The Comprehensive Effects of Carassius auratus Complex Formula against Lipid Accumulation, Hepatocarcinogenesis, and COVID-19 Pathogenesis via Stabilized G-Quadruplex and Reduced Cell Senescence.

Carassius auratus complex formula (CACF) is a traditional Chinese medicine known for its antidiabetic effects. Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide, and there are currently no effective therapies for advanced HCC. This study explores the comprehensive effects and possible mechanisms of CACF on HCC. The results show that CACF reduces the viability of hepatoma cells in vitro, while benefiting normal hepatocytes. In addition, CACF inhibits hepatoma cell growth in a zebrafish xenotransplantation model and decreases lipid accumulation, represses inflammation and cell proliferation markers in fatty acid translocase (CD36) transgenic zebrafish, and inhibits the expression of cell proliferation and ß-catenin downstream targets in telomerase (tert) transgenic zebrafish models. Ingenuity Pathway Analysis reveals that CACF exerts multiple functions, including reduction of inflammation and inhibition of lipid transporter and PPAR signaling pathway. Surprisingly, CACF also regulates the expression of genes and reduces coronavirus infection and pathogenesis in a zebrafish model. CACF treatment is validated to regulate the expression of genes for anti-coronavirus activity. Mechanistically, CACF stabilizes G-quadruplex and reduces cell senescence associated ß-galactosidase activity. In summary, CACF may be a promising therapeutic agent with multiple functions including anticancer, anti-inflammation, and anti-microorganisms in a zebrafish model.

Improving red-color performance, immune response and resistance to Vibrio parahaemolyticus on white shrimp Penaeus vannamei by an engineered astaxanthin yeast.

Astaxanthin (AST), a super antioxidant with coloring and medical properties, renders it a beneficial feed additive for shrimp. This study conducted a white shrimp feeding trial of 3S, 3'S isoform AST, which was derived from metabolic-engineered Kluyveromyces marxianus fermented broth (TB) and its extract (TE) compared to sources from two chemically synthetic ASTs (Carophyll Pink [CP] and Lucantin Pink [LP]), which contain 3S, 3'S, 3R, 3'S (3S, 3'R) and 3R, 3'R isoforms ratio of 1:2:1. The effects on red coloration, immune parameters and resistance to Vibrio infection were evaluated. Four AST sources were incorporated into the diets at concentrations of 0 (control), 100 mg kg-1 (TB100, TE100, CP100, and LP100), and 200 mg kg-1 (TB200, TE200, CP200, and LP200). Results revealed that in week 4, shrimps that received AST-supplemented feeds, especially TB100, TB200, and TE200, significantly increased redness (a*) values. Immune responses including phagocytosis activity, superoxide-anion production, phenoloxidase activity, and immune-related genes were examined on days 0, 1, 2, 4, 7, 14, 21, and 28. Generally, shrimps that received AST-supplemented feeds exhibited higher immune responses on days 7 and 14 than the control feed. Gene expression levels of superoxide dismutase and glutathione peroxidase were significantly upregulated on days 7 and 14 in shrimps that received AST-supplemented feeds, while genes of penaeidins, antilipopolysaccharide factor, and lysozyme were upregulated on days 4, 7, and 14, especially received TB200 and TE200. Furthermore, shrimps that received TB100, TE100, CP100, and LP100 7 days were then challenged with Vibrio parahaemolyticus and the result demonstrated higher survival rates especially TB100 at 168 h than the control feed. In conclusion, incorporating AST into the diets enhanced shrimp red coloration, immune parameters, and resistance against V. parahaemolyticus infection. The K. marxianus-derived AST exhibited higher performance than did chemical AST to be a potential feed additive in shrimp aquaculture.

The Functional DNA Methylation Signatures Relevant to Altered Immune Response of Neonatal T Cells with l-Arginine Supplementation.

l-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4+ T cells. The biological activities of CD4+ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4+ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4+ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4+ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.

Guava (Psidium guajava) leaf extract enhances immunity, growth, and resistance against Vibrio parahaemolyticus in white shrimp Penaeus vannamei.

This study investigated the effects of guava leaf extract (GLE) on immune responses, growth performance, and resistance to Vibrio parahaemolyticus in white shrimp (Penaeus vannamei). To examine the effect of GLE on the immune response of white shrimps, they were treated with various concentrations of GLE on hemocyte (in vitro) and were orally administered (in vivo) feed containing various concentrations of 0, 1, 5, and 10 g kg-1 GLE (control, GLE1, GLE5, and GLE10, respectively) for 28 days. Furthermore, their growth performance was evaluated for 56 days. In a separate experiment, the shrimps were challenged with V. parahaemolyticus injection after 7 days of culture. In vitro experiments indicated that GLE is nontoxic and can activate immune response. In vivo experiments revealed that the GLE5 led to the highest total hemocyte count, phenoloxidase activity, phagocytic activity, and superoxide anion production and the highest upregulation of lipopolysaccharide, ß-1,3-glucan-binding protein, peroxinectin, lysozyme, crustin, penaeidin 2, penaeidin 3, clotting protein, superoxide dismutase, and glutathione peroxidase. Moreover, better growth performance was observed in the GLE groups, with GLE5 exhibiting the highest specific growth rate, weight gain, and feed conversion rate. In addition, GLE5 enhanced resistance to V. parahaemolyticus, with a survival rate of 72.27%. In conclusion, GLE was found to be effective in enhancing nonspecific immune response and growth performance and in reducing V. parahaemolyticus infection in white shrimp.

Effectiveness and healthcare costs of eribulin versus capecitabine among metastatic breast cancer patients in Taiwan.

OBJECTIVE: To compare the real-world effectiveness and costs of eribulin to those of capecitabine in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. METHODS: This study extracted data from the Health and Welfare Database in Taiwan to identify MBC patients, and then eribulin and capecitabine users were matched at a 1:1 ratio by age, residential region, Charlson Comorbidity Index score, and molecular subtype of BC cell. The overall survival (OS) and time-to-treatment discontinuation (TTD) curves were plotted using the Kaplan-Meier method. Healthcare utilization and costs between the two groups were compared. RESULTS: A total of 24,550 MBC patients were identified, and 298 patients were enrolled in each group after matching. The median OS was 11.8 months for eribulin (95%CI: 11.5-13.5 months) and 15.2 months for capecitabine (95%CI: 15.3-17.9 months; HR = 1.7, p < 0.0001). The median TTD was 4.0 months for eribulin and 6.6 months for capecitabine (HR = 1.6; p < 0.0001). No significant difference was found between the two groups in patients with >4 prior chemotherapy agents (OS: HR 1.1, 95%CI 0.8-1.5; TTD: HR 1.2, 95%CI 0.9-1.7). The total healthcare costs per patient during the treatment period were NT$580,523.8 for eribulin versus NT$497,223.8 for capecitabine (p < 0.0001), and total medication costs were NT$438,335.8 and NT$348,438.4 (p < 0.0001), respectively. CONCLUSION: Although eribulin showed an attenuated effect in the real-world setting in Taiwan, it may serve as an alternative for capecitabine in a heavy pretreated population. The total healthcare and medication costs were found to be higher with eribulin treatment.

Resveratrol intake during pregnancy and lactation re-programs adiposity and ameliorates leptin resistance in male progeny induced by maternal high-fat/high sucrose plus postnatal high-fat/high sucrose diets via fat metabolism regulation.

BACKGROUND: Maternal obesity is an emerging problem in the modern world. Growing evidence suggests that intrauterine high-fat (HF) exposure may predispose progeny to subsequent metabolic challenges. Progeny born to mothers who ate an HF diet also tends to eat an HF diet when growing and aggravate metabolic issues. Thus, the generational transmission of obesity is cyclical. Developing a strategy to prevent the occurrence of metabolic syndrome related to prenatal and/or postnatal HF diet is important. In this study, the reprogramming effects of maternal resveratrol treatment for the progeny with maternal HF/postnatal HF diets were investigated. METHODS: Sprague-Dawley dams were fed either a control or a high-fat/high sucrose diet (HFHS) from mating to lactation. After weaning, the progeny was fed chow or an HF diet. Four experimental groups were yielded: CC (maternal/postnatal control diet), HC (maternal HF/postnatal control diet), CH (maternal control/postnatal HFHS diet), and HH (maternal/postnatal HFHS diet). A fifth group (HRH) received a maternal HFHS diet plus maternal resveratrol treatment and a postnatal chow diet to study the effects of maternal resveratrol therapy. RESULTS: Maternal resveratrol treatment lessened the weight and adiposity of progeny that were programmed by combined prenatal and postnatal HFHS diets. Maternal resveratrol therapy ameliorated the decreased abundance of the sirtuin 1 (SIRT1) enzyme in retroperitoneal tissue and the altered leptin/soluble leptin receptor ratio of progeny. Maternal resveratrol therapy also decreased lipogenesis and increased lipolysis for progeny. CONCLUSIONS: Maternal resveratrol intervention can prevent adiposity programmed by maternal and postnatal HFHS diets by inducing lipid metabolic modulation. This study offers a novel reprogramming role for the effect of maternal resveratrol supplements against obesity.

Resveratrol prevents combined prenatal NG-nitro-L-arginine-methyl ester (L-NAME) treatment plus postnatal high-fat diet induced programmed hypertension in adult rat offspring: interplay between nutrient-sensing signals, oxidative stress and gut microbiota.

Oxidative stress, nutrient-sensing signals, high-fat (HF) intake and dysbiosis of gut microbiota are involved in the development of hypertension, a disorder that can originate in early life. We examined whether postnatal HF diet can aggravate maternal NG-nitro-L-arginine-methyl ester (L-NAME) treatment-induced programmed hypertension and whether resveratrol therapy can prevent it. Pregnant Sprague-Dawley rats received L-NAME administration at 60 mg/kg/day subcutaneously during pregnancy alone, or with additional resveratrol (R) 50 mg/L in drinking water during the pregnancy and lactation. The offspring were onto either regular chow or HF diet (D12331) from weaning to 16 weeks of age. Male offspring rats were assigned to five groups (N=8/group): control, L-NAME, HF, L-NAME+HF and L-NAME+HF + R at weaning at 3 weeks of age. Rats were sacrificed at 16 weeks of age. We observed that postnatal HF diet exacerbates maternal L-NAME treatment-induced programmed hypertension in male adult offspring, which resveratrol attenuated. Combined L-LAME and HF diet-induced hypertension is related to increased oxidative stress, inhibiting AMP-activated protein kinase (AMPK)/ peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) pathway and altered gut microbiota compositions. L-NAME+HF caused an increase of the Firmicutes to Bacteroidetes ratio, which resveratrol therapy prevented. Additionally, the abundances of phylum Verrucomicrobia and genus Akkermansia were amplified by resveratrol therapy. Conclusively, our data highlighted the interactions between maternal NO deficiency, HF diet, AMPK/PGC-1α pathway and gut microbiota in which the blood pressure of adult offspring can be modified by resveratrol. Resveratrol might be a useful reprogramming strategy to prevent L-NAME and HF diet-induced hypertension of developmental origin.

Early Supplementation of d-Cysteine or l-Cysteine Prevents Hypertension and Kidney Damage in Spontaneously Hypertensive Rats Exposed to High-Salt Intake.

SCOPE: We investigate whether early supplementation of precursors of hydrogen sulfide (H2 S), d- or l-cysteine can prevent hypertension and kidney damage in spontaneously hypertensive rats (SHR) treated with high-salt. METHODS AND RESULTS: We examine 12-week-old male SHRs from four groups: SHR, high salt SHR (SHRs received 1% NaCl in drinking water for 8 weeks), high salt SHR+d (SHRs received high salt and d-cysteine), and high salt SHR+l (SHRs received high salt and l-cysteine). d- or l-cysteine was supplemented at 8 mmol kg-1 body weight/day between 4 and 6 weeks of ages. High salt intake exacerbate hypertension and kidney damage in SHRs, which is prevented by d- or l-cysteine supplementation. d- or l-Cysteine supplementation reduce the degree of high salt-induced oxidative stress damage. Renal 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and activity are reduced by d- or l-cysteine supplementation. Additionally, d- or l-Cysteine supplementation reduce renal angiotensin I and angiotensin II concentrations, decrease mRNA expression of Ren, and increase protein levels of type 2 angiotensin II receptor. CONCLUSION: Early supplementation of d- or l-cysteine before hypertension becomes evident and may protect against hypertension and kidney damage in adult SHRs exposed to high salt consumption via regulation of oxidative stress, renin-angiotensin system, and H2 S-generating pathways.

Health care utilization of home care patients at an academic medical center in Taiwan.

BACKGROUND: Previous surveys of home care patients in Taiwan have primarily concentrated on patients' status and needs. The aim of this study was to review the actual health care utilization of home care patients during the course of 1 year. METHODS: Home care patients at an academic medical center in Taiwan were selected and their insurance claims data at this hospital in 2001 were analyzed. Analyses included the patients' patterns and diagnoses of visits and admissions, and their drug utilization. For diagnoses made at outpatient departments, the grouping system from the National Hospital Ambulatory Medical Care Survey in the United States was used. The Anatomical Therapeutic Chemical Classification system was applied to drug grouping. RESULTS: The home care agency of the hospital cared for 165 patients (66 women, 99 men) in 2001. In total, these 165 patients received 1,358 home visits, 2,751 outpatient visits, and 108 inpatient admissions. While the most frequent diagnoses for all visits were cerebrovascular disease, hypertension, diabetes mellitus, chronic and unspecified bronchitis, psychoses, and other disorders of the central nervous system, the most frequent diagnoses at discharge from the hospital were urinary tract infection and pneumonia. In all visits, 12,282 items of drugs were prescribed in 2,337 prescriptions. On average, each prescription contained 5.3 +/- 2.8 items of drugs. The most frequently prescribed drugs were antacids, expectorants, laxatives, selective calcium channel blockers, and antithrombotic agents. CONCLUSION: The home care agency of the hospital should pay more attention to provision of comprehensive care and review of drug prescribing.