Effect of Metformin Therapy on Biological Properties and Prognosis of Breast Cancer Patients Complicated with Type-2 Diabetes.

Objectives: To evaluate the effect of Metformin therapy on patients of breast cancer with complications of Type-2 diabetes. Methods: Altogether 102 cases of breast cancer complicated with Type-2 diabetes admitted into Hebei General Hospital from January 2019 to December 2020 were included in the study. They were divided into two groups per whether Metformin was administered in the regimen, namely Metformin group and non-Metformin group. In the meanwhile, 106 cases of breast cancer without Type-2 diabetes admitted in the same period were selected to form a control group. Three groups were compared in terms of general data (incl. age, body mass, family history, menopause or not), clinical staging, tumor histological differentiation, molecular subtyping (Incl. Luminal A, Luminal B, ERBB2+, Basal-like) and prognosis. Results: Compared with the control group, Metformin group and non-Metformin group presented more patients with an older age and post-menopause state (P<0.05), but the latter two groups were not significantly different (P > 0.05). Patients in Metformin group and non-Metformin group had higher clinical staging and histological differentiation and more cases of Basal-like subtype than those in the control group (P < 0.05), without significant difference between those two groups (P > 0.05). More cases of local relapse, lymphatic and distant metastasis were seen in Metformin and non-Metformin groups, but the differences were not significant (P > 0.05). Both groups had lower 5-year survival rates than the control group (P < 0.05). Metformin group had a higher overall survival rate as well as a survival rate free of other lethal reasons than the non-Metformin group (P < 0.05) but was not significantly different from the control group in the survival rate free of other lethal reasons (P > 0.05). Conclusions: Type-2 diabetes remains one of the risk factors affecting breast cancer development, progress and prognosis, which could lower the 5-year overall survival rate among breast cancer patients. This is especially evident among menopaused women. Metformin therapy may improve the prognosis of patients of breast cancer complicated with Type-2 diabetes.

Diagnostic Value Comparison of Urothelium Carcinoma Among Urine Exfoliated Cells Fluorescent In Situ Hybridization (FISH) Examination, Computerized Tomography (CT) Scan, and Urine Cytologic Examination.

BACKGROUND This study aimed to compare the clinical effectiveness of urine exfoliated cells FISH examination, CT scan, and urine cytologic examination on the diagnosis of upper urinary tract urothelium carcinoma with hematuresis symptom. MATERIAL AND METHODS A total of 30 patients with suspicious upper urinary tract urothelium carcinoma between Aug 2010 and Aug 2011 were enrolled, including 23 males and 7 females. All the subjects received urine exfoliated cells FISH examination, CT scan, and urine cytologic examination. Twenty-one cases were diagnosed as urothelium carcinoma, including 14 cases of carcinoma of renal pelvis and 7 cases of carcinoma of ureter. There were 6 cases in stage Ta/T1, 12 cases in stage T2, and 3 cases in T3/T4. The other 9 cases consisted of 1 case of neuroendocrine carcinoma of the renal pelvis, 2 cases of nephrotuberculosis, and 6 cases of renal clear cell carcinoma. RESULTS The total sensitivity of FISH examination, CT scan, and urine cytologic examination on upper urinary tract urothelium carcinoma was 85.7%, 66.7%, and 28.6%, respectively (P<0.05). The tumor staging detection on Ta/T1, T2, and T3/T4 by FISH was 66.7%, 91.7%, 100%; by CT scan 33.3%, 75.0%, 100%; and by urine cytologic examination 0%, 25.0%, and 100%. Their diagnostic specificities were 88.9%, 77.8%, and 100%, respectively (P<0.05). CONCLUSIONS The diagnostic sensitivity on upper urinary tract urothelium carcinoma was highest in FISH examination, followed by CT scan and urine cytologic examination. FISH technique obviously improves the diagnosis of upper urinary tract urothelium carcinoma.

Brachytherapy in the treatment of breast cancer.

Brachytherapy is an important radio-therapeutic modality for a variety of malignancies, including prostate cancer, cervix cancer, breast cancer, vagina cancer, endometrium cancer, head and neck cancer, and many more. This technique has been shown to be an effective and safe non-pharmaceutical treatment with fewer serious complications and better outcome than other treatments for breast cancer. Every year, hundreds of thousands of patients around the world benefit from brachytherapy, which reliably delivers a relatively higher radiation dose to the intended target. However, the follow-up time, patient eligibility criteria, treatment strategy, and radiation doses used in published studies are somewhat inconsistent, making it difficult to strictly compare and evaluate the performance of the treatment. More rigorous studies are required to confirm the safety of this technique and to make outcome data more comparable. In this review, we focus on recent advances in breast brachytherapy techniques and provide an overview of outcomes, cosmetic outcome, toxicity, complications, and limitations of brachytherapy for the treatment of breast cancer. We also summarize the clinical outcomes and toxicity results in patients receiving or not receiving brachytherapy.

Irisin ameliorates UUO-induced renal interstitial fibrosis through TGF-ß1/periostin/MMP-2 signaling pathway.

Renal fibrosis is the most common pathway in progressive kidney diseases. The unilateral ureteral obstruction (UUO) model is used to induce progressive renal fibrosis. We evaluated the effects of irisin on renal interstitial fibrosis in UUO mice. The GSE121190, GSE36496, GSE42303, and GSE96101 datasets were downloaded from the Gene Expression Omnibus (GEO) database. In total, 656 differentially expressed genes (DEGs) were identified in normal and UUO mouse renal samples. Periostin and matrix metalloproteinase-2 (MMP-2) were selected to evaluate the effect of irisin on renal fibrosis in UUO mice. In UUO mice, irisin ameliorated renal function, decreased the expression of periostin and MMP-2, and attenuated epithelial-mesenchymal transition and extracellular matrix deposition in renal tissues. In HK-2 cells, irisin treatment markedly attenuated TGF-ß1-induced expression of periostin and MMP-2. Irisin treatment also inhibited TGF-ß1-induced epithelial-mesenchymal transition, extracellular matrix formation, and inflammatory responses. These protective effects of irisin were abolished by the overexpression of periostin and MMP-2. In summary, irisin treatment can improve UUO-induced renal interstitial fibrosis through the TGF-ß1/periostin/MMP-2 signaling pathway, suggesting that irisin may be used for the treatment of renal interstitial fibrosis.

Comprehensive analysis of pan-cancer reveals the potential of SLC16A1 as a prognostic and immunological biomarker.

SLC16A1 plays an important role in the development of multiple cancer types. Pan-cancer analysis may have significant impacts on the exploration of the relationship between SLC16A1 gene expression, prognosis and the molecular mechanisms of tumorigenesis. In this study, through the analysis of TCGA and GEO datasets, we explored the expression level and survival prognosis of SLC16A1 in pan-cancer, and further explored the differences in SLC16A1 gene mutation, methylation, and phosphorylation between tumor and normal tissues. In addition, we focused on the biological function of this gene and the relationship between the prognosis and immune infiltration by immune infiltration analysis and enrichment analysis, in order to evaluate the diagnostic and prognostic significance of SLC16A1 in carcinomas. The study found that SLC16A1 was highly expressed in 14 kinds of tumors, and there were statistically significant differences in the prognosis of 9 tumors. The phosphorylation level of S467 increased in OV, RCC, and UCEC. There was a statistically negative correlation between the CD8+ T-cell infiltration level and the SLC16A1 expression in HNSC, LUSC, SARC, TGCT, and KIRC. The cancer-related fibroblasts were positively correlated with SLC16A1 expression in BLCA, BRCA, KIRC, KIRP, PAAD, PCPG, and THCA. The enrichment analysis indicated that the tumorigenesis mechanism of this gene was mainly related to "glycolysis and glucose metabolism synthesis." SLC16A1 was a promising prognostic and immunological biomarker in pan-cancer.

Global research trends in unilateral ureteral obstruction-induced renal fibrosis: A bibliometric and visualized study.

BACKGROUND: Renal fibrosis is considered the pathway from almost all chronic kidney diseases (CKD) to end-stage renal diseases. The unilateral ureteral obstruction (UUO) model is a well-established experimental animal model to simulate renal fibrosis associated with obstructive nephropathy in an accelerated manner. In this study, in order to understand the development trends of research on UUO-induced renal fibrosis between 2005 and 2022 and predict prospects, we conducted a comprehensive bibliometric and visualized study using Web of Science (WoS). METHODS: The articles regarding UUO-induced renal fibrosis were culled from the "Core Collection" of the WoS database. VOSviewer software and the R-Bibliometrix Package were used in visual analysis of countries/regions, journals, authors, keywords, institutions, and highly cited articles in this field. RESULTS: The number of articles regarding UUO-induced renal fibrosis has obviously increased annually. China had the largest number of publications in this field. The most frequently used keywords were "inflammation," "transforming growth factor-beta1," "oxigative stress," "smad3," "beta-catenin," and "autophagy." Am J Physiol-Renal was the leading journal. The most highly influential documents were published by Higgins DF and his colleagues, with 46 local citations and 749 global citations. The leading institution was Nanjing Medical University. Furthermore, Zhang Y. was the author who contributed most to this field. CONCLUSION: Our results suggest that the molecular mechanism of UUO-induced renal fibrosis remains a research hot topic, especially on the inflammatory response and oxidative stress, and international cooperation is expected to expand and deepen in the future.

Pan-Cancer Analysis and Experimental Validation of SOX4 as a Potential Diagnosis, Prognosis, and Immunotherapy Biomarker.

INTRODUCTION: SOX4 plays an important role in tumorigenesis and cancer progression. The role of SOX4 in pan-cancer and its underlying molecular mechanism in liver hepatocellular carcinoma (LIHC) are not fully understood. In this study, a comprehensive analysis and experimental validation were performed to explore the function of SOX4 across tumor types. METHODS: Raw data in regard to SOX4 expression in malignant tumors were downloaded from the TCGA and GTEx databases. The expression levels, prognostic values, genetic mutation, and DNA promoter methylation of SOX4 across tumor types were explored via systematic bioinformatics analysis. The ceRNA regulatory network, immune characteristics, and prognostic models were analyzed in LIHC. Finally, we conducted in vitro experiments including Western blotting, cell proliferative assay, trypan blue staining, and fluorescence microscopy to further explore the function of SOX4 in LIHC. RESULTS: SOX4 expression was significantly upregulated in 24 tumor types. SOX4 expression level was strongly associated with unfavorable prognoses, genetic mutations, and DNA methylation levels across different tumor types. Especially in LIHC, LINC00152/hsa-miR-139-3p/SOX4 was identified as a crucial ceRNA network. Moreover, this study also provides insight into the roles of SOX4 expression in immune cell infiltration, macrophage polarization, immune subtype, molecular subtype, and immunomodulators, as well as the tumor immune microenvironment (TIME)-related prognosis, in LIHC. The study established six favorable prognostic models to predict LIHC prognosis based on the SOX4-associated genes. Finally, lenvatinib treatment can increase the expression of SOX4 in hepatocellular carcinoma cells and lead to drug resistance. Silencing SOX4 can effectively eliminate the drug resistance caused by lenvatinib treatment and inhibit the proliferation of cancer cells. CONCLUSIONS: This study highlights that SOX4 may serve as a promising therapeutic target for tumor treatment.

lncRNA MIR4435-2HG Accelerates the Development of Bladder Cancer through Enhancing IQGAP3 and CDCA5 Expression.

Background: Bladder cancer (BCa) is one of the most prevalent cancers occurring in the urinary system. Long noncoding RNAs (lncRNAs), in recent years, have emerged as crucial regulators in various biological processes of tumors. Aim: To identify the role of MIR4435-2 host gene (MIR4435-2HG) and uncover its molecular mechanism in BCa. Methods: Firstly, quantitative real-time PCR (RT-qPCR) analysis was used to examine MIR4435-2HG expression in BCa cells. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and transwell assays were implemented to identify the role of MIR4435-2HG in BCa. RNA-binding protein immunoprecipitation (RIP), RNA pull down, and luciferase reporter assays were applied to explore the potential mechanism of MIR4435-2HG in BCa. Results: MIR4435-2HG was highly expressed in BCa. Moreover, MIR4435-2HG silencing abrogated BCa cell proliferation, migration, and invasion. In terms of underlying mechanism, MIR44352HG acted as a microRNA-2467-3p (miR-2467-3p) sponge to control the expression of IQ motif containing GTPase activating protein 3 (IQGAP3) and cell division cycle associated 5 (CDCA5), resulting in activation of the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and PI3K/AKT/mTOR signaling pathways. Conclusion: MIR4435-2HG involves in the progression of BCa, which might provide novel insights for BCa treatment.

Folate Receptor-Alpha Targeted 7x19 CAR-γδT Suppressed Triple-Negative Breast Cancer Xenograft Model in Mice.

Background: Triple-negative breast cancer (TNBC) is the worst prognosis subtype of breast cancer due to lack of specific targets. Recent studies have shown that immunotherapy may solve that problem by targeting folate receptor-alpha (FRα). Methods: Gene modified γδ T cells were manufactured to express FRa specific chimeric antigen receptor (FRa CAR) and secrete interleukin-7 (IL-7) and chemokine C-C motif ligand 19 (CCL19). CAR-γδT cells that secrete IL-7 and CCL19 (7 × 19 CAR-γδT) were evaluated for their antitumor activity both in vitro and in vivo. Results: 7 × 19 CAR-γδT showed remarkable antitumor activity in vitro. Combined with PBMC, 7 × 19 CAR-γδT inhibited TNBC xenograft model growth superiorly compared with single-application or conventional CAR-γδT cells. Histopathological analyses showed increased DC or T cells infiltration to tumor tissues. Conclusion: Taken together, our results showed that 7 × 19 CAR-γδT have remarkable anti-TNBC tumor activity and showed a broad application prospect in the treatment of incurable TNBC patients.

m6A-induced LINC00958 promotes breast cancer tumorigenesis via the miR-378a-3p/YY1 axis.

Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) play critical roles in human breast cancer (BC) tumorigenesis. However, the mechanisms by which lncRNA and N6-methyladenosine (m6A) regulate BC tumorigenesis are still unclear. In the present research, LINC00958 was markedly overexpressed in BC tissue and cells, and LINC00958 upregulation promoted the tumor progression of BC cells. Mechanistically, m6A methyltransferase-like 3 (METTL3) gave rise to the upregulation of LINC00958 by promoting its RNA transcript stability. Moreover, LINC00958 acted as a competitive endogenous RNA for miR-378a-3p to promote YY1. Overall, these data provide novel insight into how m6A-mediated LINC00958 regulates BC tumorigenesis.

Development and validation of a nomogram to better predict hypertension based on a 10-year retrospective cohort study in China.

Background: Hypertension is a highly prevalent disorder. A nomogram to estimate the risk of hypertension in Chinese individuals is not available. Methods: 6201 subjects were enrolled in the study and randomly divided into training set and validation set at a ratio of 2:1. The LASSO regression technique was used to select the optimal predictive features, and multivariate logistic regression to construct the nomograms. The performance of the nomograms was assessed and validated by AUC, C-index, calibration curves, DCA, clinical impact curves, NRI, and IDI. Results: The nomogram140/90 was developed with the parameters of family history of hypertension, age, SBP, DBP, BMI, MCHC, MPV, TBIL, and TG. AUCs of nomogram140/90 were 0.750 in the training set and 0.772 in the validation set. C-index of nomogram140/90 were 0.750 in the training set and 0.772 in the validation set. The nomogram130/80 was developed with the parameters of family history of hypertension, age, SBP, DBP, RDWSD, and TBIL. AUCs of nomogram130/80 were 0.705 in the training set and 0.697 in the validation set. C-index of nomogram130/80 were 0.705 in the training set and 0.697 in the validation set. Both nomograms demonstrated favorable clinical consistency. NRI and IDI showed that the nomogram140/90 exhibited superior performance than the nomogram130/80. Therefore, the web-based calculator of nomogram140/90 was built online. Conclusions: We have constructed a nomogram that can be effectively used in the preliminary and in-depth risk prediction of hypertension in a Chinese population based on a 10-year retrospective cohort study. Funding: This study was supported by the Hebei Science and Technology Department Program (no. H2018206110).

PP2 Ameliorates Renal Fibrosis by Regulating the NF-κB/COX-2 and PPARγ/UCP2 Pathway in Diabetic Mice.

Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy (DN). We aimed to evaluate the effects of PP2 on renal fibrosis of DN. GSE33744 and GSE86300 were downloaded from the GEO database. Firstly, 839 DEGs were identified between nondiabetic and diabetic mice renal glomerular samples. COX-2 was selected to assess the effects of PP2 on renal glomerulosclerosis. In db/db mice, PP2 decreased the expression of COX-2, phosphorylated p65, and fibrotic proteins, accompanied with attenuated renal glomerulosclerosis. In cultured glomerular mesangial cells, high glucose- (HG-) induced p65 phosphorylation and COX-2 expression were attenuated by PP2 or NF-κB inhibitor PDTC. PP2, PDTC, or COX-2 inhibitor NS-398 ameliorated abnormal proliferation and expression of fibrotic proteins induced by HG. Secondly, 238 DEGs were identified between nondiabetic and diabetic mice renal cortex samples. UCP2 was selected to assess the effects of PP2 on renal tubulointerstitial fibrosis. In db/db mice, PP2 decreased the expression of PPARγ and UCP2, accompanied with attenuated renal tubulointerstitial fibrosis and EMT. In cultured proximal tubular cells, HG-induced PPARγ and UCP2 expression was inhibited by PP2 or PPARγ antagonist GW9662. PP2, GW9662, or UCP2 shRNA ameliorated HG-induced EMT. These results indicated that PP2 ameliorated renal fibrosis in diabetic mice.

Circular RNA cir-ITCH Is a Potential Therapeutic Target for the Treatment of Castration-Resistant Prostate Cancer.

cir-ITCH, a well-known tumor-suppressive circular RNA, plays a critical role in different cancers. However, its expression and functional role in prostate cancer (PCa) are unclear. Herein, we explored the potential mechanism and tumor-inhibiting role of cir-ITCH in PCa. Using reverse transcriptase polymerase chain reaction assay, we analyzed the expression of cir-ITCH in PCa and paired adjacent nontumor tissue samples resected during surgical operation, as well as in two cell lines of human PCa (LNCaP and PC-3) and the immortalized normal prostate epithelial cell line (RWPE-1). Cell viability and migration of PCa cell lines were evaluated using CCK-8 and wound-healing assays. Expression of key proteins of the Wnt/ß-catenin and PI3K/AKT/mTOR pathways was detected using western blotting. We found that cir-ITCH expression was typically downregulated in the tissues and cell lines of PCa compared to that in the peritumoral tissue and in RWPE-1 cells, respectively. The results showed that cir-ITCH overexpression significantly inhibits the proliferation, migration, and invasion of human PCa cells and that reciprocal inhibition of expression occurred between cir-ITCH and miR-17. Proteins in the Wnt/ß-catenin and PI3K/AKT/mTOR pathways were downregulated by overexpression of cir-ITCH both in androgen receptor-positive LNCaP cells and androgen receptor-negative PC-3 cells. Taken together, these data demonstrated that cir-ITCH plays a tumor-suppressive role in human PCa cells, partly through the Wnt/ß-catenin and PI3K/AKT/mTOR pathways. Thus, cir-ITCH may serve as a novel therapeutic target for the treatment of PCa, especially castration-resistant prostate cancer.

Antitumor activity of NKG2D CAR-T cells against human colorectal cancer cells in vitro and in vivo.

Colorectal cancer is one of the most common malignancies worldwide, as it is often diagnosed at an advanced stage. Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable success and emerged as one of the most promising therapeutic strategies in multiple malignancies. The purpose of this study was to investigate the anti-tumor activity of NKG2D CAR-T cells against human colorectal cancer cells. A non-viral third-generation NKG2D CAR was constructed, and subsequently transduced into T cells to obtain the NKG2D CAR-T cells. In vitro, NKG2D CAR-T cells showed cytotoxicity against human colorectal cancer cells in a dose-dependent manner compared with untransduced T cells. In addition, IL-2 and IFN-γ secreted by these cells were significantly higher than those by untransduced T cells. In vivo, NKG2D CAR-T cells significantly suppressed tumor growth, reduced tumor sizes and extended overall survival of mice in a xenograft model of HCT-116 cells. Furthermore, human NKG2D-positive lymphocytes infiltration could be found in the tumor sections of NKG2D CAR-T cells-treated mice. There were no severe pathological changes found in vital organs in any of the treatment groups. NKG2D CAR-T cells showed excellent killing effect and represented a promising immunotherapeutic strategy against human colorectal cancer.

Association of body mass and systemic immune-inflammation indices with endocrine therapy resistance in luminal breast cancers.

OBJECTIVE: To explore correlations between body mass index (BMI), preoperative systemic immune-inflammation index (SII) and endocrine therapy resistance, and evaluate BMI and SII as predictors of resistance, in patients with luminal breast cancer. METHODS: This retrospective study included patients with luminal breast cancer who underwent endocrine therapy at Hebei General Hospital. Relationships between BMI and SII subgroups, and clinicopathological parameters were analysed using χ2-tests. Disease-free survival was assessed using Log-rank statistics. Multivariate analysis of factors related to disease progression were analysed using Cox proportional hazards model. RESULTS: Out of 161 patients, those with normal BMI and low SII had significantly lower endocrine resistance rates versus those with high BMI and SII, and BMI was significantly positively correlated with SII. High BMI or SII was associated with significantly lower disease-free survival rates. Hazard ratios for disease progression risk were 6.036, 3.508 and 1.733, for SII, BMI and TNM stage, respectively. CONCLUSION: In patients with luminal breast cancer, high BMI (>23 kg/m2) and SII (>518 × 109/L) levels may predict high endocrine resistance rates. BMI, SII and TNM stage were independent prognostic factors for endocrine therapy resistance.

Effects of isoliquiritigenin on ovarian cancer cells.

BACKGROUND: Ovarian cancer is one of the most fatal gynecologic malignancies, with most patients diagnosed at the late stage due to insidious onset and lack of early onset specific symptoms. Previous studies have implied that isoliquiritigenin (ILQ) is a promising chemopreventive agent against oral cancer. AIM: This study aimed to investigate effects of ILQ and elucidate the related mechanism. MATERIALS AND METHODS: Ovarian cancer cell lines, SKOV3 and OVCAR3, were treated with various concentrations of ILQ to detect the dose-dependent effects of ILQ and select the suitable concentration. CCK8 assay and clone formation efficiency assays were used to detect viability and proliferation. The cell migration, invasion, and apoptosis were evaluated by wound healing assays, transwell, and flow cytometry assays. The expression of apoptosis-related proteins (Caspase-3, Caspase3-p17, Bcl-2, Bax, and Bim) and related-signaling pathway proteins were also detected by Western blot. RESULTS: It was observed that the treatment of ILQ inhibited the survival and proliferation of SKOV3 and OVCAR3 cells. ILQ treatment inhibited migration and invasion, and induced apoptosis in SKOV3 and OVCAR3 cells. Also, the ILQ treatment increased the Bax/Bcl-2 ratio in SKOV3 and OVCAR3 cells, suggesting that a mitochondrial apoptotic pathway was triggered. It was also observed that, after treated with ILQ, the phosphorylated form of Akt and mTOR decreased and the expression of GSK3ß increased, while P70/S6K decreased. ILQ treatment also decreased the expression of Wnt3a and, therefore, caused the decrease of phosphorylated ERK. ILQ also suppressed the PI3K/Akt/mTOR pathway by reduced the expression level of p-Akt, p-mTOR, P70/S6K and Cyclin D1 in Ishikawa and ES-2 cells. CONCLUSION: The data suggested that ILQ inhibited viability, proliferation, and invasion, and induced apoptosis of SKOV3 and OVCAR3 cells through the PI3K/Akt/mTOR pathway. Together, the data revealed that ILQ treatment may be used as a novel strategy for ovarian cancer therapy.

Pathogenic mechanism of miR-21 in autoimmune lymphoid hyperplasia syndrome.

miR-21 plays an important role in immune responses and inflammatory diseases, but the mechanism of action of miR-21 in autoimmune lymphoid hyperplasia syndrome still remains unclear. The aim of the present study was to assess the mechanism of miR-21 in autoimmune disease, particularly, the autoimmune lymphoid hyperplasia syndrome. The pathology and immunity-related phenotypes of miR-21 transgenic mice, and the lymphocyte subsets were analyzed. The related T cell subsets and germinal center B (GCB) cells generated at the germinal center were detected with flow cytometry. The target genes of miR-21 were evaluated with the luciferase reporter gene method. The homeostatic proliferation of the lymphocytes was detected with the EdU incorporation assay. Inflammatory infiltration occurred to the lung and liver of the transgenic mice at 8 weeks. The frequency of the regulatory helper T cells decreased slightly. Significantly increased double negative T cells were observed in the spleen of the transgenic mice (P<0.05). The immunoglobulins IgG1, IgG2a, IgG2b, and IgG3 in the serum of the transgenic mice aged 8 weeks were significantly higher than those in the wild-type mice aged 8 weeks (P<0.05). The percentages of the GCB cells in the peripheral lymphoid organs such as lymph nodes, mesenteric lymph nodes, PP and spleen in the transgenic mice aged 8-52 weeks increased significantly (P<0.05). The percentage (26.32%) of the newly-formed GCB cells derived from transgenic mice was significantly higher than that (3.87%) of the GCB cells derived from the wild-type mice. miR-21 played a role of negative feedback regulation by inhibiting the NF-κB signal pathway. The highly-expressed miR-21 B cells promoted homeostatic proliferation of the T cells. miR-21 can promote homeostatic proliferation of lymphocytes by inhibiting the NF-κB signal pathway.

PGC-1α, glucose metabolism and type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by glucose metabolic disturbance. A number of transcription factors and coactivators are involved in this process. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is an important transcription coactivator regulating cellular energy metabolism. Accumulating evidence has indicated that PGC-1α is involved in the regulation of T2DM. Therefore, a better understanding of the roles of PGC-1α may shed light on more efficient therapeutic strategies. Here, we review the most recent progress on PGC-1α and discuss its regulatory network in major glucose metabolic tissues such as the liver, skeletal muscle, pancreas and kidney. The significant associations between PGC-1α polymorphisms and T2DM are also discussed in this review.

Regulatory non-coding RNA: new instruments in the orchestration of cell death.

Non-coding RNA (ncRNA) comprises a substantial portion of primary transcripts that are generated by genomic transcription, but are not translated into protein. The possible functions of these once considered 'junk' molecules have incited considerable interest and new insights have emerged. The two major members of ncRNAs, namely micro RNA (miRNA) and long non-coding RNA (lncRNA), have important regulatory roles in gene expression and many important physiological processes, which has recently been extended to programmed cell death. The previous paradigm of programmed cell death only by apoptosis has recently expanded to include modalities of regulated necrosis (RN), and particularly necroptosis. However, most research efforts in this field have been on protein regulators, leaving the role of ncRNAs largely unexplored. In this review, we discuss important findings concerning miRNAs and lncRNAs that modulate apoptosis and RN pathways, as well as the miRNA-lncRNA interactions that affect cell death regulation.

Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice.

Renal tubular epithelial cells (RTEC) apoptosis, which plays a key role in the pathogenesis and progression of diabetic nephropathy (DN), is believed to be contributive to the hyperglycemia-induced kidney failure, though the exact mechanisms remain elusive. In this study, we investigated how inhibition of c-Src/p38 MAPK pathway would affect RTEC apoptosis. The c-Src inhibitor PP2 i.p. administered every other day for 8 weeks to diabetic db/db mice significantly reduced their kidney weights, daily urinary volumes, blood glucose, blood urea nitrogen, serum creatinine, triglyceride and urine albumin excretion, whereas deactivation of c-Src and p38 MAPK were also observed, along with decreases in both Bax/Bcl-2 ratio and cleaved caspase-3 level in the kidneys. In vitro, exposure of HK-2 cells (a human RTEC line), to high glucose (HG) promoted phosphorylation of c-Src and p38 MAPK, and subsequently, as revealed by western blotting, TUNEL assay and flow cytometry, increased cell death, which can be inhibited by PP2. Especially, a specific p38 MAPK inhibitor, SB203580, that both attenuated HG-induced c-Src activation and abrogated the expression of PPARγ and CHOP, also reduced apoptosis. Taken together, PP2 inhibits c-Src and therefore reduces apoptosis in RTEC, which at least in part, is due to suppressed p38 MAPK activation in diabetic kidney.