045, P=0.044)was the prognostic factor, while there was insufficient evidence to show whether gender, marriage, race, primary site, histological grade,surgery, pathological type, T stage or N stage was associated with the prognosis of the patients. CONCLUSION: Brain metastasis is a rare metastatic type of esophageal cancer. Age is associated with worse prognosis, while the influences of other risk factors are not clear.Active treatment can lead to better prognosis.

Esophageal cancer is a common malignant tumor of the upper gastrointestinal tract. Early symptoms of the disease are inconspicuous and the disease is often diagnosed at a later stage, leading to higher morbidity and mortality. Esophageal cancer morbidity and mortality in both genders ranks among the top 10 most common cancers. Early detection and early treatment are effective means to reduce the incidence and mortality of esophageal cancer. Tumor markers play an important role in early diagnosis, treatment monitoring and prognosis evaluation of esophageal cancer. This paper reviews the clinical application of tumor markers related to esophageal cancer and the exploration and application progress of new tumor markers for esophageal cancer.