Protective effect of punicalagin against intracerebral haemorrhage via improvement in blood-brain barrier integrity, and suppression of reactive oxygen species and NF-κB-mediated NLRP3 inflammasome

Purpose: To study the effect of punicalagin in a rodent model of intracerebral haemorrhage (ICH). Methods: Collagenase type IV (0.2 U) was used to induce ICH in Sprague-Dawley rats. The animals were randomly assigned to 5 treatment groups (n = 24) as follows: group I (normal control animals), group II (ICH control group administered saline), and groups III, IV and V (ICH + punicalagin at doses of 12.5, 25, 50 mg/kg, respectively). Results: Punicalagin treatment improved brain tissue architecture and blood-brain barrier integrity, and reduced ICH-mediated oxidative stress. It effectively upregulated the expression of Nrf-2/HO-1, and enhanced the activation of NF-kB and NLRP3 inflammasome (p < 0.05). Furthermore, punicalagin significantly down-regulated ICH injury-induced increase in IL-1β and IL-18 (p < 0.05). Conclusion: These results suggest that punicalagin is a potential therapeutic candidate for the management of ICH

Innate Host Response in Primary Human Hepatocytes with Hepatitis C Virus Infection

The interaction between hepatitis C virus (HCV) and innate antiviral defense systems in primary human hepatocytes is not well understood. The objective of this study is to examine how primary human hepatocytes response to HCV infection.An infectious HCV isolate JFH1 was used to infect isolated primary human hepatocytes. HCV RNA or NS5A protein in the cells was detected by real-time PCR or immunofluorescence staining respectively. Apoptosis was examined with flow cytometry. Mechanisms of HCV-induced IFN-β expression and apoptosis were determined.Primary human hepatocytes were susceptible to JFH1 virus and released infectious virus. IFN-α inhibited viral RNA replication in the cells. IFN-β and interferon-stimulated genes were induced in the cells during acute infection. HCV infection induced apoptosis of primary human hepatocytes through the TRAIL-mediated pathway. Silencing RIG-I expression in primary human hepatocytes inhibited IFN-β and TRAIL expression and blocked apoptosis of the cells, which facilitated viral RNA replication in the cells. Moreover, HCV NS34A protein inhibited viral induced IFN-β expression in primary human hepatocytes.Innate host response is intact in HCV-infected primary human hepatocytes. RIG-I plays a key role in the induction of IFN and TRAIL by viruses and apoptosis of primary human hepatocytes via activation of the TRAIL-mediated pathway. HCV NS34A protein appears to be capable of disrupting the innate antiviral host responses in primary human hepatocytes. Our study provides a novel mechanism by which primary human hepatocytes respond to natural HCV infection

Further validation of the Health Scale of Traditional Chinese Medicine (HSTCM)

<p>Abstract</p> <p>Background</p> <p>Few health measurement scales are based on Chinese medicine theory. The Health Scale of Traditional Chinese Medicine (HSTCM) was developed to fill this gap. The aim of this study is to validate the HSTCM.</p> <p>Methods</p> <p>A convenience sample of 630 participants was recruited in 11 settings. All participants were asked to complete the HSTCM and World Health Organization Quality of Life Measure-Abbreviated Version (WHOQOL-BREF).</p> <p>Results</p> <p>Properties of the HSTCM were tested. Intra-class correlation coefficient representing the inter-interviewer reliability was 0.99 (95%CI) for the overall instrument. Spearman-Brown correlation coefficient and Cronbach's coefficient alpha were 0.81 and 0.94 respectively, indicating satisfactory internal reliability and inter-interviewer reliability. Spearman's rho correlation coefficient between the HSTCM and WHOQOL-BREFF was -0.67. A receiver operating characteristic (ROC) curve analysis was performed to test the discriminate validation. Areas under the ROC curve analysis for the HSTCM and its domains ranged 0.71–0.87 and all the lower levels of 95%CI were greater than 0.50.</p> <p>Conclusion</p> <p>The HSTCM was validated as a generic health scale and may complement existing health measurement scales in Chinese medicine health care.</p

Chinese Medicinal Herbs for Childhood Pneumonia: A Systematic Review of Effectiveness and Safety

Objective. To assess the efficacy and safety of Chinese medicinal herbs for Childhood Pneumonia. Methods. We included randomized controlled trials (RCTs). The searched electronic databases included PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, CBM, CNKI, and VIP. All studies included were assessed for quality and risk bias. Review Manager 5.1.6 software was used for data analyses, and the GRADEprofiler software was applied to classify the systematic review results. Results. Fourteen studies were identified (n=1.824). Chinese herbs may increase total effective rate (risk ratio (RR) 1.18; 95% confidence interval (CI), 1.11–1.26) and improve cough (total mean difference (MD), −2.18; 95% CI, (−2.66)–(−1.71)), fever (total MD, −1.85; 95% CI, (−2.29)–(−1.40)), rales (total MD, −1.53; 95% CI, (−1.84)–(−1.23)), and chest films (total MD, −3.10; 95% CI, (−4.11)–(−2.08)) in Childhood Pneumonia. Chinese herbs may shorten the length of hospital stay (total MD, −3.00; 95% CI, (−3.52)–(−2.48)), but no significant difference for adverse effects (RR, 0.39; 95% CI, 0.09–1.72) was identified. Conclusion. Chinese herbs may increase total effective rate and improve symptoms and signs. However, large, properly randomized, placebo-controlled, double-blind studies are required

A Unique Human Immunoglobulin Heavy Chain Variable Domain-Only CD33 CAR for the Treatment of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) remains a challenging pediatric and adult disease. Given the elevated expression of the CD33 antigen on leukemic blasts, therapeutic approaches to AML now feature the approved antibody drug conjugate (Mylotarg, GO) and investigational CART cell approaches incorporating CD33-binding domains derived from humanized scFvs. We designed a functional chimeric antigen receptor utilizing a human targeting sequence, derived from a heavy chain variable domain, termed CAR33VH. Lentiviral-based expression vectors which encoded CAR constructs incorporating the novel binding domain (CAR33VH), or the My96 scFv control binder (My96CAR) in frame with a CD8 hinge and transmembrane domain, a 4-1BB costimulatory domain and a CD3 zeta activation domain, were transduced into primary human CD4+ and CD8+ T cells, and CAR expression was confirmed by flow cytometry. CAR33VH, similar to My96CAR, demonstrated robust and specific cytotoxicity in short-term and long-term co-incubation killing assays against CD33+ AML lines. In overnight cytokine release assays in which CAR T cells were challenged with the CD33+ tumor cells HL-60, MOLM-14 and KG-1a, CAR33VH elicited IFN-gamma, TNF-alpha and IL-2. This was seen with CD33+ cell lines, but not when CAR T were cultured alone. Studies with a CD33− cell line engineered to stably express the full length CD33 variant 1, or the naturally occurring CD33 splice variant 2, revealed that both CAR33VH and My96CAR, target the V domain of CD33, suggesting a similar therapeutic profile. Colony-formation assays utilizing peripheral blood CD34+ hematopoietic stem cells treated with CAR33VH, My96CAR, or with an untransduced T cell control, yielded similar numbers of BFU-E erythroid and CFU-GM myeloid colonies, suggesting a lack of CAR-related overt toxicity. In an in vivo AML model, NSG mice engrafted with MOLM-14 cells stably expressing firefly luciferase, both CAR33VH and CARMy96 efficiently eliminated tumors. In conclusion, we demonstrate for the first time the feasibility and efficacy of employing human variable domain-only binder derived from a phage display library in an anti-AML CAR design. CAR33VH, comprised of a human heavy-chain variable fragment-only antigen binding domain, was efficient in tumor killing in vitro and in vivo, and showed comparable functionality to the scFv-based My96CAR