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Arsenic, as a metal element, has metallic and non-metallic properties and is widely distributed in nature. In the list of carcinogens of the International Agency for Research on Cancer, arsenic is clearly listed as the first class of carcinogens. Chronic arsenic poisoning caused by arsenic contamination of drinking water is a major health problem facing human beings worldwide. This kind of pollution occurs naturally due to geological structure, and the most serious one can lead to cancer, among which skin cancer is the most specific. In addition, epidemiological studies have shown that long-term arsenic exposure can also lead to bladder cancer, lung cancer, and liver cancer, etc. However, there have been a number of different views on the potential mechanisms of arsenic carcinogenesis. Carcinogenesis through signal transduction pathway is one of the important molecular mechanisms, including Wnt, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase-protein kinase B-mammalian target of rapamycin (PI3K/AKT/mTOR), nuclear factor kappa-B (NF-κB) and transforming growth factor-β (TGF-β). When there is a problem in the upstream and downstream or one of its links in the signal transduction pathway, the proliferation and differentiation of human cells are out of control, which can lead to cancer.
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Objective To investigate the effects of ferulic acid (FA) and adipose-derived mesenchymal stem cells(ADMSCs)on rat hepatic stellate cells (HSCs) by regulating TGF-β/smad signal transduction pathway.Methods HSCs were divided into 4 groups:blank control group,FA control group,ADMSCs control group and FA+ADMSCs group.The apoptosis rate of HSCs in each group was detected by flow cytometry.The expression levels of TGF-β1,Smad2,Smad3 and Smad7 mRNA in HSCs were detected by qRT-PCR.The TGF-β1 and Smad7 protein levels,and phosphorylated-Smad2/3 (p-Smad2/3)expression were detected by Western blot.Results Compared with the other 3 groups,the apoptosis rate of HSCs in the FA+ADMSCs group was significantly increased(P＜0.05),while the expression levels of TGF-β1,Smad2 and Smad3 mRNA were significantly decreased,and the Smad7 mRNA expression was increased;moreover,the expression levels of TGF-β1 protein and p-Smad2/3 were significantly decreased,while the Smad7 protein expression was significantly increased(P＜0.05).Conclusion FA can enhance the effect of ADMSCs for down-regulating the TGF-β1 expression in HSCs,and then leads to the decrease of downstream p-Smad2/3 activity and Smad7 expression increase,thus participates in promoting cellular apoptosis.
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Objective To observe the effects of Qishu granule on PI3K/Akt signaling transduction pathways in the process of hepatic fibrosis, and further explain the anti-hepatic fibrosis mechanism of Qishu granule.Methods Wistar rats were randomly divided into normal group, model group, experimental control group and Qishu granule group. Liver fibrosis was duplicated in rats by intraperitoneal injection of CCl4, and the rats were given appropriate treatment at the same day. Rats in Qishu granule group were given a gavage 2 g/(kg?d), 1.0 mL/100 g, while rats in experimental control group and normal group were given the same amount of aquae sterilisata. Rats in each group were taken liver tissue samples in the 1st, 2nd and 4th week, and were checked for the protein expression levels of p-Akt (Ser473), p-Akt (Thr308), Bad (Ser136) and Caspase9 by Western blot.Results Compared with the model group, expression levels of p-Akt (Ser473), p-Akt (Thr308), Bad (Ser136) and Caspase9 in model and Qishu granule groups increased in every time points (P0.05).Conclusion Qishu granule could regulate PI3K/Akt signaling transduction pathways, and inhibit the occurrence and development of liver fibrosis.
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BACKGROUND: Calcium calmodulin-dependent kinase Ⅱ (CaMKⅡ) can be more active in patients with left ventricular hypertrophy (LVH), which in turn causes phosphorylation of ryanodine receptors, resulting in inactivation and the instability of intracellular calcium homeostasis. The present study aimed to determine the effect of CaMKⅡ–ryanodine receptor pathway signaling in rabbits with left ventricular hypertrophy and triggered ventricular arrhythmia. METHODS: Forty New Zealand rabbits were randomized into four groups (10 per group): sham group, LVH group, KN-93 group (LVH+KN-93), and ryanodine group (LVH+ryanodine). Rabbits in the LVH, KN-93, and ryanodine groups were used to establish a left ventricular hypertrophy model by the coarctation of the abdominal aorta, while those in the sham group did not undergo the coarctation. After eight weeks, action potentials (APs) were recorded simultaneously in the endocardium and epicardium, and a transmural electrocardiogram (ECG) was also recorded in the rabbit left ventricular wedge model. Drugs were administered to the animals in the KN-93 and ryanodine groups, and the frequency of triggered APs and ventricular tachycardia was recorded after the rabbits were given isoprenaline (1 mol/L) and high-frequency stimulation. RESULTS: The frequency (animals/group) of triggered APs was 0/10 in the sham group, 10/10 in the LVH group, 4/10 in the KN-93 group, and 1/10 in the ryanodine group. The frequencies of ventricular tachycardia were 0/10, 9/10, 3/10, and 1/10, respectively. The frequencies of polymorphic ventricular tachycardia or ventricular fibrillation were 0/10, 7/10, 2/10, and 1/10, respectively. The frequencies of triggered ventricular arrhythmias in the KN-93 and ryanodine groups were much lower than those in the LVH group (P<0.05). CONCLUSIONS: KN-93 and ryanodine can effectively reduce the occurrence of triggered ventricular arrhythmia in rabbits with LVH. The CaMKⅡ–ryanodine signaling pathway can be used as a new means of treating ventricular arrhythmia.
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TMPRSS3 (transmembrane protease, serine 3) is a member of Ⅱ transmembrane serine proteases (TTSPs), and like the other members of this family, it contains typical domains including a serine protease domain, a transmembrane domain, a LDL receptor-like domain (LDLRA), and a scavenger receptor cysteine-rich domain (SRCR). Four alternative protein isoforms have been described, and isoform A is thought to be primary isoform which is expressed in many tissues, especially in the cochlea. TMPRSS3 protein is primarily localized in the endoplasmic reticulum membranes where it may be anchored by its transmembrane domain. TMPRSS3 is mutated in non-syndromic autosomal recessive deafness (DFNB8/10). Therefore TMPRSS3 is thought to be involved in the development and maintenance of the inner ear, and isoform D may be proposed as a novel diagnostic marker in ovarian carcinoma. TMPRSS3 protein is the first protease which mutation could lead to deafness. These data indicate that important signaling pathways in the inner ear are controlled by proteolytic cleavage. However, it is not clear about TMPRSS3 substrates and its function. The epithelial amiloride-sensitive sodium channel (ENaC) which is regulated by membrane-bound channel activating serine proteases (CAPs), a member of TTSPs, may be a potential substrate of TMPRSS3, but this hypothesis is still to be verified in vivo. With the development of protease research and the application of protease proteomics, substrate degradomes of a protease may therefore represent an important tool for the research of TMPRSS3 function and its molecular mechanism.
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LRRC4, a novel member of LRR (leucine-rich repeat) superfamily, is cloned by expressed sequence tag (EST)-mediated positional cloning strategy combined with 5′-RACE technology. Normal expression of LRRC4 is highly specific for brain, whereas absent or significantly down-regulated in primary tumors including glioma, meningioma and pituitary adenoma. LRRC4 is a functional gene in neural development and axon growth, and associated with glioma grade progression. LRRC4 expression is gradually reduced, even absent accompany with glioma grade increase. Absent expression of LRRC4 is involved in the late event of malignant glioma progression.The reexpression of LRRC4 can decrease a series of growth factors/neurotrophic factors (IGF, EGF, PDGF, CNTF, bFGF,GDNF and BDNF) or receptors gene expression to regulate RTK-mediated many signaling transduction pathway, such as K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF-?B, p70S6/PKC, STAT3 and JNK2/c-Jun/mp53, which block U251 cells in late phase of G1 to inhibit glioma cells proliferation and invasion. This inhibitory effect of LRRC4 is dependent on its LRR domain. LRRC4 induces glioma cells to differentiate into astrocyte-like cells more than apoptosis.
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Aim To explore the relations between anti-apoptotic role of dipfluzine (DIP) and the death signaling transduction pathway initiated by CD95 molecules, and the transcription factor involved in the transcription regulation of CD95 molecules in the hippocampal CA1 region after transient forebrain ischemia. Methods The rat forebrain transient ischemia model was established through 15 min ischemia followed by 3 days reperfusion by using the four-vessel method. The rats were divided randomly into five groups: sham control group, ischemia / reperfusion (I/R) group, DIP treated groups (20, 40 and 80 mg·kg-1 body weight, ig, separately). Western blotting and RT-PCR were performed to detect the expression changes of Fas, FasL, caspase 10 p20, caspase 8, I-κB-α, and p-I-κB-α molecules in protein and mRNA levels, separately, and immunohistochemistry for molecular localization of Fas and FasL in rat hippocampus. Results The expression of Fas, FasL, and caspase 10 p20 in protein and mRNA levels increased after I/R, which was inhibited significantly after treatment with 20 and 40 mg·kg-1 of DIP (P<0.01). In 80 mg·kg-1 of DIP group, the expression of Fas and FasL protein was not significantly different from that of I/R group (P>0.05). The expression of caspase 8 and I-κB-α showed no significant differences in all groups (P>0.05), and no gene expression was observed for p-I-κB-α protein in the study. DIP significantly affected molecular distribution of Fas and FasL protein in CA1 subregion of hippocampus. Conclusion DIP inhibits the death signaling transduction pathway initiated by CD95 molecules in rat hippocampal CA1 subregion, and NF-κB transcription factor may not be involved in the transcription regulation of CD95 molecules after transient forebrain ischemia.
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Aim To investigate the effects of leptin on ?1(Ⅰ) collagen mRNA expression and protein production, and the roles of Janus kinase/signal transducers and activators transcription(JAK/STAT) signaling transduction pathway in increased ?1(Ⅰ) collagen mRNA expression stimulated by leptin in activated hepatic stellate cells(HSCs).Methods Firstly, ?1(Ⅰ) collagen mRNA expression and protein production as well as JAK1 and STAT3 phosphorylation induced by leptin at different doses in a human HSC cell line, LX-2 were determined by RT-PCR, ELISA, and Western-blot.Secondly, the effects of JAK1 inhibitor AG490 on JAK1 phosphorylation and ?1(Ⅰ) collagen mRNA expression stimulated by leptin were detected by Western blot and RT-PCR. Thirdly, the roles of AG490 and transfection with STAT3 antisense oligonucleotide(STAT3-ASON) in STAT3 phosphorylation after leptin were detected by Western blot. Finally, the effect of transfection with STAT3-ASON on ?1(Ⅰ) collagen mRNA expression after leptin was measured by RT-PCR.Results Leptin increased ?1(Ⅰ) collagen mRNA expression and protein production in a dose-dependent manner in LX-2, reaching a maximal level at 80 ?g?L-1 leptin. In addition, phosphorylation of JAK1 and STAT3 after leptin exhibited a time-dependent effect. Besides, JAK1 inhibitor AG490 completely blocked JAK1 and STAT3 phosphorylation and increased in ?1(Ⅰ) collagen gene expression after leptin in LX-2. Transfection with STAT3-ASON blocked STAT3 phosphorylation and increased ?1(Ⅰ) collagen mRNA by leptin in LX-2.Conclusion Leptin had a direct action on liver fibrogenesis by stimulating ?1(Ⅰ) collagen mRNA expression and protein production in activated HSC, and JAK/STAT signaling transduction pathway was involved in the process. JAK1 inhibitor AG490 and transfection with STAT3-ASON blocked the transduction pathway effectively in LX-2. Leptin may be an important factor in the development of hepatic fibrosis. Activated JAK1 and STAT3 signaling in human HSC line provided a novel molecular target for therapeutic intervention of liver fibrosis.
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During the last forty years, although cytotoxic chemotherapy for gastric cancer patients has improved to some extent, its therapeutic effect is limited. Simultaneously, great progression of oncobiology to increase our understanding of the molecular basis of gastric cancer has been made. Currently the cancer cell has been characterized by several genetic changes that lead to altered cellular functions. In addition, multiple cancer-cell environment factors affect the tumor cell via various receptors and subsequent signaling pathways. The increasing knowledge of cellular signaling offers the opportunity to develop novel substances that target specific pathway molecules.