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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. [ABSTRACT FROM AUTHOR]

Background and Aim: The purpose of this study was to analyze factors associated with the overall survival (OS) of atezolizumab/bevacizumab combination therapy for advanced hepatocellular carcinoma (aHCC). We also assessed the OS of patients with ineffective therapy and those who discontinued treatment owing to adverse events (AEs). Methods: This retrospective multicenter study involved 139 patients with aHCC who received atezolizumab/bevacizumab combination therapy between November 2020 and September 2022. Results: The median duration of treatment was 136.5 days, and the median observation period was 316 days. The overall response rate was 40%, and the disease control rate was 78% according to mRECIST criteria. Grade ≥2 AEs occurred in 63 patients (43%) and led to treatment discontinuation in 16 patients. Multivariate analysis revealed that treatment response and occurrence of grade ≥2 AEs after therapy, as well as low level of albumin‐bilirubin (ALBI) grade and low level of des‐gamma carboxy prothrombin (DCP) before therapy, were extracted as factors that contributed to OS. Log‐rank tests with the Kaplan–Meier method showed significant differences in OS among these factors. The OS of patients who discontinued owing to AEs was significantly shorter than that of other patients. Conclusion: Not only factors before therapy but also treatment response and the appearance of AEs are involved in OS for atezolizumab/bevacizumab combination therapy. Although the development of AEs also contributed to OS, appropriate management of AEs is important to avoid discontinuing treatment with this combination. [ABSTRACT FROM AUTHOR]

Background and Aim: Molecular‐targeted therapies such as sorafenib and lenvatinib have long been used as first‐line treatment for advanced hepatocellular carcinoma (aHCC). However, adverse events or limited therapeutic effects may necessitate the change to another therapeutic option, known as post‐progression therapy. To investigate the significance of post‐progression therapy, we analyzed the outcomes of aHCC patients following first‐line molecular‐targeted therapy in a real‐world study. Methods: This retrospective, multicenter study involved patients with aHCC who received sorafenib or lenvatinib as first‐line therapy between January 2011 and September 2021. Results: In total, 513 patients were analyzed: 309 treated with sorafenib and 204 with lenvatinib. The overall response and disease control rates were 15 and 50%, respectively, in the sorafenib group and 30 and 75%, respectively, in the lenvatinib group (P < 0.001). Kaplan–Meier analysis revealed no significant differences in progression‐free survival and overall survival (OS) between the two treatments. Multivariate analysis revealed that fibrosis‐4 index, disease control rate, post‐progression therapy, and use of an immune checkpoint inhibitor (ICI) were significantly associated with OS. OS was significantly longer in patients who received post‐progression therapy than in those who did not (log‐rank P < 0.001). Most patients who received an ICI as post‐progression therapy had previously received lenvatinib. Among lenvatinib‐treated patients, OS was significantly longer in patients who received an ICI than in patients received another or no post‐progression therapy (P = 0.004). Conclusion: The introduction of newer drugs for post‐progression therapy is expected to prolong survival. ICI‐based regimens appear to be effective after lenvatinib. [ABSTRACT FROM AUTHOR]

A 12‐week feeding trial was designed to assess the probiotic potential of indigenous Bacillus amyloliquefaciens and/or Bacillus subtilis singly or in combination with Bacillus licheniformis in an extruded feed for olive flounder (Paralichthys olivaceus) juveniles. A high fish meal (FM) diet (control) and a low‐FM diet containing an alternative protein blend (30% FM replacement, FM30) were formulated. Three other experimental diets were prepared by inclusion of B. amyloliquefaciens (BA), B. subtilis (BS), or a mixture of B. amyloliquefaciens, B. subtilis, and B. licheniformis (BASL) into FM30 diet, with a final concentration of 106 CFU/g diet. Results indicated that the FM30 diet was well tolerated by flounder, and the overall performance was not affected by dietary treatments. Lysozyme activity and total immunoglobulin level were significantly reduced in flounders when fed with the FM30 diet compared with the BASL and BA diets, respectively. The Bacillus additives neither enriched the relative abundance of the corresponding Bacillus spp. in the relevant gut microbiota of olive flounder nor modulated the presumptive gene functions of the gut microbiome. Despite the absence of growth‐promoting effect, the tested probiotics could still be economically viable for use as immunostimulants in commercial flounder diets with partial FM replacement. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study examined the effects of road transportation on metabolic and immunological responses in dairy heifers. Twenty Holstein heifers in early pregnancy were divided into non-transported (NT; n = 7) and transported (T; n = 13) groups. Blood was collected before transportation (BT), immediately after transportation for 100 km (T1) and 200 km (T2), and 24 h after transportation (AT). The T heifers had higher ( P < 0.05) blood cortisol and non-esterified fatty acid concentrations after T1 and T2 than did NT heifers. By contrast, the T heifers had lower ( P < 0.05) serum triglyceride concentrations after T1 and T2 than had the NT heifers. The serum cortisol and triglyceride concentrations returned (P > 0.05) to the BT concentrations at 24 h AT in the T heifers. The granulocyte-to-lymphocyte ratio and the percentage of monocytes were higher ( P < 0.05) after T2 in the T heifers than in the NT heifers, suggesting that transportation stress increased the numbers of innate immune cells. T heifers had higher ( P < 0.01) plasma haptoglobin concentrations than NT heifers 24 h AT. In conclusion, transportation increased cortisol secretion and was correlated with increased metabolic responses and up-regulation of peripheral innate immune cells in dairy heifers. [ABSTRACT FROM AUTHOR]

We describe a case of serum amyloid A ( SAA) and C-reactive protein ( CRP) positive nodule detected by immunohistochemical analysis in a 37-year-old woman with alcohol-related cirrhosis. Imaging studies at first admission pointed to hepatocellular carcinoma ( HCC), a dysplastic nodule, an inflammatory pseudotumor or focal nodular hyperplasia ( FNH). Ultrasonography-guided biopsy in Segment 2 showed minimal atypical changes, except for a slight increase in cell density and micronodular cirrhosis in the non-nodular portion. gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging carried out after a year and a half revealed hypervascularity in the arterial phase and isointensity in the hepatobiliary phase. Three years thereafter, however, the imaging displayed a change from isointensity to a defect in the hepatobiliary phase, and the nodule demonstrated minimal histological atypia. Immunohistochemical staining of the nodule was positive for SAA, CRP, liver fatty acid-binding protein and glutamine synthetase, but negative for β-catenin, heat shock protein 70 and Glypican 3. Organic anion transporter ( OATP)8 staining was weaker in the nodule than in the non-nodular portion of the alcohol-related micronodular cirrhosis. The nodule was diagnosed as an SAA and CRP positive nodule, and HCC was ruled out. Despite the change from isointensity to a defect in the hepatobiliary phase, no evidence of HCC was found in the biopsy specimen. The change may be explained more by the weak OATP8 staining compared with that of alcohol-related liver cirrhosis than by malignant transformation into HCC. [ABSTRACT FROM AUTHOR]

Activation-induced cytidine deaminase (AID) contributes to inflammation-associated carcinogenesis through its mutagenic activity. In our study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells that accumulate stepwise genetic alterations. For this purpose, hepatic progenitor cells enriched from the fetal liver of AID transgenic (Tg) mice were transplanted into recipient 'toxin-receptor mediated conditional cell knockout' (TRECK) mice, which have enhanced liver regeneration activity under the condition of diphtheria toxin treatment. Whole exome sequencing was used to determine the landscape of the accumulated genetic alterations in the transplanted progenitor cells during tumorigenesis. Liver tumors developed in 7 of 11 (63.6%) recipient TRECK mice receiving enriched hepatic progenitor cells from AID Tg mice, while no tumorigenesis was observed in TRECK mice receiving hepatic progenitor cells of wild-type mice. Histologic examination revealed that the tumors showed characteristics of hepatocellular carcinoma and partial features of cholangiocarcinoma with expression of the AID transgene. Whole exome sequencing revealed that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Microarray analyses revealed that the majority of the mutations (>80%) were present in actively transcribed genes in the liver-lineage cells. These findings provided the evidence suggesting that accumulation of genetic alterations in fetal hepatic progenitor cells progressed to liver cancers, and the selection of mutagenesis depends on active transcription in the liver-lineage cells. [ABSTRACT FROM AUTHOR]

Aim: Toll-like receptor 4 (TLR-4) is the major receptor used for recognition of specific gram negative bacteria by the host immune system. The role of TLR-4 has been revealed in preterm parturition. This study aims to demonstrate the immunohistochemical expression of TLR-4 with regard to histological layers and anatomical regions of the human fetal membranes. Material and Methods: Fetal membranes were obtained from the uterine fundus and low segment. Immunohistochemical staining for TLR-4 and hematoxylin and eosin stain were performed. Results: The chorion expressed significantly higher levels of TLR-4 than the amnion ( P = 0.001). There was no difference in the expression of TLR-4 between the uterine fundus and the uterine low segment ( P = 0.942). There was no significant difference in TLR-4 expression according to the presence of histological chorioamnionitis ( P = 0.444). TLR-4 expression decreased significantly with the progression of gestation ( P = 0.002). Conclusions: The level of expression of TLR-4 did not differ according to anatomic location, but did differ according to the histological layer of the human fetal membranes and gestational age. These results suggest that TLR-4 may be involved in preterm parturition. [ABSTRACT FROM AUTHOR]

To determine the anti-complement activity of natural diterpenes, chromatographic separation of the acetone-soluble fraction from the roots of Clerodendrum bungei (Verbenaceae) led to the isolation of five diterpenoids. An acetone-soluble extract of the roots of C. bungei exhibited significant anti-complement activity on the classical pathway complement system, which was expressed as total hemolytic activity. Five compounds isolated from the roots of C. bungei, namely 12- O- β- d-glucopyranosyl-3,11,16-trihydroxyabieta-8,11,13-triene (1), 3,12- O- β- d-diglucopyranosyl-11,16-dihydroxyabieta-8,11,13-triene (2), ajugaside A (3), uncinatone (4) and 19-hydroxyteuvincenone F (5). Compounds 1, 2, 3, 4 and 5 showed inhibitory activity against complement system with 50% inhibitory concentrations (IC50) values of 24 µ m, 138 µ m, 116 µ m, 87 µ m and 232 µ m. Among the compounds tested, 1 showed the most potent anti-complement activity (IC50, 24 µ m). Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and Purpose: The macrophage-derived chemokine (MDC/CCL22) is a prototypic Th2-type chemokine intimately involved in Th2-skewed allergic diseases, such as atopic dermatitis and asthma. The statins (3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors) have been demonstrated to relieve allergic inflammation. However, the immunological effects and mechanisms of statins against atopic dermatitis remain unknown, at least in vitro. This study aimed to define how different statins affect MDC expression in HaCaT cells, a human keratinocyte cell line.Experimental Approach: To measure the effects of statins on MDC expression in HaCaT cells, we used a cell viability assay, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay and Western blotting analyses.Key Results: Fluvastatin, but not atorvastatin or simvastatin, inhibited MDC expression induced by interferon (IFN)-gamma and NF-kappaB activation. A NF-kappaB inhibitor, but not a STAT1 inhibitor, suppressed MDC expression in HaCaT cells. Further, inhibition of p38 mitogen-activated protein kinases (MAPKs) significantly suppressed IFN-gamma-induced MDC expression and NF-kappaB activation. Interestingly, fluvastatin suppressed IFN-gamma-induced NF-kappaB activation in parallel with p38 MAPK phosphorylation.Conclusions and Implications: These results indicate that fluvastatin inhibited expression of the CC chemokine MDC induced by IFN-gamma in HaCaT cells, by inhibiting NF-kappaB activation via the p38 MAPK pathway. This blockade of a Th2 chemokine by fluvastatin may suppress the infiltration of Th2 cells into skin lesions and lessen the skin inflammation seen in atopic dermatitis, suggesting a potential therapeutic use of fluvastatin for this condition. [ABSTRACT FROM AUTHOR]

Abstract: The present study was to see whether echinomycin-induced apoptosis would be NF-κB-dependent and if so, whether echinomycin would activate or inhibit NF-κB as well as resultant chemokine IL-8 expression. In HT-29 cells echinomycin activated NF-κB in time-dependent manner. EMSA in the presence of antibodies specific for p50 and p65 subunits indicated that echinomycin-induces the translocation of p50–p65 heterodimeric subunits of NF-κB. Levels of IκB were detected at initial echinomycin treatment and thereafter decreased, faintly seen after a 6h treatment. In contrast p-IκB levels were clearly detected throughout 6–24h of echinomycin treatment, albeit initially fainted. To clarify the role of NF-κB on IL-8 expression in echinomycin-mediated apoptosis of HT-29 cells, ELISA plus RT-PCR clearly showed that IL-8 production is inducible by echinomycin treatment. Using a specific inhibitor, IL-8 regulation at echinomycin treatment in HT-29 cells occurred via both caspase-3 and NF-κB-dependent signal pathway. To confirm whether two different pathways (NF-κB and caspase) would be coupled, only NF-κB inhibitor (PDTC) and caspase-3 specific inhibitor (Z-DEVD-FMK) together significantly attenuated echinomycin-initiated apoptosis of HT-29 cells, pretreatment of HT-29 cells with PDTC rarely affected echinomycin-induced caspase-3 activation. So echinomycin-induced apoptosis in HT-29 cells occurs via NF-κB activation independent of caspase-3 activation modulating the resultant-linked key chemokine IL-8 expression and echinomycin-induced apoptosis is NF-κB-dependant and directly related to NF-κB activation, consequently regulating IL-8 expression. [Copyright &y& Elsevier]

Aims Methods Results Conclusion To elucidate the relationship between fatty liver index (FLI) and somatic composition among health checkup recipients (4533 men and 4877 women).Fat (F) index, fat‐free (FF) index, and fat mass to fat‐free mass (F‐FF) ratio was measured by bioimpedance analysis. Skeletal muscle mass (SMM) loss was defined as FF index <18 kg/m2 in men and FF index <15 kg/m2 in women. The impact of FLI on the somatic composition (i.e., F index, FF index, and F‐FF ratio) was retrospectively investigated.The median age in men and women was 54 and 52 years (p < 0.0001). The median body mass index in men and women was 23.4 and 21.1 kg/m2 (p < 0.0001). The prevalence of fatty liver on ultrasonography was 52.5% in men and 22.1% in women. The median FLI in men and women was 25.1 and 6.9 (p < 0.0001). Fatty liver index correlated significantly with F index (r > 0.5 in all analyses). In all analyses, the decreased SMM group had significantly lower FLI than the nondecreased SMM group. In receiver operating characteristic (ROC) curve analysis for the SMM decrease, in both genders, area under the ROCs of FLI were all over 0.80 (optimal cut‐off point: 19.7 in men and 8.4 in women). The FLI correlated significantly with F‐FF ratio (r > 0.5 in all analyses).The FLI can be a good indicator of not only fat mass but also FF mass and body composition balance in health checkup subjects. The FLI may not be just a marker of hepatic steatosis. [ABSTRACT FROM AUTHOR]

The present study evaluated the anticomplement effects of isolated compounds from black coloured rice bran in the classical pathway of the complement system. Using column chromatography, three compounds: oryzafuran, quercetin and protocatechuic acid, were isolated and evaluated for in vitro anticomplement activity. Oryzafuran showed the most potent inhibitory activity against the complement system, with 50% inhibitory concentration (IC50) values of 126.2 µg/mL. This is the first report of anticomplement activity of isolated compounds from black coloured rice bran. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

To examine the neuroprotective effects of black galingale, its protection was tested against glutamate-induced neurotoxicity in primary cortical cultured neurons. It was found that an aqueous extract of this medicinal plant exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. In order to clarify the neuroprotective mechanism(s) of this observed effect, isolation was performed to seek and identify active fractions and components. By such fractionation, bioactive methoxyflavone derivatives were isolated from the methanol extracts from the air-dried rhizomes of black galingale. 5-Hydroxy-3,7,3′,4′-tetramethoxyflavone exhibited significant neuroprotective activities against glutamate-induced toxicity, exhibiting cell viability of about 60-70%, at concentrations ranging from 0.1 μ m to 10 μ m. Therefore, the neuroprotective effect of black galingale might be due to the inhibition of glutamate-induced toxicity by the methoxyflavone derivatives it contains. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The neuroprotective effects of Paulownia tomentosa against glutamate-induced neurotoxicity were studied in primary cultured rat cortical cells. It was found that the aqueous extract of this medicinal plant significantly attenuated glutamate-induced toxicity. In order to clarify the mechanism(s) underlying this neuroprotective effect, the active fractions and components were isolated and identified. Five compounds were isolated as the methanol extracts from air-dried flowers of P. tomentosa. Isoatriplicolide tiglate exhibited significant neuroprotective activity against glutamate-induced toxicity at concentrations ranging from 1 µ m to 10 µ m, and exhibited cell viability of approximately 43-78%. Therefore, the neuroprotective effect of P. tomentosa might be due to the inhibition of glutamate-induced toxicity by the sesquiterpene lactone derivative it contains. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) promotes cell senescence in brain tissue, which contributes to Parkinson's disease. Furthermore, PQ induces heart failure and oxidative damage, but it remains unknown whether and how PQ induces cardiac aging. Here, we demonstrate that PQ induces phenotypes associated with senescence of cardiomyocyte cell lines and results in cardiac aging‐associated phenotypes including cardiac remodeling and dysfunction in vivo. Moreover, PQ inhibits the activation of Forkhead box O3 (FoxO3), an important longevity factor, both in vitro and in vivo. We found that PQ‐induced senescence phenotypes, including proliferation inhibition, apoptosis, senescence‐associated β‐galactosidase activity, and p16INK4a expression, were significantly enhanced by FoxO3 deficiency in cardiomyocytes. Notably, PQ‐induced cardiac remolding, apoptosis, oxidative damage, and p16INK4a expression in hearts were exacerbated by FoxO3 deficiency. In addition, both in vitro deficiency and in vivo deficiency of FoxO3 greatly suppressed the activation of antioxidant enzymes including catalase (CAT) and superoxide dismutase 2 (SOD2) in the presence of PQ, which was accompanied by attenuation in cardiac function. The direct in vivo binding of FoxO3 to the promoters of the Cat and Sod2 genes in the heart was verified by chromatin immunoprecipitation (ChIP). Functionally, overexpression of Cat or Sod2 alleviated the PQ‐induced senescence phenotypes in FoxO3‐deficient cardiomyocyte cell lines. Overexpression of FoxO3 and CAT in hearts greatly suppressed the PQ‐induced heart injury and phenotypes associated with aging. Collectively, these results suggest that FoxO3 protects the heart against an aging‐associated decline in cardiac function in mice exposed to PQ, at least in part by upregulating the expression of antioxidant enzymes and suppressing oxidative stress. [ABSTRACT FROM AUTHOR]