Objective To explore the inhibitory effect of tetramethylpyrazine (TMP) on ultraviolet A-induced senescence as well as matrix metalloproteinase-1 (MMP-1) and-3 (MMP-3) mRNA expressions in human dermal fibroblasts (HDFs).Methods HDFs were isolated from the prepuce by enzymatic digestion, and subjected to primary culture.Cultured HDFs were randomly divided into several groups: control group cultured in high-glucose DMEM medium and receiving no treatment, three TMP groups treated with 20, 50 and 100 mg/L TMP respectively, UVA group receiving UVA radiation alone, UVA + TMP groups pretreated with 20, 50 and 100 mg/L TMP respectively for different durations followed by UVA radiation.UVA radiation was given once daily for 5 consecutive days.The 55th passage HDFs served as the P55 group (senescence control group).Subsequently, CCK-8 assay was performed to evaluate the proliferative activity of HDFs in vitro, optical microscopy to observe the morphologic changes of HDFs after UVA radiation, β-galactosidase staining to estimate the senescence in HDFs, and real-time fluorescence-based quantitative PCR to quantify the mRNA expressions of MMP-1 and MMP-3 in HDFs.Statistical analysis was carried out by one-way analysis of variance (ANOVA) followed by least significant difference (LSD)-t test or Dunnett's T3 test.Results Compared with the control group, the proliferation of HDFs was significantly but transiently inhibited in vitro after the treatment with 100 mg/L TMP for 48 hours (P ＜ 0.05), but showed no significant changes after the treatment with 20 or 50 mg/L TMP for 24, 48 or 72 hours or after the treatment with 100 mg/L TMP for 24 or 72 hours (all P ＜ 0.05).The pretreatments with TMP of 20, 50 and 100 mg/L for 24, 48 and 72 hours all promoted the proliferation of HDFs to a certain degree in the UVA + TMP groups compared with the UVA group, with significant differences in cellular proliferative activity among the UVA group, UVA + TMP groups and control group at 24, 48 and 72 hours (F =17.451,15.231, 23.535, all P ＜ 0.01).Compared with the UVA group, the proliferative activity of HDFs was significantly increased in UVA + 100-mg/L TMP group at 24, 48, 72 hours, UVA + 50-mg/L TMP group at 24 and 72 hours and UVA + 20-mg/L TMP group at 72 hours.After repetitive UVA radiation, HDFs in the UVA group experienced an increase in cell volume, granule acount, and β-galactosidase expression, which was similar to the changes in the P55 group, while the pretreatments with 20, 50 and 100 mg/L TMP for 24 hours suppressed these UVA-induced changes in HDFs.The percentage of β-galactosidase-positive HDFs was 68.417％ ± 1.181％ in the UVA group, 58.167％ ± 5.620％ in the UVA + 20-mg/L TMP group, 45.167％ ± 5.502％ in the UVA + 50-mg/L TMP group, 43.000％ ± 2.000％ in the UVA + 100-mg/L TMP group, 33.667％ ± 5.865％ in the control group, and 76.000％ ± 6.557％ in the P55 group, with significant differences among these groups (F =45.918, P ＜ 0.01).Furthermore, the UVA group significantly differed from the UVA + TMP groups and control group in the percentage of β-galactosidase-positive HDFs and mRNA expressions of MMP-1 and MMP-3 (all P ＜ 0.05).Conclusion TMP can protect HDFs against senescence induced by repetitive UVA radiation, and down-regulate the mRNA expressions of MMP-1 and MMP-3 during senescence.

Background: Aberrant Bcl-2 transcription is closely related with nodal diffuse large B-cell lymphoma (DLBCL), however, the relationship between Bcl-2 and primary gastrointestinal DLBCL (PGI-DLBCL) was not fully studied.Aims: To investigate the relationship between Bcl-2 gene amplification and protein expression and clinicopathological characteristics, immunophenotype and prognosis of PGI-DLBCL.Methods: Clinical data was collected from 136 PGI-DLBCL patients receiving surgical treatment, and a telephone interview was conducted for survival information.Bcl-2 gene amplification and protein expression in tumor tissue were determined by fluorescence in situ hybridization and immuno-histochemistry, respectively, and relationships between Bcl-2 and clinicopathological characteristics, immunophenotype and prognosis of PGI-DLBCL were analyzed.Results: Among 136 PGI-DLBCL patients, 33 (24.3%) showing gene amplification and 90 (66.2%) showing protein expression of Bcl-2;gene amplification was correlated with primary tumor location, Ann Arbor stage, serum lactate dehydrogenase level, B symptom and International Prognostic Index (IPI) score (P<0.05), while protein expression was correlated with primary tumor location and immunophenotype (P<0.05).5-year overall survival (OS) in patients positive for Bcl-2 gene amplification and patients with non-GCB immunophenotype and positive for Bcl-2 protein expression were inferior to those negative ones (41.5%vs.71.5%, P<0.05;54.6% vs.84.6%, P<0.05).In Bcl-2 gene amplification or protein expression positive patients, 5-year OS of CHOP chemotherapy was inferior to that of rituximab combined with CHOP chemotherapy (48.6%vs.80.3%, P<0.05;66.4%vs.83.4%, P<0.05).Conclusions: Detection of Bcl-2 gene amplification is useful for prediction of prognosis in PGI-DLBCL.Both patients with Bcl-2 gene amplification and non-GCB patients with Bcl-2 protein expression have a poorer prognosis.Rituximab may improve the prognosis in patients with Bcl-2 gene amplification or protein expression.

Liver fibrosis is a major disease that affects human health. Currently,drugs used for the treatment of hepatic fibrosis have such problems as low drug solubility,lack of liver specificity and possible occurrence of side-effects. In order to improve the anti-fibrosis therapeutic efficacy,various nano-drug delivery systems and targeting strategies are explored in liver fibrosis therapy. This review summarizes the drug delivery systems and targeting strategies that have been applied to liver fibrosis therapy in recent years from the types of carriers and modified ligands,which serve as a basis of designing safe and effective drug delivery systems for liver fibrosis therapy.

Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.