Oral mucositis, a severe oral ulceration, is a common toxic effect of radio- or chemoradio-therapy and a limiting factor to using the maximum dose of radiation for effective cancer treatment. Among cancer patients, at least 40% and up to 70%, of individuals treated with standard chemotherapy regimens or upper-body radiation, develop oral mucositis. To date, there is no FDA approved drug to treat oral mucositis in cancer patients. The key challenges for oral mucositis treatment are to repair and protect ulcerated oral mucosa without promoting cancer cell growth. Oral mucositis is the result of complex, multifaceted pathobiology, involving a series of signaling pathways and a chain of interactions between the epithelium and submucosa. Among those pathways and interactions, the activation of nuclear factor-kappa B (NF-κB) is critical to the inflammation process of oral mucositis. We recently found that activation of TGFβ (transforming growth factor β) signaling is associated with the development of oral mucositis. Smad7, the negative regulator of TGFβ signaling, inhibits both NF-κB and TGFβ activation and thus plays a pivotal role in the prevention and treatment of oral mucositis by attenuating growth inhibition, apoptosis, and inflammation while promoting epithelial migration. The major objective of this review is to evaluate the known functions of Smad7, with a particular focus on its molecular mechanisms and its function in blocking multiple pathological processes in oral mucositis.
Animals ; Humans ; Mouth Diseases ; metabolism ; pathology ; prevention & control ; Smad7 Protein ; metabolism ; Stomatitis ; metabolism ; pathology ; prevention & control

Transforming growth factor-β (TGF-β) is a driving force of renal fibrosis, which may lead to chronic kidney diseases and even end stage renal diseases. By activating canonical and non-canonical signaling pathways, TGF-β promotes the synthesis of extracellular matrix while preventing their degradation. In the injured kidney, TGF-β induces apoptosis, proliferation and fibrotic response of renal cells including epithelial cells, endothelial cells, podocytes, fibroblasts, pericytes and macrophages, and it also promotes transdifferentiation, activation and proliferation of myofibroblasts. Additionally, TGF-β exerts profibrotic effects by interplaying with other signaling pathways like BMP-7, Wnt/β-catenin and MAP kinase. Smad3 is the central pathological gene in renal fibrosis, and epigenetic regulation of TGF-β/Smad3 is a hot topic in kidney field. Although direct targeting TGF-β may cause side effects including tumorigenesis and immune diseases, the therapeutic strategies targeting the balance of downstream Smad3 and Smad7 may prevent or delay the progression of fibrotic kidney disease.
Epigenesis, Genetic ; Fibrosis ; Humans ; Kidney Diseases ; pathology ; Signal Transduction ; Smad3 Protein ; metabolism ; Smad7 Protein ; metabolism ; Transforming Growth Factor beta ; metabolism

OBJECTIVETo investigate the relationship between expression of Smad3, Smad7 and ventricular remodeling in rats after myocardial infarction.

METHODSMyocardial infarction was induced by left anterior descending coronary artery ligation in rats (n = 11) and sham-operated rats were used as control (n = 10). The rats were sacrificed 8 weeks later. Heart weight/body weight (HW/BW), mean blood pressure, left ventricular end diastolic pressure (LVEDP), collagen content in the un-infarcted area were examined. The mRNA levels of transforming growth factor (TGF)beta(1), Smad 3, Smad7 were determined by RT-PCR.

RESULTCompared with controls, the level of HW/BW, LVEDP and collagen content were significant increased. The mRNA expression of TGFbeta(1) and Smad3 was significantly increased in areas of myocardial infarction, border of the infarction, interventricular septum and right ventricle. The expression of Smad7 mRNA in these areas was decreased.

CONCLUSIONThese results indicated that TGFbeta(1)-Smads signaling was correlated to the ventricular remodeling after myocardial infarction. Smad3 might promote the process while Smad7 inhibit the process.

Animals ; Male ; Myocardial Infarction ; metabolism ; physiopathology ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Smad3 Protein ; genetics ; metabolism ; Smad7 Protein ; genetics ; metabolism ; Transforming Growth Factor beta ; metabolism ; Ventricular Remodeling

OBJECTIVETo explore the effects of Sini Decoction (SD) on the expressions of Samd2 and Smad7 isoproterenol (Iso) induced myocardial fibrosis rats.

METHODSTotally 19 Wistar rats were randomly divided into 3 groups, i.e., the control group, the model group, and the SD group. Iso was injected to rats in the model group and the SD group, while normal saline was injected to rats in the control group. SD was given to rats in the SD group by gastrogavage, while normal saline was administered to rats in the control group and the model group by gastrogavage. Four weeks later Masson staining and electron microscopic analysis were performed in each group. The protein and mRNA expressions of Smad2 and Smad7 were detected using immunohistochemical assay and RT-PCR.

RESULTSMasson staining showed the IOD value of the myocardial collagen fiber was 9 303 in the model group, 2 459 in the SD group, and 4 224 in the control group, indicating the myocardial fibrosis was more obvious in the model group than in the SD group and the control group. The IOD value of Smad2 protein was 20 275 and the mRNA IOD of Smad2 protein was 0. 919 in the model group, while they were respectively 9 949 and 0. 561 in the SD group, indicating the protein and mRNA expressions of Smad2 were obviously higher in the model group than in the SD group (P < 0.05). The IOD value of Smad7 protein was 25 667 and the mRNA IOD of Smad7 protein was 0.222 in the model group, while they were respectively 93 147 and 0. 412 in the SD group, indicating the protein and mRNA expressions of Smad7 was obviously lower in the model group than in the SD group (P < 0.05).

CONCLUSIONSD could effectively inhibit Iso induced myocardial fibrosis, and its mechanism may be associated with down-regulating the expression of Smad2 and up-regulating the expression of Smad7.

Animals ; Cardiomyopathies ; metabolism ; pathology ; Drugs, Chinese Herbal ; pharmacology ; Fibrosis ; Isoproterenol ; adverse effects ; Male ; Myocardium ; metabolism ; pathology ; Rats ; Rats, Wistar ; Smad2 Protein ; metabolism ; Smad7 Protein ; metabolism

OBJECTIVETo establish a rabbit model of silicotic pulmonary fibrosis and to investigate the effect of cordyceps sinensis in this model.

METHODSThirty healthy male white rabbits were randomly divided into control group, silicosis model group, and intervention group. The rabbits in silicosis model group and intervention group received endotracheal perfusion of silicon dioxide suspension (120 mg/kg), and the control group was treated with the same volume of saline. All the rabbits were sacrificed 30 days later. The lung coefficient was calculated by comparing the lung weight and body weight; the right lung tissue was stained with hematoxylin-eosin (HE). The content of hydroxyproline in lung tissue was measured by alkaline hydrolysis. The mRNA levels of transforming growth factor beta 1 (TGF-β₁) and mothers against decapentaplegic homolog 7 (Smad7) in rabbit lung sections were determined by real-time PCR.

RESULTSNo abnormalities were observed by HE staining in the lung tissues of control group, while fibrosis and silicotic nodules were discovered in the silicosis model group and intervention group. The lung coefficient and the content of hydroxyproline in lung tissue were significantly higher in the silicosis model group than in the control group and intervention group (P < 0.05 or P < 0.01). Compared with the control group, the silicosis model group and intervention group had significantly increased TGF-β₁ mRNA levels but significantly reduced Smad7 mRNA levels (P < 0.02). Compared with the silicosis model group, the intervention group had a significantly reduced TGF-β₁ mRNA level but a significantly increased Smad7 mRNA level (P < 0.05).

CONCLUSIONCordyceps sinensis is able to reduce the expression of TGF-β₁ mRNA and increase the expression of Smad7 mRNA in lung tissues of rabbits with silicotic pulmonary fibrosis, and thus postpone the progression of fibrosis.

Animals ; Cordyceps ; chemistry ; Disease Models, Animal ; Lung ; metabolism ; Male ; Pulmonary Fibrosis ; drug therapy ; metabolism ; Rabbits ; Silicosis ; drug therapy ; metabolism ; Smad7 Protein ; metabolism ; Transforming Growth Factor beta1 ; metabolism

OBJECTIVETo examine the expression of TGF-beta1, Smad7 and cell apoptosis in oral lichen planus (OLP) and to evaluate the possible pathogenesis of oral lichen planus.

METHODSImmunohistochemical technique was used to study the expression of TGF-beta1 and Smad7 in the epithelia cells of 17 OLP cases and 7 normal oral mucosa (NOM). TUNEL was used for detecting the cell apoptosis in 17 OLP cases and 7 NOM.

RESULTSTGF-beta1 was moderately positive in the epithelia cells of OLP. All the epithelia cells in OLP showed strong cytoplasmic staining. The expression of TGF-beta1 and Smad7 were significantly increased in OLP compared with that in NOM (P < 0.05). Cell apoptotic index (AI) was remarkably increased in epithelia cells in OLP cases, and the cell apoptosis was localized in basal and suprabasal epithelial layers. There was a positive correlation between TGF-beta1 expression and cell apoptosis in the epithelia of OLP (r = 0.69, P <0.05).

CONCLUSIONSHigh expression of TGF-beta1 and Smad7 in the epithelia of OLP suggests that TGF-beta1-Smad7 signal pathway was disturbed in oral lichen planus. The imbalance of TGF-beta1-Smad7 pathway may contribute to the mechanisms of cell apoptosis of epithelial cells in OLP.

Apoptosis ; Case-Control Studies ; Epithelium ; metabolism ; pathology ; Female ; Humans ; Lichen Planus, Oral ; metabolism ; Male ; Mouth Mucosa ; metabolism ; pathology ; Smad7 Protein ; metabolism ; Transforming Growth Factor beta1 ; metabolism

OBJECTIVETo investigate the effect of Smad7 on the expressions of collagen I and alpha-smooth muscle actin (alpha-SMA) in HSC-T6 cell line activated by transforming growth factor-beta1 (TGF-beta1).

METHODSHSC-T6 cells stably expressing M2-flag protein were selected after co-infection of the cells with pTRE-Smad7-M2-flag and pTet-on. The optimal dose of doxycycline for inducing Smad7 was determined, and the effects of Smad7 over-expression on the expressions of collagen I and alpha-SMA in the cells activated by TGF-beta1 and on Smad2/3 phosphorylation were evaluated using Western blotting.

RESULTSThe optimal dose of doxycycline for inducing Smad7 expression was 2 mg/L. Smad7 over-expression induced by doxycycline decreased the expressions of collagen I and alpha-SMA in HSC-T6 cells activated by TGF-beta1, and down-regulated the level of Smad2/3 phosphorylation.

CONCLUSIONSmad7 over-expression inhibits Smad2/3 phosphorylation, and decreases the expression of collagen I and alpha-SMA in HSC-T6 cells induced by TGF-beta1 to inhibit the progression of liver fibrosis.

Actins ; genetics ; metabolism ; Cells, Cultured ; Collagen Type I ; genetics ; metabolism ; Genetic Therapy ; Hepatocytes ; cytology ; metabolism ; Humans ; Liver Cirrhosis ; metabolism ; therapy ; Smad7 Protein ; pharmacology ; Transforming Growth Factor beta1 ; pharmacology

OBJECTIVETo investigate the expression of TGF-betaR I, Smad2, Smad3 and Smad7 in keloids, normal scars and normal skins. Discuss the significance of these proteins in the course of keloid.

METHODSImmunohistochemistry method was used to detect the expression intensity and distribution of these proteins in above 3 kinds of different tissues in 44 cases. Statistics was used to analyze the data.

RESULTSThe expression of TGF-betaR I were much stronger in keloid than in the other two tissues. The expression of Smad7 were lower in keloids. The increase expression of Smad2,3 were not obvious, but they were found to accumulate in the nucleus.

CONCLUSIONSThe results indicate that over-expression of TGF-betaR I, low-expression of Smad7 and accumulation of Smad2,3 may be one of the etiological factors of keloids. This research may provide a new idea to prevent and treat keloids or other fibrosis diseases in the future.

Adolescent ; Adult ; Female ; Humans ; Keloid ; metabolism ; Male ; Middle Aged ; Protein-Serine-Threonine Kinases ; metabolism ; Receptors, Transforming Growth Factor beta ; metabolism ; Smad2 Protein ; metabolism ; Smad3 Protein ; metabolism ; Smad7 Protein ; metabolism ; Young Adult

OBJECTIVETo observe Smads protein expression in lung tissue of quartz exposed mice and to explore its association with pulmonary fibrosis in silicosis.

METHODSThe experimental mice were divided into control and quartz groups. 0.2 g/kg weight of quartz was injected intratracheally in quartz group. Samples were collected at the 1st, 3rd, 5th, 7th, 14th and 28th day after injection. Immunohistochemical methods with quantitative image analysis were used to assay the protein expression of transforming growth factor beta(1) (TGF-beta(1)), Smad 2/3, Smad 4, and Smad 7 protein levels. Protein expression level is presented by positive unit (PU).

RESULTSSmad 2/3 protein expression increased from day 3, reaching its peak level in day 14 [(42.2 +/- 2.4) PU], and decreased gradually. The elevation of Smad 4 protein level began from day 5, and the highest degree came into day 14 [(40.0 +/- 1.8) PU], decreased thereafter. The expression of Smad 7 presented a decreasing tendency at the beginning and reaching the lowest level in day 14 [(33.5 +/- 3.3) PU]. It seemed to elevate in day 28, but was still lower than the controls. There were positive correlation between Smad 2/3, Smad 4 and TGF-beta(1) (r = 0.91, r = 0.71, respectively, P < 0.05) and also between Smad 2/3 and hydroxyproline contents of lung tissue (r = 0.85, P < 0.05) except Smad 7.

CONCLUSIONSmad protein may have certain association with pulmonary fibrosis in silicosis.

Animals ; DNA-Binding Proteins ; immunology ; metabolism ; Lung ; metabolism ; Male ; Mice ; Mice, Inbred Strains ; Pulmonary Fibrosis ; chemically induced ; metabolism ; Quartz ; toxicity ; Smad2 Protein ; Smad3 Protein ; Smad4 Protein ; Smad7 Protein ; Trans-Activators ; immunology ; metabolism ; Transforming Growth Factor beta ; metabolism

OBJECTIVES: Stably expressed transforming growth factor -beta 1(TGF-β1)MCs were obtained and the effects of centellaasiatica (CA) granule on the expressions of Smad 2/3, Smad 7 and collagen Ⅳ and the level of Smad 2/3 phosphorylation were observed. METHODS: Lipofectin method was used to transfect TGF-β1 vector into MC, and the stably expressed TGF-β1 cell lines were selected by G418. The cells were divided into three groups. Control group:normal MC + RPMI 1640 + 10% normal rat serum; TGF-β1 group:stably expressed TGF-β1 MC + RPMI 1640 + 10% normal rat serum; CA group:stably expressed TGF-β1 MC + RPMI 1640 + 10% rat serum containing high CA. The experiments were repeated for five times. The contents of TGF-β1 and collagen Ⅳ in the culture medium were detected with ELISA, the expressions of mRNA and protein of TGF-β1, Smad 2/3, Smad 7 and the level of Smad 2/3 phosphorylation were detected by using real time quantitative polymerase chain reaction and Western blot. RESULTS: The contents of TGF-β1 and collagen Ⅳ in the culture medium of stably-expressed TGF-β1 MC were increased significantly, and the CA could reverse the effects of TGF-β1. The expressions of mRNA and protein of TGF-β1, Smad 2/3 and the level of Smad 2/3 phosphorylation were increased significantly in TGF-β1 transfected MC, and CA could dramatically reduce the expressions of mRNA and protein of TGF-β1, Smad 2/3 and the level of Smad 2/3 phosphorylation. The high expression of TGF-β1 decreased the expression of Smad 7 mRNA and protein, and the CA could antagonize the effect of mRNA expression. CONCLUSIONS The MCs stably-expressed TGF-β1 can activate the TGF-β1/Smad signal pathway and increase the expression of collagen Ⅳ. CA can decrease the occurrence of diabetic nephropathy(DN) by reducing the production of collagen Ⅳ through inhibiting the TGF-β1/Smad signal pathway.
Animals ; Cells, Cultured ; Centella ; chemistry ; Collagen Type IV ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Mesangial Cells ; drug effects ; metabolism ; Rats ; Signal Transduction ; Smad Proteins ; metabolism ; Smad2 Protein ; metabolism ; Smad3 Protein ; metabolism ; Smad7 Protein ; metabolism ; Transforming Growth Factor beta1 ; metabolism