The immune regulation and therapeutic potential of the SMAD gene family in breast cancer.

Breast cancer is a serious threat to human health. The transforming growth factor-ß signaling pathway is an important pathway involved in the occurrence and development of cancer. The SMAD family genes are responsible for the TGF-ß signaling pathway. However, the mechanism by which genes of the SMAD family are involved in breast cancer is still unclear. Therefore, it is necessary to investigate the biological roles of the SMAD family genes in breast cancer. We downloaded the gene expression data, gene mutation data, and clinical pathological data of breast cancer patients from the UCSC Xena database. We used the Wilcox test to estimate the expression of genes of the SMAD family in cancers. And the biological functions of SMAD family genes using the DAVID website. The Pearson correlation method was used to explore the immune cell infiltration and drug response of SMAD family genes. We conducted in biological experiments vitro and vivo. In this study, we integrated the multi-omics data from TCGA breast cancer patients for analysis. The expression of genes of SMAD family was significantly dysregulated in patients with breast cancer. Except for SMAD6, the expression of other SMAD family genes was positively correlated. We also found that genes of the SMAD family were significantly enriched in the TGF-ß signaling pathway, Hippo signaling pathway, cell cycle, and cancer-related pathways. In addition, SMAD3, SMAD6, and SMAD7 were lowly expressed in stage II breast cancer, while SMAD4 and SMAD2 were lowly expressed in stage III cancer. Furthermore, the expression of genes of the SMAD family was significantly correlated with immune cell infiltration scores. Constructing a xenograft tumor mouse model, we found that SMAD3 knockdown significantly inhibited tumorigenesis. Finally, we analyzed the association between these genes and the IC50 value of drugs. Interestingly, patients with high expression of SMAD3 exhibited significant resistance to dasatinib and staurosporine, while high sensitivity to tamoxifen and auranofin. In addition, SMAD3 knockdown promoted the apoptosis of BT-549 cells and decreased cell activity, and BAY-1161909 and XK-469 increased drug efficacy. In conclusion, genes of the SMAD family play a crucial role in the development of breast cancer.

[Effect of moxibustion on renal function and hypercoagulable state in patients with idiopathic membranous nephropathy of low to medium risk with spleen-kidney deficiency and blood stasis].

OBJECTIVE: To compare the effect of moxibustion combined with basic treatment and simple basic treatment on the clinical symptoms, renal function and hypercoagulable state in patients with idiopathic membranous nephropathy (IMN) of low to medium risk with spleen-kidney deficiency and blood stasis. METHODS: A total of 60 patients with IMN of low to medium risk with spleen-kidney deficiency and blood stasis were randomized into an observation group (30 cases, 2 cases dropped off) and a control group (30 cases, 1 case dropped off). In the control group, the conventional basic treatment of anti-hypertension, regulating blood lipid and anti-coagulation was adopted. On the basis of the control group, moxibustion was applied at Shenshu (BL 23), Pishu (BL 20), Guanyuan (CV 4), Zusanli (ST 36) and Sanyinjiao (SP 6) in the observation group, once a day, 5 days a week continuously with 2 day interval. The treatment of 6 months was required in the both groups. Before treatment and 3 and 6 months into treatment, the total TCM syndrome score, the renal function indexes (24-hour urinary protein quantity [UTP], albumin [ALB], urea nitrogen [BUN] and creatinine [Scr]), the blood coagulation indexes (fibrinogen [FIB], D-Dimer [D-D], p-selection and von Willebrand factor [vWF]), total cholesterol (TC) and triacylglycerol (TG) levels were observed, and the therapeutic efficacy was evaluated on 3 and 6 months into treatment in the two groups. RESULTS: The effective rates of 3 and 6 months into treatment were 78.6% (22/28) and 89.3% (25/28) in the observation group, which were higher than 62.1% (18/29) and 75.9% (22/29) in the control group respectively (P<0.05). On 3 and 6 months into treatment, the total TCM syndrome scores were decreased compared before treatment in the both groups (P<0.05), and those in the observation group were lower than the control group (P<0.05). On 3 months into treatment, the levels of UTP, FIB, D-D, P-selection and vWF were decreased (P<0.05), the level of ALB was increased (P<0.05) compared before treatment in the observation group; the levels of UTP and FIB were decreased compared before treatment in the control group (P<0.05); the level of ALB in the observation group was higher than that in the control group (P<0.05), the levels of FIB and vWF in the observation group were lower than those in the control group (P<0.05). On 6 months into treatment, the levels of UTP, FIB, D-D, P-selection, vWF, TC and TG were decreased (P<0.05), the levels of ALB were increased (P<0.05) compared before treatment in the both groups (P<0.05); the levels of UTP, FIB, D-D, P-selection, vWF, TC and TG in the observation group were lower than those in the control group, the level of ALB in the observation group was higher than that in the control group (P<0.05). CONCLUSION: Moxibustion combined with basic treatment can effectively improve the clinical symptoms, renal function and renal microcirculation in patients with idiopathic membranous nephropathy of low to medium risk with spleen-kidney deficiency and blood stasis, the therapeutic effect is superior to the simple basic treatment.

Involvement of TCF7L2 in generation of morphine-induced antinociceptive tolerance and hyperalgesia by modulating TLR4/ NF-κB/NLRP3 in microglia.

Morphine is an opioid agonist and a nonselective mu, kappa and delta receptor agonist. It is a commonly used analgesic drug for the treatment of acute and chronic pain as well as cancer pain. Morphine is particularly important to address the problem of morphine tolerance. Tcf7l2, known as a risk gene for schizophrenia and autism, encodes a member of the LEF1/TCF transcription factor family. TCF7L2 is an important transcription factor that is upregulated in neuropathic pain models. However, the relationship between TCF7L2 and morphine tolerance has not been reported. In this study, we found that morphine tolerance led to the upregulation of TCF7L2 in the spinal cord, and also led to the upregulation of TCF7L2 expression in glial cells, which promoted inflammation related signal, and activated TLR4 / NF-κB/NLRP3 pathway. In addition, TCF7L2 regulated microglial cell activation induced by chronic morphine treatment. Mechanically, we found that TCF7L2 transcriptionally regulated TLR4 expression, and the depletion of TCF7L2 alleviated morphine tolerance induced by chronic morphine treatment, and further alleviated pain hypersensitivity induced by chronic morphine treatment. We therefore suggested that TCF7L2 regulates the activation of TLR4/ NF-κB/NLRP3 pathway in microglia, and is involved in the formation of morphine tolerance. Our results provide a new idea for the regulation mechanism of morphine tolerance.