Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.

Age-related remodelling of oesophageal epithelia by mutated cancer drivers.

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.

Changes in alanine aminotransferase and body composition and metabolic factors among individuals receiving medical health checkups.

AIM: To examine the relationship between changes in alanine aminotransferase (ALT) and those in body composition and metabolic factors in participants receiving medical health checkups (4350 men [mean age 52.5 years] and 5398 women [mean age 50.5 years]) METHODS: We divided the participants into four types based on their ALT value at baseline and 1 year: A, ALT ≤30 (baseline) and ≤30 (1 year); B, ALT ≥31 (baseline) and ≤30 (1 year); C, ALT ≤30 (baseline) and ≥31 (1 year); and D, ALT ≥31 (baseline) and ≥31 (1 year). The change in each body composition-related parameter (waist circumference, fat mass, fat-free mass, fat mass to fat-free mass ratio, etc.) after 1-year was defined as Δ. RESULTS: The mean changes in waist circumference (cm) in the four types (A, B, C, and D) were -0.33, -1.54, 0.66, and -0.29 (overall p < 0.0001) in men, and -0.19, -0.90, 0.30, and 0.090 (overall p < 0.0001) in women. The mean changes in fat mass (kg) in the four types were -0.027, -0.86, 0.62, and 0.092 (overall p < 0.0001) in men, and 0.0067, -0.48, 0.39, and 0.063 (overall p < 0.0001) in women. The mean changes in fat-free mass (kg) in the four types were -0.028, -0.55, 0.42, and -0.034 (overall p < 0.0001) in men, and -0.0091, -0.34, 0.12, and -0.045 (overall p = 0.0012) in women. The mean changes in fat mass to fat-free mass ratio in the four types were -0.00042, -0.0120, 0.00837, and 0.00171 (overall p < 0.0001) in men, and -0.00013, -0.00817, 0.00730, and 0.00628 (overall p < 0.0001) in women. CONCLUSION: A decrease in ALT to ≤30 IU/L may be associated with improved body composition balance, but caution should be exercised for the decrease in muscle mass.

Body Composition in Chronic Liver Disease.

Body composition has recently been attracting people's attention, not only from a cosmetic standpoint but also from the perspective of health and longevity. The body is classified into three components: fat, bone, and lean soft tissue, and it is common to see an increase in body fat and a decrease in total body muscle mass with aging. Aging-related loss of muscle mass and muscle function is referred to as primary sarcopenia, while sarcopenia caused by disease-specific conditions is referred to as secondary sarcopenia. On the other hand, the liver-muscle axis has been attracting attention in recent years, and it has become clear that the liver and the skeletal muscles interact with each other. In particular, patients with cirrhosis are prone to secondary sarcopenia due to protein-energy malnutrition, which is a characteristic pathophysiology of the disease, suggesting the importance of the organ-organ network. In this review, we would like to outline the latest findings in this field, with a focus on body composition in liver diseases such as liver cirrhosis, fatty liver disease, alcoholic liver disease, and hepatocellular carcinoma.

Long-Term Outcomes after Switching to Tenofovir Alafenamide in Patients with Chronic Hepatitis B.

We sought to determine the long-term outcomes of chronic hepatitis B (CHB) cases switching to tenofovir alafenamide (TAF, n = 104, median age = 63.5 years). Data at switching to TAF (baseline) and those at 1, 2, 3, 4, and 5 years from switching to TAF were compared. At baseline, HB envelop antigen (HBeAg) seropositivity was found in 20 patients (19.2%), and undetectable HBV-DNA in 77 patients (74.0%). Percentage of detectable HBV-DNA significantly reduced at any time point. HB surface antigen (HBsAg) levels significantly reduced at 3, 4, and 5 years. The percentage of HBeAg seropositivity significantly reduced at 5 years. HB core related antigen levels did not significantly change. In patients with baseline HbeAg seropositivity, HbsAg levels significantly reduced at any time point, and a similar trend was found in patients without HBeAg seropositivity. In patients with baseline FIB4 index >1.85, HBsAg levels significantly reduced at 3, 4, and 5 years, and in patients with baseline FIB4 index <1.85, HBsAg levels significantly reduced at any time point. The estimated glomerular filtration rate significantly reduced only at 5 years. The discontinuation rate owing to the side effects of TAF was 0%. In conclusion, switching to TAF therapy in patients with CHB may be effective and safe at least up to 5 years.

Stepwise co-fermented traditional Chinese medicine byproducts improve antioxidant and anti-inflammatory effects in a piglet model.

BACKGROUND: Lianhua Qingwen capsule is a traditional Chinese medicine (TCM) formula having antiviral and anti-inflammatory activities. During capsule production, a large amount of byproducts will be yielded and disposed of as waste by burying. Resourceful utilization of these kinds of TCM byproducts as feed additives through stage-based co-fermentation using enzyme and probiotics could reduce environmental stress and resource shortage. The in vitro characterization and the supplementary effects of fermented TCM byproducts (FTCM) for weaned piglets (initial body weight: 7.23 ± 0.33 kg; dose: basal diet + 300 mg kg-1 FTCM) were investigated. RESULTS: Higher reducing sugar content, total flavonoid content, flavonoid compounds (e.g. tectoridin, tricetin, flavone, apigenin, naringenin) and total antioxidant activity were determined in the FTCM compared to spontaneously fermented and unfermented materials. Supplementation of the FTCM to piglets did not significantly affect the feed intake, body weight gain and feed/gain ratio, but significantly decreased a proinflammatory cytokine, IL-8, and increased intestinal total antioxidant activity (TAC) and superoxide dismutase (SOD) activity. Moreover, FTCM supplementation increased α-diversity of the colonic microbiota accompanied with increased abundance of Prevotella genus and Treponema berlinense species. Correlation analysis indicates that T. berlinense is responsible for the decreased IL-8 level and enhanced intestinal TAC and SOD activities which might be mediated by a homoserine lactone molecule (3-oxo-C14). CONCLUSION: Overall, the stepwise co-fermentation enriched bioactive compounds within the TCM byproducts and their dietary supplementation did not generate any side effect on growth performance but displayed beneficial effects on enrichment of potential probiotic T. berlinense and relevant functions. © 2023 Society of Chemical Industry.

Expression of Immune-Related and Inflammatory Markers and Their Prognostic Impact in Colorectal Cancer Patients.

The tumor microenvironment of colorectal cancer (CRC) is heterogenous; thus, it is likely that multiple immune-related and inflammatory markers are simultaneously expressed in the tumor. The aim of this study was to identify immune-related and inflammatory markers expressed in freshly frozen CRC tissues and to investigate whether they are related to the clinicopathological features and prognosis of CRC. Seventy patients with CRC who underwent curative surgical resection between December 2014 and January 2017 were included in this study. Tissue samples were obtained from tumor and non-tumor areas in the patients' colons. The concentrations of immune-related markers (APRIL/TNFSF13, BAFF, LAG-3, PD-1, PD-L1, and CTLA-4) and inflammatory markers (CHIT, MMP-3, osteocalcin, pentraxin-3, sTNF-R1, and sTNF-R2) in the samples were measured using the Bio-plex Multiplex Immunoassay system. The concentrations of APRIL/TNFSF13, BAFF, and MMP-3 in the samples were significantly high; thus, we conducted analyses based on the cut-off values for these three markers. The high-APRIL/TNFSH13-expression group showed a significantly higher rate of metastatic lesions than the low-expression group, whereas the high-MMP-3-expression group had higher CEA levels, more lymph node metastases, and more advanced disease stages than the low-expression group. The five-year disease-free survival of the high-MMP-3-expression group was significantly shorter than that of the low-expression group (65.1% vs. 90.2%, p = 0.033). This study provides evidence that the APRIL/TNFSF13, BAFF, and MMP-3 pathway is overexpressed in CRC tissues and is associated with unfavorable clinicopathological features and poor prognosis in CRC patients. These markers could serve as diagnostic or prognostic biomarkers for CRC.

Positive Role of Delta Neutrophil Index (DNI) as a Prodiagnostic Marker in Cecal Ligation and Puncture (CLP)-Induced Sepsis Murine Model.

Sepsis is an emergent infectious disease and a leading cause of death despite immediate intervention. While Delta neutrophil index (DNI) and myeloperoxidase (MPO) are known as a prodiagnostic marker of sepsis, the preclinical evidence of the best marker of sepsis is unclear. For this, using a well-designed cecal ligation and puncture (CLP)-induced sepsis mouse model, we comparatively measured the level and cost-effectiveness of sepsis biomarkers such as DNI, myeloperoxidase (MPO), procalcitonin (PCT), and tumor necrosis factor-alpha (TNF-α). First, we found that the optimal time point for early detection is at 6 h, 24 h post-CLP. Strikingly, the peak level and fold change of DNI was revealed at 24 h, further showing the best fold change as compared with other biomarker levels. Given the fold change at 6, 24 h, PCT was next to DNI. Third, a cost-effectiveness survey showed that DNI was the best, with PCT next. Further, DNI level was moderate positively associated with PCT (ρ = 0.697, p = 0.012) and TNF-α (ρ = 0.599, p = 0.040). Collectively, these data indicate that DNI in CLP-induced sepsis mice is as effective as the existent inflammatory biomarkers such as MPO, PCT and TNF-α to predict the prognosis of sepsis. This might have clinically important implications that DNI is cost effective, thus quickly and rationally applying to diverse types of imminent sepsis regardless of species. This might be the first report on the validity of DNI in preclinical CLP-induced murine sepsis.

Ameliorating effect of CpG-ODN (oligodeoxynucleotide) against radiation-induced lung injury in mice.

While radiation-induced lung injury (RILI) is known to be progressed by Th2 skewed, pro-inflammatory immune response, there have been few therapeutic attempts through Th1 immune modulation. We investigated whether the immunostimulant CpG-oligodeoxynucleotide (CpG-ODN) would be effective against RILI by way of measuring reactive oxygen species (ROS) and nitric oxides (NO), histopathology, micro-three-dimensional computer tomography (CT), and cytokine profiling. We found that KSK CpG-ODN (K-CpG) significantly reduced histopathological fibrosis when compared to the positive control (PC) group (p < 0.01). The levels of ROS production in serum and splenocyte of PC group were significantly higher than that of K-CpG group (p < 0.01). The production of nitric oxide (NO) in CpG-ODNs group was higher than that of PC group. Last, cytokine profiling illustrated that the protein concentrations of Th1-type cytokines such as IL-12 and TNF-α as well as Th2-type cytokine IL-5 in K-CpG group inclined to be significantly (p < 0.001 or p < 0.01) higher than those of in PC group. Collectively, our study clearly indicates that K-CpG is effective against RILI in mice by modulating the innate immune response. To our knowledge, this is the first note on anti-RILI effect of human type, K-CpG, clinically implying the potential of immunotherapy for RILI control.

CRISPR/Cas9-mediated efficient and precise targeted integration of donor DNA harboring double cleavage sites in Xenopus tropicalis.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9 system has emerged as a powerful tool for knock-in of DNA fragments via donor plasmid and homology-independent DNA repair mechanism; however, conventional integration includes unnecessary plasmid backbone and may result in the unfaithful expression of the modified endogenous genes. Here, we report an efficient and precise CRISPR/Cas9-mediated integration strategy using a donor plasmid that harbors 2 of the same cleavage sites that flank the cassette at both sides. After the delivery of donor plasmid, together with Cas9 mRNA and guide RNA, into cells or fertilized eggs, concurrent cleavages at both sides of the exogenous cassette and the desired chromosomal site result in precise targeted integration without plasmid backbone. We successfully used this approach to precisely integrate the EGFP reporter gene into the myh6 locus or the GAPDH locus in Xenopus tropicalis or human cells, respectively. Furthermore, we demonstrate that replacing conventional terminators with the endogenous 3UTR of target genes in the cassette greatly improves the expression of reporter gene after integration. Our efficient and precise method will be useful for a variety of targeted genome modifications, not only in X. tropicalis, but also in mammalian cells, and can be readily adapted to many other organisms.-Mao, C.-Z., Zheng, L., Zhou, Y.-M., Wu, H.-Y., Xia, J.-B., Liang, C.-Q., Guo, X.-F., Peng, W.-T., Zhao, H., Cai, W.-B., Kim, S.-K., Park, K.-S., Cai, D.-Q., Qi, X.-F. CRISPR/Cas9-mediated efficient and precise targeted integration of donor DNA harboring double cleavage sites in Xenopus tropicalis.

Compositional analysis of the glycosaminoglycan family in velvet antlers of Sika deer (Cervus nippon) at different growing stages.

Glycosaminoglycans (GAG) from the velvet antlers of Sika deer (Cervus nippon) at the different growing stages (Fukurozuno, Anshi, and Santajo) of bred and wild deer were isolated and their concentrations and sulfation patterns were analyzed. GAG were digested with chondroitinase ABC, ACI, heparinase-I and -III, and keratanase-II into the corresponding repeating disaccharides of chondroitin sulfate (CS), dermatan sulfate (DS), hyaluronan, heparan sulfate (HS), and keratan sulfate. Cartilaginous tissues contained CS-DS at high concentrations with an almost equal ratio of 4- and 6-sulfates, while 4-sulfate-type CS-DS predominantly occupied ossified tissues, but at low concentrations. High O- and N-sulfation degrees of HS correspond to high ossification. Dynamic quantitative changes in CS-DS and compositional changes in CS-DS and HS were closely associated with the mineralization of deer antlers.

Effects of dietary multi-strain probiotics supplementation in a low fishmeal diet on growth performance, nutrient utilization, proximate composition, immune parameters, and gut microbiota of juvenile olive flounder (Paralichthys olivaceus).

A 12-week feeding trial was conducted to evaluate the effects of multi-strain probiotics (MSP) in a low fish meal (FM) diet on overall performance, gut microbiota, selected non-specific immune responses and antioxidant enzyme activities of olive flounder (Paralichthys olivaceus) juveniles. A total of 225 healthy olive flounders (initial mean body weight, 13.5 ±â€¯0.01 g) were randomly separated into 3 groups of 75 fish, each group having three replicates of 25 fish; first group was fed with a FM-based control diet (Con), 2nd group was fed with a low-FM diet containing a blend of plant and animal protein meals replacing 30% of the FM protein (FM30), and 3rd group was fed with the FM30 diet supplemented with 108-109 CFU kg-1 of the MSP (Pro). With the exception of lipid retention, which was significantly lower in fish fed the FM30 diet compared to the other two treatments, no other statistically significant differences were recorded with respect to any of the other growth and nutrient utilization parameters. Myeloperoxidase and lysozyme activities of fish fed the Pro diet were much higher and significantly different than those of fish fed the FM30 diet. Glutathione peroxidase activity was significantly higher in Pro- than in Con-fed fish, which, in turn, was significantly higher than FM30-fed fish. Expression of immune-related genes including IL-1ß, IL-6, and TNF-α was markedly upregulated in livers of the fish fed Pro diet compared to those fed the Con and FM30 diets. Furthermore, supplementation of MSP in FM30 diet enriched the Lactobacillus abundance in the fish gut as well as predictive gene functions in relation to lipid and carbohydrate metabolisms. These data suggested that the MSP could reduce the potential adverse effects of the low-FM diet and might be used as a healthy immunostimulant for olive flounder.

CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis.

Unmethylated CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) ligand, has been shown to protect against myocardial ischemia/reperfusion injury. However, the potential effects of CpG-ODN on myocardial infarction (MI) induced by persistent ischemia remains unclear. Here, we investigated whether and how CpG-ODN preconditioning protects against MI in mice. C57BL/6 mice were treated with CpG-ODN by i.p. injection 2 hr prior to MI induction, and cardiac function, and histology were analyzed 2 weeks after MI. Both 1826-CpG and KSK-CpG preconditioning significantly improved the left ventricular (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS) when compared with non-CpG controls. Histological analysis further confirmed the cardioprotection of CpG-ODN preconditioning. In vitro studies further demonstrated that CpG-ODN preconditioning increases cardiomyocyte survival under hypoxic/ischemic conditions by enhancing stress tolerance through TLR9-mediated inhibition of the SERCA2/ATP and activation of AMPK pathways. Moreover, CpG-ODN preconditioning significantly increased angiogenesis in the infarcted myocardium compared with non-CpG. However, persistent TLR9 activation mediated by lentiviral infection failed to improve cardiac function after MI. Although CpG-ODN preconditioning increased angiogenesis in vitro, both the persistent stimulation of CpG-ODN and stable overexpression of TLR9 suppressed the tube formation of cardiac microvascular endothelial cells. CpG-ODN preconditioning significantly protects cardiac function against MI by suppressing the energy metabolism of cardiomyocytes and promoting angiogenesis. Our data also indicate that CpG-ODN preconditioning may be useful in MI therapy.

Ottowia konkukae sp. nov., isolated from rotten biji (tofu residue).

A Gram-negative, aerobic, non-motile, non-spore-forming and rod-shaped bacterial strain, designated SK3863T, was isolated from rotten biji (residue remaining after making tofu). This bacterium was characterized in order to determine its taxonomic position by using the polyphasic approach. Strain SK3863T grew well at 25-37 °C on Reasoner's 2A agar plates. On the basis of 16S rRNA gene sequence similarity, strain SK3863T belonged to the family Comamonadaceae and was related to Ottowia beijingensis GCS-AN-3T (96.5 % sequence similarity) and Ottowia pentelensis RB3-7T (96.4 %). Lower sequence similarities (96.2 %) were found to all of the other recognized members of the genus Ottowia. The G+C content of the genomic DNA was 65.8 mol%. The major respiratory lipoquinone was ubiquinone 8 and the major fatty acids were C16 : 1ω6c/C16 : 1ω7c, C16 : 0 and C18 : 1ω7c/C18 : 1ω6c. Strain SK3863T could be differentiated genotypically and phenotypically from the recognized species of the genus Ottowia. The isolate therefore represents a novel species, for which the name Ottowia konkukae sp. nov. is proposed, with the type strain SK3863T (=KCCM 43236T=DSM 105395T).

Phytochemicals and antioxidant capacity of some tropical edible plants.

OBJECTIVE: To find biological functions such as antibacterial and antioxidant activities in several tropical plants and to investigate the possibility of antibiotic substitute agents to prevent and treat diseases caused by pathogenic bacteria. METHODS: Plants such as Poncirus trifoliata fruit (Makrut), Zingiber officinale Rosc (Khing), Areca catechu L. (Mak), Solanum melongena L. I (Makkhuayao), and Solanum melongena L. II (Makhurapro) were extracted by methanol, n-hexane, chloroform, ethyl acetate, butanol and water. The free radical scavenging activities were measured using 2-diphenyl-2-picryl hydrazyl photometric assay. Antibacterial activities with a minimum inhibitory concentration (MIC) were observed by agar diffusion assay against pathogenic strains of Escherichia coli, Burkholderia sp., Haemopilus somnus, Haemopilus parasuis, Clostridium perfringens, and Pantoea agglomerans. RESULTS: Poncirus trifoliata fruit methanol extract showed antibacterial activities against gram-negative and gram-positive pathogens. Additionally, this showed the strongest antibacterial activity against Burkholderia sp. and Haemopilus somnus with MIC 131 µg/mL, respectively. Areca catechu L. water extract showed antibacterial activities against Burkholderia sp., Haemopilus somnus, and Haemopilus parasuis. The MIC value for Haemopilus parasuis was 105 µg/mL in this. Antioxidant activity of Zingiber officinale Rosc n-hexane extract showed 2.23 mg/mL effective concentration 50% (EC50) value was the highest activity among tropical plants extracts. Total polyphenol content in Zingiber officinale Rosc methanol extract was 48.4 µg/mL and flavonoid content was 22.1 µg/mL showed the highest values among tested plants extracts. CONCLUSION: Taken together, these results suggest that tropical plants used in this study may have a potential benefit as an alternative antibiotics agent through their antibacterial and antioxidant activities.

Paenibacillus konkukensis sp. nov., isolated from animal feed.

A Gram-stain-positive, oxidase- and catalase-positive, aerobic, rod-shaped bacterium, designated strain SK-3146T, was isolated from animal feed. Phylogenetic analysis, based on 16S rRNA gene sequence comparisons, revealed that the strain formed a distinct lineage within the genus Paenibacillus that was closely related to Paenibacillusyunnanensis JCM 30953T (98.6 %), Paenibacillusvulneris CCUG 53270T (98.0 %) and Paenibacilluschinjuensis DSM 15045T (96.9 %). Cells were non-motile, endospore-forming and formed milky colonies on NA and R2A agar media. Growth of strain SK-3146T occurred at temperatures of 18-45 °C, at pH 6.0-9.5 and between 0.5-3.0 % NaCl (w/v). The major menaquinone was MK-7, with lesser amounts of MK-6 present. The cell wall peptidoglycan of strain SK-3146T contained meso-diaminopimelic acid. The major fatty acids were anteiso-C15 : 0 and iso-C16 : 0. The major polar lipids were diphosphatidylglycerol and phosphatidylethanolamine. The DNA G+C content was 53.8 mol% and the DNA-DNA hybridization relatedness values between strain SK-3146T and P.yunnanensis JCM 30953T and P.vulneris CCUG 53270T were 26.13±0.8 % and 38.7±0.6 %, respectively. The phenotypic, phylogenetic and chemotaxonomic results indicate that strain SK-3146T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus konkukensis sp. nov. is proposed. The type strain is SK-3146T (=KACC 18876T=LMG 29568T).

Serum IFN-λ3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C.

BACKGROUND: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-λ (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. AIM: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. MATERIALS AND METHODS: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an in-house, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-α, IFN-ß, and IFN-γ induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-α and IFN-ß were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). CONCLUSION: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC.

Comparison of Sofosbuvir Plus Ribavirin Treatment with Pegylated Interferon Plus Ribavirin Treatment for Chronic Hepatitis C Genotype 2.

BACKGROUND: Sofosbuvir plus ribavirin (RBV) therapy showed higher sustained virological response at 12 weeks after treatment (SVR12) than pegylated interferon (peg-IFN) plus RBV; however, liver function, fibrosis, and hepatocellular carcinoma markers have not been assessed so far. SUMMARY: Patients (n = 21) receiving Sofosbuvir plus RBV and those (n = 24) receiving peg-IFN plus RBV were enrolled in this study. Changes in alanine aminotransferase (ALT) and α-fetoprotein (AFP) levels, platelet (PLT) counts, FIB-4, and aspartate aminotransferase-to-platelet ratio index (APRI) in both groups were assessed in patients achieving SVR12. Also, fibrosis regression was assessed using pathophysiological biomarkers, such as hyaluronic acid, bone morphogenetic protein 7 (BMP-7), and connective tissue growth factor (CTGF) in the Sofosbuvir plus RBV group. In both groups, while the reduction in ALT levels was significant that of AFP was not. Compared with the baseline, although serum PLT count at the end of treatment (EOT) was significantly higher in the Sofosbuvir plus RBV group, it was significantly lower in the peg-IFN plus RBV group. Although a significant decline in fibrosis markers such as FIB-4 and APRI was observed between the baseline and at EOT in the Sofosbuvir plus RBV group, no significant change of these markers was observed in the peg-IFN plus RBV group. Moreover, BMP-7 and CTGF were significantly lower at EOT than the baseline in the Sofosbuvir plus RBV group. Key Message: The treatment with Sofosbuvir plus RBV results in not only a higher SVR, but also improves the liver function and the degree of fibrosis.

Wound Healing Effect of Slightly Acidic Electrolyzed Water on Cutaneous Wounds in Hairless Mice via Immune-Redox Modulation.

Acidic electrolyzed water is an innovative sanitizer having a wide-spectrum of applications in food industry, and healthcare industry but little is known on its effect and mechanism in wound healing. The study was conducted to identify the effect and mechanism of slightly acidic electrolyzed water (SAEW) on cutaneous wounds in hairless mice. SAEW (pH: 5-6.5, oxidation reduction potential: 800 mV, chlorine concentration: 25 ppm) was prepared through electrolysis of water and was applied to the wounds of hairless mice three times a day for seven days. Wound size, immune response and oxidative stress were explored and compared to conventional agents such as Betadine and alcohol. We found that SAEW-treated group showed the highest wound reduction percentage (p<0.01). Antioxidant activities such as glutathione peroxidase, catalase and myeloperoxidase activities of SAEW group surpassed the total reactive oxygen species in skin. Nuclear factor erythroid-2-related-factor-2 and aryl hydrocarbon receptor were upregulated in SAEW group. Further, SAEW recruited the production of intracellular calcium and promoted its utilization for faster healing. In line, SAEW treatment decreased pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6, keratinocyte chemoattractant, and tumor necrosis factor-α] in serum. Other hallmarks of wound healing, matrixmetalloproteinases (MMP)1 and MMP9 were also upregulated. Collectively, our study indicates that SAEW is effective in wound healing of hairless mice via immune-redox modulation, and heals better/faster than conventional agents.

Balneotherapeutic effects of high mineral spring water on the atopic dermatitis-like inflammation in hairless mice via immunomodulation and redox balance.

BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing allergic inflammatory skin disease that currently affects millions of children and adults worldwide. Drugs used to treat these inflammatory diseases include anti-histamines, corticosteroids and calcineurin inhibitors but these drugs have their limitations such as adverse effects with their long-term usage. Thus, researcher's interest in several alternative and complementary therapies are continually growing and balneotherapy is one of these approaches. Therefore, we investigate the bathing effect of high concentration mineral spring water (HMW) on redox balance and immune modulation in 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis like inflammation in hairless mice. METHODS: We induced AD-like inflammation by application of DNCB on the dorsal skin of female skh-1 hairless mice. The mice were treated with 100% pure HMW (PHMW) and 10% diluted HMW (DHMW) through bathing once a day for 4 weeks. Tacrolimus ointment (0.1%) was used as positive control (PC) and only DNCB treatment as negative control (NeC) group. The severity of skin lesion inflammation was assessed through clinical scoring and observing scratching behavior. Levels of immunoglobulin E (IgE) and inflammatory cytokines in serum were detected by ELISA and multiplex bead array system, and the levels of oxidative stress-related biomarkers and antioxidant enzyme were also measured. RESULTS: We found that HMW significantly decreased the scratching behavior in PHMW and DHMW groups at the 2nd week and in PHMW group at 4th week compared to NeC group. Likewise, serum IgE level was significantly decreased in DHMW group as compared to NeC group. In line, the level of inflammatory cytokines in serum such as interleukin (IL)-1ß, IL-13 and tumor necrosis factor-α were significantly inhibited in PHMW and DHMW groups compared to NeC group. In parallel, total reactive oxygen species (ROS) of serum level was significantly decreased in PHMW treatment groups compared to NeC group. Consistently, serum malondialdehyde (MDA) level in PHMW group was lower than in NeC group. By contrast, glutathione peroxidase (GPx) activity was significantly enhanced in PHMW than NeC. CONCLUSION: Collectively, our study indicates a balneotherapeutic effect of HMW on DNCB-induced AD like inflammation in hairless mice via immunomodulation and redox balance.