Matrix Metalloproteinase (MMP)-1 Induces Lung Alveolar Epithelial Cell Migration and Proliferation,Protects from Apoptosis,and Represses Mitochondrial Oxygen Consumption

Idiopathic pulmonary fibrosis is a devastating lung disorder of unknown etiology. Although its pathogenesis is unclear, considerable evidence supports an important role of aberrantly activated alveolar epithelial cells (AECs), which produce a large variety of mediators, including several matrix metalloproteases (MMPs), which participate in fibroblast activation and lung remodeling. MMP-1 has been shown to be highly expressed in AECs from idiopathic pulmonary fibrosis lungs although its role is unknown. In this study, we explored the role of MMP-1 in several AECs functions. Mouse lung epithelial cells (MLE12) transfected with human Mmp-1 showed significantly increased cell growth and proliferation at 36 and 48 h of culture (p < 0.01). Also, MMP-1 promoted MLE12 cell migration through collagen I, accelerated wound closing, and protected cells from staurosporine- and bleomycin-induced apoptosis compared with mock cells (p < 0.01). MLE12 cells expressing human MMP-1 showed a significant repression of oxygen consumption ratio compared with the cells with the empty vector. As under hypoxic conditions hypoxia-inducible factor-1α (HIF-1α) mediates a transition from oxidative to glycolytic metabolism, we analyzed activation of HIF-1α. Ηigher activation of this factor was detected in MMP-1-transfected cells under normoxia and hypoxia. Likewise, a significant decrease of both total and mitochondrial reactive oxygen species was observed in MMP-1-transfected cells. Paralleling these findings, attenuation of MMP-1 expression by shRNA in A549 (human) AECs markedly reduced proliferation and migration (p < 0.01) and increased the oxygen consumption ratio. These findings indicate that epithelial expression of MMP-1 inhibits mitochondrial function, increases HIF-1α expression, decreases reactive oxygen species production, and contributes to a proliferative, migratory, and anti-apoptotic AEC phenotype.     

Mfn2 Affects Embryo Development via Mitochondrial Dysfunction and Apoptosis

BackgroundGrowth factors, energy sources, and mitochondrial function strongly affect embryo growth and development in vitro. The biological role and prospective significance of the mitofusin gene Mfn2 in the development of preimplantation embryos remain poorly understood. Our goal is to profile the role of Mfn2 in mouse embryos and determine the underlying mechanism of Mfn2 function in embryo development.MethodsWe transfected Mfn2-siRNA into 2-cell fertilized eggs and then examined the expression of Mfn2, the anti-apoptotic protein Bcl-2, and the apoptosis-promoting protein Bax by Western blot. Additionally, we determined the blastocyst formation rate and measured ATP levels, mtDNA levels, mitochondrial membrane potential (ΔΨm), and apoptosis in all of the embryos.ResultsThe results indicate that the Mfn2 and Bcl-2 levels were markedly decreased, whereas Bax levels were increased in the T group (embryos transfected with Mfn2-siRNA) compared with the C group (embryos transfected with control-siRNA). The blastocyst formation rate was significantly decreased in the T group. The ATP content and the relative amounts of mtDNA and cDNA in the T group were significantly reduced compared with the C group. In the T group, ΔΨm and Ca²⁺ levels were reduced, and the number of apoptotic cells was increased.ConclusionLow in vitro expression of Mfn2 attenuates the blastocyst formation rate and cleavage speed in mouse zygotes and causes mitochondrial dysfunction, as confirmed by the ATP and mtDNA levels and mitochondrial membrane potential. Mfn2 deficiency induced apoptosis through the Bcl-2/Bax and Ca²⁺ pathways. These findings indicate that Mfn2 could affect preimplantation embryo development through mitochondrial function and cellular apoptosis.     

Clinicopathological Characteristics of Gynecological Cancer Associated with Hypoxia-Inducible Factor 1α Expression: A Meta-Analysis Including 6,612 Subjects

BackgroundGynecological cancer is characterized by tumor hypoxia. However, the role of hypoxia-inducible factor 1α (HIF-1α) in gynecological cancer remains unclear.MethodElectronic databases including Cochrane Library, PUBMED, Web of Knowledge and clinical trial registries were searched from inception through October 2014 for published, case-control studies assessing the association between HIF-1α and the clinicopathological characteristics of gynecological cancer. We pooled results from 59 studies using fixed or random-effects models and present results as odds ratios (ORs) following the PRISMA guidelines.ResultsOur meta-analysis, which included 6,612 women, demonstrated that the expression of HIF-1α was associated with the clinicopathological characteristics of gynecological cancer. The expression of HIF-1α in cancer or borderline tissue was significantly higher than that in normal tissue (cancer vs. normal: odds ratio (OR) =9.59, 95% confidence interval (CI): 5.97, 15.39, p<0.00001; borderline vs. normal: OR=4.13, 95% (CI): 2.43, 7.02, p<0.00001; cancer vs. borderline: OR=2.70, 95% (CI): 1.69, 4.31, p<0.0001). The expression of HIF-1α in III‒IV stage or lymph node metastasis was significantly higher than that in I‒II stage or that without lymph node metastasis, respectively (OR=2.66, 95% (CI): 1.87,3.79, p<0.00001; OR= 3.98, 95% (CI): 2.10,12.89, p<0.0001). HIF-1α was associated with histological grade of cancer (Grade 3 vs. Grade 1: OR=3.77, 95% (CI): 2.76,5.16, p<0.00001; Grade 3 vs. Grade 2: OR=1.62, 95% (CI): 1.20,2.19, p=0.002; Grade 2 vs. Grade 1: OR=2.34, 95% (CI): 1.82,3.00, p<0.00001),5-years disease free survival (DFS) rates (OR=2.93, 95% (CI):1.43,6.01, p=0.001) and 5-years overall survival (OS) rates (OR=5.53, 95% (CI): 2.48,12.31, p<0.0001).ConclusionHIF-1α is associated with the malignant degree, FIGO stage, histological grade, lymph node metastasis, 5-years survival rate and recurrence rate of gynecological cancer. It may play an important role in clinical treatment and prognostic evaluation.     

Hypoxia-inducible Factor-1α (HIF-1α) Protein Diminishes Sodium Glucose Transport 1 (SGLT1) and SGLT2 Protein Expression in Renal Epithelial Tubular Cells (LLC-PK1) under Hypoxia

In this work, we demonstrated the regulation of glucose transporters by hypoxia inducible factor-1α (HIF-1α) activation in renal epithelial cells. LLC-PK₁ monolayers were incubated for 1, 3, 6, or 12 h with 0% or 5% O₂ or 300 μm cobalt (CoCl₂). We evaluated the effects of hypoxia on the mRNA and protein expression of HIF-1α and of the glucose transporters SGLT1, SGLT2, and GLUT1. The data showed an increase in HIF-1α mRNA and protein expression under the three evaluated conditions (p < 0.05 versus t = 0). An increase in GLUT1 mRNA (12 h) and protein expression (at 3, 6, and 12 h) was observed (p < 0.05 versus t = 0). SGLT1 and SGLT2 mRNA and protein expression decreased under the three evaluated conditions (p < 0.05 versus t = 0). In conclusion, our results suggest a clear decrease in the expression of the glucose transporters SGLT1 and SGLT2 under hypoxic conditions which implies a possible correlation with increased expression of HIF-1α.     

Low Expression of Mfn2 Is Associated with Mitochondrial Damage and Apoptosis of Ovarian Tissues in the Premature Ovarian Failure Model

Background

This study aimed to construct a working model for detecting the mitochondrial damage and expression of Mfn2. It furthermore explored the pathogenesis of premature ovarian failure (POF) induced by cisplatin.

Method

Forty young female mice were divided randomly into two groups. The first was the treatment group intraperitoneally administered cisplatin (1.5mg/kg). The untreated control group was likewise injected with physiological saline for 10 days. One month later, we observed the ovarian weight and morphological changes, particularly the development of follicles and concentration of sex hormones. Immunohistochemistry and western blotting were used to measure the two groups. We later evaluated ovarian cell apoptosis with TUNEL and analyzed Bcl-2 and Bax levels. We used transmission electron microscopy in order to observe the ultrastructure of ovarian cells. The phosphomolybdic acid colorimetric method was used to measure the ATP content in the ovarian tissue. Finally, the mitochondrial membrane potential of ovarian cells was detected with JC-1 dye.

Results

The cisplatin resulted in a decline of body weight, reduced ovarian weight significantly, and resulted in disorders of the extrous cycle. The follicles’ number decreased within the tissue’s stromal hyperplasia. Moreover, E₂ levels were reduced, and elevated gonadotropin levels were observed. However, Mfn2 was present in the cell’s cytoplasm in both groups. Nevertheless, the Mfn2 levels and the expression of Bcl-2 were significantly decreased (p<0.05), but the expression of Bax and the apoptosis index (AI) was increased. In addition, the ATP levels (35.2 ±5.7μmol/g) of the control group were significantly higher (13.5 ± 3.8 μmol/g). Lastly, an obvious impairment of mitochondrial function and structure was observed.

Conclusion

The intreperitoneal injection of cisplatin, when administered for 10 days, establishes a POF model. Thus, the above results suggest that lower expression of Mfn2 may be involved in the mechanism of premature ovarian failure by affecting both the mitochondria’s energy metabolism and its apoptosis. This decides the termination of the follicles’ development.     

Upregulation of NLRP3 Inflammasome in the Tears and Ocular Surface of Dry Eye Patients

PurposeTo evaluate the mRNA and protein expressions of NLRP3 inflammasome and its downstream inflammatory factors in human dry eye.MethodsWe recruited 54 patients with Sjögren’s syndrome dry eye (SSDE), 50 patients with non-Sjögren’s syndrome dry eye (NSSDE), and 46 healthy controls. Tear film breakup time (TBUT), Schirmer I test, and fluorescein staining (FL) were performed on all subjects. Tear samples were obtained to analyze the inflammatory cytokine levels of IL-1β and IL-18 via enzyme-linked immunosorbent (ELISA). Conjunctival impression cytology (CIC) specimens were collected to detect the mRNA expression of NLRP3, caspase-1, IL-1β, and IL-18 using quantitative RT-PCR, and the protein expression of NLRP3 and caspase-1 by Western blotting.ResultsNLRP3 mRNA expression showed higher levels in both dry eye groups compared with controls, with a comparably significant elevation in the SSDE group (relative 2.47-fold upregulation, p<0.05). NLRP3 protein expression was also increased in SSDE group (relative1.94-fold upregulation) compared with the controls. mRNA expression of caspase-1 was significantly upregulated in both SSDE (relative 1.44-fold upregulation, p<0.05) and NSSDE (relative 1.32-fold upregulation, p<0.05). Procaspase-1 protein level was increased in SSDE (relative 1.84-fold upregulation) and NSSDE (relative 1.12-fold upregulation) versus controls; and caspase-1 protein expression was also increased in SSDE (relative 1.49-fold upregulation) and NSSDE (relative 1.17-fold upregulation) compared with the controls. The patients with SSDE and NSSDE had higher IL-1β and IL-18 mRNA values and protein expressions than the controls did. The relative mRNA expression of IL-1β upregulated 3.59-fold (p<0.001) in SSDE and 2.13-fold (p<0.01) in NSSDE compared with the controls. IL-1β protein level also showed significant upregulation in SSDE (p=0.01; vs. controls groups). IL-18 mRNA expression levels were significantly upregulated in the SSDE (relative 2.97-fold upregulation, p=0.001) and NSSDE (relative 2.05-fold upregulation, p=0.001) groups compared with the controls; tear IL-18 concentrations were also significantly increased in the SSDE (p<0.001) and NSSDE (p<0.05) groups.ConclusionsIn the current study, we found that mRNA and protein expressions of NLRP3 inflammasome were upregulated in human dry eyes, especially in SSDE; the downstream inflammatory factors caspase-1, IL-1β, and IL-18 were also elevated in dry eye patients. These observations suggest the involvement of NLRP3 inflammasome in the onset and development of the inflammation in dry eye.     

Evaluation of CT Perfusion Biomarkers of Tumor Hypoxia

BackgroundTumor hypoxia is associated with treatment resistance to cancer therapies. Hypoxia can be investigated by immunohistopathologic methods but such procedure is invasive. A non-invasive method to interrogate tumor hypoxia is an attractive option as such method can provide information before, during, and after treatment for personalized therapies. Our study evaluated the correlations between computed tomography (CT) perfusion parameters and immunohistopathologic measurement of tumor hypoxia.MethodsWistar rats, 18 controls and 19 treated with stereotactic radiosurgery (SRS), implanted with the C6 glioma tumor were imaged using CT perfusion on average every five days to monitor tumor growth. A final CT perfusion scan and the brain were obtained on average 14 days (8–22 days) after tumor implantation. Tumor hypoxia was detected immunohistopathologically with pimonidazole. The tumor, necrotic, and pimonidazole-positive areas on histology samples were measured. Percent necrotic area and percent hypoxic areas were calculated. Tumor volume (TV), blood flow (BF), blood volume (BV), and permeability-surface area product (PS) were obtained from the CT perfusion studies. Correlations between CT perfusion parameters and histological parameters were assessed by Spearman’s ρ correlation. A Bonferroni-corrected P value < 0.05 was considered significant.ResultsBF and BV showed significant correlations with percent hypoxic area ρ = -0.88, P < 0.001 and ρ = -0.81, P < 0.001, respectively, for control animals and ρ = -0.7, P < 0.001 and ρ = -0.6, P = 0.003, respectively, for all animals, while TV and BV were correlated (ρ = -0.64, P = 0.01 and ρ = -0.43, P = 0.043, respectively) with percent necrotic area. PS was not correlated with either percent necrotic or percent hypoxic areas.ConclusionsPercent hypoxic area provided significant correlations with BF and BV, suggesting that CT perfusion parameters are potential non-invasive imaging biomarkers of tumor hypoxia.     

COPS5 Protein Overexpression Increases Amyloid Plaque Burden,Decreases Spinophilin-immunoreactive Puncta,and Exacerbates Learning and Memory Deficits in the Mouse Brain

Brain accumulation of neurotoxic amyloid β (Aβ) peptide because of increased processing of amyloid precursor protein (APP), resulting in loss of synapses and neurodegeneration, is central to the pathogenesis of Alzheimer disease (AD). Therefore, the identification of molecules that regulate Aβ generation and those that cause synaptic damage is crucial for future therapeutic approaches for AD. We demonstrated previously that COPS5 regulates Aβ generation in neuronal cell lines in a RanBP9-dependent manner. Consistent with the data from cell lines, even by 6 months, COPS5 overexpression in APΔE9 mice (APΔE9/COPS5-Tg) significantly increased Aβ40 levels by 32% (p < 0.01) in the cortex and by 28% (p < 0.01) in the hippocampus, whereas the increases for Aβ42 were 37% (p < 0.05) and 34% (p < 0.05), respectively. By 12 months, the increase was even more robust. Aβ40 levels increased by 63% (p < 0.001) in the cortex and by 65% (p < 0.001) in the hippocampus. Similarly, Aβ42 levels were increased by 69% (p < 0.001) in the cortex and by 71% (p < 0.011) in the hippocampus. Increased Aβ levels were translated into an increased amyloid plaque burden both in the cortex (54%, p < 0.01) and hippocampus (64%, p < 0.01). Interestingly, COPS5 overexpression increased RanBP9 levels in the brain, which, in turn, led to increased amyloidogenic processing of APP, as reflected by increased levels of sAPPβ and decreased levels of sAPPα. Furthermore, COPS5 overexpression reduced spinophilin in both the cortex (19%, p < 0.05) and the hippocampus (20%, p < 0.05), leading to significant deficits in learning and memory skills. Therefore, like RanBP9, COPS5 also plays a pivotal role in amyloid pathology in vivo.     

Serum levels of appetite-regulating hormones and pro-inflammatory cytokines are ameliorated by a CLA diet and endurance exercise in rats fed a high-fat diet

[Purpose]

This study examined whether conjugated linoleic acid (CLA) supplementation and endurance exercise affect appetite-regulating hormones and pro-inflammatory cytokines in rats.

[Methods]

Seven-week-old male Sprague-Dawley rats were divided randomly into the high-fat diet sedentary group (HS, n=8), the 1.0% CLA supplemented high-fat diet sedentary group (CS, n=8), and the 1.0% CLA supplemented high-fat diet exercise group (CE, n=8). Rats in the CE group swam 60 min/day, 5 days/week for 4 weeks.

[Results]

Leptin and insulin levels in the CS and CE groups were significantly lower than those in the HS group (p<0.001), whereas leptin (p<0.01) and insulin (p<0.05) levels decreased significantly in the CE compared to those in the CS group. Interleukin (IL)-1β (p<0.001) and IL-6 (p<0.01) levels in the CS and CE groups decreased significantly compared to those in the HS group. Leptin (IL-1β: r=0.835, p<0.001), IL-6 (r=0.607, p<0.05), insulin (IL-1β: r=0.797, p<0.01), and IL-6 (r=0.827, p<0.01) levels were positively related with pro-inflammatory cytokine levels.

[Conclusion]

Endurance exercise may play an important role during CLA supplementation of rats on a high-fat diet.     

Azilsartan Increases Levels of IL-10, Down-Regulates MMP-2, MMP-9, RANKL/RANK,Cathepsin K and Up-Regulates OPG in an Experimental Periodontitis Model

Aims

The aim of this study was to evaluate the effects of azilsartan (AZT) on bone loss, inflammation, and the expression of matrix metallo proteinases (MMPs), receptor activator of nuclear factor κB ligand (RANKL), receptor activator of nuclear factor κB (RANK), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2), and cathepsin K in periodontal tissue in a rat model of ligature-induced periodontitis.

Materials and Methods

Male Wistar albino rats were randomly divided into 5 groups of 10 rats each: (1) nonligated, water; (2) ligated, water; (3) ligated, 1 mg/kg AZT; (4) ligated, 5 mg/kg AZT; and (5) ligated, 10 mg/kg AZT. All groups were treated with saline or AZT for 10 days. Periodontal tissues were analyzed by histopathology and immunohistochemical detection of MMP-2, MMP-9, COX-2, RANKL, RANK, OPG, and cathepsin K. Levels of IL-1β, IL-10, TNF-α, myeloperoxidase (MPO), and glutathione (GSH) were determined by ELISA.

Results

Treatment with 5 mg/kg AZT resulted in reduced MPO (p<0.05) and IL-1β (p<0.05), increased levels of IL-10 (p<0.05), and reduced expression of MMP-2, MMP-9, COX-2, RANK, RANKL, cathepsin K, and increased expression of OPG.

Conclusions

These findings reveal that AZT increases anti-inflammatory cytokines and GSH and decreases bone loss in ligature-induced periodontitis in rats.     

Carvedilol Improves Inflammatory Response,Oxidative Stress and Fibrosis in the Alcohol-Induced Liver Injury in Rats by Regulating Kuppfer Cells and Hepatic Stellate Cells

Aim

To evaluate the anti-inflammatory, anti-oxidant and antifibrotic effects of carvedilol (CARV) in rats with ethanol-induced liver injury.

Methods

Liver injury was induced by gavage administration of alcohol (7 g/kg) for 28 consecutive days. Eighty Wistar rats were pretreated with oral CARV at 1, 3, or 5 mg/kg or with saline 1 h before exposure to alcohol. Liver homogenates were assayed for interleukin (IL)-1β, IL-10, and tumor necrosis factor (TNF)-α level as well as for myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) and glutathione (GSH) levels. Serum aspartate aminotransferase (AST) activity and liver triglyceride (TG) levels were also assayed. Immunohistochemical analyses of cyclooxygenase 2 (COX-2), receptor activator of nuclear factor kappa-B/ligand (RANK/RANKL), suppressor of cytokine signalling (SOCS1), the Kupffer cell marker IBA-1 (ionized calcium-binding adaptor molecule 1), intercellular adhesion molecule 1 (ICAM-1), superoxide dismutase (SOD-1), and glutathione peroxidase (GPx-1) expression were performed. Confocal microscopy analysis of IL-1β and NF-κB expression and real-time quantitative PCR analysis for TNFα, PCI, PCIII, and NF-κB were performed.

Results

CARV treatment (5 mg/kg) during the alcohol exposure protocol was associated with reduced steatosis, hepatic cord degeneration, fibrosis and necrosis, as well as reduced levels of AST (p < 0.01), ALT (p < 0.01), TG (p < 0.001), MPO (p < 0.001), MDA (p < 0.05), and proinflammatory cytokines (IL-1β and TNF-α, both p < 0.05), and increased levels of the anti-inflammatory cytokine IL-10 (p < 0.001) and GSH (p < 0.05), compared to the alcohol-only group. Treatment with CARV 5 mg/kg also reduced expression levels of COX-2, RANK, RANKL, IBA-1, and ICAM-1 (all p < 0.05), while increasing expression of SOCS1, SOD-1, and GPx-1 (all p < 0.05) and decreasing expression of IL-1β and NF-κB (both, p < 0.05). Real-time quantitative PCR analysis showed that mRNA production of TNF-α, procollagen type I (PCI), procollagen type III (PCIII), and NF-κB were decreased in the alcohol-CARV 5 mg/kg group relative to the alcohol-only group.

Conclusions

CARV can reduce the stress oxidative, inflammatory response and fibrosis in ethanol-induced liver injury in a rat model by downregulating signalling of Kuppfer cells and hepatic stellate cells (HSCs) through suppression of inflammatory cytokines.     

Determinants of muscle power and force as assessed by Jumping Mechanography in rural Indian children

Objectives:To: 1. Assess muscle function (MF) of rural Indian children (6-11y, n=232), using Jumping Mechanography (JM) and hand dynamometer, 2. Investigate gender differences, 3. Identify determinants of MF.Methods:Data on anthropometry, muscle mass%, diet, physical activity, sunlight exposure, MF (maximum relative power Pmax/mass, maximum relative force Fmax/BW by JM; relative grip strength (RGS) by hand dynamometer) were collected. Pearson’s correlation and hierarchical linear regression was performed.Results:Pmax/mass, Fmax/BW and RGS of the group were 31.7±5.0W/kg, 3.0±0.3 and 0.4±0.1 (mean±SD), respectively. The Pmax/mass Z-score was –1.1±0.9 and Fmax/BW Z-score was –0.9±1 (mean±SD) which was significantly lower than the machine reference data (p<0.05). Positive association of muscle mass% and protein intake was observed with all MF parameters and moderate+vigorous physical activity with Fmax/BW (p<0.05). Determinants of MF identified through regression for Pmax/mass were age (β=1.83,95% CI=0.973 – 2.686), muscle mass% (β=0.244,95% CI=0.131–0.358) and protein intake (β=3.211,95% CI=1.597–4.825) and for Fmax/BW was protein intake (β=0.130,95% CI=0.023–0.237) (p<0.05). Male gender was a positive predictor of having higher Pmax/mass (β=1.707,95% CI=0.040–3.373) (p<0.05).Conclusion:MF was lower than in western counterparts. To optimize MF of rural Indian children, focus should be on improving muscle mass, ensuring adequate dietary protein, and increasing physical activity, especially in girls.     

Liveable residential space,residential density,and hypertension in Hong Kong: A population-based cohort study

BackgroundHypertension is a leading preventable risk factor of chronic disease and all-cause mortality. Housing is a fundamental social determinant of health. Yet, little is known about the impacts of liveable residential space and density on hypertension.Methods and findingsThis retrospective observational study (median follow-up of 2.2 years) leveraged the FAMILY Cohort, a large territory-wide cohort in Hong Kong, Special Administrative Region, People’s Republic of China to quantify associations of objectively measured liveable space and residential density with blood pressure outcomes among adults aged ≥16 years. Blood pressure outcomes comprised diastolic blood pressure (DBP), systolic blood pressure (SBP), mean arterial pressure (MAP), and hypertension. Liveable space was measured as residential floor area, and density was assessed using the number of residential units per building block and neighborhood residential unit density within predefined catchments. Multivariable regression models examined associations of liveable floor area and residential density with prevalent and incident hypertension. We investigated effect modifications by age, sex, income, employment status, and housing type. Propensity score matching was further employed to match a subset of participants who moved to smaller residences at follow-up with equivalent controls who did not move, and generalized linear models examined the impact of moving to smaller residences upon blood pressure outcomes. Our fully adjusted models of prevalent hypertension outcomes comprised 30,439 participants at baseline, while 13,895 participants were available for incident models at follow-up. We found that each interquartile range (IQR) increment in liveable floor area was associated with lower DBP (beta [β] = −0.269 mm Hg, 95% confidence interval [CI]: −0.419 to −0.118, p < 0.001), SBP (β = −0.317 mm Hg, −0.551 to −0.084, p = 0.008), MAP (β = −0.285 mm Hg, −0.451 to −0.119 with p < 0.001), and prevalent hypertension (odds ratio [OR] = 0.955, 0.918 to 0.993, p = 0.022) at baseline. Each IQR increment in residential units per building block was associated with higher DBP (β = 0.477 mm Hg, 0.212 to 0.742, p = <0.001), SBP (β = 0.750 mm Hg, 0.322 to 1.177, p = <0.001), MAP (β = 0.568 mm Hg, 0.269 to 0.866, p < 0.001), and prevalent hypertension (OR = 1.091, 1.024 to 1.162, p = 0.007). Each IQR increase in neighborhood residential density within 0.5-mi street catchment was associated with lower DBP (β = −0.289 mm Hg, −0.441 to −0.137, p = <0.001), SBP (β = −0.411 mm Hg, −0.655 to −0.168, p < 0.001), MAP (β = −0.330 mm Hg, −0.501 to −0.159, p = <0.001), and lower prevalent hypertension (OR = 0.933, 0.899 to 0.969, p < 0.001). In the longitudinal analyses, each IQR increment in liveable floor area was associated with lower DBP (β = −0.237 mm Hg, −0.431 to −0.043, p = 0.016), MAP (β = −0.244 mm Hg, −0.444 to −0.043, p = 0.017), and incident hypertension (adjusted OR = 0.909, 0.836 to 0.988, p = 0.025). The inverse associations between larger liveable area and blood pressure outcomes were more pronounced among women and those residing in public housing. In the propensity-matched analysis, participants moving to residences of lower liveable floor area were associated with higher odds of incident hypertension in reference to those who did not move (OR = 1.623, 1.173 to 2.199, p = 0.002). The major limitations of the study are unmeasured residual confounding and loss to follow-up.ConclusionsWe disentangled the association of micro-, meso-, and macrolevel residential densities with hypertension and found that higher liveable floor area and neighborhood scale residential density were associated with lower odds of hypertension. These findings suggest adequate housing in the form of provisioning of sufficient liveable space and optimizing residential density at the building block, and neighborhood levels should be investigated as a potential population-wide preventive strategy for lowering hypertension and associated chronic diseases.

In a cohort study, Dr. Chinmoy Sarkar and colleagues investigate the association between liveable residential space, residential density and hypertension in Hong Kong.     

Worst case scenario match analysis and contextual variables in professional soccer players: a longitudinal study

This study aimed to describe the worst-case scenarios (WCS) of professional soccer players by playing position in different durations and analyse WCS considering different contextual variables (match half, match location and match outcome). A longitudinal study was conducted in a professional soccer team. Data were collected from different WCS durations in the total distance (TD), high-speed running distance (HSRD), and sprinting distance (SPD). A mixed analysis of variance was performed to compare different WCS durations between playing positions and contextual variables, making pairwise comparisons by Bonferroni post hoc test. Positional differences were found for TD (p < 0.01, ω_p² = 0.02), HSRD (p < 0.01, ω_p² = 0.01) and SPD (p < 0.01, ω_p² = 0.02). There was a significant interaction when comparing WCS by match half in TD (F = 6.1, p < 0.01, ω_p² = 0.07) but no significant differences in HSRD (p = 0.403, ω_p² = 0) or SPD (p = 0.376, ω_p² = 0). A significant interaction was identified when comparing WCS by match location in TD (F = 51.5, p < 0.01, ω_p² = 0.14), HSRD (F = 19.15, p < 0.01, ω_p² = 0.05) and SPD (F = 8.95, p < 0.01, ω_p² = 0.01) as well as WCS by match outcome in TD (F = 36.4, p < 0.01, ω_p² = 0.08), HSRD (F = 13.6, p < 0.01, ω_p² = 0.04) and SPD (F = 7.4, p < 0.01, ω_p² = 0.02). Positional differences exist in TD, HSRD, and SPD in match-play WCS, and contextual variables such as match half, match location and match outcome have a significant impact on the WCS of professional soccer players.     

Atorvastatin Decreases Bone Loss,Inflammation and Oxidative Stress in Experimental Periodontitis

The aim of this study is to determine the effects of Atorvastatin treatment, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, in periodontal disease. Male Wistar albino rats were randomly divided into five groups of ten rats each: (1) non-ligated treatment (NL), (2) ligature only (L), (3) ligature plus 1 mg/kg Atorvastatin daily for 10 days, (4) ligature plus 5 mg/kg Atorvastatin daily for 10 days, and (5) ligature plus 10 mg/kg Atorvastatin daily for 10 days. Following the treatment course, the periodontal tissue of the animals was analyzed by Measurement of alveolar bone loss, Histopathology and immunohistochemistry to determine of the expression of COX-2, MMP-2, MMP9, and RANKL/RANK/OPG. ELISA assay was used to quantitate the levels of IL-1β, IL-10, TNF-α, myeloperoxidase, malondialdehyde, and glutathione. The periodontal group treated with 10 mg/kg of Atorvastatin (3.9±0.9 mm; p<0.05) showed reverse the alveolar bone loss caused Experimental Periodontal Disease compared to (L) (7.02±0.17 mm). The periodontal group treated with 10 mg/kg of Atorvastatin showed a significant reduction in MPO and MDA (p<0.05) compared to ligature only group (L). Similarly in this group, the levels of the proinflammatory cytokines IL-1β and TNF-α were significantly decreased (p<0.05). Furthermore, MMP-2, MMP-9, RANKL/RANK, and COX-2 were all downregulated by Atorvastatin treatment, while OPG expression was increased. The findings support a role of Atorvastatin for reducing the bone loss, inflammatory response, oxidative stress, and expression of extracellular matrix proteins, while reducing RANK/RANKL and increase OPG in periodontal disease.     

The inhibiting effect of glucosamine sulfate combined with loxoprofen sodium on chondrocyte apoptosis in rats with knee osteoarthritis

Objectives:To explore the efficacy of glucosamine sulfate (GS) combined with loxoprofen sodium (LS) in rats with knee osteoarthritis (KOA) and its effect on chondrocytes.Methods:We randomly assigned 40 SPF SD rats to normal group (NG), control group (CG), treatment group (TG), and model group (MG). CG and TG were processed with continuous irrigation of LS and GS. NG and MG were given normal saline. We collected 3 mL of venous blood from the rat’s lower limb for the detection of serum IL-1β, IL-6, IL-8, and TNF-α by ELISA. Four weeks after irrigation, 5 rats in each group were randomly selected for anesthesia. The water content was detected, and the chondrocytes were collected. MTT assay was used to detect apoptosis, and Western blot (WB) to measure concentrations of Bax, Bcl-2, Caspase3, Caspase9, TLR4, and NF-kB.Results:The levels of IL-1 β, IL-6, IL-8, and TNF-α decreased in CG and TG, but increased in MG (P<0.05). After treatment, the expression of inflammatory factors was highest in MG (P<0.05).Conclusions:GS combined with LS showed good efficacy in rats with knee osteoarthritis, which may be achieved by inhibiting the expression of inflammatory factors and knee chondrocyte apoptosis via the TLR4-NF-kB pathway.     

BRMS1 Suppresses Glioma Progression by Regulating Invasion,Migration and Adhesion of Glioma Cells

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. However, the expression and function of BRMS1 in glioma have not been reported. In this study, we investigated whether BRMS1 play a role in glioma pathogenesis. Using the tissue microarray technology, we found that BRMS1 expression is significantly decreased in glioma compared with tumor adjacent normal brain tissue (P<0.01, χ² test) and reduced BRMS1 staining is associated with WHO stages (P<0.05, χ² test). We also found that BRMS1 was significantly downregulated in glioma cell lines compared to normal human astrocytes (P<0.01, χ² test). Furthermore, we demonstrated that BRMS1 overexpression inhibited glioma cell invasion by suppressing uPA, NF-κB, MMP-2 expression and MMP-2 enzyme activity. Moreover, our data showed that overexpression of BRMS1 inhibited glioma cell migration and adhesion capacity compared with the control group through the Src-FAK pathway. Taken together, this study suggested that BRMS1 has a role in glioma development and progression by regulating invasion, migration and adhesion activities of cancer cells.