Combining 2'-fucosyllactose and galactooligosaccharides exerts anti-inflammatory effects and promotes gut health.

This study investigated the potential of 2'-Fucosyllactose (2'-FL) and galactooligosaccharides (GOS) combinations as a novel and cost-effective substitute for human milk oligosaccharides (HMOs) in promoting gut health and reducing inflammation. In vitro studies using Caco-2 cells showed that 2'-FL and GOS combinations (H1: GOS:2'-FL ratio of 1.8:1; H2: ratio of 3.6:1) reduced lipopolysaccharide-induced inflammation by decreasing pro-inflammatory markers, while individual treatments had no significant effects. In a mouse model of dextran sulfate sodium (DSS)-induced colitis, combined 2'-FL and GOS supplementation alleviated symptoms, improved gut permeability, and enhanced intestinal structure, with the GH1 group (H1 combo with DSS) being the most effective. 2'-FL and GOS combinations also enhanced short-chain fatty acid production in infant fecal batch fermentation and mouse fecal analysis, with GH1 showing the most promising results. GH1 supplementation altered gut microbiota in mice with DSS-induced colitis, promoting microbial diversity and a more balanced Firmicutes to Bacteroidota ratio. Infant formula products (IFPs) containing 2'-FL and GOS combinations (IFP2: 174 mg GOS and 95 mg 2'-FL per 14 g serving, 1.8:1 ratio; IFP3: 174 mg GOS and 48 mg 2'-FL per 14 g serving, 3.6:1 ratio) demonstrated gastrointestinal protective and anti-inflammatory properties in a coculture model of Caco-2 and THP-1 cells. These findings suggest that 2'-FL and GOS combinations have potential applications in advanced infant formulas and supplements to promote gut health and reduce inflammation.

KL-Biome (Postbiotic Formulation of Lactiplantibacillus plantarum KM2) Improves Dexamethasone-Induced Muscle Atrophy in Mice.

Sarcopenia refers to an age-related decrease in muscle mass and strength. The gut-muscle axis has been proposed as a promising target to alleviate muscle atrophy. The effect of KL-Biome-a postbiotic preparation comprising heat-killed Lactiplantibacillus plantarum KM-2, its metabolites, and an excipient (soybean powder)-on muscle atrophy was evaluated using dexamethasone (DEX)-induced atrophic C2C12 myoblasts and C57BL/6J mice. KL-Biome significantly downregulated the expression of genes (Atrogin-1 and MuRF1) associated with skeletal muscle degradation but increased the anabolic phosphorylation of FoxO3a, Akt, and mTOR in C2C12 cells. Oral administration of KL-Biome (900 mg/kg) for 8 weeks significantly improved muscle mass, muscle function, and serum lactate dehydrogenase levels in DEX-treated mice. KL-Biome administration increased gut microbiome diversity and reversed DEX-mediated gut microbiota alterations. Furthermore, it significantly increased the relative abundances of the genera Subdologranulum, Alistipes, and Faecalibacterium prausnitzii, which are substantially involved in short-chain fatty acid production. These findings suggest that KL-Biome exerts beneficial effects on muscle atrophy by regulating gut microbiota.

A New Equation to Estimate Peripherally Inserted Central Catheter Length.

Background and Objectives: Peripherally inserted central catheter (PICC) placement plays an important role in clinical practice. This study aimed to provide an equation for the proper estimation of catheter length in cases of PICC placement without imaging guidance in relation to patient height, weight, sex, and age. Materials and Methods: For 1137 PICC placement cases in both arm veins of 954 patients at a single center, the elbow crease to the cavoatrial junction length (ECL) was calculated as follows: ECL = (PICC length) + (distance from the elbow crease to the puncture site). We analyzed the relationship between ECL and patient characteristics and suggested a new equation for ECL based on height, weight, sex, and age. Results: The average ECL was 48.0 ± 2.4 cm in the right side and 51.0 ± 3.0 cm in the left side. ECL in the right arm was significantly correlated with patient height, sex, and age, whereas the ECL in the left arm was additionally significantly correlated with patient weight. The ECL (cm) prediction model was as follows: right ECL = 26.32 + 1.33 × (female = 1, male = 2) - 0.02 × age (years) + 0.13 × height (cm); left ECL = 22.09 + 1.28 × (female = 1, male = 2) + 0.02 × age (years) + 0.14 × height (cm) + 0.042 × weight (kg). Conclusions: The appropriate PICC length was predicted based on the patient's height, weight, sex, and age. The equations in our study can help predict the optimal catheter length and can be automatically calculated using computerized patient information for bedside procedures in PICC.

Age- and dose-dependent effect of statin use on the risk of osteoporotic fracture in older adults.

Previous studies have revealed the protective effects of statins on bone but the association of statins use with osteoporosis-related measurement has shown controversial results. In this study, we found an age, dose andduration-dependent osteoprotective effect of statins in general older population. PURPOSE: Previous studies have revealed the protective effects of statins on bone but the association of statins use with osteoporotic fractures has shown controversial results. METHODS: In this study with Korean National Health Insurance Service-Senior cohort database, a total of 365,656 elderly without previous history of osteoporosis and who were started on statin since January 1 2004 were included and observed until December 31 2012. Hazard rations (HR) for major osteoporotic fractures were calculated using the weighted Cox proportional hazards model with inverse-probability of treatment weighting method. RESULTS: During 6.27 years of follow-up period, 54,959 osteoporotic fractures occurred and the majority of fractures (69.5%) were vertebral fractures. Compared with non-users, statin use was associated with a decreased risk of all outcomes with adjusted HR (95% CI) of 0.77 (0.72-0.83; P < 0.001) for major osteoporotic fractures, 0.49 (0.38-0.62; P < 0.001) for hip fractures, and 0.70 (0.64-0.77; P < 0.001) for vertebral fractures. When outcomes were examined separately by sex, the results were broadly comparable in terms of patterns of risk reduction by statin use. The patients with statin initiated at age ≥ 80 years had the highest risk reduction for most outcomes relative to non-users. Higher cumulative dose of statin was negatively associated with the osteoporotic fracture risk; 0.97 (0.91-1.02) for 30-364 cumulative daily defined dose (cDDD), 0.45 (0.40-0.51) for 365-1,094 cDDD, and 0.22 (0.15-0.33) for ≥ 1,095 cDDD. CONCLUSIONS: Our results showed that statin use was associated with significant reduction in the risk of osteoporotic fractures in general older population.

Glyoxal-derived advanced glycation end-products, Nε-carboxymethyl-lysine, and glyoxal-derived lysine dimer induce apoptosis-related gene expression in hepatocytes.

BACKGROUND: Advanced glycation end-products (AGEs) are proteins or lipids that have been glycated nonenzymatically by reducing sugars and their derivatives such as methylglyoxal. AGEs are known to cause inflammation, oxidative stress, and diseases in the human body. The toxic effects of AGEs and their structures on the origin of the protein being modified have not been well studied. METHODS AND RESULTS: Five different types of AGEs: AGE1 (glucose-derived), AGE2 (glyceraldehyde-derived), AGE3 (glycolaldehyde-derived), AGE4 (methylglyoxal-derived), and AGE5 (glyoxal-derived); were used to examine the effect of AGEs on HepG2 cells. AGE2 through 5 increase the production of reactive oxygen species (ROS) in liver cells, an initiating factor for apoptosis. At the mRNA and protein levels, AGE5 treatment showed the greatest increase in expression of apoptosis-related factors such as Bax, p53, and Caspase 3. Quantitative analysis revealed that Nε-carboxymethyl-lysine (CML) and glyoxal-lysine dimer (GOLD) were the important types of AGE5. The ROS generation and the expression of apoptotic factors both increased when cells were treated with CML and GOLD. CONCLUSION: These findings suggest that AGE5 treatment activates the apoptosis-related gene expression in hapatocytes, with CML and GOLD as potential major AGE compounds.

False-positive supraclavicular lymph node detected on chest computed tomography in oncology patients: Clinical implication based on subsequent neck ultrasonography and ultrasonography-guided tissue sampling.

PURPOSE: The purpose of this study was to assess the prevalence and clinical implications of false-positive supraclavicular lymph node (LN) detected on chest computed tomography (CT), using subsequent neck ultrasonography (US) and US-guided tissue sampling. METHODS: Among 172 patients with suspected supraclavicular LNs identified on CT, 87 underwent neck US or US-guided tissue sampling. Receiver operating characteristic curve and logistic regression analyses were performed to determine the diagnostic performance of US and independent predictors of false-positive LNs. RESULTS: Among 87 patients, 49 (56.3%) were pathologically confirmed as metastases, 26 (29.9%) were negative for malignancy, and 12 (13.8%) had pseudolesions or schwannomas. The diagnostic indices were as follows: sensitivity, 91.8%; specificity, 92.3%; PPV, 95.7%; NPV, 85.7%; and accuracy, 92.0% (AUC = 0.921; 95% CI: 0.832-0.970, p < 0.001). The false-positive group had a higher mean age than the true-positive group (mean age, 69.8 ± 9.2 vs. 63.9 ± 9.8, p = 0.003). Logistic regression analyses revealed that age ≥ 65 years was the only independent predictor of false-positive LNs (OR = 4.391; 95% CI: 1.037-18.582; p = 0.044). CONCLUSION: Subsequent US can be helpful for evaluating suspicious supraclavicular LNs detected on CT to establish appropriate management, especially in older patients.

Bevacizumab versus PARP-inhibitors in women with newly diagnosed ovarian cancer: a network meta-analysis.

BACKGROUND: In women with newly diagnosed ovarian cancer, bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi) exhibit improved progression-free survival (PFS) when administered concurrent with chemotherapy and/or maintenance therapy, but no study has directly compared their effects. Therefore, this study aimed to compare the efficacy and safety of bevacizumab and PARPi in women with newly diagnosed ovarian cancer using a network meta-analysis. METHODS: PubMed, Medline, and Embase databases were searched, and five randomized trials assessing PFS in women with newly diagnosed ovarian cancer treated with either bevacizumab, PARPi, or placebo or no additional agent (controls) were identified. PFS was compared in the overall population with ovarian cancer, women with a BRCA1/2 mutation (BRCAm) and women with homologous-recombination deficiency (HRD). Adverse events (grade ≥ 3) were compared in all populations of the included studies. RESULTS: PARPi improved PFS significantly more than bevacizumab in women with a BRCAm (HR 0.47; 95% CI 0.36-0.60) and with HRD (HR 0.66; 95% CI 0.50-0.87). However, in the overall population with ovarian cancer, no significant difference in PFS was observed between women treated with PARPi and those treated with bevacizumab. PARPi exhibited the highest surface under the cumulative ranking probabilities value as the most effective treatment for PFS (PARPi vs. bevacizumab: 98% vs. 52% in the overall population with ovarian cancer; 100% vs. 50% in women with BRCAm; 100% vs. 50% in women with HRD). For adverse events, the risk of all treatments was similar. However, PARPi had a higher adverse risk than the control group (relative risk 2.14; 95% CI 1.40-3.26). CONCLUSIONS: In women with newly diagnosed ovarian cancer, PARPi might be more effective in terms of PFS compared to bevacizumab. The risk of serious adverse events was similar for PARPi and bevacizumab.

Association between oral health and thyroid disorders: A population-based cross-sectional study.

OBJECTIVES: In this study, we aimed to determine the relationship between oral health status and thyroid dysfunction. METHODS: A population-based cross-sectional analysis using data from the Korean National Health and Nutrition Examination Survey (KNHNES) was performed. We investigated the association between oral health-related parameters and the prevalence of thyroid diseases. In addition, the relationship between oral health status and thyroid function test (TFT) results was analyzed. One-way analysis of variances or chi-square test was used for comparisons between oral health-related parameters and presence of thyroid diseases. Univariable and multivariable logistic regression analyses were conducted to evaluate the associations between participants' characteristics including oral health-related parameters and the abnormal results of TFTs. RESULTS: A total of 18,034 adults were surveyed. Histories of thyroid diseases were found to be more common in people who brushed their teeth frequently or used oral hygiene products. However, histories of periodontitis and community periodontal index (CPI) did not show significant associations with histories of thyroid diseases. Among 14,860 participants without history of thyroid disorders, people having higher CPI values demonstrated higher probabilities of abnormal TFTs (OR 1.381, 95% CI 1.241-1.537, p < .0001); however, statistical significance was not found after adjusting for the other variables. CONCLUSIONS: Our study demonstrated that good oral health-related behavior was associated with more frequent thyroid disease history. High CPI showed a significant association with TFT abnormalities; however, the significance of this association became lower when other variables such as age and sex were adjusted. Further studies will be needed to determine how the control of oral health-related conditions actually has a causal relationship with thyroid disease/dysfunction through prospective cohort studies.

Age at Menopause and Suicidal Ideation in Menopausal Women: A Study of Korea National Health and Nutrition Examination Survey Data.

BACKGROUND: Although menopause is considered a risk factor for depression, no association has been established between the risk of suicidal ideation and age at menopause. This study aimed to evaluate the association between age at menopause and suicidal ideation in middle-aged menopausal Korean women. METHODS: This cross-sectional study used data from the Korea National Health and Nutrition Examination Survey (2013-2018). Women aged 40-65 years were divided into the following three categories: primary ovarian insufficiency (POI), early menopause, and menopause, according to age at natural menopause (< 40, 40-45, and > 45 years, respectively). Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: Among 2,232 menopausal women, 25 (1.1%) experienced POI and 114 (5.1%) experienced early menopause. The PHQ-9 items that pertained to low self-esteem and suicidal ideation scored higher in women with POI than in those who experienced menopause after 45 years of age. The prevalence of suicidal ideation differed significantly according to age at menopause (POI, 30.0%; early menopause, 12.7%; menopause, 8.0%; P = 0.016). Logistic regression analysis revealed that POI was significantly associated with suicidal ideation after the adjustment for age, body mass index, and education, household income, and walking levels (odds ratio, 4.2; 95% confidence interval, 1.0-17.7). CONCLUSION: Korean middle-aged women with POI were more likely to have suicidal ideation than those who experienced menopause at 45 years or above, despite not being diagnosed with major depressive disorder.

Homeostasis effects of fermented Maillard reaction products by Lactobacillus gasseri 4M13 in dextran sulfate sodium-induced colitis mice.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) continues to increase worldwide. Multiple factors, including diet, loss of the intestinal barrier function, and imbalance of the immune system can cause IBD. A balanced diet is important for maintaining a healthy bowel and preventing IBD from occurring. The effects of probiotic Lactobacillus gasseri-fermented Maillard reaction products (MRPs) prepared by reacting whey protein with galactose on anti-inflammation and intestinal homeostasis were investigated in this study, which compared MPRs and probiotics separately. RESULTS: In an animal colitis model induced by 2% dextran sulfate sodium (DSS), FWG administration alleviated colon length loss and maintained intestinal immune system homeostasis as reflected by down-regulated interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α output, and metallopeptidase-9, and epithelial barrier balance as reflected by up-regulated occludin, E-cadherin, and zonula occludens-1 production in the colon. Furthermore, the expression of splenic cytokines such as IL-6, TNF-α, and IL-10 was up-regulated in the FWG-treated mice in a comparable amount to the control group to ensure the balance of immune responses. CONCLUSION: This study showed that the use of FWG protects the intestines from colitis caused by DSS and maintains immune balance. FWG increased antioxidant enzyme activity, increased intestinal permeability, and regulated the balance of pro- and anti-inflammatory cytokines in the intestines and spleen. Continued intake of FWG can alleviate IBD symptoms through the preservation of mucosal immune responses, epithelial junction and homeostasis through the regulated splenic cytokines. © 2021 Society of Chemical Industry.

Clinical Validation of Dental Implant Stability by Newly Designed Damping Capacity Assessment Device during the Healing Period.

Background and Objectives: To evaluate the stability of a dental implant and the effectiveness of a newly designed damping capacity assessment device by improving the number of blows and strength evaluated by a prospective clinical study. Materials and Method: The stability of dental implants was measured in 50 implants in a total of 38 patients. Measurements were performed using Anycheck and Periotest M devices, twice in total, divided into buccal and lingual directions. In addition, measurements were performed on the day of surgery, two weeks, one month, two months, and three months after surgery for a total of five times. After the standardization of the measured values, the differences and changes over time for each device were observed. Result: No difference in standardized values between the two devices was observed at any time point. In both devices, stability decreased at two weeks postoperatively but gradually increased thereafter. No differences were observed in the values according to the measurement direction. Conclusions: The damping capacity of Anycheck was similar to that of Periotest M. After a slight decrease in stability two weeks after implant placement, implant stability increased over time.

Exosomes released from Shiga toxin 2a-treated human macrophages modulate inflammatory responses and induce cell death in toxin receptor expressing human cells.

Shiga toxins (Stxs) produced by Stx-producing Escherichia coli are the primarily virulence factors of hemolytic uremic syndrome and central nervous system (CNS) impairment. Although the precise mechanisms of toxin dissemination remain unclear, Stxs bind to extracellular vesicles (EVs). Exosomes, a subset of EVs, may play a key role in Stx-mediated renal injury. To test this hypothesis, we isolated exosomes from monocyte-derived macrophages in the presence of Stx2a or Stx2 toxoids. Macrophage-like differentiated THP-1 cells treated with Stxs secreted Stx-associated exosomes (Stx-Exo) of 90-130 nm in diameter, which induced cytotoxicity in recipient cells in a toxin receptor globotriaosylceramide (Gb3 )-dependent manner. Stx2-Exo engulfed by Gb3 -positive cells were translocated to the endoplasmic reticulum in the human proximal tubule epithelial cell line HK-2. Stx2-Exo contained pro-inflammatory cytokine mRNAs and proteins and induced more severe inflammation than purified Stx2a accompanied by greater death of target cells such as human renal or retinal pigment epithelial cells. Blockade of exosome biogenesis using the pharmacological inhibitor GW4869 reduced Stx2-Exo-mediated human renal cell death. Stx2-Exo isolated from human primary monocyte-derived macrophages activated caspase 3/7 and resulted in significant cell death in primary human renal cortical epithelial cells. Based on these results, we speculate that Stx-containing exosomes derived from macrophages may exacerbate cytotoxicity and inflammation and trigger cell death in toxin-sensitive cells. Therapeutic interventions targeting Stx-containing exosomes may prevent or ameliorate Stx-mediated acute vascular dysfunction.

Shift work sleep disorder is closely associated with an increased risk for periodontal disease.

AIM: This study aimed to investigate the association between work patterns and periodontal disease. MATERIALS AND METHODS: Data were collected from the Korea National Health and Nutrition Examination Survey between 2007 and 2012, and data from 22,508 subjects aged ≥19 years were included. An individual's work pattern was classified as either daytime or shift work. Sleep duration was categorized into three ranges: ≤5, 6-8, and ≥9 h/day. A multivariate logistic regression model was used to determine the adjusted odds ratio (OR) for CPI (Community Periodontal Index) ≥3. The CONTRAST statement was used to show the interaction effect of work patterns and sleep duration. RESULTS: The adjusted OR of shift work was 2.168 (CI: 1.929-2.438, p < .0001). Participants who sleep ≤5 or ≥9 h/day showed ORs 0.735 and 0.663, respectively (p = .0181). Interaction effect analysis revealed that the work pattern had a strong influence on periodontal condition when combined with the sleep amount. Shift workers with ≤5 or ≥ 9 h of sleep showed significantly increased ORs for CPI ≥3 (2.1406 and 2.3251, respectively, p < .0001). The ORs for daytime workers were comparable to the original values (≤5: 0.7348, p = .0292; ≥9: 0.6633, p = .0428). CONCLUSION: Altered sleep patterns caused by shift work have more influence on periodontal disease than sleep duration.

TLR2 and the NLRP3 inflammasome mediate IL-1ß production in Prevotella nigrescens-infected dendritic cells.

Prevotella nigrescens is an oral pathogen that is frequently observed in the subgingival plaque of periodontitis patients. Interleukin-1ß (IL-1ß) is known to be involved in the immunopathology of periodontal diseases and has been implicated in the destruction of bone. In this study, we investigated the mechanism of IL-1ß production by P. nigrescens in murine bone marrow-derived dendritic cells (BMDCs). Our results showed that a host receptor, Toll-like receptor 2 (TLR2), but not TLR4 is required for pro-IL-1ß induction and nucleotide-binding oligomerization domain like receptor pyrin domain containing 3 (NLRP3) priming in BMDCs in response to P. nigrescens and activation of the NLRP3 inflammasome is necessary for processing of pro-IL-1ß into mature IL-1ß. In addition, an inhibitor assay revealed that production of reactive oxygen species, P2X7R activity, and release of cathepsin B are involved in IL-1ß production in BMDCs in response to P. nigrescens.

Primary transcriptome and translatome analysis determines transcriptional and translational regulatory elements encoded in the Streptomyces clavuligerus genome.

Determining transcriptional and translational regulatory elements in GC-rich Streptomyces genomes is essential to elucidating the complex regulatory networks that govern secondary metabolite biosynthetic gene cluster (BGC) expression. However, information about such regulatory elements has been limited for Streptomyces genomes. To address this limitation, a high-quality genome sequence of ß-lactam antibiotic-producing Streptomyces clavuligerus ATCC 27 064 is completed, which contains 7163 newly annotated genes. This provides a fundamental reference genome sequence to integrate multiple genome-scale data types, including dRNA-Seq, RNA-Seq and ribosome profiling. Data integration results in the precise determination of 2659 transcription start sites which reveal transcriptional and translational regulatory elements, including -10 and -35 promoter components specific to sigma (σ) factors, and 5'-untranslated region as a determinant for translation efficiency regulation. Particularly, sequence analysis of a wide diversity of the -35 components enables us to predict potential σ-factor regulons, along with various spacer lengths between the -10 and -35 elements. At last, the primary transcriptome landscape of the ß-lactam biosynthetic pathway is analyzed, suggesting temporal changes in metabolism for the synthesis of secondary metabolites driven by transcriptional regulation. This comprehensive genetic information provides a versatile genetic resource for rational engineering of secondary metabolite BGCs in Streptomyces.

Photochemical Carbopyridylation of Alkenes Using N-Alkenoxypyridinium Salts as Bifunctional Reagents.

N-Alkenoxypyridinium salts have been used as synthons for the umpolung reaction of enolates for the preparation of α-functionalized carbonyl compounds. In contrast, we found that the photoreduction of N-alkenoxypyridinium salts generates α-carbonyl radicals after cleavage of the N-O bond, thereby allowing simultaneous incorporation of α-keto and pyridyl groups across unactivated alkenes. In the process, the formed α-carbonyl radicals engage unactivated alkenes to afford alkyl radical intermediates poised for subsequent addition to pyridinium salts, which ultimately affords a variety of γ-pyridyl ketones under mild reaction conditions. This transformation is characterized by a broad substrate scope and good functional-group compatibility, and the utility of this transformation was further demonstrated by the late-stage functionalization of complex biorelevant molecules.

Regioselective C-H Functionalization of Heteroarene N-Oxides Enabled by a Traceless Nucleophile.

Although N-alkenoxyheteroarenium salts have been widely used as umpoled synthons with nucleophilic (hetero)arenes, the use of electron-poor heteroarenes has remained unexplored. To overcome the inherent electron deficiency of quinolinium salts, a traceless nucleophile-triggered strategy was designed, wherein the quinolinium segment is converted into a dearomatized intermediate, thereby allowing simultaneous C8-functionalization of quinolines at room temperature. Experimental and computational studies support the traceless operation of a nucleophile, which enables the previously inaccessible transformation of N-alkenoxyheteroarenium salts. Remarkably, the generality of this strategy has been further demonstrated by broad applications in the regioselective C-H functionalization of other electron-deficient heteroarenes such as phenanthridine, isoquinoline, and pyridine N-oxides, offering a practical tool for the late-stage functionalization of complex biorelevant molecules.

Do hassles and uplifts trajectories predict mortality? Longitudinal findings from the VA Normative Aging Study.

We examined whether longitudinal patterns of hassles and uplifts trajectories predicted mortality, using a sample of 1315 men from the VA Normative Aging Study (mean age = 65.31, SD = 7.6). In prior work, we identified different trajectory classes of hassles and uplifts exposure and intensity scores over a period of 16 years. In this study, we used the probabilities of these exposure and intensity class memberships to examine their ability to predict mortality. Men with higher probabilities of high hassle intensity trajectory class and high uplift intensity class had higher mortality risks. In a model combining the probabilities of hassle and uplift intensities, the probability of high intensity hassle class membership significantly increased the risk of mortality. This suggests that appraisals of hassles intensity are better predictors of mortality than simple exposure measures, and that uplifts have no independent effects.

Establishment of a mouse model for pulmonary inflammation and fibrosis by intratracheal instillation of polyhexamethyleneguanidine phosphate.

Although several animal models have been developed to study human pulmonary fibrosis, lack of a perfect model has raised the need for various animal models of pulmonary fibrosis. In this study, we evaluated the pulmonary effect of polyhexamethyleneguanidine phosphate instillation into the lungs of mice to determine the potential of these mice as a murine model of pulmonary fibrosis. Intratracheal instillation of polyhexamethyleneguanidine phosphate induced severe lung inflammation manifested by the infiltration of mononuclear cells and neutrophils and increased production of IL-6, TNF-α, CCL2 and CXCL1. The lung inflammation gradually increased until 28 days after polyhexamethyleneguanidine phosphate exposure, and increases of collagen deposition and TGF-ß production, which are indicators of pulmonary fibrosis, were seen. Our study showed that intratracheal instillation of polyhexamethyleneguanidine phosphate induces pulmonary inflammation and fibrosis in mice.

Genome-scale analysis reveals a role for NdgR in the thiol oxidative stress response in Streptomyces coelicolor.

BACKGROUND: NdgR is an IclR-type transcription factor that regulates leucine biosynthesis and other metabolic pathways in Streptomyces coelicolor. Recent study revealed that NdgR is one of the regulatory targets of SigR, an oxidative stress response sigma factor, suggesting that the NdgR plays an important physiological role in response to environmental stresses. Although the regulatory functions of NdgR were partly characterized, determination of its regulon is required for better understanding of the transcriptional regulatory network related with the oxidative stress response. RESULTS: We determined genome-wide binding loci of NdgR by using chromatin immunoprecipitation coupled with sequencing (ChIP-seq) and explored its physiological roles. The ChIP-seq profiles revealed 19 direct binding loci with a 15-bp imperfect palindromic motif, including 34 genes in their transcription units. Most genes in branched-chain amino acid and cysteine biosynthesis pathways were involved in the NdgR regulon. We proved that ndgR is induced by SigR under the thiol oxidation, and that an ndgR mutant strain is sensitive to the thiol oxidizing agent, diamide. Through the expression test of NdgR and the target genes for NdgR under diamide treatment, regulatory motifs were suggested. Interestingly, NdgR constitutes two regulatory motifs, coherent and incoherent feed-forward loops (FFL), in order to control its regulon under the diamide treatment. Using the regulatory motifs, NdgR regulates cysteine biosynthesis in response to thiol oxidative stress, enabling cells to maintain sulfur assimilation with homeostasis under stress conditions. CONCLUSIONS: Our analysis revealed that NdgR is a global transcriptional regulator involved in the regulation of branched-chain amino acids biosynthesis and sulphur assimilation. The identification of the NdgR regulon broadens our knowledge regarding complex regulatory networks governing amino acid biosynthesis in the context of stress responses in S. coelicolor.