Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix‑coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti‑β1‑integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)‑2 and MMP‑9 expression. Furthermore, incubation with blocking anti‑β1‑integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia.

Osteoarthritis (OA) is a chronic joint disease involving cartilage erosion and matrix degradation. Costunolide is a sesquiterpene lactone that has been demonstrated to exert anti‑inflammatory activities in a wide variety of cells. The aim of the present study was to investigate the effect of costunolide in OA treatment, using rat chondrocytes and an OA rat model, in which animals were subjected to destabilization of the medial meniscus. The results revealed that costunolide (2‑6 µM) had no effect on chondrocyte viability or phenotype maintenance. Costunolide decreased the interleukin (IL)‑1β‑induced upregulation of matrix metalloproteinases (MMPs), inducible nitric oxide synthase, cyclooxygenase‑2 and IL‑6, and increased the expression of collagen II and transcription factor SOX‑9, which were inhibited by IL‑1β. Costunolide significantly decreased p65 phosphorylation induced by IL‑1β and the translocation of p65 into the nucleus of rat chondrocytes, as observed by western blot analysis and immunofluorescence staining. In addition, activation of the Wnt/β‑catenin signaling pathway was inhibited by costunolide, as demonstrated by the level of activation of β‑catenin and the transfer of β‑catenin into the nucleus induced by IL‑1β. In vivo, cartilage treated with costunolide exhibited attenuated degeneration and lower Mankin scores compared with the OA group. The present study investigated the anti‑osteoarthritic effects of costunolide, which exerted anti‑inflammatory activities and inhibited MMPs expression. Taken together, these results indicate that costunolide may have a potential value in the treatment of OA.

Osteoarthritis (OA) is a common degenerative joint disease in older adults. A number of previous studies have demonstrated that natural flavonoids can serve as promising therapeutic drugs for OA. Kaempferol, a phytochemical ingredient mainly present in various fruits, has exhibited its prominent anti‑inflammatory and antioxidant effects in numerous diseases. However, whether Kaempferol ameliorates the deterioration of arthritis remains to be elucidated. The aim of the present study was to investigate the therapeutic role of Kaempferol on OA in rat chondrocytes. The results revealed that Kaempferol significantly inhibited the interleukin (IL)‑1β‑induced protein expression of inflammatory mediators such as inducible nitric oxide synthase and cyclo‑oxygenase‑2. In addition, the common matrix degrading enzymes [matrix metalloproteinase (MMP)‑1, MMP‑3, MMP‑13 and a disintegrin and metalloproteinase with thrombospondin motif‑5] induced by IL‑1β were also suppressed by Kaempferol, and consequently abolished the degradation of collagen II. Furthermore, the anti‑inflammatory effect of Kaempferol was mediated by the inhibition of the mitogen activated protein kinase‑associated extracellular signal‑regulated kinase and P38 signaling pathways. These results collectively indicated that Kaempferol can potentially prevent OA development and serve as a novel pharmacological target in the treatment of OA.

It is well known that transforming growth factor β (TGFβ), which is able to stimulate multiple intracellular signaling pathways, exerts an important role in Marfan syndrome, although the effects of TGFβ on congenital ectopia lentis (CEL) have yet to be fully elucidated. In the present study, the expression levels of TGFβ and matrix metalloproteinases (MMPs) were investigated in the aqueous humor of patients with ectopic lentis who differed in terms of the severity of the disease. A total of 17 CEL patients with 21 eyes (aged 12.76±9.37 years) and 12 congenital cataract (CC) patients with 17 eyes (aged 6.82±9.18 years) were randomized in the present study. The levels of active TGFβ and MMPs in the aqueous humor were analyzed with Luminex xMAP® technology by using commercially available Bio‑Plex Pro™ Human MMP and TGFβ assays. The distance from the lens edge to the pupil edge and the white to white corneal diameter (i.e. the horizontal distance between the borders of the corneal limbus) were measured, and the ratio was calculated as the degree of lens dislocation. The association between TGFβ and MMP levels and the degree of lens dislocation was analyzed using Spearman's correlation test. Compared with the patients with CC, the level of TGFβ2 in the patients with CEL was increased significantly. Specifically, the level of TGFβ2 in the CEL patients was 855.19 pg/ml (744.33, 1,009.24), whereas it was 557.08 (438.24, 692.71) pg/ml in the CC patients (P<0.001). In addition, it was noted that the levels of MMP‑2 and ‑10 in the aqueous humor of the patients with CEL were higher compared with those in the CC patients, although this increase did not reach the level of statistical significance. Notably, the levels of MMP‑8 and ‑9 in the aqueous humor of patients with CEL were significantly lower compared with those in the CC patients (P=0.014 and P=0.002, respectively). Furthermore, a marginal correlation was identified between the severity of ectopic lentis and the levels of TGFβ2 in the aqueous humor (r2=0.379; P=0.003) of the patients with CEL. Taken together, these results demonstrated that a significant correlation existed between high levels of aqueous humor TGFβ2 and the severity of ectopia lentis in patients with CEL. In addition, aqueous humor TGFβ2 levels in the CEL patients were significantly higher compared with those in CC patients.

Whether Slit homologue 2 (Slit2) inhibits or promotes tumor cell migration remains controversial, and the role of Slit2‑Roundabout 1 (Robo1) signaling in oral cancer remains to be fully elucidated. The aim of the present study was to investigate the role of Slit2‑Robo1 signaling in the adhesion, invasion and migration of tongue carcinoma cells, and the mechanism by which Slit2‑Robo1 signaling inhibits or promotes tumor cell migration. Tca8113 tongue carcinoma cells were treated with the monoclonal anti‑human Robo1 antibody, R5, to inhibit the Slit2‑Robo1 signaling pathway, with immunoglobulin (Ig)G2b treatment as a negative control. The expression levels of Slit2 and Robo1 were determined using flow cytometry. The effects of R5 on the adhesion, invasion and migration of Tca8113 tongue carcinoma cells were investigated. Gelatin zymography was used to investigate the activity of matrix metalloproteinase 2 (MMP2) and MMP9. Western blot analysis was used to evaluate the expression levels of E‑cadherin in Tca8113 cells treated with 10 µg/ml of either R5 or IgG2b. Slit2 and Robo1 proteins were found to be expressed in the Tca8113 cells. R5 significantly inhibited the adhesion, invasion and migration of Tca8113 cells in vitro. R5 also inhibited the activities of MMP2 and MMP9, and increased the expression of E‑cadherin in the Tca8113 cells. These results suggested that Slit2‑Robo1 signaling promoted the adhesion, invasion and migration of tongue carcinoma cells by upregulating the expression levels of MMP2 and MMP9 and, downregulating the expression of E‑cadherin.

Pelvic organ prolapses (POP) notably reduces the quality of life in elderly populations due to bladder and bowel dysfunction, incontinence, and coital problems. Extracellular matrix (ECM) disorder is a pivotal event in the progression of POP, but to date, its specific underlying mechanism remains unclear. The ligaments of patients with POP and healthy controls were collected to compare the expression of Homeobox11 (HOXA11) and transforming growth factor β (TGF‑β1) via immunohistochemical analysis. HOXA11 and TGF‑β1 were overexpressed or knocked down in fibroblast cells to explore their effects on the expression of collagen and matrix metalloproteinases (MMPs). HOXA11 and TGF‑β1 were greatly reduced in the ligaments of patients with POP. The overexpression and downregulation of HOXA11 and TGF‑β1 can mediate ECM disorder via regulating expression of collagen (Col) and MMPs. In addition, HOXA11 and TGF‑β1 exerted synergistic effect on the expression of Col and MMPs. The present study identified that HOXA11 and TGF‑β1 serve critical roles in mediating ECM disorders, which may be of clinical significance for the diagnosis and treatment of patients with POP.

In the present study, the expression of Beclin 1 in osteoarthritis (OA) cartilage tissue was investigated, and also its role in proliferation, apoptosis and expression of matrix metalloproteinases (MMPs) in chondrocytes obtained from patients with OA. Beclin 1 expression in cartilage tissue from OA patients, and in the age- and sex-matched controls, was detected by immunohistochemistry, semi-quantitative polymerase chain reaction and western blotting. Chondrocytes were divided into control and Beclin 1-overexpressed groups. After transfection for 48, 72 and 96 h, cell viability, apoptosis, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway and MMPs were examined. The mRNA and protein expression levels of Beclin 1 were significantly decreased in cartilage tissue from OA patients compared with the sex- and age-matched controls (P<0.05). In chondrocytes from OA patients, Beclin 1 overexpression significantly increased cell viability (P<0.05). Beclin 1 overexpression additionally decreased the degree of apoptosis, as demonstrated by Hoechst staining and flow cytometric analysis. B-cell lymphoma-2 (Bcl-2) was upregulated, and Bcl-2 associated X was downregulated, following Beclin 1 overexpression (P<0.05). The PI3K/Akt/mTOR signaling pathway was mitigated following Beclin 1 overexpression (P<0.05). In addition, MMP1, MMP3 and MMP13 were downregulated after Beclin 1 overexpression (P<0.05). Taken together, low expression levels of Beclin 1 may contribute towards the degeneration of chondrocytes. Beclin 1 overexpression increased cell viability, inhibited apoptosis and MMPs, likely via the PI3K/Akt/mTOR signaling pathway.

The present study explored whether miR‑145‑5p can aggravate the development and progression of rheumatoid arthritis (RA) by regulating the expression of matrix metalloproteinases (MMPs). ELISAs, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), and western blotting were used to examine the expression levels of MMP‑1, MMP‑3, MMP‑9, and MMP‑13 in fibroblast‑like synoviocytes (FLS) from patients with RA. Levels of MMP‑1, MMP‑3, MMP‑9, and MMP‑13 were assessed in the right hind ankles of a murine collagen‑induced arthritis (CIA) model by RT‑qPCR and immunohistochemical (IHC) analysis. The effects of activation or inhibition of the nuclear factor‑κB (NF‑κB) pathway on MMPs were evaluated by RT‑qPCR and western blotting. Subcellular localization of NF‑κB p65 was visualized by confocal microscopy. Overexpression of miR‑145‑5p increased the expression of MMP‑3, MMP‑9, and MMP‑13 in RA‑FLS. Moreover, injection of a miR‑145‑5p agomir into mice increased MMP‑3, MMP‑9, and MMP‑13, as demonstrated by RT‑qPCR and IHC analysis. A chemical inhibitor that selectively targets NF‑κB (BAY11‑7082) significantly attenuated MMP‑9 expression, while it did not influence the levels of MMP‑3 and MMP‑13. Immunofluorescence analysis revealed that nuclear localization of p65 was significantly enhanced, indicating that miR‑145‑5p enhances activation of the NF‑κB pathway by promoting p65 nuclear translocation. miR‑145‑5p overexpression also significantly increased phosphorylated p65 levels; however, the levels of IkB‑a were reduced in response to this miRNA. Moreover, our results indicated that miR‑145‑5p aggravated RA progression by activating the NF‑κB pathway, which enhanced secretion of MMP‑9. In conclusion, modulation of miR‑145‑5p expression is potentially useful for the treatment of RA inflammation, by regulating the expression of MMPs, and MMP‑9 in particular, through inhibition of the NF‑κB pathway.

The present study was designed to examine the expression and function of matrix metalloproteinase‑19 (MMP‑19), which is downregulated following respiratory syncytial virus (RSV) infection. The diverse expression levels of MMP were examined using a designed cDNA expression array. The expression and secretion of MMP‑19 was examined using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis and ELISA, respectively. The proliferation of epithelial cells and lung fibroblasts were examined using flow cytometry. The epithelial‑mesenchymal transition (EMT) was also examined by performing western blot and RT‑qPCR analyses. The results of the cDNA assay showed that infection with RSV resulted in the abnormal expression of certain metalloproteinases. Among these, the expression of MMP‑19 decreased 3 and 7 days following infection. By using flow cytometric, western blot and RT‑qPCR analyses, the present study demonstrated that the downregulation of MMP‑19 inhibited the proliferation of epithelial cells, promoted the EMT and induced the proliferation of lung fibroblasts. Taken together, the findings of the present study suggested that the downregulation of MMP‑19 following RSV infection may be associated with the development of airway hyper‑responsiveness.

One of the major reasons for failure after total joint arthroplasty is aseptic loosening of the implant. At articulating surfaces, defined as the interface between implant and surrounding bone cement, wear particles can be generated and released into the periprosthetic tissue, resulting in inflammation and osteolysis. The aim of the present study was to evaluate the extent to which osteoblasts and macrophages are responsible for the osteolytic and inflammatory reactions following contact with generated wear particles from Ti‑6Al‑7Nb and Co‑28Cr‑6Mo hip stems. To this end, human osteoblasts and THP‑1 monocytic cells were incubated with the experimentally generated wear particles as well as reference particles (0.01 and 0.1 mg/ml) for 48 h under standard culture conditions. To evaluate the impact of these particles on the two cell types, the release of different bone matrix degrading matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and relevant cytokines were determined by multiplex enzyme‑linked immunosorbent assays. Following incubation with wear particles, human osteoblasts showed a significant upregulation of MMP1 and MMP8, whereas macrophages reacted with enhanced MMP3, MMP8 and MMP10 production. Moreover, the synthesis of TIMPs 1 and 2 was inhibited. The osteoblasts and macrophages also responded with modified expression of the inflammatory mediators interleukin (IL)‑6, IL‑8, monocyte chemoattractant protein‑1 and vascular endothelial growth factor. These results demonstrate that the release of wear particles affects the release of proinflammatory cytokines and has a negative impact on bone matrix formation during the first 48 h of particle exposure. Human osteoblasts are directly involved in the proinflammatory cascade of bone matrix degradation. The simultaneous activation and recruitment of monocytes/macrophages boosted osteolytic processes in the periprosthetic tissue. By the downregulation of TIMP production and the concomitant upregulation of MMPs as a response to particle exposure, bone formation around implants may be suppressed, resulting in implant failure.

Osteoarthritis (OA) is a common degenerative disease that can lead to severe joint pain and loss of function, seriously threatening the health and normal life of patients. At present, the pathogenesis of OA remains to be clarified. Recent studies have shown that fatty acid‑binding protein 4 (FABP4) is increased in the plasma and synovial fluid of patients with OA. However, the effect of FABP4 on OA is unclear. The present study established IL‑1β‑induced ATDC5 cells with FABP4 knockdown. Next, cell viability was detected with Cell Counting Kit‑8 assay. The content of inflammatory factors, prostaglandin E2 and glycosaminoglycan (GAG) was detected via ELISA. The levels of reactive oxygen species (ROS) and superoxide dismutase (SOD) in cells were detected by using ROS and SOD kits, respectively. TUNEL staining was used to detect the apoptosis level. Western blotting was used to detect the expression levels of proteins. The results revealed that FABP4 was upregulated in IL‑1β‑induced ATDC5 cells. Knockdown of FABP4 increased cell viability, reduced inflammatory damage, oxidative stress and apoptosis in IL‑1β‑induced ATDC5 cells. Following FABP4 knockdown, the expression of matrix metalloproteinases (MMP3, MMP9 and MMP13) of IL‑1β‑induced ATDC5 cells was reduced, and the expression of GAG was promoted. FABP4 knockdown also inhibited the expression of NF‑κB p65 and enhanced peroxisome proliferator‑activated receptor (PPAR)γ expression. However, the presence of PPARγ inhibitor blocked the aforementioned effects of FABP4 on IL‑1β‑induced ATDC5 cells. In conclusion, FABP4 knockdown suppressed the inflammation, oxidative stress, apoptosis and extracellular matrix degradation of IL‑1β‑induced chondrocytes by activating PPARγ to inhibit the NF‑κB signaling pathway.

The histone deacetylase inhibitor trichostatin A (TSA) has been demonstrated to alleviate certain symptoms associated with osteoarthritis (OA). However, the exact mechanisms underlying this protective effect remain to be elucidated. The present study therefore examined the effects of TSA on the expression levels of interleukin‑1β (IL‑1β)-induced matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in vitro and in vivo. In vitro, reverse transcription‑quantitative polymerase chain reaction was performed to investigate alterations in mRNA expression levels in TSA-treated chondrocytes in the presence or absence of IL‑1β; in addition, protein expression and acetylation levels were assessed by western blotting. In vivo, TSA was administered to rats by intra‑articular injection, following which the mRNA and protein expression levels were analyzed. In addition, macroscopic and histological observations were conducted. Chondrocytes treated with IL‑1β demonstrated increased mRNA and protein expression levels of MMP‑1, MMP‑3 and MMP-13, and decreased expression levels of TIMP‑1 mRNA and protein; these alterations were significantly attenuated by TSA treatment. In addition, increased MMPs and decreased TIMP‑1 expression levels were observed in vivo in the OA rat model. TSA treatment demonstrated in vivo efficacy through the attenuation of various OA‑associated molecular and physiological changes. Taken together, the results of the present study suggest that TSA has potential therapeutic value for the treatment of OA.

The aim of the present study was to investigate whether class C1 decoy oligodeoxynucleotides (ODNs) can inhibit the expression of pro‑fibrotic genes associated with rat hepatic stellate cell (HSC) activation and hepatic fibrosis. Luciferase reporter assays were performed to test the promoter activities of transforming growth factor (TGF)‑β and its downstream target genes following transfection of decoy ODNs and plasmids into HSC‑T6 cells, and western blot assays were performed to measure the protein expression of those genes following decoy ODN transfection. Class C1 decoy ODNs were confirmed to inhibit the promoter activity of TGF‑β and its downstream target genes, such as type 1 collagen (COLI)α1, tissue inhibitor of metalloproteinases (TIMP)1 and α‑smooth muscle actin by Gaussia luciferase reporter assay, and to further downregulate the expression of TGF‑β, SMAD3, COLIα1 and TIMP1 by western blotting in activated HSC‑T6 cells. In conclusion, class C1 decoy ODNs inhibited pro‑fibrotic gene expression in rat HSCS by downregulating TGF‑β signaling.

Recent epidemiological studies have demonstrated that metformin lowers the risk of several types of cancer in diabetic patients. Matrix metalloproteinases (MMPs) play a crucial role in the degradation of the vascular basement membrane extracellular matrix proteins, thereby promoting endothelial cell invasion, migration and angiogenesis in the incidence and progression of tumors. The aim of this study was to investigate the effects of metformin on human umbilical vein endothelial cell (HUVEC) proliferation and migration, as well as on MMP-2 and MMP-9 expression. Cell proliferation was determined by cell counting and MTT colorimetric assays. Cell migration was assessed by the wound repair method. Quantitative real-time reverse transcription PCR was performed to quantify the mRNA expression of MMPs. Metformin at concentrations of 0.5-3.0 mM effectively reduced the number of endothelial cells by 5.5-55%, without being cytotoxic to the cells. Similarly, cell proliferation and migration were markedly inhibited by metformin. In addition, treatment with metformin demonstrated a strong (P<0.001) suppressive effect on the mRNA levels of MMP-2 and -9 in the endothelial cells. The inhibitory effects of metformin on endothelial cell number, migration, and MMP expression were reversed partially by compound C, which is an inhibitor of AMP-activated protein kinase (AMPK). The present study reports that metformin considerably inhibited the proliferation, migration, and MMP-2 and -9 expression of HUVECs, and the effect was partially AMPK-dependent. The obtained findings provide a molecular rationale, whereby metformin can exert anticancer effects.

Prostate cancer (PCa) is one of the most common types of cancer in the urinary system in men. Zeylenone (Zey), a naturally occurring cyclohexene oxide, has an anticancer effect. In the present study, the role and potential mechanism of Zey in PCa were examined. The proliferative, invasive and migratory capacities of DU145 cells were analyzed using Cell Counting Kit‑8, transwell and wound healing assays, respectively. The expression levels of matrix metalloproteinase (MMP)‑2 and MMP‑9 were determined with an ELISA. Reverse transcription‑quantitative polymerase chain reaction and western blotting assays were performed to evaluate the expression levels of extracellular matrix, epithelial‑mesenchymal transition and Wnt/β‑catenin pathway‑associated factors. In the present study, it was observed that Zey not only suppressed the viability of DU145 cells; however, it additionally attenuated the invasive and migratory capacities of cells in a concentration‑dependent manner. Treatment of Zey decreased the expression levels of MMP‑2, MMP‑9 and fibronectin‑1; whereas, it increased tissue inhibitor of metalloproteinases‑1 and collagen‑1 expression levels. Additionally, the vimentin expression level was downregulated, however, the epithelial‑cadherin expression level was upregulated in cells treated with Zey. Furthermore, Zey decreased the expression levels of wnt5a, β‑catenin and cyclin D1. In conclusion, the present results demonstrated that Zey decreased the viability and metastasis of human PCa cells (DU145), via the Wnt/β‑catenin signaling pathway. Therefore, Zey may be applied as a novel drug for treating PCa in the future.

3‑(5‑hydroxymethyl‑2‑furyl)‑1‑benzyl‑indazole (YC‑1) is understood to protect against ischemic stroke, but the molecular basis for its neuroprotection remains to be fully characterized. The present study investigated the influence of YC‑1 on inflammatory responses following experimental stroke. Previous studies indicated that nuclear factor (NF)‑κB‑driven signals serve a pivotal role in mediating inflammatory responses following stroke. Ischemic stroke results in activation of NF‑κB to induce gene expression of factors including inducible nitric oxide synthase, interleukin (IL)‑1β, IL‑6 and matrix metalloproteinases (MMPs). The results of the present study demonstrated that YC‑1 effectively reduced brain infarction and brain edema, and improved blood‑brain barrier leakage. Additionally, animals treated with YC‑1 exhibited significant reductions in neutrophil and macrophage infiltration into the ischemic brain. Furthermore, YC‑1 effectively inhibited NF‑κB translocation and binding activity, and the activity and expression of MMP‑9 following ischemic stroke. In conclusion, YC‑1 may effectively attenuate NF‑κB‑induced inflammatory damage following cerebral ischemia‑reperfusion.

Mori folium, the leaf of Morus alba L. (Moraceae), has been widely used in traditional medicine for the treatment of various diseases. It has been recently reported that Mori folium possesses potential chondroprotective effects in interleukin (IL)‑1β‑stimulated human chondrocytes; however, its protective and therapeutic potential against osteoarthritis (OA) in an animal model remains unclear. In this study, as part of an ongoing screening program to evaluate the anti‑osteoarthritic potential of Mori folium, the protective effects of a water extract of Mori folium (MF) on cartilage degradation and inflammatory responses in a monosodium iodoacetate (MIA)‑induced OA rat model were evaluated. The results demonstrated that administration of MF had a tendency to attenuate the damage to articular cartilage induced by MIA, as determined by knee joint swelling and the histological grade of OA. The elevated levels of matrix metalloproteinases‑13 and two bio‑markers for the diagnosis and progression of OA, such as the cartilage oligomeric matrix protein and C‑telopeptide of type II collagen, were markedly ameliorated by MF administration in MIA‑induced OA rats. In addition, MF significantly suppressed the production of pro‑inflammatory cytokines, including IL‑1β, IL‑6 and tumor necrosis factor‑α. MF also effectively inhibited the expression of inducible nitric oxide (NO) synthase and cyclooxygenase‑2, thus inhibiting the release of NO and prostaglandin E2. Although further work is required to fully understand the critical role and clinical usefulness, these findings indicate that MF may be a potential therapeutic option for the treatment of OA.

The hysteresis of keratinocyte (KC) re‑epithelialization is an important factor resulting in chronic wounds; however, the molecular mechanisms involved in this cellular response remain yet to be completely elucidated. The present study demonstrated the function of transcription factor Forkhead box O3a (FoxO3a) in KC growth and migration functional effects, resulting in restrained KC re‑epithelialization during wound healing. In chronic wound tissue samples, the expression of FoxO3a was significantly increased when compared with the acute wound healing group (P<0.01). Overexpressing FoxO3a significantly inhibited, whereas silencing endogenous FoxO3a enhanced, the growth and migration of HaCaT cells in vitro. Further investigation revealed that FoxO3a negatively regulated matrix metalloproteinases 1 and 9, and increased the expression of tissue inhibitor of metalloproteinase 1. In addition, the upregulation of FoxO3a retarded, whereas the downregulation of FoxO3a accelerated, transforming growth factor‑β1‑induced epithelial‑mesenchymal transition in HaCaT cells. Mechanistically, the overexpression of FoxO3a inactivated β‑catenin signaling and markedly reduced the levels of nuclear β‑catenin. These results reveal a novel mechanism of FoxO3a in regulating KC re‑epithelialization, and provide novel targets for the prevention and treatment of chronic wounds.

Tanshinone II A (TSIIA) is a diterpene quinone extracted from the roots of Salvia miltiorrhiza with anti-inflammatory and anti‑oxidant properties that is used to treat atherosclerosis. In the current study, morphological analyses were conducted to evaluate the effects of TSIIA on atherosclerotic vulnerable plaque stability. Additionally, receptor of advanced glycation end products (RAGE), adhesion molecule, and matrix‑metalloproteinases (MMPs) expression, and nuclear factor-κB (NF‑κB) activation were examined in apolipoprotein E (apoE)‑deficient mice treated with TSIIA. Eight‑week‑old apoE-/- mice were administered TSIIA and fed an atherogenic diet for 8 weeks. TSIIA exhibited no effects on plaque size. Analysis of the vulnerable plaque composition demonstrated decreased numbers of macrophages and smooth muscle cells, and increased collagen content in apoE‑deficient mice treated with TSIIA compared with untreated mice. Western blotting revealed that TSIIA downregulated the expression levels of vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule‑1 (ICAM‑1), and MMP‑2, ‑3, and ‑9, suppressed RAGE, and inhibited NF‑κB, JNK and p38 activation. The present study demonstrated that the underlying mechanism of TSIIA stabilization of vulnerable plaques involves interfering with RAGE and NF‑κB activation, and downregulation of downstream inflammatory factors, including ICAM‑1, VCAM‑1, and MMP‑2, ‑3 and ‑9 in apoE-/- mice.

Insufficient trophoblast invasion is associated with preeclampsia (PE) development. Retinol-binding protein 4 (RBP4) is important for regulating cell differentiation, migration and invasion. The aim of the present study was to determine RBP4 expression and function in the human placenta and to examine the underlying mechanisms. In the present study, RBP4 expression was determined in serum samples from 35 pregnant women with PE and 30 healthy pregnant women using enzyme-linked immunosorbent assays. Cell proliferation was assessed by Cell Counting Kit-8 assays, and cell invasion was examined with transwell assays. RBP4 concentrations were significantly lower in the PE group when compared with the control group. RBP4 overexpression enhanced HTR8/SVneo cell proliferation and invasion, and the levels of phosphorylated (p-) phosphoinositide 3-kinase (PI3K) and p-protein kinase B (AKT) in HTR8/SVneo cells. RBP4 knockdown significantly inhibited HTR8/SVneo cell proliferation and invasion, and repressed the expression of matrix metalloproteinases. In addition, RBP4 knockdown significantly reduced the levels of p-PI3K and p-AKT in HTR8/SVneo cells. Taken together, the results of the present study demonstrated that RBP4 overexpression increased HTR8/SVneo cell proliferation and invasion by suppressing PI3K/AKT signaling and RBP4 knockdown induced the opposite effects.