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This article, titled "[Retracted] A disintegrin and metallproteinase 15 knockout decreases migration of fibroblast-like synoviocytes and inflammation in rheumatoid arthritis," was published in Molecular Medicine Reports in 2015. However, it has since been retracted by the journal's editor due to concerns raised by a reader. The reader pointed out that certain data in the article appeared to be similar to data from other articles written by different authors at different research institutes. The authors were asked for an explanation but did not respond. The editor apologizes for any inconvenience caused. [Extracted from the article]

Lower back pain (LBP) is one of the most common reasons for seeking medical advice in orthopedic clinics. Increasingly, research has shown that symptomatic intervertebral disc degeneration (IDD) is mostly related to LBP. This review first outlines the research and findings of studies into IDD, from the physiological structure of the intervertebral disc (IVD) to various pathological cascades. The vicious cycles of IDD are re-described in relation to the analysis of the relationship among the pathological mechanisms involved in IDD. Interestingly, a 'chief molecule' was found, hypoxia-inducible factor-1α (HIF-1α), that may regulate all other mechanisms involved in IDD. When the vicious cycle is established, the low oxygen tension activates the expression of HIF-1α, which subsequently enters into the hypoxia-induced HIF pathways. The HIF pathways are dichotomized as friend and foe pathways according to the oxygen tension of the IVD microenvironment. Combined with clinical outcomes and previous research, the trend of IDD development has been predicted in this paper. Lastly, an early precautionary diagnosis and treatment method is proposed whereby nucleus pulposus tissue for biopsy can be obtained through IVD puncture guided by B-ultrasound when the patient is showing symptoms but MRI imaging shows negative results. The assessment criteria for biopsy and the feasibility, superiority and challenges of this approach have been discussed. Overall, it is clear that HIF-1α is an indispensable reference indicator for the accurate diagnosis and treatment of IDD. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effects of sufentanil on sepsis-induced acute lung injury (ALI), and identify the potential molecular mechanisms underlying its effect. In order to achieve this, a rat sepsis model was established. Following treatment with sufentanil, the lung wet/dry (W/D) weight ratio was calculated. Histopathological analysis was performed via hematoxylin and eosin staining. Levels of inflammatory factors in bronchoalveolar lavage fluid were determined via ELISA. Furthermore, malondialdehyde (MDA) content and the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in tissue homogenates were assessed using commercial kits. Western blot analysis was performed to determine kininogen-1 (KNG1) protein expression. In addition, alveolar epithelial type II cells (AEC II) were stimulated with lipopolysaccharide (LPS) to mimic ALI. The levels of inflammation and oxidative stress were evaluated following overexpression of KNG1. Protein expression levels of nuclear factor-κB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling were determined via western blot analysis. The results of the present study demonstrated that sufentanil alleviated histopathological injury and the W/D ratio in lung tissue. Following treatment with sufentanil, levels of inflammatory factors also decreased, accompanied by decreased concentrations of MDA, and increased activities of SOD, CAT and GSH-Px. Notably, KNG1 was decreased in lung tissues following treatment with sufentanil. Furthermore, overexpression of KNG1 attenuated the inhibitory effects of sufentanil on LPS-induced inflammation and oxidative stress in AEC II. Sufentanil markedly downregulated NF-κB expression, while upregulating Nrf2 and HO-1 expression levels, which was reversed following overexpression of KNG1. Taken together, the results of the present study suggested that sufentanil may alleviate inflammation and oxidative stress in sepsis-induced ALI by downregulating KNG1 expression. [ABSTRACT FROM AUTHOR]

Gene expression alterations in periodontal ligament stem cells (PDLSCs) during bisphosphonate (BP) usage and the transcriptomic mechanism underlying BP-related osteonecrosis of the jaw have not been fully elucidated. In the present study, human PDLSCs were isolated from adults with no history of periodontal disease, and subsequently incubated and treated with zoledronate on days 3 and 5. Subsequently, PDLSCs from all timepoints were screened using an Affymetrix Gene Expression Array. Limma differential expression analysis was performed on a normalized gene expression matrix, followed by cluster analysis, pathway and network analyses. Overall, 906 genes (352 upregulated and 554 downregulated) exhibited differential expression levels between days 0 and 5, and these were termed slow-response genes. These slow-response genes were enriched in cellular stress response signaling pathways (upregulated genes), as well as proliferation- and ossification-associated signaling pathways (downregulated genes). Furthermore, 168 (day 3 vs. 0) and 105 (day 5 vs. 3) genes were differentially expressed between adjacent timepoints. These genes were also enriched in stress response- and proliferation-associated signaling pathways, but not in ossification-associated signaling pathways. Poly(ADP-ribose) polymerase 1 (PARP1) and CYLD lysine 63 deubiquitinase (CYLD) had the most protein-protein interaction partners among the slow-response genes and were connected with both stress- (e.g. caspase-1) and ossification-associated genes [e.g. secreted phosphoprotein 1 and collagen type I α1 chain (COL1A1)]. BP treatment induced stress response-like transcriptional alterations in PDLSCs, followed by inhibition of proliferation and ossification. These alterations may contribute to the onset of jaw osteonecrosis. PARP1 and CYLD may be two key genes involved in this pathological procedure. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is characterized by acute hypoxic respiratory failure, pulmonary edema and inflammatory infiltration. ALI has a high mortality rate (~30%) in the clinical setting; therefore, focusing on the treatment of lung edema and inflammatory responses in ALI is of significance. The present study investigated the effect of the p38 mitogen-activated protein kinase (p38MAPK) inhibitor, SB203580, on lung edema and inflammatory responses in ALI in vivo. A mouse model of ALI was established to assess the effect of SB203580 on edema, proinflammatory cytokine production, and the expression of interferon regulatory factor 5 (IRF5) and inducible nitric oxide synthase (iNOS) in lung tissues using immunoblotting, immunohistochemistry, immunofluorescence, hematoxylin and eosin staining, and ELISA. SB203580 inhibited LPS-induced lung injury and proinflammatory cytokine expression, including tumor necrosis factor-α and interleukin-1β. SB203580 also downregulated LPS-induced IRF5 and iNOS expression, which are widely used as markers of proinflammatory macrophages. Collectively, the present study demonstrated that SB203580 protected against inflammatory responses and lung injury by inhibiting lung edema and downregulating proinflammatory mediators in LPS-induced lung injury. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion (MI/R) injury is a complex pathological process that occurs when tissues are reperfused following a prolonged period of ischemia. Troxerutin has been reported to have cardioprotective functions. However, the underlying mechanism by which troxerutin protects against MI/R injury has not been fully elucidated. The aim of the present study was to explore whether troxerutin-mediated protection against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced H9C2 cell injury was associated with the inhibition of oxidative stress and the inflammatory response by regulating the PI3K/AKT/hypoxia-inducible factor-1α (HIF-1α) signaling pathway. The results of the present study suggested that troxerutin pretreatment prevented the OGD/R-induced reduction in cell viability, and the increase in lactate dehydrogenase activity and apoptosis. Troxerutin reversed OGD/R-induced the inhibition of the PI3K/AKT/HIF-1α signaling pathway as demonstrated by the increased expression of PI3K and HIF-1α, and the increased ratio of phosphorylated AKT/AKT. LY294002, a selective PI3K inhibitor, inhibited the PI3K/AKT/HIF-1α signaling pathway and further attenuated the protective effect of troxerutin against OGD/R-induced H9C2 cell damage. Furthermore, small interfering (si)RNA-mediated knockdown of HIF-1α reduced troxerutin-induced protection against OGD/R injury. Troxerutin pretreatment alleviated OGD/R-induced oxidative stress, as demonstrated by the reduced generation of reactive oxygen species and malonaldehyde content, and the increased activities of superoxide dismutase and glutathione peroxidase, which were reduced by HIF-1α-siRNA. Troxerutin-induced decreases in the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α in OGD/R conditions were also reduced by HIF-1α-siRNA. The results from the present study indicated that troxerutin aggravated OGD/R-induced H9C2 cell injury by inhibiting oxidative stress and the inflammatory response. The primary underlying protective mechanism of troxerutin was mediated by the activation of the PI3K/AKT/HIF-1α signaling pathway. [ABSTRACT FROM AUTHOR]

Exaggerated inflammatory response and gut microbial dysbiosis play a crucial role in necrotizing enterocolitis (NEC). The probiotic Saccharomyces boulardii (SB) is a yeast that has a beneficial effect on NEC; however, the association between its protective effects and the regulation of the inflammation-related sirtuin 1 (SIRT1)/nuclear factor-κB (NF-κB) signaling pathway and gut microbiota in NEC is unknown. In the present study, the NEC model was established by artificial feeding and lipopolysaccharide (LPS), hypoxia and hypothermia stimulation. Mice were divided into normal, control (artificial feeding), NEC and NEC + SB groups. Hematoxylin and eosin staining demonstrated that SB improved the pathological damage of the intestine caused by NEC in neonatal mice. Furthermore, downregulation of SIRT1 and upregulation of NF-κB expression were confirmed by immunofluorescence staining, western blotting and reverse transcription-quantitative PCR (RT-qPCR) in NEC mice. SB treatment concurrently inhibited the NEC roles on the SIRT1 and NF-κB pathway at both the protein and mRNA levels. Deletion of SIRT1 [SIRT1 knockout (KO)] in the intestine abolished all the effects of SB in NEC mice, including protection of pathological damage and inhibition of the SIRT1/NF-κB pathway activation. The abundance of gut microbial composition, as determined by RT-qPCR, was significantly decreased in the control group compared with the normal group. A further decrease in microbiota abundance was observed in the NEC group, and SB administration significantly improved the enrichment of gut microbiota in neonatal mice with NEC. As anticipated, the increased abundance of gut microbiota modulated by SB was markedly reduced in SIRT1KO NEC mice. The present study revealed that the protective role of SB on NEC was associated with the SIRT1/NF-κB pathway and gut microbiota regulation. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) induces inflammatory stress and apoptosis. Pulmonary epithelial cell apoptosis has been shown to accelerate the progression of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and is the leading cause of mortality in patients with ALI/ARDS. Nephroblastoma overexpressed (NOV; also known as CCN3), an inflammatory modulator, is reported to be a biomarker in ALI. Using an LPS-induced ALI model, we investigated the expression of CCN3 and its possible molecular mechanism involved in lung alveolar epithelial cell inflammation and apoptosis. Our data revealed that LPS treatment greatly increased the level of CCN3 in human lung alveolar type II epithelial cells (A549 cell line). The A549 cells were also transfected with a specific CCN3 small interfering RNA (siRNA). CCN3 knockdown not only largely attenuated the expression of inflammatory cytokines, interleukin (IL)-1β and transforming growth factor (TGF)-β1, but also reduced the apoptotic rate of the A549 cells and altered the expression of apoptosis-associated proteins (Bcl-2 and caspase-3). Furthermore, CCN3 knockdown greatly inhibited the activation of nuclear factor (NF)-κB p65 in the A549 cells, and TGF-β/p-Smad and NF-κB inhibitors significantly decreased the expression level of CCN3 in A549 cells. In conclusion, our data indicate that CCN3 knockdown affects the expression of downstream genes through the TGF-β/p-Smad or NF-κB pathways, leading to the inhibition of cell inflammation and apoptosis in human alveolar epithelial cells. [ABSTRACT FROM AUTHOR]

Gout is a type of serious arthritis that is caused by hyperuricemia. Celery is an umbelliferous plant that was shown to exhibit anti-inflammatory activity in rodent. The present study aimed to investigate the effects and potential preliminary mechanisms of celery seed aqueous extract (CSAE) and celery seed oil extract (CSOL) for gout treatment. The components of CSAE and CSOL were systematically analyzed. In mice with hyperuricemia induced by potassium oxonate and yeast extract, CSAE and CSOL treatment reduced the serum levels of uric acid and xanthine oxidase. In addition, CSAE and CSOL reduced the levels of reactive oxygen species and increased the serum levels of superoxide dismutase and glutathione peroxidase in mouse serum. In rats with acute gouty arthritis induced by intra-articular injection of monosodium urate crystals, CSAE and CSOL treatment alleviated the swelling of the ankle joints and reduced inflammatory cell infiltration around the ankle joints. In addition, CSAE and CSOL reduced the levels of interleukin (IL)-1β and tumor necrosis factor α and increased the levels of IL-10. The results of the present study suggested that celery seed extracts may have anti-gout properties, partially through anti-inflammatory and antioxidative effects. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated the effects of hyperuricemia on the damage to target organs, including the kidneys, joints and the heart. However, it is unclear whether hyperuricemia results in damage to the intestines. The aim of the present study was to investigate intestinal barrier dysfunction in a mouse model of hyperuricemia constructed by knocking out the urate oxidase (Uox) gene. The morphology of the intestine was assessed via hematoxylin and eosin, and alcian blue staining. The serum and intestinal tissue levels of uric acid, tumor necrosis factor (TNF)-α and interleukin (IL)-6, in addition to the presence of uremic toxins in the serum, were assessed. The levels of diamine oxidase (DAO), D-lactate (D-LAC) and endotoxins in the serum, which are markers of the intestinal permeability, were measured using ELISA. The expression of the intestinal tight junction proteins zona occludens-1 (ZO-1) and occludin were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemical analysis. The Uox-knockout mice spontaneously developed hyperuricemia. Histopathological analysis indicated notable intestinal defects including sparse villi, mucosal edema and a declining mucus layer in hyperuricemic mice. The expression levels of ZO-1 and occludin in the intestines were downregulated, and the serum levels of DAO, D-LAC and endotoxins were higher in the hyperuricemic mice, compared with control mice. The serum and intestinal tissue levels of IL-6 and TNF-α were significantly increased. Additionally, the expression levels of the serum uremic toxins, serum creatinine, blood urea nitrogen were significantly increased in hyperuricemic mice compared with the control mice, while only a marked increase in indoxyl sulfate (IS) and p-cresol sulfate was reported. Collectively, the results of the present study suggested that intestinal barrier dysfunction and subsequent enhanced intestinal permeability may occur as a result of hyperuricemia in mice. Furthermore, we proposed that the loss of intestinal epithelium barrier function may be associated with uric acid-induced inflammatory responses; however, further investigation is required. [ABSTRACT FROM AUTHOR]

The inflammatory response plays a vital role in cerebral aneurysm (CA) formation and progression. Tanshinone IIA (Tan IIA) is one of the major active components of Chinese medicine Danshen (Salvia miltiorrhiza Bunge) and is widely used for the treatment of cardiovascular diseases, due to its anti-inflammatory effects. The aim of the present study was to investigate whether Tan IIA can attenuate CA formation in rat models, and determine its underlying mechanisms. CAs were induced in rats surgically and through high-salt diet treatments. The Tan IIA-treated group displayed relatively mild symptoms, as compared with the control group. Tan IIA treatment reduced macrophage infiltration and nuclear factor (NF)-κB activation in aneurysmal walls. Next, lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage cells were used to examine the anti-inflammatory effects of Tan IIA on macrophages. It was found that Tan IIA reversed LPS-induced differentiation of RAW 264.7 cells and suppressed NF-κB pathway activation. In conclusion, these findings demonstrated that Tan IIA can suppress CA formation by inhibiting inflammatory responses in macrophages. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) is a common clinicopathological condition. Currently, the pathogenesis of NASH remains unknown, and no optimal therapy option currently exists. It has previously been demonstrated that diallyl disulfide (DADS) was capable of attenuating liver dysfunction, as DADS supplementation had a positive impact on liver regeneration, proliferation and oxidative damage. Thus, DADS could serve as a potential therapeutic agent that can protect against the effects of NASH. The present study aimed to evaluate the effect of DADS on NASH and to understand the associated underlying molecular mechanisms. A methionine- and choline-deficient diet (MCD) and high-fat diet (HFD) are the two common animal models that induce NASH. C57BL/6J mice were fed an MCD for 4 weeks, or an HFD for 20 weeks, in the present study. The mice were treated with or without DADS (20, 50 and 100 mg/kg) for 4 or 20 weeks. For the histopathological examination, hematoxylin and eosin staining, oil red O staining and immunohistochemical analyses were performed using the liver sections. Biochemical assays and ELISA were performed to measure the serum biochemical indicators of hepatic function and inflammatory indicators, respectively. Reverse transcription-quantitative PCR, immunofluorescence and western blotting were used to detect expression levels of the genes involved in the molecular mechanisms underlying DADS protection. MCD or HFD induced the histological features of NASH in mice, including significant vacuolated hepatocytes, marked inflammatory cell infiltration and severe micro- and macro-vesicular steatosis. Serum alanine transferase and aspartate aminotransferase levels, as well as the contents of liver triglyceride and total cholesterol, were significantly increased in these two models. DADS attenuated these histological and biochemical changes. DADS ameliorated hepatic steatosis by regulating sterol regulatory element-binding transcription factor 1, apolipoprotein A1, cyclic AMP-responsive element-binding protein H and fibroblast growth factor 21. Furthermore, DADS was revealed to prevent lipotoxicity via peroxisome proliferator-activated receptor α elevation and stearoyl-coenzyme A desaturase 1 inhibition in HFD-fed mice. In addition, DADS markedly inhibited lipid peroxidation by modulating malondialdehyde and superoxide dismutase, and it also decreased tumor necrosis factor-α production, interleukin-6 production and macrophage influx, as well as suppressing nuclear factor-κB activation, indicating suppression of MCD-induced hepatic inflammation. Taken together, the results have shown that DADS exerts beneficial effects on MCD- or HFD-induced NASH by suppressing key regulators of lipid metabolism, lipid peroxidation and inflammation. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a major cause of morbidity and mortality globally, and is characterized by widespread inflammation in the lungs. Increased production of reactive oxygen species is hypothesized to be associated with ALI. Matrine and lycopene are active products present in traditional Chinese medicine. Matrine is an effective inhibitor of inflammation, whereas lycopene decreases lipid peroxidation. Therefore, it was hypothesized that combinatorial treatment with matrine and lycopene may provide synergistic protection against ALI. In the present study, mice were treated with dexamethasone (DEX; 5 mg/kg), matrine (25 mg/kg), lycopene (100 mg/kg), and matrine (25 mg/kg) + lycopene (100 mg/kg) for 7 days prior to injury induction using lipopolysaccharide (LPS; 5 mg/kg) for 6 h. Lung tissues were collected following the sacrifice of the mice and hematoxylin and eosin staining was used for histological analysis. Malondialdehyde (MDA), glutathione (GSH) and myeloperoxidas (MPO) levels were examined by respective kits. The expressions of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were evaluated by ELISA. The expressions of IκBα and NF-κB p65 were examined by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. The results indicated that the combined treatment exhibited a similar effect to DEX, both of which attenuated lung structural injuries, downregulated the expressions of IL-6, TNF-α, MPO and MDA, and upregulated that of GSH. Furthermore, the combined treatment and DEX inhibited NF-κB p65 activation. The present study revealed that combined treatment with matrine and lycopene exhibited protective effects on an LPS-induced mouse model of ALI, suggesting that they may serve as a potential alternative to glucocorticoid therapy for ALI. [ABSTRACT FROM AUTHOR]

Autophagy serves an important role in numerous diseases, as well as in infection and inflammation. Irreversible pulpitis (IP) is one of the most common inflammatory endodontic diseases, and autophagy has been reported to regulate IP in vitro. However, the level of autophagy in the IP pathogenic process in vivo remains unknown. The aim of the current study was, thus, to investigate the levels of autophagy-associated proteins in rats with IP in vivo. A rat dental IP model was successfully constructed, and five different time points (0, 1, 3, 5 and 7 days) were investigated. The levels of the autophagy-related 5 (ATG5), ATG7, light chain 3 (LC3) and Beclin-1 proteins exhibited a time-dependent increase in rats with IP, whereas the levels of mammalian target of rapamycin and p62/sequestosome 1 were decreased. In addition, the levels of ATG proteins were specifically increased in odontoblasts and microvascular endothelial cells in pulpitis tissue. Based on these findings, autophagy may serve an important role in IP, and the present study data provide a new insight into the IP pathogenesis and treatment. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) induces aberrant expression of microRNAs (miRNAs), causing various secondary injury responses, including inflammation, apoptosis and oxidative stress. However, the mechanisms underlying miRNA-mediated apoptosis have not been fully elucidated. In the present study, a rat SCI model was established and a miRNA microarray was analyzed to detect miRNA expression profiles at different times post-SCI. The Basso, Beattie and Bresnahan score, cresyl violet staining and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling staining were used to evaluate locomotor activity, lesion volume and neuronal cell apoptosis, respectively, at different time points post-SCI. It was observed that numerous miRNAs were altered at 14 days post-SCI and miR-124 was one of the most notably downregulated miRNAs. The present results demonstrated that overexpression of miR-124 by agomir-124 improves functional recovery, decreases lesion size and suppresses neuronal cell apoptosis in a rat SCI model. Luciferase reporter assay demonstrated that miR-124 inhibited apoptosis regulator BAX (Bax) expression, a key molecule in the activation of the mitochondrial apoptotic pathway, by targeting its 3′-untranslated region in BV-2 cells. Furthermore, restoration of Bax by pc-DNA-Bax inhibits the protective effect of miR-124 in H2O2-treated BV-2 cells. Notably, the present results demonstrated that miR-124 may block the mitochondrial apoptotic pathway by inhibiting Bax, cleaved-caspase-9 and cleaved-caspase-3 expression in rats following SCI. Collectively, the present results suggested that miR-124 may improve functional recovery and supress neuronal cell apoptosis by blocking the mitochondrial apoptotic pathway in SCI rats, suggesting that miR-124 may serve as a potential therapeutic target in SCI treatment. [ABSTRACT FROM AUTHOR]

It has been previously reported that hepatitis B e-antigen (HBeAg) induces microRNA (miR)-155 expression and promotes liver injury by increasing inflammatory cytokine production in macrophages. Moreover, it was previously demonstrated that miR-210 alleviates lipopolysaccharide-stimulated proinflammatory cytokine production in macrophages. In addition, accumulating evidence suggests that miR-210 is able to suppress hepatitis B virus (HBV) replication in HepG2.2.15 cells. However, it remains unclear whether miR-210, similar to miR-155, affects the progress of hepatitis B by regulating macrophage function. Reverse transcription-quantitative polymerase chain reaction analysis was used to detect miR-210 levels in serum and cells. HBV-associated antigens stimulated different types of macrophages and facilitated the observation of the effects of these antigens on miR-210 expression in macrophages. Co-culture of peripheral blood monocytes from healthy controls and the serum of patients with chronic hepatitis B (CHB) was conducted to evaluate the effect of HBV-associated elements in the serum on the expression of the macrophage miR-210 in vivo. It was observed that miR-210 expression levels were decreased in the peripheral blood monocytes (PBMs) and serum of patients with CHB and negatively associated with serum alanine aminotransferase and aspartate aminotransferase, but not other clinical parameters including hepatitis B surface antigen (HBsAg), HBeAg, anti-HBe antibody (HBeAb) and hepatitis B core antibody (HBcAb) and HBV-DNA. Notably, it was demonstrated that miR-210 expression was not affected by treatment with HBV-associated antigens in different types of macrophages. Notably, the serum of patients with CHB was able to markedly downregulate the miR-210 expression of PBMs in healthy controls. These findings suggested that, unlike the induction of miR-155 by HBeAg, there may be certain other elements, apart from HBV-associated antigens, regulating miR-210 levels in the serum and PBMs of patients with CHB that affect macrophage activation. [ABSTRACT FROM AUTHOR]

Since obesity is largely responsible for the growing incidence of renal tubulointerstitial inflammation, exploration into the mechanisms of obesity-associated tubulointerstitial inflammation is essential. Studies have demonstrated that mammalian target of rapamycin (mTOR) is a crucial molecule in the pathogenesis of renal inflammation, including regulating the expression of inflammatory factors. The purpose of the present study was to further elucidate the role of mTOR in obesity-associated tubulointerstitial inflammation. In the clinical study, obese and healthy subjects were recruited for physical examination, as well as the collection of blood and urine samples. Further study was performed on a high fat diet (HFD)-induced obese rat model and a cultured human renal tubular epithelial cell line (HK-2). The clinical study demonstrated that the participants with obesity had increased serum lipids, creatinine (Cr), urinary albumin to creatinine ratio (UACR) and urinary neutrophil gelatinase-associated lipocalin (u-NGAL). Moreover, the level of urinary monocyte chemoattractant protein-1 (u-MCP-1) was increased in the participants with obesity, and it was positively correlated with free fatty acid (FFA), UACR and u-NGAL. In the in vivo study, the results indicated that the levels of serum lipids, Cr and blood urea nitrogen (BUN), as well as 24 h urine protein and u-NGAL, were significantly increased in the HFD-fed obese rats. In addition, the infiltration of CD68+ cells into the renal interstitial area and the release of interleukin-1β (IL-1β) was observed in the kidneys of obese rats. Meanwhile, the supernatant from HK-2 cells treated with palmitic acid stimulated THP-1 monocyte migration. The upregulation of MCP-1, phosphorylated forkhead boxO1 (p-FOXO1), and phosphorylated mTOR (p-mTOR) was observed in vivo and in vitro. However, inhibition of mTOR was able to alleviate the above effects. Overall, these results demonstrated that activated mTOR induced FOXO1 phosphorylation, which mediates renal MCP-1 release, causes tubulointerstitial inflammation and ultimately leads to pathological renal changes and dysfunction. However, inhibition of mTOR may play a renoprotective role during the progression of obesity-associated tubulointerstitial inflammation. [ABSTRACT FROM AUTHOR]

Chronic non-bacterial prostatitis (CNBP) is a common urinary disease and no standard treatments are available at present. Although autophagy serves an important role in a variety of chronic diseases, its role in CNBP is yet to be fully elucidated. Therefore, the present study aimed to investigate the effects of rapamycin-induced autophagy on CNBP by establishing a rat model. In the present study, a total of 30 male Sprague-Dawley rats were randomly divided into three groups (n=10 per group): i) Control, in which rats underwent a sham operation; ii) the model (CNBP), in which rats were castrated and administered 17β-estradiol (0.25 mg/kg via subcutaneous injection) for 30 consecutive days; and iii) rapamycin treatment, in which rats were employed in accordance with the CNBP model, but also received a daily intraperitoneal injection of rapamycin (1 mg/kg) from the 16th day post-surgery for 15 days. Alterations in histology and the levels of autophagy-associated markers, and components of the NLRP3 inflammasome, were measured in the prostate tissues of the rats. The levels of molecules located further downstream of the NLRP3 inflammasome pathway, including interleukin (IL)-1β and IL-18, were also measured. The results demonstrated that, compared with the control group, increased infiltration levels of inflammatory cells and glandular epithelial degeneration were observed in the prostate tissues of rats with CNBP. Furthermore, a significant increase in the concentration of IL-1β and IL-18 in the serum, as well as the increased expression levels of NLRP3, ASC and caspase-1 in prostate tissues were also observed. In addition, reductions in the number of autophagosomes and the expression levels of autophagy-associated, including microtubule-associated protein 1 light chain 3β (LC3B) and Beclin 1, were also detected in the CNBP group; however, treatment with rapamycin reversed these effects. Collectively, the findings of the present study indicated that the NLRP3 inflammasome-mediated inflammatory response was activated by a hormonal imbalance in the prostate glands of rats; however, these effects may be suppressed via rapamycin-induced autophagy. [ABSTRACT FROM AUTHOR]

Palmitic acid (PA) can induce lipotoxic damage to cardiomyocytes, although its precise mechanism of action has not been completely elucidated. Growth arrest-specific transcript 5 (GAS5) is a long noncoding RNA that serves a regulatory role in several pathological processes, including tumorigenesis, stroke, cardiac fibrosis and osteoarthritis; however, its role in PA-induced myocardial injury remains elusive. The present study aimed to explore the role and underlying mechanism of GAS5 on PA-induced myocardial injury. The expression of GAS5 in PA-treated cardiomyocytes (H9c2 cells) was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and its effects on PA-induced myocardial injury were measured by Cell Counting Kit-8 and lactate dehydrogenase (LDH) assays. The activities of cytokines and nuclear factor (NF)-κB were also detected by enzyme-linked immunosorbent assay, while interactions between GAS5 and microRNA (miR)-26a were evaluated by luciferase reporter assay and RT-qPCR. The regulation of GAS5 on high mobility group box 1 (HMGB1) expression was detected by RT-qPCR and western blotting. The results demonstrated that GAS5 was significantly upregulated in cardiomyocytes following treatment with PA. GAS5-knockdown increased the viability of PA-treated cardiomyocytes and reduced the activity of LDH, tumor necrosis factor-α and interleukin-1β. Furthermore, the present study identified that GAS5 specifically binds to miR-26a, and a reciprocal negative regulation exists between the two. The present study also demonstrated that GAS5 downregulation inhibited HMGB1 expression and NF-κB activation, while these suppressive effects were mediated by miR-26a. In conclusion, the present study demonstrated that PA can induce GAS5 expression and that the downregulation of GAS5 alleviated PA-induced myocardial inflammatory injury through the miR-26a/HMGB1/NF-κB axis. These data may provide a novel insight into the mechanism of myocardial lipotoxic injury. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a clinically common and severe complication of ischemia-reperfusion (I/R), associated with high morbidity and mortality rates, and prolonged hospitalization. Rapamycin is a type of macrolide, primarily used for anti-rejection therapy following organ transplantation and the treatment of autoimmune diseases. Rapamycin has been identified to exert a protective effect against AKI induced by renal I/R as an autophagy inducer. However, whether rapamycin preconditioning may relieve AKI following cerebral I/R (CIR) remains to be fully elucidated. The purpose of the present study was to investigate the effects of CIR on the renal system of rats and the role of rapamycin in AKI following CIR. In the present study, a CIR model was established in Sprague-Dawley rats via a 90-min period of middle cerebral artery occlusion and 24 h reperfusion, and pretreatment with an intraperitoneal injection of rapamycin (dosage: 1 mg/kg; 0.5 h) prior to CIR. The levels of serum creatinine and blood urea nitrogen (BUN), and the expression of inflammation-, apoptosis- and autophagy-associated markers were subsequently measured. In addition to certain histopathological alterations to the kidney, it was identified that CIR significantly increased the levels of serum creatinine, BUN, tumor necrosis factor-α and interleukin-1β, and significantly induced apoptosis and autophagy. It was observed that rapamycin induced autophagy through the mammalian target of rapamycin complex 1/autophagy-related 13/unc-51 like autophagy activating kinase 1 signaling pathway, and that rapamycin pre-treatment significantly improved renal function and alleviated renal tissue inflammation and cell apoptosis in rats following CIR. In conclusion, the results suggested that rapamycin may alleviate AKI following CIR via the induction of autophagy. [ABSTRACT FROM AUTHOR]

PM2.5 is a particle with a diameter <2.5 µm that is often involved in air pollution. Nanoparticles <100 nm are thought to invade the trachea and lungs to cause inflammation, possibly through the activation of macrophages. On the other hand, titanium dioxide (TiO2) particles can be used in models of nano-micro-sized particles, as one can prepare the particles with such sizes. TiO2 particles are classified into Rutile, Anatase, and Brookite types by their crystal structure. Among them, Anatase-type TiO2 particles with a primary diameter of 50 nm (A50) were reported to induce interleukin (IL)-1β production and secretion effectively in phorbol 12-myristate 13-acetate-treated human monocytic leukemia THP-1 cells (THP-1 macrophages). We previously designed and synthesized dehydroxymethyl-epoxyqinomicin (DHMEQ) as an inhibitor of NF-κB. The present study investigated whether the NF-κB inhibitor DHMEQ inhibits TiO2 nanoparticle-induced IL-1β production in THP-1 macrophages, and determined the mechanism. As a result, DHMEQ inhibited A50-induced IL-1β secretion in ELISA assays at nontoxic concentrations. It decreased the expression of IL-1β mRNA, which was dependent on NF-κB. Although NLR family pyrin domain containing 3 (NLRP3)-inflammasome-caspase-1 activation is required for the maturation of IL-1β, and DHMEQ reduced the NLRP3 mRNA expression and caspase-1 activity; a caspase-1 inhibitor did not influence the A50-induced IL-1β production. Therefore, it is likely that inhibition of pro-IL-1β expression by DHMEQ may be sufficient to inhibit mature IL-1β production. Thus, DHMEQ may be useful for the amelioration of inflammation in the trachea and lungs caused by inhalation of PM2.5. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative disease that ultimately leads to joint deformity. The pathogenesis of OA is believed to involve abnormal chondrocyte death, with ferroptosis serving a key role in chondrocyte damage. The present study investigated whether acetyl zingerone (AZ), a newly identified antioxidant derived from curcumin, can alleviate the progression of OA. To investigate this, the present study performed various experiments, including crystal violet staining, flow cytometry, immunofluorescence and western blot analysis. In addition, dual validation was performed using in vivo and in vitro experiments; a mouse OA model was constructed for the in vivo experiments, and chondrocytes were used for the in vitro experiments. Destabilization of the medial meniscus (DMM) surgery was performed to establish an OA model in mice and IL-1β was used to induce an OA model in vitro. The results indicated that AZ may promote chondrocyte viability and the expression of extracellular matrix components. Furthermore, AZ reduced the occurrence of ferroptosis by promoting the expression of glutathione peroxidase 4, inhibiting cartilage destruction and osteophyte formation, and alleviating damage to articular cartilage caused by DMM surgery. Mechanistically, the activation of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 may be responsible for the anti-ferroptosis effects of AZ on chondrocytes. These findings indicated that AZ may be considered a promising candidate for OA therapy. [ABSTRACT FROM AUTHOR]

Myocardial ischemia, hypoxia and reperfusion injury are induced by aortic occlusion, cardiac arrest and resuscitation during cardiopulmonary bypass (CPB), which can severely affect cardiac function. The aim of the present study was to investigate the effects of hydrogen‑rich solution (HRS) and aquaporin (AQP) on cardiopulmonary bypass (CPB)‑induced myocardial injury, and determine the mechanism of the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway. Sprague Dawley rats were divided into a sham operation group, a CPB surgery group and a HRS group. A CPB model was established, and the hemodynamic parameters were determined at the termination of CPB. The myocardial tissues were observed by hematoxylin and eosin, and Masson staining. The levels of myocardial injury markers [adult cardiac troponin I (cTnI), lactate dehydrogenase (LDH), creatine kinase MB (CK‑MB) and brain natriuretic peptide (BNP)], inflammatory factors [interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α (TNF‑α)] and oxidative stress indicators [superoxide dismutase (SOD), malondialdehyde (MDA) and myeloperoxidase (MPO)] were determined by ELISA. Furthermore, H9C2 cells were treated with HRS following hypoxia/reoxygenation. Cell viability and cell apoptosis were investigated. The expression of apoptosis regulator Bcl‑2 (Bcl‑2), apoptosis regulator Bax (Bax), caspase 3, AQP‑1, AQP‑4, phosphorylated (p)‑Akt, heme oxygenase 1 (HO‑1) and nuclear factor erythroid 2‑related factor 2 (Nrf2) were investigated using western blotting and quantitative‑polymerase chain reaction of tissues and cells. Following CPB, myocardial cell arrangement was disordered, myocardial injury markers (cTnI, LDH, CK‑MB and BNP), inflammatory cytokines (IL‑1β, IL‑6 and TNF‑α) and MDA levels were significantly increased compared with the sham group; whereas the SOD levels were significantly downregulated following CPB compared with the sham group. HRS attenuated myocardial injury, reduced the expression levels of cTnI, LDH, CK‑MB, BNP, IL‑1β, IL‑6, TNF‑α, MDA and MPO, and increased SOD release. Levels of Bcl‑2, AQP‑1, AQP‑4, p‑Akt, HO‑1 and Nrf2 were significantly increased following HRS; whereas Bax and caspase‑3 expression levels were significantly reduced following CPB. HRS treatment significantly increased the viability of myocardial cells, reduced the rate of myocardial cell apoptosis and the release of MDA and LDH compared with the CPB group. A PI3K inhibitor (LY294002) was revealed to reverse the protective effect of HRS treatment. HRS was demonstrated to attenuate CPB‑induced myocardial injury, suppress AQP‑1 and AQP‑4 expression following CPB treatment and protect myocardial cells via the PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

With extensive pharmacological actions, quercetin has anti-oxidant, free radical scavenging, anti-tumor, anti-inflammatory, anti-bacterial and anti-viral activity. Quercetin also reduces blood glucose and reduces high blood pressure, and has immunoregulation and cardiovascular protection functions. Additionally, it has been reported that it can reduce depression. The current study evaluated whether quercetin protects against inflammation, matrix metalloproteinase-2 (MMP-2) activation and apoptosis induction in a rat model of cardiopulmonary resuscitation (CPR), and whether Bmi-1 expression was involved in the effects. In CPR model rats, treatment with quercetin significantly recovered left ventricular ejection fraction, left ventricular fractional shortening, ejection fraction (%), and left ventricle weight/body weight. Treatment with quercetin significantly inhibited ROS generation, inflammation and MMP-2 protein expression in the rat model CPR. Finally, quercetin significantly suppressed caspase-3 activity and activated Bmi-1 protein expression in the rat model of CPR. The results demonstrated that quercetin protects against inflammation, MMP-2 activation and apoptosis induction in a rat model of CPR, and that this may be mediated by modulating Bmi-1 expression. [ABSTRACT FROM AUTHOR]

Elderly patients are at high risk of developing postoperative cognitive dysfunction (POCD) after prolonged exposure to inhaled anesthetics. However, the pathogenesis of POCD remains unknown. Hypoxia‑inducible factor‑1α (HIF‑1α) is activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF‑1α in isoflurane‑induced neuroinflammation and the resulting cognitive impairment. Following a 4‑h exposure to 1.5% isoflurane in 20‑month‑old rats, increased expression of HIF‑1α protein, activation of nuclear factor (NF)‑κB signaling and increased expression of TNF‑1α were observed in the hippocampus of isoflurane‑exposed rats compared with the control group. Pharmacological inhibition of HIF‑1α activation by 5‑[1‑(phenylmethyl)‑1H‑indazol‑3‑yl]‑2‑furanmethanol (YC‑1) markedly suppressed the enhanced expression of HIF‑1α, disrupted NF‑κB signaling pathway activity and inhibited the isoflurane‑induced increase of TNF‑1α expression. YC‑1 pretreatment also significantly attenuated isoflurane‑induced cognitive deficits according to the results of the Morris water maze task. These results suggest that hippocampal HIF‑1α appears to be involved in an upstream mechanism of isoflurane‑induced cognitive impairment. Further research is warranted to fully clarify the pathogenesis and investigate HIF‑1α as a potential therapeutic target for POCD. [ABSTRACT FROM AUTHOR]

As the first barrier to the outside environment, airway epithelial cells serve a central role in the initiation and development of airway inflammation. Chemokines are the most direct and immediate cell factors for the recruitment and migration of inflammatory cells. The present review focused on the role of epithelial chemokines in the pathogenesis of airway inflammation in asthma. In addition to traditional CC family chemokines and CXC family chemokines, airway epithelial cells also express other chemokines, including thymic stromal lymphopoietin and interleukin‑33. By expressing and secreting chemokines, airway epithelial cells serve a key role in orchestrating airway inflammation in asthma. [ABSTRACT FROM AUTHOR]

Previous studies have indicated that smooth muscle myosin light chain kinase (MLCK) has a prominent role in the regulation of smooth muscle contraction, which tends to be upregulated in asthma. In recent years, numerous studies have reported that MLCK is intimately connected with the immunoregulatory mechanism of T cells. The imbalance of T helper type 1 cells (Th1)/Th2 constitutes the immune‑associated pathological basis of chronic asthma. Th2‑associated cytokines, including interleukin‑4, ‑5, ‑13, ‑25 and ‑33, are involved in airway inflammation, hyperresponsiveness and remodeling, which leads to a progressive decline in lung function. The purpose of the present study was to verify whether inhibition of bronchial MLCK attenuated the expression Th2‑associated cytokines in asthmatic mice, including the above‑mentioned ones. Female BALB/c mice were used to establish an ovalbumin (OVA)‑induced model of asthma, of which one group was treated with the MLCK inhibitor (5‑iodonaphthalene‑1‑sulfonyl) homopiperazine (ML‑7). The inhibitor of MLCK, ML‑7 attenuated airway inflammation and remodeling by reducing inflammatory cell infiltration and the secretion of Th2 cytokines in mice model of asthma, which may represent a promising therapeutic strategy for asthma. [ABSTRACT FROM AUTHOR]

Inflammation serves a critical role in driving sympathetic neural remodeling following myocardial infarction (MI), and activin A has been implicated as an important mediator of the inflammatory response post‑MI. However, whether activin A impacts sympathetic neural remodeling post‑MI remains unclear. In the present study, the authors assessed the effects of activin A on sympathetic neural remodeling in a rat model of MI. Rats were randomly divided into sham, MI, and MI + follistatin‑300 (FS, activin A inhibitor) groups. Cardiac tissues from the peri‑infarct zone were assessed for expression of sympathetic neural remodeling and inflammatory factors in rats 4 weeks post‑MI by western blotting and immunohistochemical methods. Heart function was assessed by echocardiography. It is demonstrated that FS administration significantly reduced post‑MI upregulation of activin A, nerve growth factor protein lever, and the density of nerve fibers with positive and protein expression of sympathetic neural remodeling markers in nerve fibers, which included growth associated protein 43 and tyrosine hydroxylase. In addition, inhibition of activin A reduced cardiac inflammation post‑MI based on the reduction of i) interleukin‑1 and tumor necrosis factor‑α protein expression, ii) numbers and/or proportional area of infiltrating macrophages and myofibroblasts and iii) phosphorylated levels of p65 and IκBα. Furthermore, activin A inhibition lessened heart dysfunction post‑MI. These results suggested that activin A inhibition reduced sympathetic neural remodeling post‑MI in part through inhibition of the inflammatory response. The current study implicates activin A as a potential therapeutic target to circumvent sympathetic neural remodeling post‑MI. [ABSTRACT FROM AUTHOR]

Chronic constriction injury (CCI) of the sciatic nerve may induce dorsal root ganglion (DRG) neuronal hyperexcitability and behaviorally expressed hyperalgesia. CCI is a model of neuropathic pain. To investigate the association between the expression of protease activated receptor 2 (PAR2), TMEM16A and neuropathic pain, the expression of PAR2 and TMEM16A proteins in the DRG neurons of rats following CCI of the sciatic nerve was investigated. Following the creation of the CCI model, the thermal withdrawal latency (TWL) was examined by a hot plate test. An immunofluorescence assay and western blot assay were performed to determine the expression of PAR2 and TMEM16A proteins in the ipsilateral L4‑6 DRG neurons. The concentration of inositol 1,4,5‑triphosphate (IP3) in the L4‑6 DRG was determined by ELISA. In the CCI‑D7 (7 days after CCI) and CCI‑D14 (14 days after CCI) treatment groups, the TWL of rats was significantly shorter than that in the sham operated group (P<0.01; n=12). The expression of PAR2 and TMEM16A proteins in the CCI‑D7 and CCI‑D14 groups were significantly upregulated compared with the sham operated group (P<0.05; n=12). Additionally, it was revealed that PAR2 and TMEM16A were co‑expressed in DRG neurons. It was also observed that IP3 significantly increased in the CCI‑D7 and CCI‑D14 groups compared with the sham operation group (P<0.05; n=6) as PAR2 and TMEM16A also increased. These findings suggest that the upregulation of PAR2 and TMEM16A in DRG neurons, the co‑expression of the two proteins and increasing IP3 are critical to the development of neuropathic pain. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX), as a pharmaceutical, is frequently used in tumor chemotherapy and is also a part of the established treatment of a number of autoimmune inflammatory disorders. Radiolabeled MTX has been studied as a tumor-diagnostic agent in a number of published studies. In the present study, the potential use of technetium-99m-labelled MTX (99mTc-MTX) as a radiotracer was investigated for the identification of inflammatory target sites. The labelling of MTX was carried out via a 99mTc-gluconate precursor. Evaluation studies included in vitro stability, plasma protein binding assessment, partition-coefficient estimation, in vivo scintigraphic imaging and ex vivo animal experiments in an animal inflammation model. MTX was successfully labelled with 99mTc, with a radiochemical purity of >95%. Stability was assessed in plasma, where it remained intact up to 85% at 4 h post-incubation, while protein binding of the radiotracer was observed to be ~50% at 4 h. These preclinical ex vivo and in vivo studies indicated that 99mTc-MTX accumulates in inflamed tissue, as well as in the spinal cord, joints and bones; all areas with relatively high remodeling activity. The results are promising, and set the stage for further work on the development and application of 99mTc-MTX as a radiotracer for inflammation associated with rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

To investigate the effects of catalpol on corneal neovascularization (CNV) and associated inflammation, eye drops (5 mM catalpol or PBS) were administered four times daily to alkali-burn rat models of CNV and inflammation. Clinical evaluations of CNV and the degree of inflammation were performed on days 0, 4, 7, 10 and 14 under slit lamp microscopy. Eyes were collected on day 14 and prepared for hematoxylin and eosin, and immunofluorescence staining; corneal cell apoptosis was investigated via terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. Protein expression levels of angiogenic and proinflammatory factors, including vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), tumor necrosis factor-α (TNF-α) and necrosis factor-κB (NF-κB) were determined by western blotting. The effects of catalpol on cell proliferation were investigated in vitro using human umbilical vein endothelial cells (HUVECs) and a Cell Counting kit-8 (CCK-8); alterations in migration and tube formation were investigated via HUVEC wound closure and tube formation assays. HUVEC viability and proliferative ability were inhibited in a dose-dependent manner; catalpol also decreased HUVEC cell migration and tube forming ability. Within alkali-burn rat models, decreased inflammation and CNV was associated with catalpol administration; as demonstrated with TUNEL, corneal cell apoptosis was decreased in response to catalpol. Western blot analysis revealed reduced protein expression levels of VEGF and TNF-α; however, PEDF and phosphorylated-NF-κB p65 were increased due to catalpol administration. The present study demonstrated the inhibitory effects exerted by catalpol on CNV and inflammation within alkali-burned rat models. Topical application of catalpol in vivo was associated with reduced CNV and inflammation; therefore, catalpol may be considered an anti-inflammatory agent for the clinical treatment of CNV. [ABSTRACT FROM AUTHOR]

Migri-Heal®, is a novel herbal remedy that was introduced for the treatment of migraine headaches. Previous studies revealed that this drug may reduce nitric oxide (NO) in an in vitro inflammatory model. The aim of the present study was to investigate the anti-inflammatory effect of Migri-Heal® on primary mix glial cells stimulated with LPS. In the current study, neonatal rat primary mix glial cells were isolated from the mixed glial cultures via shaking, and cultured in Dulbecco's' modified Eagle's medium supplemented with 10% fetal bovine serum. Following pretreatment with Migri-Heal® (25, 75, 100, 150, 200 and 300 µg/ml) and cells were treated with LPS (10 µg/ml) for 1 h, and incubated for 48 h. The present study determined that 150 µg/ml Migri-Heal® significantly reduced the production of NO in rat mix glial cells stimulated with 10 µg/ml LPS. Migri-Heal® also suppressed mRNA expression level of LPS-induced inducible nitric oxide synthase and tumor necrosis factor a, which was accompanied by inhibition of the transcription factor nuclear factor-κB. Additionally, MTT assay determined that Migri-Heal® was not cytotoxic, suggesting that the anti-inflammatory effects of Migri-Heal® observed were not due to cell death. In conclusion, the findings of the present study demonstrated that Migri-Heal® may be useful as a potential anti-inflammatory agent in inflammatory diseases. However, additional studies are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Interleukin-37 (IL-37), a novel member of the IL-1 cytokine family has been identified as a natural suppressor of innate immunity and inflammatory responses. The present study aimed to determine the expression of IL-37 in peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis (AR), and examine the possible immunosuppressive effect of IL-37 on inflammatory mediators and CD4+ T cells in the pathogenesis of AR. The expression levels of IL-37 were determined in PBMCs from 39 patients with AR and 43 controls using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and flow cytometry. Cytokines in the supernatants of the PBMCs and CD4+ T cells, which were stimulated with lipopolysaccharide in the presence or absence of IL-37, were assayed using enzyme-linked immunosorbent assays and RT-qPCR analysis. The results showed that the patients with AR exhibited significantly decreased expression of IL-37, and increased expression levels of interleukin (IL)-1β and IL-6 in PBMCs. Recombinant IL-37 (rIL-37) inhibited the production of IL-1p and IL-6, and enhanced the production of IL-27 in PBMCs from the patients with AR and the control individuals. rIL-37 also markedly decreased the expression of IL-17 by CD4+ T cells in the patients with AR and controls. These results suggested that IL-37 may be an important cytokine in the pathogenesis of AR. It may have a protective role in AR by inhibiting the production of proinflammatory cytokines and through suppressive regulation of the Th17 response. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is a highly prevalent disease characterized by mucosal inflammation of the nose and paranasal sinuses. CRS can be divided into two main categories, CRS with nasal polyps (NPs; CRSwNP) and CRS without NPs (CRSsNP). Although the pathophysiology of CRS remains unclear, DNA methylation has been implicated in the etiology of CRSwNP. The aim of the present study was to elucidate whether DNA methylation of specific genes is involved in the development of NPs. In total, 18 individuals were included in the present study, and were divided into three groups: CRSwNP (n=7), CRSsNP (n=7) and healthy controls (n=4). NP tissues were obtained from the seven patients with CRSwNP and biopsies of the inferior turbinate mucosa from all three groups were used as controls. Methylated genes detected by methyl-CpG-binding domain sequencing were validated by methylation-specific polymerase chain reaction (PCR), bisulfite sequencing, and reverse transcription-quantitative PCR (RT-qPCR). Methyl-CpG-binding domain sequencing identified 43,674 CpG islands in 518 genes. The promotor regions of 10 and 30 genes were hypermethylated and hypomethylated, respectively, in NP samples compared with controls. The top four genes with altered hypomethylation in NP tissues were, Keratin 19 (KRT19), nuclear receptor subfamily 2 group F member 2 (NR2F2), A Disintegrin-like And Metallopeptidase (Reprolysin Type) with Thrombospondin type 1 motif 1 (ADAMTS1) and zinc finger protein 222 (ZNF222). RT-qPCR demonstrated that the expression levels of KRT19, NR2F2 and ADAMTS1 were significantly increased in NP tissues; however, there was no difference in the levels of ZNF222 between NP and control tissues. Further studies are required to confirm the relevance of these epigenetic modifications in the mechanisms underlying NP formation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Arterial stiffening is associated with increased cardiovascular risk. Whether exposure to relatively high levels of air pollution is associated with arterial stiffening is unclear. We aimed to assess the association between exposure to major air pollutants and arterial stiffening. PubMed, SCOPUS and Web of Science databases (through 31 January 2017) were searched using a combination of terms related to exposure to gaseous [nitrogen dioxide (NO2), nitrogen oxides (NOx) and sulphur dioxide (SO2)] or particulate matter pollutants (PM2.5, PM10 and PM10-2.5), arterial stiffness (pulse wave velocity) and reflected waves (augmentation index, augmentation pressure). Pertinent information were extracted from selected studies. In this systematic review were included 8 studies with available data on air pollution and arterial stiffness/reflected waves parameters (8 studies explored the effects of exposure to particulate matter pollutants, 3 studies the effects of exposure to gaseous pollutants); seven of them reported increased arterial stiffness/reflected waves after exposure to air pollution (6 of 8 studies after particulate matter pollutants; 2 of 3 studies after gaseous pollutants). Arterial stiffness and reflected waves were increased in the majority of the studies after both short- and long-term exposure to air pollutants. In conclusion, available evidence supports an association of main air pollutants with increased arterial stiffness and reflected waves. This finding may have implications for population-based strategies for the reduction of arterial stiffness, a vascular biomarker and an intermediate endpoint for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Sobokchukeo-Tang (ST) is a well-known formula that is used for treating primary dysmenorrhea caused by blood stasis syndrome (BSS) in Korea and China. The current study investigated the anti-inflammatory and anti-adipogenesis effects of ST on adipocytes and macrophages. The anti-inflammatory efficacy of ST was evaluated in RAW 264.7 cells and differentiated THP-1 cells. To induce inflammation, the cells were treated with lipopolysaccharide (LPS; 1 μg/ml). Following the induction of inflammation, the levels of proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the cell supernatant were detected using enzyme-linked immunosorbent assay. 3T3-L1 preadipocytes differentiated into adipocytes in response to insulin, isobutyl-1-methylxanthine and dexamethasone (MDI). To confirm the anti-adipogenesis efficacy of ST, we investigated Oil Red O staining was performed, triglyceride (TG) and leptin secretion were measured, and the protein expression of lipid metabolism-associated factors was determined. ST significantly inhibited TNF-α and IL-6 production in the LPS-treated RAW 264.7 cells compared with LPS stimulation alone. In addition, the concentrations of IL-6 and TNF-α were significantly inhibited by ST in LPS-treated THP-1 cells. Lipid accumulation was reduced by ST, similarly to the positive control treatment, SB203580. In the ST-treated group, the TG and leptin concentrations were inhibited by up to 50 and 83%, respectively, compared with MDI induction only. The ST-treated group reduced the protein expression of peroxisome proliferator-activated receptor-γ and CCAAT/enhancer-binding protein α compared with MDI induction only. The results of the present study demonstrated that ST exerts anti-inflammatory effects on LPS-treated mouse and human macrophage cell lines. ST inhibited adipogenesis in MDI-induced 3T3-L1 adipocytes, as indicated by the significant reduction in TG and leptin concentrations without cytotoxicity. Thus, ST may be useful as a therapeutic agent for preventing lipid-associated diseases, including obesity and atherosclerosis. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-1β is a pathogenic factor associated with the destruction of periodontal tissue in periodontitis. IL-1β processing is regulated by cytosolic machinery known as the inflammasome. Porphyromonas gingivalis infection and lipopolysaccharide (LPS) have an important role in the destruction of periodontal tissue in periodontitis. P. gingivalis infection and LPS have been reported to activate the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in human oral cells. Stem cell therapy exhibits anti-inflammatory effects and stem cell-conditioned culture media (SCM) shows similar beneficial effects. The present study tested the hypothesis that SCM inhibits activation of the inflammasome and protects human gingival epithelial cells (GECs) against LPS-induced inflammatory damage. Human GECs were treated with or without LPS plus SCM or control cell media. NLPR3 inflammasome components and inflammatory factors were measured by western blotting and immunofluorescence. The present study revealed that LPS induced an increase in the expression of inflammasome components, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. Co-immunoprecipitation revealed increased binding of NLRP3 and ASC, and immunofluorescence showed an increased co-localization of ASC and caspase-1, suggesting that LPS stimulated assembly of the NLRP3 inflammasome. SCM inhibited the overexpression and assembly of NLRP3 inflammasome components induced by LPS. Furthermore, SCM blocked the increase in IL-1β production induced by LPS and inhibited the translocation of the inflammatory factor, NF-κB, into the nuclei. Consequently, SCM protected cells against LPS-induced damage, as suggested by the recovery of disturbed E-cadherin staining pattern, which indicates a disruption in epithelial integrity. In conclusion, treatment with SCM may attenuate LPS-induced inflammatory damage in human GECs via inhibition of NLRP3 inflammasome activation, suggesting a potential therapeutic use for SCM. [ABSTRACT FROM AUTHOR]

Traditional herbal formulas made from Scutellariae Radix (SR), the root of Scutellaria baicalensis, have previously been used in the treatment of inflammatory diseases, such as atherosclerosis. The aim of the present study was to investigate the effects of SR on low-density lipoprotein (LDL) oxidation and inflammation in macrophages, which are early events in the development of atherosclerosis. High-performance liquid chromatography photo-diode array analysis was used to obtain a three-dimensional chromatogram of SR. The antioxidative effects of SR were evaluated by determining its scavenging activities against ABTS and DPPH radicals. The inhibitory effect of SR on LDL oxidation was examined using a thiobarbituric acid-reactive substance assay and a relative electrophoretic mobility assay. In addition, the anti-inflammatory effects of SR were evaluated in lipopolysaccharide (LPS)-induced RAW264.7 murine macrophage cells. The results showed that SR exhibited radical-scavenging activities in a dose-dependent manner; in addition, SR attenuated the Cu2+-induced oxidation of LDL as well as significantly inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in LPS-induced RAW264.7 cells. Furthermore, SR induced the protein expression of heme oxygenase-1 (HO-1) in RAW264.7 cells. In conclusion, the results of the present study demonstrated that SR decreased the oxidation of LDL and suppressed inflammatory responses in macrophages, which occurred at least in part via the induction of HO-1. These results therefore suggested that SR may be a potential therapeutic agent for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) is one of the most intractable diseases. The lack of effective therapeutic measures remains a major problem due to the poor understanding of the cause of NP. The aim of the present study was to investigate the effect of the long non-coding RNA small nucleolar RNA host gene 5 (SNHG5) in NP and the underlying molecular mechanism in order to identify possible therapeutic targets. A chronic constriction injury (CCI) mouse model was used to investigate whether SNHG5 prevents NP and the inflammatory response. Luciferase and RNA pull-down assays were used to detect the binding between SNHG5 and miR-142-5p as well as between miR-142-5p and CAMK2A. Western blot and qPCR were used to detect the RNA and protein expression. The results indicated that SNHG5 significantly inhibited CCI-induced NP. In addition, SNHG5 inhibited the inflammatory response through decreasing the release and the mRNA expression of interleukin (IL)-1β, IL-6, IL-10 and tumor necrosis factor-α. Mechanistically, SNHG5 acted via sponging microRNA-142-5p, thereby upregulating the expression of calcium/calmodulin-dependent protein kinase II α (CAMK2A). Further investigation indicated that CAMK2A knockdown also inhibited CCI-induced NP and inflammation. In summary, the present study demonstrated that SNHG5 silencing could alleviate the neuropathic pain induced by chronic constriction injury via sponging miR-142-5p and regulating the expression of CAMK2A. [ABSTRACT FROM AUTHOR]

Natural and synthetic fibres and particles are being introduced into the workplace and environment daily. Comparative analyses of the induced signalling pathways are essential in order to understand the potential hazards of these particles. To identify the molecular characteristics of particles and fibres, we selected crocidolite and chrysotile asbestos as representatives for fibered dust and titanium dioxide (TiO2) (100-200 nm), zirconium dioxide (ZrO2) (50-100 nm) and hematite (Fe2O3) (20 nm) as representatives for bio-persistent granular dust. SV-40 virus-transformed human bronchial epithelial cells (BEAS-2B) were exposed to well-defined fibres and particles. RT2 Profiler™ PCR Array Human Stress & Toxicity PathwayFinder was used to compare the relative mRNA expression of 84 genes. A detailed characterization of the dust samples used in this study was accomplished to ensure comparability to other studies. Investigation of mRNA expression of 84 signalling molecules attributed to pathways such as DNA damage and repair; oxidative/metabolic stress; growth arrest and senescence; inflammation, proliferation and carcinogenesis; and heat shock and apoptosis revealed that crocidolite and chrysotile asbestos induced mRNA expression of pathway molecules involved in proliferation and carcinogenesis, as well as inflammation. Titanium dioxide, zirconium dioxide and hematite mainly induced pathway molecules responsible for oxidative/metabolic stress and inflammation. Our findings suggest that the hazards of fibered dust mainly include the induction of direct toxicity by altering signalling pathways such as carcinogenesis and proliferation, while granular dust shows indirect toxicity by altering signalling pathways involved in inflammatory processes. PCR arrays, therefore, may be a helpful tool to estimate the hazard risk of new materials. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a common clinical emergency and all-trans retinoic acid (ATRA) can alleviate organ injury. Therefore, the present study investigated the role of ATRA in ALI. Lipopolysaccharide (LPS)-induced ALI rats were treated with ATRA and the arterial partial pressure of oxygen (PaO2), lung wet/dry weight (W/D) ratio and protein content in the bronchial alveolar lavage fluid (BALF) were measured to evaluate the effect of ATRA on ALI rats. Alveolar macrophages were isolated from the BALF. The phagocytic function of macrophages was detected using the chicken erythrocyte phagocytosis method and flow cytometry. The viability of macrophages was measured using a Cell Counting Kit-8 assay, and apoptosis was analyzed using a TUNEL assay and flow cytometry. The expression levels of Toll-like receptor 4 (TLR4) and cluster of differentiation (CD)14 on the macrophage membrane were detected by immunofluorescence staining. The protein levels of TLR4, CD14, phosphorylated (p)-65, p65, p-IκBα and IκBα were analyzed using western blotting. The concentrations of IL-6, IL-1β and macrophage inflammatory protein-2 in the plasma of rats were detected by ELISA. Macrophages were treated with IAXO-102 (TLR4 inhibitor) to verify the involvement of CD14/TLR4 in the effect of ATRA on ALI. ATRA provided protection against LPS-induced ALI, as evidenced by the increased PaO2 and reduced lung W/D ratio and protein content in the BALF. ATRA enhanced macrophage phagocytosis and viability and reduced apoptosis and inflammation in ALI rats. Mechanically, ATRA inhibited CD14 and TLR4 expression and NF-κB pathway activation. ATRA enhanced macrophage phagocytosis and reduced inflammation by inhibiting the CD14/TLR4-NF-κB pathway in LPS-induced ALI. In summary, ATRA inactivated the NF-κB pathway by inhibiting the expression of CD14/TLR4 receptor in the alveolar macrophages of rats, thus enhancing the phagocytic function of macrophages in ALI rats, improving the activity of macrophages, inhibiting apoptosis, reducing the levels of inflammatory factors, and consequently playing a protective role in ALI model rats. This study may offer novel insights for the clinical management of ALI. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M. tuberculosis) infection and has the highest mortality rate of any single infectious disease worldwide. The aim of the present study was to investigate the function of microRNA (miR)-502-3p in M. tuberculosis-infected macrophages. The Gene Expression Omnibus database was used to analyze miR-502-3p expression in patients with TB and healthy individuals. THP-1 and RAW 264.7 cells were transfected with miR-502-3p mimic, miR-502-3p inhibitor, pcDNA3.1-ROCK1 or their negative controls. The expression levels of miR-502-3p and inflammatory cytokines were evaluated using reverse transcription-quantitative PCR. The colony-forming unit assay was performed to assess the survival of M. tuberculosis in macrophages, and Toll-like receptor (TLR)4/NF-κB signaling pathway-associated protein expression levels were detected by western blotting. The nuclear translocation of NF-κB p65 was detected via immunocytochemistry. TargetScan was used to predict the binding sites between miR-502-3p and ROCK1. The interaction between miR-502-3p and Rho-associated coiled-coil-forming protein kinase 1 (ROCK1) was confirmed using a dual-luciferase reporter assay; ROCK1 was demonstrated to be a direct target gene of miR-502-3p. Results from the present study demonstrated that miR-502-3p expression was significantly increased during M. tuberculosis infection in macrophages. Upregulation of miR-502-3p expression levels significantly enhanced the survival of intracellular M. tuberculosis. IL-6, TNF-α, and IL-1β mRNA expression levels were significantly upregulated during M. tuberculosis infection but were downregulated by miR-502-3p overexpression. Moreover, miR-502-3p mimics transfection significantly downregulated TLR4/NF-κB signaling pathway-associated protein expression and significantly reduced nuclear transcription of NF-κB in M. tuberculosis-infected macrophages. ROCK1 overexpression reversed the miR-502-3p inhibitory effect on cytokine production in M. tuberculosis-infected macrophages. In conclusion, miR-502-3p/ROCK1 may serve an anti-inflammatory role and may improve the survival of M. tuberculosis within macrophages, which may provide a promising therapeutic target for TB. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is an IgE-mediated upper airway disease with a high worldwide prevalence. MicroRNA (miR)-205-5p upregulation has been observed in AR; however, its role is poorly understood. The aim of the present study was to investigate the effect of miR-205-5p on AR-associated inflammation. To establish an AR model, BALB/c mice were sensitized using an intraperitoneal injection of ovalbumin (OVA) on days 0, 7 and 14, followed by intranasal challenge with OVA on days 21–27. A lentiviral sponge for miR-205-5p was used to downregulate miR-205-5p in vivo via intranasal administration on days 20–26. Reverse transcription-quantitative PCR revealed that miR-205-5p was upregulated in AR mice. Notably, miR-205-5p knockdown reduced the frequency of nose-rubbing and sneezing, and attenuated pathological alterations in the nasal mucosa. The levels of total and OVA-specific IgE, cytokines IL-4, IL-5 and IL-13, and inflammatory cells, were decreased by miR-205-5p knockdown in AR mice. In addition, miR-205-5p knockdown inhibited nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation by reducing the expression levels of NLRP3, apoptosisassociated specklike protein containing a CARD, cleaved caspase-1 and IL-1β by western blot analysis. B-cell lymphoma 6 (BCL6) was confirmed as a target of miR-205-5p by luciferase reporter assay. In conclusion, the present findings suggested that miR-205-5p knockdown may attenuate the inflammatory response in AR by targeting BCL6, which may be a potential therapeutic target for AR. [ABSTRACT FROM AUTHOR]

Psoralen (PSO) exerts anti-inflammatory pharmacological effects and plays an important role in a variety of inflammatory diseases. However, the effects of PSO with allergic rhinitis (AR) are yet to be reported. In the present study, an in vitro AR model was generated by inducing JME/CF15 human nasal epithelial cells with IL-13, after which MTT was used to assess the cytotoxicity of PSO. The expression levels of inflammatory cytokines (granulocyte-macrophage colony-stimulating factor and Eotaxin) were determined by ELISA. Furthermore, the expression of inflammatory IL-6 and −8, as well as mucin 5AC, was assessed by reverse transcription-quantitative PCR and western blotting, and cellular reactive oxygen species were detected using a 2′,7′-dichlorodihydrofluorescein diacetate fluorescent probe. Western blotting was also used to detect the expression and phosphorylation of c-Fos and c-Jun in the activator protein 1 (AP-1) pathway, as well as the expression of cystatin-SN (CST1). PSO inhibited the inflammatory response and mucus production in IL-13-induced JME/CF15 cells. Furthermore, the levels of c-Fos and c-Jun phosphorylation in the AP-1 pathway were decreased in IL-13-induced JME/CF15 cells following PSO treatment. The expression of pathway proteins was activated by the addition of PMA, an AP-1 pathway activator, which concurrently reversed the inhibitory effects of PSO on the inflammatory response and mucus formation. The addition of an AP-1 inhibitor (SP600125) further inhibited pathway activity, and IL-13-induced inflammation and mucus formation was restored. In conclusion, PSO regulates the expression of CST1 by inhibiting the AP-1 pathway, thus suppressing the IL-13-induced inflammatory response and mucus production in nasal mucosal epithelial cells. [ABSTRACT FROM AUTHOR]

Genetic and nongenetic factors associated with an increased inflammatory response may mediate a link between severe coronavirus disease 2019 (COVID-19) and serious mental illness (SMI). However, systematic assessment of inflammatory response-related factors associated with SMI that could influence COVID-19 outcomes is lacking. In the present review, dietary patterns, smoking and the use of psychotropic medications are discussed as potential extrinsic risk factors and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphisms are considered as potential intrinsic risk factors. A genetics-based prediction model for SMI using ACE-I/D genotyping is also proposed for use in patients experiencing severe COVID-19. Furthermore, the literature suggests that ACE inhibitors may have protective effects against SMI or severe COVID-19, which is often linked to hypertension and other cardiovascular comorbidities. For this reason, we hypothesize that using these medications to treat patients with severe COVID-19 might yield improved outcomes, including in the context of SMI associated with COVID-19. [ABSTRACT FROM AUTHOR]

In recent decades, the role of microRNAs (miRs) in the development of pneumonia has been reported by a number of researchers. The present study aimed to investigate the role of miR-409-3p in lipopolysaccharide (LPS)-induced human bronchial epithelial cells and the implication for bronchopneumonia. An in vitro inflammation model was established using LPS-induced BEAS-2B cells. Cell apoptosis was determined by flow cytometry. Inflammatory factors were detected by ELISA and reverse transcription-quantitative PCR. Protein levels of Janus kinase 1 (JAK1)/STAT3 and suppressor of cytokine signaling (SOCS)3 were determined by western blotting. Dual-luciferase reporter assay was performed to confirm the interaction between miR-409-3p and SOCS3. LPS treatment significantly increased miR-409-3p expression and decreased the expression levels of SOCS3 in BEAS-2B cells. Dual-luciferase reporter assay demonstrated that miR-409-3p directly targeted and negatively regulated SOCS3. Inhibition of miR-409-3p markedly decreased the levels of TNF-α, IL-6 and IL-1β, and suppressed apoptosis induced by LPS, which was reversed by SOCS3-knockdown. The inhibition of SOCS3 significantly activated JAK1/STAT3 signaling, as well as enhancing the levels of TNF-α, IL-6 and IL-1β, and promoting apoptosis, which was reversed by the JAK1 inhibitor Tofacitinib. Suppression of miR-409-3p improved LPS-induced inflammation through SOCS3 in LPS-treated BEAS-2B cells, and this may be caused by regulating JAK1/STAT3 signaling. [ABSTRACT FROM AUTHOR]