Integrated bioinformatics analysis and network pharmacology to explore the potential mechanism of Patrinia heterophylla Bunge against acute promyelocytic leukemia.

INTRODUCTION: Current treatment with arsenic trioxide and all-trans retinoic acid has greatly improved the therapeutic efficacy and prognosis of acute promyelocytic leukemia (APL), but may cause numerous adverse effects. Patrinia heterophylla Bunge (PHEB), commonly known as "Mu-Tou-Hui" in China, is effective in treating leukemia. However, no studies have reported the use of PHEB for APL treatment. In this study, we aimed to investigate the potential anticancer mechanism of PHEB against APL. METHODS: Public databases were used to search for bioactive compounds in PHEB, their potential targets, differentially expressed genes associated with APL, and therapeutic targets for APL. The core targets and signaling pathways of PHEB against APL were identified by the protein-protein interaction network, Kaplan-Meier curves, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and compound-target-pathway network analysis. Molecular docking was performed to predict the binding activity between the most active compounds and the key targets. RESULTS: Quercetin and 2 other active components of PHEB may exert anti-APL effects through proteoglycans in cancer, estrogen signaling, and acute myeloid leukemia pathways. We also identified 6 core targets of the bioactive compounds of PHEB, including protein tyrosine phosphatase receptor type C, proto-oncogene tyrosine-protein kinase Src, mitogen-activated protein kinase phosphatase 3 (MAPK3), matrix metalloproteinase-9, vascular endothelial growth factor receptor-2, and myeloperoxidase, most of which were validated to improve the 5-year survival of patients. Molecular docking results showed that the active compound bound well to key targets. CONCLUSION: The results not only predict the active ingredients and potential molecular mechanisms of PHEB against APL, but also help to guide further investigation into the anti-APL application of PHEB.

A comprehensive review of the botany, ethnopharmacology, biochemistry, pharmacology, pharmacokinetics and toxicity of Filifolium sibiricum (L.)Kitam.

Filifolium sibiricum (L.)Kitam (F. sibiricum), a compositae plant, is especially used to inhibit drug-resistant bacteria in folk medicine. Modern pharmacological studies also confirmed a variety of pharmacological properties about sedative activities, antibacterial activity, anti-inflammatory activity, analgesic activities, antitussive and asthma relieving. In this paper, the research progress of F. sibiricum in botany, ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and toxicology was reviewed. Prospects for future investigation and application of this herb were also discussed. Information on F. sibiricum was gathered from various sources, including books on traditional Chinese herbal medicine and scientific databases such as PubMed, Google Scholar, Science Direct, Baidu Scholar, CNKI and other professional websites. The results indicate that ~ 66 chemical compounds were isolated and identified from F. sibiricum. Among them, flavonoids are generally considered to be the main bioactive and characteristic ingredients. F. sibiricum is a traditional Chinese medicine with pharmacological activities such as the immune system, nervous system, respiratory system and cardiovascular and cerebrovascular systems. Most importantly, we should concentrate on developing new drugs related to F. sibiricum, so as to exert greater potential for treatment.

Antibiotic Cross-linked Micelles with Reduced Toxicity for Multidrug-Resistant Bacterial Sepsis Treatment.

One potential approach to address the rising threat of antibiotic resistance is through novel formulations of established drugs. We designed antibiotic cross-linked micelles (ABC-micelles) by cross-linking the Pluronic F127 block copolymers with an antibiotic itself, via a novel one-pot synthesis in aqueous solution. ABC-micelles enhanced antibiotic encapsulation while also reducing systemic toxicity in mice. Using colistin, a hydrophilic, potent ″last-resort" antibiotic, ABC-micelle encapsulation yield was 80%, with good storage stability. ABC-micelles exhibited an improved safety profile, with a maximum tolerated dose of over 100 mg/kg colistin in mice, at least 16 times higher than the free drug. Colistin-induced nephrotoxicity and neurotoxicity were reduced in ABC-micelles by 10-50-fold. Despite reduced toxicity, ABC-micelles preserved bactericidal activity, and the clinically relevant combination of colistin and rifampicin (co-loaded in the micelles) showed a synergistic antimicrobial effect against antibiotic-resistant strains of Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. In a mouse model of sepsis, colistin ABC-micelles showed equivalent efficacy as free colistin but with a substantially higher therapeutic index. Microscopic single-cell imaging of bacteria revealed that ABC-micelles could kill bacteria in a more rapid manner with distinct cell membrane disruption, possibly reflecting a different antimicrobial mechanism from free colistin. This work shows the potential of drug cross-linked micelles as a new class of biomaterials formed from existing antibiotics and represents a new and generalized approach for formulating amine-containing drugs.

Increasing Enteral Protein Intake in Critically Ill Trauma and Surgical Patients.

BACKGROUND: Published guidelines recommend providing at least 2 g/kg/d of protein for critically ill surgical patients. It may be difficult to achieve this level of intake using standard enteral formulas, thus necessitating protein or amino acid supplementation. Herein, we report our approach to enteral protein supplementation and its relationship with urinary nitrogen excretion and serum transthyretin concentrations. METHODS: This was a retrospective cohort study in which we reviewed critically ill trauma and surgical patients treated with supplemental enteral protein according to a protocol aiming to deliver a total of 2 g/kg/d of protein. We collected detailed nutrition data over a 2-week period after admission and obtained additional data through discharge to determine caloric and protein intake as well as complications. We also compared urine nitrogen excretion and transthyretin concentrations between these patients and a control group who did not receive supplemental protein. RESULTS: Fifty-three subjects received early protein supplementation. Formula and protein supplement each provided ≈1.2 g/kg/d of protein by intensive care unit day 4. This resulted in a median total protein intake of 2.2 g/kg/d through day 14. One patient developed acute kidney injury, and 1 patient had 3 episodes of vomiting. By the third week, serum transthyretin concentrations increased to a median of 21 mg/dL compared with 13 mg/dL in subjects not receiving early supplementation. CONCLUSION: It is safe to deliver supplemental protein enterally to critically ill surgical and trauma patients and reach 2 g/kg/d of protein intake during the first week of illness.

Piperlongumine Suppresses Dendritic Cell Maturation by Reducing Production of Reactive Oxygen Species and Has Therapeutic Potential for Rheumatoid Arthritis.

Piperlongumine (PLM) is a natural product from the plant Piper longum that inhibits platelet aggregation, atherosclerosis plaque formation, and tumor cell growth. It has potential value in immunomodulation and the management of autoimmune diseases. In this study, we investigated the role of PLM in regulating the differentiation and maturation of dendritic cells (DCs), a critical regulator of immune tolerance, and evaluated its clinical effects in a rheumatoid arthritis mouse model. We found that PLM treatment reduced LPS-induced murine bone marrow-derived DC maturation, characterized by reduced expression of CD80/86, secretion of MCP-1, IL-12p70, IL-6, TNFα, IFN-γ, and IL-23, and reduced alloproliferation of T cells; however, PLM does not affect cell differentiation. Furthermore, PLM reduced intracellular reactive oxygen species (ROS) production by DCs and inhibited the activation of p38, JNK, NF-κB, and PI3K/Akt signaling pathways. Conversely, PLM increased the expression of GSTP1 and carbonyl reductase 1, two enzymes that counteract ROS effects. ROS inhibition by exogenous N-acetyl-l-cysteine suppressed DC maturation. PLM treatment improved the severity of arthritis and reduced in vivo splenic DC maturation, collagen-specific CD4(+) T cell responses, and ROS production in mice with collagen-induced arthritis. Taken together, these results suggest that PLM inhibits DC maturation by reducing intracellular ROS production and has potential as a therapeutic agent for rheumatoid arthritis.

Impact of partial reimbursement on hepatitis B antiviral utilization and adherence.

AIM: To determine the impact of partial reimbursement for antivirals on antiviral utilization and adherence for chronic hepatitis B patients. METHODS: This was a retrospective cohort study. Two separate cohorts were enrolled, including 14163 and 16288 chronic hepatitis B outpatients, respectively. These patients were referred to Beijing You'an Hospital before and after the new partial reimbursement for antivirals, which was implemented on July 1, 2011. Demographic characteristics (including medical insurance status), routine biochemical, virological and serology laboratory test results, and antiviral agents' prescription information were collected from an electronic database. Patients were also defined as new and existing patients according to treatment history. Antiviral utilization, medication possession ratio and persistence rate were calculated and compared among the patients with different characteristics. A questionnaire survey was conducted among 212 randomly sampled outpatients from the same hospital to confirm the validity of the electronic database. Propensity score matching was used to adjust the distribution of patient's characteristics which may influence the antiviral utilization. χ(2) test or ANOVA was adopted and multivariate logistic regression was used to determine the factors associated with antiviral utilization and good adherence. RESULTS: A total of 13364 outpatients from each cohort were enrolled after the propensity score matching. The antiviral utilization rate for the insured patients increased from 57.4% to 75.9% (P < 0.0001) after the reimbursement, and the rate among those who paid out-of-pocket increased from 54.9% to 56.7% (P = 0.028). Approximately 71% of the patients had a medication possession ratio of more than 80% in each cohort before reimbursement. This increased to 79.2% and 73.1% for insured patients and those who paid out-of-pocket, respectively (P < 0.0001). Insured patients and those who paid out-of-pocket had the similar persistence rates before reimbursement. But after reimbursement, insured patients had higher persistence rates than those who paid out-of-pocket at 6 (86.5% vs 81.5%, P < 0.0001), 9 (79.7% vs 69.9%, P < 0.0001), 12 (73.4% vs 61.9%, P < 0.0001), and 15 mo (66.6% vs 53.1%, P < 0.0001). The reimbursement could significantly improve adherence for the insured patients than those who paid out-of-pocket even after adjusting other covariates, with an interaction odds ratio of 1.422 (95%CI: 1.220-1.657, P < 0.0001). The questionnaire survey supported the validity of the electronic database. CONCLUSION: The reimbursement policy shows a positive impact on antiviral utilization as well as adherence for insured chronic hepatitis B patients.

Immune response in infants after universal high-dose hepatitis B vaccination: A community-based study in Beijing, China.

BACKGROUND: Vaccination of infants beginning at birth is recommended to prevent Hepatitis B virus (HBV) infection in China. Compared to 5 µg/dose vaccine administered in other regions in China, a three-dose HB recombinant yeast vaccine at 10 µg/dose has been administered for infants within 24h after birth, 1 month and 6 months of age in Beijing since 2006. In a community-based retrospective cohort study, factors influencing immunologic vaccine response were evaluated. METHODS: A total of 3670 infants who completed a 3-dose 10 µg recombinant HB vaccine regimen and born to hepatitis B antigen negative mothers were included. The effect on anti-HBs titers of maternal nutrient status, infants' birth condition, growth factors, timeliness of vaccination, dosing interval and the interval until post-vaccination serologic testing (PVST) were evaluated. RESULTS: A total of 3666 infants with no markers of HBV infection were included in analysis. The mean anti-HB titers were 1767.17 mIU/ml. Only 16.9% of the infants completed their PVST within 30-59 days after the final dose of vaccination. Multivariate linear regression analysis showed that delay in PVST (ß=-0.097, p<0.0001) and maternal folic acid supplementation (ß=0.067, p=0.002) were associated with log-transformed anti-HB titers. Also a trend toward significant association was observed between the calcium supplementation of infants and log-transformed anti-HBs titers (ß=0.062, p=0.057). Longer interval between dose 2 and dose 3 was not observed to increase the anti-HB titers after cofactors adjustment. CONCLUSIONS: Our findings illustrate the importance of timing of PVST to avoid unnecessary revaccination. Multi-center large cohort studies should verify the effect and magnitude of folate and calcium supplementation on HB vaccine response.

Bioactive phenolics from the fruits of Livistona chinensis.

This study investigated the antioxidant and cytotoxic activity of the phenolics isolated from the fruits of Livistona chinensis. Four new compounds, 1-{ω-isoferul[6- (4-hydroxybutyl)pentadecanoic acid]}-glycerol (1), E-[6'-(5″-hydroxypentyl)tricosyl]-4-hydroxy-3-methoxycinnamate (2), 2-(3'-hydroxy-5'-methoxyphenyl)-3-hydroxylmethyl-7-methoxy-2,3-dihydrobenzofuran-5- carboxylic acid (3), 7-hydroxy-5,4'-dimethoxy-2-arylbenzofuran (4), together with eleven known phenolics (5-15), were isolated and identified. Among these compounds, 1-4, 5-O-caffeoylshikimic acid (5), caffeic acid (7), and 3-O-caffeoylshikimic acid (8) showed potent antioxidant activity. 1-5, and 8 showed potent antiproliferative activities with IC(50) values among 5-150 µM against HepG2 human liver cancer, HL-60 human myeloid leukemia, K562 human myeloid leukemia, and CNE-1 human nasopharyngeal carcinoma cell lines. On the basis of these findings, it could be proposed that the fruits of L. chinensis may serve as attractive mines of powerful anticancer and antioxidant agents for various purposes.

Antioxidant flavanes from Livistona chinensis.

Three new flavanes and eight known flavonoids were isolated from the fruits of Livistona chinensis. The structure of the new flavanes were established as 2S,3S-3,5,7,3',5'-pentahydroxyflavane (1), 2R,3R-3,5,6,7,8,4'-hexahydroxyflavane (2) and 2R,3R-3,5,6,7,8,3',5'-heptahydroxyflavane (3), respectively, on the basis of chemical and spectroscopic data. The antiproliferative activity against four human tumor cell lines (HL-60, Mata, HepG2 and CNE-1) was evaluated. 1 had significantly antiproliferative effects against HL-60 and CNE-1 with the IC(50) of 0.2 ± 0.01 and 1.0 ± 0.1 µM, respectively, overpowering the reference compound in the assay (cisplatin). Most compounds also exhibited potent antioxidant activity.

Effect of hyperbaric oxygen treatment on mitochondrial free radicals after transient focal cerebral ischemia in rats / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effect of hyperbaric oxygen(HBO)therapy on mitochondrial free radicals after transient focal cerebral ischemia in rats.</p><p><b>METHODS</b>The male SD rats were randomly assigned into two groups, control and HBO groups. All animals were subjected to 90 min intra-luminal middle cerebral artery occlusion (MCAO) with the regional cerebral blood flow monitored in vivo by laser Doppler flowmetry. HBO treatment was performed in a pressure chamber with 100% O(2)(3 ATM 1 h) 3 h after ischemia. Twenty-four hours after ischemia, mitochondria in the ischemic core and penumbra were isolated and the contents of H(2)O(2), O(2)(*-), MDA, SOD, GSH-PX and GSH in mitochondria were measured respectively.</p><p><b>RESULT</b>After cerebral ischemia-reperfusion, contents of mitochondrial H(2)O(2), O(2)(*-), MDA increased, while the SOD, GSH-PX and GSH in the mitochondria decreased significantly both in the ischemic core and the ischemic penumbra, compared with those in the normal controls(P<0.05). In the ischemic penumbra, HBO therapy increased significantly the content of O(2)(*-)(P<0.05), enhanced the activity of SOD, and decreased the level of MDA (P<0.05). However, HBO therapy did not change the level of MDA, though it also increased the content of O(2)(*-) and the activity of SOD in the ischemic core. HBO therapy had no significant effect on the contents of H(2)O(2), GSH-PX and GSH in the ischemic mitochondria.</p><p><b>CONCLUSION</b>HBO therapy initiated early after acute transient cerebral ischemia in rats can increase the mitochondrial free radicals level, but also increase the activity of the anti-radical enzymes. HBO treatment inhibits the lipid peroxidation damage of mitochondria in the ischemic penumbra, but not in the ischemic core, which indicates that the mitochondrial function plays a role in the reaction of the free radical in the ischemic area after HBO therapy.</p>