BACKGROUND: Capsular contracture is the most troublesome complication in breast implant surgery. Although capsule formation can be seen as a normal reaction to a foreign body, it can induce pain, hardness, deformity, and other pathologic problems. Surgical intervention is required in severe cases, but even surgery cannot guarantee a successful outcome without recurrence. This experimental study confirms that single topical administration of leukotriene antagonist zafirlukast (Accolate, Astrazeneca) reduces peri-implant capsule formation and prevents capsular contracture. METHODS: Twelve smooth-surfaced cohesive gel implants were implanted in New Zealand White rabbits. These miniature implants were designed to be identical to currently used products for breast augmentation. The rabbits were divided into 2 groups. In the experimental group (n=6), the implant and normal saline with zafirlukast were inserted in the submuscular pocket. In the control group (n=6), the implant and normal saline alone were used. Two months later, the implants with peri-implant capsule were excised. We evaluated capsule thickness and collagen pattern and performed immunohistochemical staining of myofibroblasts, transforming growth factor (TGF)-beta1, 2. RESULTS: The thickness of the capsules in the experimental group was reduced in both dorsal and ventral directions. The collagen pattern showed parallel alignment with low density, and the number of myofibroblasts as well as the amounts of TGF-beta1 and TGF-beta2 were reduced in the experimental group. CONCLUSIONS: We suggest that single topical administration of leukotriene antagonist zafirlukast can be helpful in reducing capsule formation and preventing capsular contracture via myofibroblast suppression, modulation of fibroblastic cytokines, and anti-inflammatory effect.
Administration, Topical ; Breast ; Breast Implants ; Capsules ; Collagen ; Congenital Abnormalities ; Contracture ; Cytokines ; Fibroblasts ; Foreign Bodies ; Hardness ; Implant Capsular Contracture ; Myofibroblasts ; Rabbits* ; Recurrence ; Transforming Growth Factor beta1 ; Transforming Growth Factor beta2 ; Transforming Growth Factors

OBJECTIVETo evaluate the effect of Valeriana officinalis var latifolia(VOL) on expression of transforming growth factor beta 1 (TGF-beta 1) in hypercholesterolemic rats and study its possible mechanisms.

METHODDietary-induced hypercholesterolemia was induced in male Wistar rats by given 4% cholesterol and 1% cholic acid diet for 16 weeks. Changes of serum lipid, urinary albumin, renal function and Mesangial matrix index were assessed. Moreover, immunohistochemical stain for TGF-beta 1 and type IV collagen were performed.

RESULTVOL could reduce the serum levels of total cholesterol, low density lipoprotein, urinary albumin and serum creatinine. Light microscopy and immunohistochemical stain revealed that in the same time of lowing serum lipid, Mesangial matrix index was significantly reduced, accompanied by decreased expression of TGF-beta 1 and type IV collagen.

CONCLUSIONVOL has the protective effect on lipid-induced nephropathy, and the inhibition of TGF-beta 1 expression might be the mechanism of VOL on renal protection.

Administration, Oral ; Animals ; Drugs, Chinese Herbal ; administration & dosage ; isolation & purification ; pharmacology ; Hypercholesterolemia ; metabolism ; pathology ; Kidney Glomerulus ; metabolism ; Male ; Phytotherapy ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry ; Rats ; Rats, Wistar ; Transforming Growth Factor beta ; metabolism ; Transforming Growth Factor beta1 ; Valerian ; chemistry

BACKGROUNDNatural articular cartilage has a limited capacity for spontaneous regeneration. Controlled release of transforming growth factor-beta1 (TGF-beta1) to cartilage defects can enhance chondrogenesis. In this study, we assessed the feasibility of using biodegradable chitosan microspheres as carriers for controlled TGF-beta1 delivery and the effect of released TGF-beta1 on the chondrogenic potential of chondrocytes.

METHODSChitosan scaffolds and chitosan microspheres loaded with TGF-beta1 were prepared by the freeze-drying and the emulsion-crosslinking method respectively. In vitro drug release kinetics, as measured by enzyme-linked immunosorbent assay, was monitored for 7 days. Lysozyme degradation was performed for 4 weeks to detect in vitro degradability of the scaffolds and the microspheres. Rabbit chondrocytes were seeded on the scaffolds containing TGF-beta1 microspheres and incubated in vitro for 3 weeks. Histological examination and type II collagen immunohistochemical staining was performed to evaluate the effects of released TGF-beta1 on cell adhesivity, proliferation and synthesis of the extracellular matrix.

RESULTSTGF-beta1 was encapsulated into chitosan microspheres and the encapsulation efficiency of TGF-beta1 was high (90.1%). During 4 weeks of incubation in lysozyme solution for in vitro degradation, the mass of both the scaffolds and the microspheres decreased continuously and significant morphological changes was noticed. From the release experiments, it was found that TGF-beta1 could be released from the microspheres in a multiphasic fashion including an initial burst phase, a slow linear release phase and a plateau phase. The release amount of TGF-beta1 was 37.4%, 50.7%, 61.3%, and 63.5% for 1, 3, 5, and 7 days respectively. At 21 days after cultivation, type II collagen immunohistochemical staining was performed. The mean percentage of positive cells for collagen type II in control group (32.7% +/- 10.4%) was significantly lower than that in the controlled TGF-beta1 release group (92.4% +/- 4.8%, P < 0.05). Both the proliferation rate and production of collagen type II in the transforming growth factor-beta1 microsphere incorporated scaffolds were significantly higher than those in the scaffolds without microspheres, indicating that the activity of TGF-beta1 was retained during microsphere fabrication and after growth factor release.

CONCLUSIONChitosan microspheres can serve as delivery vehicles for controlled release of TGF-beta1, and the released growth factor can augment chondrocytes proliferation and synthesis of extracellular matrix. Chitosan scaffolds incorporated with chitosan microspheres loaded with TGF-beta1 possess a promising potential to be applied for controlled cytokine delivery and cartilage tissue engineering.

Animals ; Cartilage ; metabolism ; Cell Proliferation ; Chitosan ; administration & dosage ; Chondrocytes ; cytology ; Drug Carriers ; Microspheres ; Rabbits ; Tissue Engineering ; methods ; Transforming Growth Factor beta1 ; administration & dosage ; chemistry

The renoprotective activities of white ginseng radix and rootlet were compared in spontaneously hypertensive rat (SHR) with diabetes. During oral administration of white ginseng radix (Ginseng Radix Alba, GRA) and white ginseng rootlet (Ginseng Radix Palva, GRP) for four weeks, arterial blood pressure and blood glucose levels were determined at every 10 days. In both GRA- and GRP-treatment groups, arterial blood pressures started to go down after 10 days of administration and maintained throughout the study period. After four weeks administrations of GRA and GRP, diastolic blood pressures were significantly decreased with 17% and 9%, respectively. GRA treatment also decreased blood glucose levels after 10 days of administration when compared with diabetic SHR group. At the end of the experiment, serum creatinine (Scr) and blood urea nitrogen (BUN) were not significantly different between the groups, except 62% higher value of BUN in diabetic SHR group when compared with SHR group. In the diabetic SHR group, the excretion of urinary albumin was increased significantly when compared with SHR. The level of urinary albumin in GRA treated group was markedly reduced when compared with diabetic SHR group (67.8 4.7 vs. 131.3 13.5 mg/24 h). To examine the effects of ginseng radices on an overt diabetic nephropathy, index of kidney hypertrophy and transforming growth factor-beta1 (TGF-beta1) protein levels were evaluated. The glomerular and tubular cells stained positive for TGF-beta1 seemed to be more abundant in diabetic SHR than in those with SHR, and GRA treated rats showed somewhat less TGF-beta1 protein in glomerular and tubular cells when compared with diabetic SHR. Our results suggest that GRA might be a useful antihypertensive and antidiabetic agent with renoprotective effect.
Administration, Oral ; Animals ; Arterial Pressure ; Blood Glucose ; Blood Urea Nitrogen ; Creatinine ; Diabetic Nephropathies ; Hypertrophy ; Kidney ; Panax* ; Rats ; Rats, Inbred SHR* ; Transforming Growth Factor beta1

PURPOSE: Wound represents a major health challenge as they consume a large amount of healthcare resources to improve patient's quality of life. Many scientific studies have been conducted in search of ideal biomaterials with wound-healing activity for clinical use and collagen has been proven to be a suitable candidate biomaterial. This study intended to investigate the wound healing activity of collagen peptides derived from jellyfish following oral administration. METHODS: In this study, collagen was extracted from the jellyfish--Rhopilema esculentum using 1% pepsin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fourier transform infrared (FTIR) were used to identify and determine the molecular weight of the jellyfish collagen. Collagenase II, papain and alkaline proteinase were used to breakdown jellyfish collagen into collagen peptides. Wound scratch assay (in vitro) was done to determine migration potential of human umbilical vein endothelial cells (HUVEC) covering the artificial wound created on the cell monolayer following treatment with collagen peptides. In vivo studies were conducted to determine the effects of collagen peptides on wound healing by examining wound contraction, re-epithelialization, tissue regeneration and collagen deposition on the wounded skin of mice. Confidence level (p < 0.05) was considered significant using GraphPad Prism software. RESULTS: The yield of collagen was 4.31%. The SDS-PAGE and FTIR showed that extracted collagen from jellyfish was type I. Enzymatic hydrolysis of this collagen using collagenase II produced collagen peptides (CP) and hydrolysis with alkaline proteinase/papain resulted into collagen peptides (CP). Tricine SDS-PAGE revealed that collagen peptides consisted of protein fragments with molecular weight <25 kDa. Wound scratch assay showed that there were significant effects on the scratch closure on cells treated with collagen peptides at a concentration of 6.25 μg/mL for 48 h as compared to the vehicle treated cells. Overall treatment with collagen peptide on mice with full thickness excised wounds had a positive result in wound contraction as compared with the control. Histological assessment of peptides treated mice models showed remarkable sign of re-epithelialization, tissue regeneration and increased collagen deposition. Immunohistochemistry of the skin sections showed a significant increase in β-fibroblast growth factor (β-FGF) and the transforming growth factor-β (TGF-β) expression on collagen peptides treated group. CONCLUSION Collagen peptides derived from the jellyfish-Rhopilema esculentum can accelerate the wound healing process thus could be a therapeutic potential product that may be beneficial in wound clinics in the future.
Administration, Oral ; Animals ; Collagen ; administration & dosage ; isolation & purification ; metabolism ; pharmacology ; Fibroblast Growth Factors ; metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Male ; Regeneration ; Scyphozoa ; chemistry ; Skin ; metabolism ; Skin Physiological Phenomena ; Stimulation, Chemical ; Transforming Growth Factor beta1 ; metabolism ; Wound Healing ; drug effects

OBJECTIVETo investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, cilazapril, on the progressive renal injury in spontaneous hypertensive rats (SHR) with diabetes.

METHODSDiabetic hypertensive rats (SHR-DM) were induced by streptozotozin injected in male SHR (7-week-old),and divided into an untreated and three treated groups: 1) cilazapril treated group; 2) bosentan+amlodipine treated group; and 3) amlodipine treated group. Wistar Kyoto rats (WKY) and SHR rats served as normotensive and hypertensive control, respectively. The mean arterial blood pressure, renal function, endothelin and angiotensin II levels as well as the protein expression of renal extracellular matrix components and transforming growth factor (TGF)-beta1 were determined at the end of the 4th week.

RESULTSMean arterial blood pressure significantly increased in SHR and SHR-DM rats compared to WKY rats. All the therapies reduced the blood pressure to normal levels. However, the enhanced urinary protein excretion, the decreased creatinine clearance as well as the increased plasma and intrarenal endothelin and angiotens in II levels were found in the untreated SHR-DM and prevented by treatment with bosentan+amlodipine and cilazapril. Similarly, these two kinds of therapies in SHR-DM abolished the overexpression of renal TGF-beta1 by Western blot analysis and reduced the accumulation of collagen type IV, laminin and fibronectin proteins by an immunochemical approach. Amlodipine monotherapy had no detectable effects on the above parameters.

CONCLUSIONBosentan combined with amlodipine can offer similar renoprotective effects on that of cilazapril and may be a potent therapy to attenuate renal injury by reducing renal protein levels of TGF-beta1 in diabetes with a hypertensive state.

Amlodipine ; administration & dosage ; Angiotensin II ; analysis ; Animals ; Calcium Channel Blockers ; administration & dosage ; Collagen Type IV ; analysis ; Diabetic Nephropathies ; prevention & control ; Drug Therapy, Combination ; Endothelin Receptor Antagonists ; Hypertension ; complications ; drug therapy ; Kidney ; drug effects ; Male ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Sulfonamides ; administration & dosage ; Transforming Growth Factor beta ; analysis ; Transforming Growth Factor beta1

OBJECTIVETo investigate the relationship of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor beta1 (TGF-beta1) with the occurrence of ankylosing spondylitis (AS), and the effects of Bushen Tongdu Decoction (BTD) on serum TNF-alpha and TGF-beta1, levels in patients.

METHODSSeventy five AS patients were assigned to two groups, 30 in the group I treated with Azulfidine and35 in the group II treated with BTD. ELISA was adopted to detect the levels of TNF-alpha and TGF-beta1, in patients before and after 24-week treatment. Meantime, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured as well. Besides, the levels of TNF-alpha and TGF-beta1 in 30 healthy persons were also detected for normal control.

RESULTSBefore treatment, as compared with normal control, the TNF-alpha increased and TGF-beta1 decreased (P < 0.01) in the two treatment groups; the serum level of TNF-alpha was positively correlated with ESR and CRP (r = 0.296, r = 0.249; P < 0.05), but the serum level of TGF-beta1 showed no correlation with them (r = -0.222, r = -0.203; P > 0.05). After treatment, TGF-beta1 increased, while TNF-alpha, CRP and ESR decreased in group II (P < 0.01).

CONCLUSIONBTD can regulate TNF-alpha and TGF-beta1 levels to suppress the immune inflammatory reaction so as to treat AS.

Adult ; Blood Sedimentation ; C-Reactive Protein ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Male ; Middle Aged ; Spondylitis, Ankylosing ; blood ; drug therapy ; physiopathology ; Transforming Growth Factor beta1 ; blood ; Tumor Necrosis Factor-alpha ; blood ; Young Adult

OBJECTIVETo study the effects of Aloe coarse polysaccharide on the levels of growth factors (EGF, TGF-alpha, TGF-beta1) and interleukins (IL-1beta, IL-6, IL-8) and tumor necrosis factor (TNF) in cultured keratinocytes.

METHODThe cultured keratinocytes were treated with Aloe coarse polysaccharide at concentrations of 75, 150, 300, 600, 1 200 mg x L(-1) land the equal volume of media as control group. The levels of EGF, TGF-alpha, TGF-beta1, IL-1beta, IL-6, IL-8 and TNF in the supernatants of cultured keratinocytes were assayed by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA).

RESULTCompared with the control group, the levels of EGF, TGF-alpha, IL-1beta, IL-6 and IL-8 were significantly increased by treatment with Aloe coarse polysaccharide (P < 0.05, P < 0.01) and in a dose dependent manner, and the levels of TGF-beta1 and TNF were also increased but no statistical significance.

CONCLUSIONAloe coarse polysaccharide may promote keratinocytes to secrete EGF, TGF-alpha, IL-1beta, IL-6 and IL-8.

Aloe ; chemistry ; Cells, Cultured ; Cytokines ; secretion ; Dose-Response Relationship, Drug ; Epidermal Growth Factor ; secretion ; Humans ; Interleukin-1beta ; secretion ; Interleukin-6 ; secretion ; Interleukin-8 ; secretion ; Keratinocytes ; secretion ; Plants, Medicinal ; chemistry ; Polysaccharides ; administration & dosage ; isolation & purification ; pharmacology ; Transforming Growth Factor alpha ; secretion ; Transforming Growth Factor beta1 ; secretion ; Tumor Necrosis Factors ; secretion

BACKGROUNDTransforming growth factor (TGF) beta(1)-Smads signal plays an important role in cardiac remodeling following myocardial infarction (MI). In addition, both angiotensin converting enzyme inhibitor (ACEI) and angiotensin II type I receptor blocker (ARB) can effectively prevent left ventricular remodeling. The current study focused on whether the combination of ACEI and ARB is more beneficial for preventing ventricular remodeling and whether Smad proteins mediate this beneficial effect.

METHODSMI was induced by ligating the left anterior descending coronary artery in rats. Twenty-four hours after ligation, the survived rats were randomly divided into five groups and treated for 8 weeks: placebo group, ACEI group (benazepril 10 mg.kg(-1).d(-1)), ARB group (irbesartan 50 mg.kg(-1).d(-1)), ACEI + ARB group (benazepril 10 mg.kg(-1).d(-1) + irbesartan 50 mg.kg(-1).d(-1)) and control group (sham-operated rats). After 8 weeks, we examined the following indexes: the ratio of ventricular weight to body weight (VW/BW), left ventricular end diastolic dimension (LVDd), ejection fraction (EF), fractional shortening (FS), ratio of E-wave to A-wave velocity, collagen of noninfarcted zone, the mRNA expression of TGFbeta(1), Smad 2, and Smad 3 by RT-PCR in noninfarcted zone, the protein expression of Smad 2 and Smad 3 in noninfarcted zone by Western blot.

RESULTSVW/BW significantly increased in the placebo groups compared with that in the control group (P < 0.01). This increase was limited in ACEI, ARB, and combined groups (P < 0.01 compared with placebo group). There was no significant difference among the three actively treated groups. Collagen was increased in placebo group (5.68 +/- 0.5)% compared with that in control group (P < 0.01). ACEI, ARB and combined treatment attenuated this increase of collagen [(4.3 +/- 0.5)%, (3.5 +/- 0.5)%, (3.2 +/- 0.4)%] in comparison with that in placebo group (P < 0.01 respectively). Combined treatment showed more significant effect on collagen deposition. EF and FS significantly decreased, LVDd and E/A significantly increased in placebo group compared with that in control group (P < 0.01 respectively). ACEI, ARB and combined treatment ameliorated these indexes (P < 0.01 compared with placebo group). The mRNA expression of TGFbeta(1), Smad 2, and Smad 3 (0.700 +/- 0.045, 0.959 +/- 0.037 and 0.850 +/- 0.051) increased in placebo group compared with that in control group (P < 0.01). ACEI, ARB and combined treatment normalized the increase (P < 0.01). Furthermore, ARB and combined treatment proved to be more effective in decreasing TGF beta(1) and Smad mRNA expression than ACEI treatment (P < 0.01). The expression of Smad 2 and Smad 3 protein increased in placebo group compared with that in control group (P < 0.01). ACEI, ARB and combined treatment normalized the increase (P < 0.01). Furthermore, ARB and combined treatment proved to be more effective than ACEI alone (P < 0.01).

CONCLUSIONSTGFbeta(1)-Smads signal activation is correlated with ventricular remodeling following MI. ACEI and ARB treatment prevents ventricular remodeling by inhibiting expression of Smad 2 and Smad 3. ARB and combined treatment are more effective than ACEI alone.

Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; therapeutic use ; Angiotensin-Converting Enzyme Inhibitors ; administration & dosage ; therapeutic use ; Animals ; Drug Therapy, Combination ; Echocardiography ; Male ; Myocardial Infarction ; drug therapy ; Rats ; Rats, Wistar ; Smad2 Protein ; analysis ; genetics ; Smad3 Protein ; analysis ; genetics ; Transforming Growth Factor beta ; genetics ; Transforming Growth Factor beta1 ; Ventricular Remodeling ; drug effects

OBJECTIVETo study the effect of 1,25-(OH)2D3 supplementation during gestation and lactation on TGF-β1 and Smad3 expression in lungs of rat offspring with asthma.

METHODSThirty-two female Wistar rats were randomly divided into four groups: low-, medium- and high-dose 1,25-(OH)2D3 supplementation and control groups (n=8 each). From the 7th day of gestation, the three 1,25-(OH)2D3 supplementation groups were administered with 2,10 and 20 μg/mL of 1,25-(OH)2D3 respectively every other day until weaning (rat offspring: 21 days old). The control group received normal saline instead. Then, bronchial asthma was induced in rat offspring from the 4 groups. The protein and mRNA expression of TGF-β1 and Smad3 in the lung tissue was measured by immunochemistry and RT-PCR.

RESULTSEosinophil cell infiltration and airway inflammation decreased in rat offspring from the low- and medium-dose 1,25-(OH)2D3 groups, but increased in rat offspring of the high-dose 1,25-(OH)2D3 group compared with the control group. Immunohistochemistry of lung tissues showed that the expression of TGF-β1 protein and pSmad3 decreased in rat offspring from the low- and medium-dose 1,25-(OH)2D3 groups (P<0.05), but increased significantly in rat offspring from the high-dose 1,25-(OH)2D3 group compared with the control group (P<0.05). PCR showed that the expression of TGF-β1 and Smad3 mRNA in the lung tissue decreased in rat offspring from the low- and medium-dose 1,25-(OH)2D3 groups (P<0.05), but increased significantly in rat offspring from the high-dose 1,25-(OH)2D3 group compared with the control group (P<0.05).

CONCLUSIONS1,25-(OH)2D3 supplementation plays a role in regulating the immune system in asthmatic rats. Its mechanism may be associated with regulation of the expression of TGF-β/Smad signal pathway-related proteins through the vitamin D receptor signal pathway.

Animals ; Asthma ; metabolism ; Cholecalciferol ; administration & dosage ; analogs & derivatives ; Dietary Supplements ; Female ; Lactation ; metabolism ; Lung ; metabolism ; pathology ; Male ; Pregnancy ; RNA, Messenger ; analysis ; Rats ; Rats, Wistar ; Signal Transduction ; Smad3 Protein ; genetics ; physiology ; Transforming Growth Factor beta1 ; genetics ; physiology