28-day repeated-dose toxicity of orally administered Jinmao Jiedu granule in Sprague-Dawley rats.

Jinmao Jiedu granule is a Chinese medicine preparation consisting of Actinidia valvata Dunn, Salvia chinensis Benth, Iphigenia indica Kunth, and chicken gizzard. For many years, it has been employed in adjuvant therapy for cancer, especially liver cancer. However, the potential toxicity of the granule has not been reported. The present study aimed to assess the repeated-dose toxicity of orally administered Jinmao Jiedu granules for Sprague-Dawley (SD) rats. SD rats were orally administered Jinmao Jiedu granules at doses of 2.85, 5.70, and 11.40 g/kg in a 28-day subchronic toxicity study. No adverse clinical signs associated with treatment were noted throughout the experiment. There were no treatment-related toxicity alterations in body weight, hematology, clinical biochemistry, urinalysis, necropsy, and histopathology in rats compared with the control group. The No Observed Adverse Effect Level (NOAEL) of the Jinmao Jiedu granule was higher than 11.40 g/kg/day in rats.

LEPR/FOS/JUNB signaling pathway contributes to chronic restraint stress-induced tumor proliferation.

BACKGROUND & AIMS: Psychosocial stress has become an unavoidable part of life, which was reported to promote tumor development. Chronic stress significantly promotes the norepinephrine (NE) secretion and the expression of leptin receptor (LEPR), leading to tumor invasion, metastasis, and proliferation. However, the mechanism of chronic stress-induced tumor proliferation remains unclear. METHODS: To reveal the effect of chronic stress on tumor proliferation, subcutaneous tumor models combined with chronic restraint stress (CRS) were established. Combined with the transcript omics database of liver cancer patients, the target pathways were screened and further verified by in vitro experiments. RESULTS: The results showed that the CRS with subcutaneous tumor transplantation (CRS + tumor) group exhibited significantly larger tumor sizes than the subcutaneous tumor transplantation (tumor) group. Compared with the tumor group, CRS obviously increased the mRNA levels of LEPR, FOS, and JUNB of tumor tissues in the CRS + tumor group. Furthermore, the treatment with norepinephrine (NE) significantly elevated the survival rate of H22 cells and enhanced the expression of LEPR, FOS, and JUNB in vitro. Silencing LEPR significantly reduced the expression of FOS and JUNB, accompanied by a decrease in H22 cell viability. CONCLUSIONS: Our study demonstrated that CRS activates the LEPR-FOS-JUNB signaling pathway by NE, aggravating tumor development. These findings might provide a scientific foundation for investigating the underlying pathological mechanisms of tumors in response to chronic stress.

A magnetic graphene oxide and UiO-66 based homogeneous dual recognition electrochemical aptasensor for accurate and sensitive detection of aflatoxin B1.

Aflatoxin (AFs) contamination is one of the serious food safety issues. Aflatoxin B1 (AFB1) is the most common and toxic aflatoxin, which has been classified as a class 1 carcinogen by the International Agency for Research on Cancer (IARC). It is extremely destructive to liver tissue. Developing a convenient and sensitive detection technique is essential. In this paper, we developed a homogeneous dual recognition strategy based electrochemical aptasensor for accurate and sensitive detection of aflatoxin B1 (AFB1) based on the magnetic graphene oxide (MGO) and UiO-66. The MGO was synthesized for the recognition and magnetic separation of AFB1 from complex samples. UiO-66/ferrocenecarboxylic acid (Fc)/aptamer composites were constructed as both recognition and signal probes. The probes would specifically capture AFB1 enriched by MGO, which enables dual recognition in homogeneous solution, thus further improving the accuracy of AFB1 detection. The electrochemical aptasensor for AFB1 had a linear range from 0.005 to 500 ng mL-1. Additionally, the limit of detection was 1 pg mL-1. It shows a favorable potential for both sensitive and accurate detection of AFB1 in real samples.

HIF1α/miR-146α/TRAF6/NF-κB axis modulates hepatic iron overload-induced inflammation.

Transfusional therapy is used to cure anemia but raises the risk of hepatic iron overload (IO), which triggers oxidative stress damage, inflammation, and failure even fibrosis. microRNAs play a vital role in developing hepatic diseases. This study presented the mechanism by which IO induce hepatic inflammation through microRNAs. In this study, microRNA expression profiling in the liver was observed after IO for 2 weeks, in which the target microRNA will be found. IO activating the miR-146α/TRAF6/NF-κB pathway was validated, and the molecular mechanism of the IO-induced decrease of miR-146α in the liver was studied in vivo and in vitro. The expression of TRAF6/NF-κB (p65)-dependent inflammatory factors increased, whereas the expression of miR-146α decreased during the IO-induced inflammatory response in the liver. The reduced expression of HNF4α caused by HIF1α and miR-34α may decrease the expression of miR-146α. Overexpression of miR-146α alleviated the hepatic inflammatory response caused by IO. Our findings indicate that miR-146α is a key factor in inducing hepatic IO inflammation, which will be another potential target to prevent IO-induced hepatic damage.

Probiotics formulation and cancer nanovaccines show synergistic effect in immunotherapy and prevention of colon cancer.

Probiotics play essential roles in immune modulation. Combining probiotics with cancer vaccines potentially can achieve a synergistic effect. To maximize the efficacy of probiotics, proper probiotics formulation is necessary. Herein, Lactobacillus rhamnosus and Bifidobacterium longum are coated with lipid membrane to achieve the goal of losing less activity and bettering colonization in colon. In the subcutaneous transplanted colon cancer mouse model, probiotics formulation showed potent preventive and therapeutic efficacy, and the efficacy could be further improved by combining with cancer nanovaccines. Probiotics formulation can perform as immune adjuvants to enhance the innate immune response or as in-situ cancer vaccines. In the study of preventing chemical-induced orthotopic colon cancer model, probiotics formulation alone efficiently reduced tumor number in colon and the efficacy is improved by combining with cancer nanovaccines. All in all, the studies demonstrated that probiotics formulation can assist to maximize the efficacy of cancer nanovaccines.

Effects of Chinese herbal diet on hematopoiesis, immunity, and intestines of mice exposed to different doses of radiation.

Radiotherapy causes a series of side effects in patients with malignant tumors. Polygonati Rhizoma, Achyranthis Bidentatae Radix, and Epimedii Folium are all traditional Chinese herbs with varieties of functions such as anti-radiation and immune regulation. In this study, the above three herbs were used as a herbal diet to study their effects on the hematopoietic, immune, and intestinal systems of mice exposed to three doses of radiation. Our study showed that the diet had no radiation-protective effect on the hematopoietic and immune systems. However, at the radiation dose of 4 Gy and 8 Gy, the diet showed an obvious radiation-protective effect on intestinal crypts. At the dose of 8 Gy, we also found that the Chinese herbal diet had an anti-radiation effect on reducing the loss of the inhibitory nNOS+ neurons in the intestine. That provides a new diet for relieving the symptoms of hyperperistalsis and diarrhea in patients after radiotherapy.

Sesamol Attenuates Amyloid Peptide Accumulation and Cognitive Deficits in APP/PS1 Mice: The Mediating Role of the Gut-Brain Axis.

Alzheimer's disease (AD), a neurodegenerative disease, is the leading cause of dementia. Sesamol is a lignan extracted from sesame oil and has been found to exert neuroprotective effects. The present study aimed to investigate the neuroprotective effects of sesamol on APPswe/PS1dE9 transgenic AD mice. The AD mice were fed with a diet supplemented with sesamol (0.075 w/w %). Sesamol treatment improved spatial memory and learning ability in AD mice, improved neuronal damage, and decreased Aß accumulation. Sesamol protected the synaptic ultrastructure and inhibited neuroinflammatory responses in the brain of AD mice. Sesamol also significantly inhibited the overactivated microglia and reduced the overexpression of TNF-α and IL-1ß in the brain of AD mice. Notably, sesamol reshaped gut microbiota by significantly decreasing the relative abundance of Helicobacter hepaticus, Clostridium, and Bacillaceae, enhancing the relative abundance of Rikenellaceae and Bifidobacterium in AD mice. It has been found that sesamol protected the gut barrier integrity and prevented the LPS leakage into the serum. Importantly, sesamol remarkably enhanced the content of SCFAs, including acetate, propionate, isobutyrate, butyrate, and valerate, in AD mice. Correlation analysis indicated that there was a strong correlation between the levels of SCFAs and cognitive functions. These results demonstrated that sesamol attenuated AD-related cognitive dysfunction and neuroinflammatory responses, which could be partly explained by its role in mediating the gut microbe-SCFA-brain axis. Thus, sesamol is a promising nutritional intervention strategy to prevent AD via the microbiota-gut-brain axis.

Immunotherapy and Prevention of Cancer by Nanovaccines Loaded with Whole-Cell Components of Tumor Tissues or Cells.

Tumor tissues/cells are the best sources of antigens to prepare cancer vaccines. However, due to the difficulty of solubilization and delivery of water-insoluble antigens in tumor tissues/cells, including water-insoluble antigens into cancer vaccines and delivering such vaccines efficiently to antigen-presenting cells (APCs) remain challenging. To solve these problems, herein, water-insoluble components of tumor tissues/cells are solubilized by 8 m urea and thus whole components of micrometer-sized tumor cells are reasssembled into nanosized nanovaccines. To induce maximized immunization efficacy, various antigens are loaded both inside and on the surface of nanovaccines. By encapsulating both water-insoluble and water-soluble components of tumor tissues/cells into nanovaccines, the nanovaccines are efficiently phagocytosed by APCs and showed better therapeutic efficacy than the nanovaccine loaded with only water-soluble components in melanoma and breast cancer. Anti-PD-1 antibody and metformin can improve the efficacy of nanovaccines. In addition, the nanovaccines can prevent lung cancer (100%) and melanoma (70%) efficiently in mice. T cell analysis and tumor microenvironment analysis indicate that tumor-specific T cells are induced by nanovaccines and both adaptive and innate immune responses against cancer cells are activated by nanovaccines. Overall, this study demonstrates a universal method to make tumor-cell-based nanovaccines for cancer immunotherapy and prevention.

Pyruvate accumulation may contribute to acceleration-induced impairment of physical and cognitive abilities: an experimental study.

BACKGROUND: Fatigue can be induced after acceleration exposure, however its mechanism is still unclear. The aim of the present study was to examine whether metabolites' changes can decrease cognitive and physical function after acceleration. METHODS: Graybiel scale and Fatigue Self-rating scale were used to assess the seasickness and fatigue degrees of 87 male seafarers respectively after sailing. To test the effect of pyruvate on cognitive and physical functions, five different doses of pyruvate were administrated into rats. Insulin can reduce the accumulation of pyruvate. To observe the insulin effect on pyruvate, cognitive and physical functions after acceleration, insulin administration or treatment of promoting insulin secretion was used. Physical and cognitive functions were assessed using open field test (OFT), morris water maze (MWM) and loaded swimming test (LST) in animals. RESULTS: Physical and cognitive abilities were decreased obviously, and serum pyruvate increased mostly in human and rats after acceleration. Compared with vehicle group, physical and cognitive abilities were significantly decreased after pyruvate administration. Besides, we found a significant decline in adenosine triphosphate (ATP) concentration and pyruvate dehydrogenase (PDH) activity in the hippocampus, prefrontal cortex, liver, and muscle of rats treated with acceleration or pyruvate injection, while insulin administration or treatment of promoting insulin secretion markedly alleviated this decline and the impairment of physical and cognitive abilities, compared with the control group. CONCLUSION: Our results indicate that pyruvate has a negative effect on physical and cognitive abilities after acceleration. Insulin can inhibit pyruvate accumulation and cognitive and physical function after acceleration exposure.

A Highly Efficient Tumor-Targeting Nanoprobe with a Novel Cell Membrane Permeability Mechanism.

Efficient tumor targeting has been a great challenge in the clinic for a very long time. The traditional targeting methods based on enhanced permeability and retention (EPR) effects show only an ≈5% targeting rate. To solve this problem, a new graphene-based tumor cell nuclear targeting fluorescent nanoprobe (GTTN), with a new tumor-targeting mechanism, is developed. GTTN is a graphene-like single-crystalline structure amphiphilic fluorescent probe with a periphery that is functionalized by sulfonic and hydroxyl groups. This probe has the characteristic of specific tumor cell targeting, as it can directly cross the cell membrane and specifically target to the tumor cell nucleus by the changed permeability of the tumor cell membranes in the tumor tissue. This new targeting mechanism is named the cell membrane permeability targeting (CMPT) mechanism, which is very different from the EPR effect. These probes can recognize tumor tissue at a very early stage and track the invasion and metastasis of tumor cells at the single cell level. The tumor-targeting rate is improved from less than 5% to more than 50%. This achievement in efficient and accurate tumor cell targeting will speed up the arrival of a new era of tumor diagnosis and treatment.

Is preterm birth associated with asthma among children from birth to 17 years old? -A study based on 2011-2012 US National Survey of Children's Health.

BACKGROUND: Preterm birth can interrupt lung development in utero and is associated with early life factors, which adversely affects the developing respiratory system. Studies on preterm birth and asthma risk are comparatively sparse and the results are not consistent. METHODS: Multivariate analyses were performed on a cross-sectional data from the National Survey of Children's Health (NSCH) collected in 2011 to 2012. The NSCH was a nationally representative telephone survey sponsored by the Maternal and Child Health Bureau and conducted by the National Center for Health Statistics. A cross-sectional analysis using data from the US on 90,721 children was conducted to examine the relationship between preterm birth and asthma risk. RESULTS: A total of 90,721 children under 17 years were included and 12% of the children were reported as preterm birth. The prevalence of diagnosed asthma was 15%, with a male to female ratio of 1.26:1. Children who were born preterm were 1.64 times (95% confidence interval: 1.45-1.84) more likely to develop asthma compared with those who were born term after controlling for confounders. Similarly, children who were low birth weight were 1.43 times (95% confidence interval: 1.25-1.63) more likely for asthma, and the odds ratio increased to 1.77 for those both preborn and low birth weight. Child's gender, race/ethnicity, age, family structure, family income levels, and household smoking were significantly associated with the odds of reported asthma. CONCLUSIONS: Preterm birth was associated with increased risk of asthma among US children, supporting the notion that preterm birth may play a critical role in asthma development.

The hepatocyte-specific HNF4α/miR-122 pathway contributes to iron overload-mediated hepatic inflammation.

Hepatic iron overload (IO) is a major complication of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, a decrease in microRNA-122 (miR-122) expression was observed in a genetic knockout (Hfe-/-) mouse model of IO. Because hepatocyte-enriched miR-122 is a key regulator of multiple hepatic pathways, including inflammation, it is of interest whether hepatocyte directly contributes to IO-mediated hepatic inflammation. Here, we report that IO induced similar inflammatory responses in human primary hepatocytes and Thp-1-derived macrophages. In the mouse liver, IO resulted in altered expression of not only inflammatory genes but also >230 genes that are known targets of miR-122. In addition, both iron-dextran injection and a 3% carbonyl iron-containing diet led to upregulation of hepatic inflammation, which was associated with a significant reduction in HNF4α expression and its downstream target, miR-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophages are not the only target of IO. Most importantly, hepatocyte-specific overexpression of miR-122 rescued IO-mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major hemoglobinopathy.

Corticosterone increases intracellular Zn(2+) release in hippocampal HT-22 cells.

The previous studies suggested that the hippocampal zinc dyshomeostasis and high glucocorticoid level might hurt hippocampal function. However, the effect of corticosterone (CORT) on hippocampus zinc homeostasis is not fully characterized. In this study, we investigated the intracellular Zn(2+) concentration in hippocampal HT-22 cells after CORT treatment. The cells were incubated with 10µM CORT for 0h-24h, 0µM-50µM CORT for 6h and 2.5µM glucocorticoid receptor antagonist RU486 administered 30min before CORT application. The results showed that 10µM CORT increased the intracellular Zn(2+) level after 6h, which was diminished by 2.5µM RU486. Co-treatment of ZnSO4 and CORT augmented the increase in Zn(2+) level. TPEN, a membrane-permeable chelator for intracellular Zn(2+) greatly attenuated the Zn(2+) increase by CORT, while DTPA, a chelator for extracellular Zn(2+), had no same effects. CCK-8 tests demonstrated that 10µM CORT treatment for 6h had no inhibition effect on cells. However, intracellular reactive oxygen species (ROS) production increased and adenosine triphosphate (ATP) level decreased significantly after same CORT treatment, which was corrected by TPEN and aggravated by ZnSO4. It could be suggested that the increased intracellular Zn(2+) by CORT was greatly dependent on intracellular Zn(2+) release, but not extracellular Zn(2+) intake. Meanwhile, our results demonstrated that increased intracellular Zn(2+) by CORT resulted in ROS generation and decreased ATP level in cells, which have possible roles in the hippocampal function disorder induced by stress.

Effects of different doses and duration of iron supplementation on curing iron deficiency anemia: an experimental study.

Many controversies persist with respect to the dosage and therapeutic duration concerning iron deficiency anemia (IDA) treatment. To identify the most suitable cure, this study evaluated the effect of iron supplementation with different doses and for different time periods in rats with iron deficiency anemia. The rats were randomly divided into five groups [normal control (NC), low- iron diet control (LC), normal doses of iron group (NI), middle dose of iron group (MI), and high dose of iron group (HI)]. Each group was subdivided into two subgroups (2 and 4 weeks). The rats were maintained on low-iron diets and treated with oral iron dextran at different dosages. Finally, we investigated red blood cell parameters, iron absorption and metabolism, oxidative stress, and the antioxidant capacity. Our study indicated that through the administration of normal dose iron by gavage to IDA rats, the levels of the red blood cell parameters can be restored in only 2 weeks. In the HI group, iron absorption and transferrin receptor expressions were markedly reduced after 2 weeks. However, the iron content, ferritin and hepcidin expressions were notably increased, and the changes were more apparent after 4 weeks. With increasing doses of iron supplementation and durations of treatment, the liver malondialdehyde (MDA) content in the LC, MI, and HI groups was markedly increased, whereas the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were obviously reduced. This study demonstrated that the dose of iron treatment for IDA should be controlled in a safe range, and a reasonable duration is also critical for IDA therapeutics.