Discovery of Novel 3,11-Bispeptide Ester Arenobufagin Derivatives with Potential in Vivo Antitumor Activity and Reduced Cardiotoxicity.

Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11-bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3-monopeptide ester derivative. The in vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10 mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration-dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11-bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.

Hui Medicine Moxibustion Promotes the Absorption of Lumbar Disc Herniation and the Recovery of Motor Function in Rats through Fas/FasL Signaling Pathway.

Objectives: To study the resorption of the herniated lumbar disc (RHLD) and its mechanism in the SD rats of lumbar intervertebral disc herniation treated with Hui medicine moxibustion (HMM). Methods: Forty SD rats were randomly divided into four groups, normal group, lumbar disc herniation (LDH) group, HMM group, and antagonist (HMM+Met12) group, with 10 rats in each group. The rat model of LDH was prepared with the method of lumbar epidural emplacement of the caudal intervertebral disc. In the HMM group and HMM+Met12 groups, 4 weeks after modeling, HMM therapy was performed in the lumbar spine for 3 months with 1 time per day and 20 min each time, the samples were collected 8 weeks after the treatment. The histological degeneration was observed through HE staining, and the neovascularization of intervertebral disc tissues was detected by the expression of CD34 and vascular endothelial growth factor (VEGF). The apoptosis of nucleus pulpous cells was detected by TUNEL assay, and the activity of caspase-3, -8, and -9 and extracellular matrix enzymes was detected by western blotting. Results: HMM treatment significantly improved the behavioral ability of rats with LDH surgery. The morphological structure was obviously destroyed in the LDH group, but disc structure was significantly repaired in the HMM group, and mild structure alterations were observed in the HMM+Met12 group. Higher levels of CD34 and VEGF were detected in the HMM group indicating that neovascularization is formed. The expression level of FasL was significantly increased in the HMM group. The protein expression levels of cleaved-caspase-3, cleaved-caspase-8, and cleaved-caspase-9 in nucleus pulposus (NP) tissues were also elevated when treated with HMM, and the TUNEL staining showed the same results. The protein expression levels of matrix metalloproteinases- (MMP-) 1, MMP-2, MMP-3, MMP-13, and ADAMTS-4 were markedly promoted in the HMM group. Met12, a small peptide antagonist of FasL, significantly reduced the effects of HMM. Conclusion: HMM can promote the formation of neovascularization of lumbar intervertebral disc, support the apoptosis of NP cells through Fas/FasL signaling, and regulate the degradation of extracellular matrix enzyme, which then accelerates the absorption of lumbar intervertebral disc herniation and the recovery of motor function in rats.

Effect of cornstalk biochar on phytoremediation of Cd-contaminated soil by Beta vulgaris var. cicla L.

Cadmium (Cd) contamination is the most common and extensive heavy metal pollution in the farmland of China. Phytoremediation is considered as a promising measure for Cd-contaminated soil remediation, but the remediation efficiency still needs to be enhanced. Biochar as an effective amendment medium is widely manufactured and studied for the soil remediation of heavy metals. In this study, a greenhouse pot trial was conducted to investigate the effects of cornstalk biochar on Cd accumulation of Beta vulgaris var. cicla L. (Beta vulgaris) in Cd contaminated soil. The Cd availability, speciation and nutrients in soil, biomass and Cd chemical forms in the Beta vulgaris root were studied to explore the mechanism that how the cornstalk biochar promoted Cd accumulation in Beta vulgaris. Biochar amendment reduced the DTPA-extractable Cd concentration and stimulated the growth of root. Compared to the Beta vulgaris without biochar treatment, the results of 5% biochar amendment showed that the root dry weight of Beta vulgaris increased to 267%, Cd accumulation in Beta vulgaris increased to 206% and the Cd concentration in leaves and roots increased by 36% and 52%, respectively. Additionally, after 5% biochar was applied to soil, the total content of organic matter-bound Cd and residual Cd increased by 38%, while the content of Fe-Mn oxides-bound Cd decreased by 40%. Meanwhile, Cd may mainly bind to the root cell wall and the ratio of NaCl-extracted Cd to HAc-extracted Cd increased to 166% with 5% biochar amendment. According to our study, Cd in soil can be removed by Beta vulgaris and phytoremediation efficiency can be improved with biochar amendment. The combination of phytoremediation and biochar amendment is a promising strategy for the Cd-contaminated soil remediation.

Review of antidepressants in clinic and active ingredients of traditional Chinese medicine targeting 5-HT1A receptors.

Serotonin, which also named as 5-hydroxytryptamine (5-HT), is a neurotransmitter, which plays significant roles in a wide range of physiological and pathological processes. Depression is a complex disease that involves numerous factors, increasing evidences have showed that the level of 5-HT was lower in depressed patients and the administration of some selective serotonin re-uptake inhibitors exhibited antidepressant effects. The 5-HT1A receptor is a key protein in the brain serotonin system, modulating the release of 5-HT and other neurotransmitters. Behavioral and molecular biological studies have demonstrated that the differences of 5-HT1A receptor regulation was connected with depression and the responses to antidepressants. In this review, the authors will introduce the structure and function of 5-HT1A receptor and summarize some antidepressants targeting 5-HT1A receptor, including 5-HT1A receptor agonists and antagonists in a clinic, active ingredients of traditional Chinese medicine. And we found the major of drugs by targeting 5-HT1A receptor on the market or in clinical trials mostly have the similar functional groups, such as piperazine, piperidine, and pyrimidine. There are also some literatures found that these functional groups may be the site produce activity. So, we hope that it may provide basis and references for the research of the clinical drugs for depression.

Characterizing the microbiome in petroleum reservoir flooded by different water sources.

Petroleum reservoir is an unusual subsurface biosphere, where indigenous microbes lived and evolved for million years. However, continual water injection changed the situation by introduction of new electron acceptors, donors and exogenous microbes. In this study, 16S-rRNA gene sequencing, comparative metagenomics and genomic bins reconstruction were employed to investigate the microbial community and metabolic potential in three typical water-flooded blocks of the Shen84 oil reservoir in Liaohe oil field, China. The results showed significant difference of microbial community compositions and metabolic characteristics existed between the injected water and the produced water/oil mixtures; however, there was considerable uniformity between the produced samples in different blocks. Microbial communities in the produced fluids were dominated by exogenous facultative microbes such as Pseudomonas and Thauera members from Proteobacteria phylum. Metabolic potentials for O2-dependent hydrocarbon degradation, dissimilarly nitrate reduction, and thiosulfate­sulfur oxidation were much more abundant, whereas genes involved in dissimilatory sulfate reduction, anaerobic hydrocarbon degradation and methanogenesis were less abundant in the oil reservoir. Statistical analysis indicated the water composition had an obvious influence on microbial community composition and metabolic potential. The water-flooding process accompanied with introduction of nitrate or nitrite, and dissolved oxygen promoted the alteration of microbiome in oil reservoir from slow-growing anaerobic indigenous microbes (such as Thermotoga, Clostridia, and Syntrophobacter) to fast-growing opportunists as Beta- and Gama- Proteobacteria. The findings of this study shed light on the microbial ecology change in water flooded petroleum reservoir.

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

Prevalence and risk factors of gallbladder polypoid lesions in Chinese petrochemical employees.

AIM: To investigate the prevalence and risk factors of polypoid lesions of the gallbladder (PLGs) in petrochemical employees in Ningbo, Zhejiang Province, China. METHODS: All active and retired employees aged 20-90 years (n = 11098) of a refinery and chemical plant in eastern China were requested to participate in a health survey. The participants were subjected to interview, physical examination, laboratory assessments and ultrasonography. All the participants were invited to have a physical examination after a face-to-face interview. Fasting blood samples were obtained from the antecubital vein, and the samples were used for the analysis of biochemical values. Abdominal ultrasonography was conducted. RESULTS: A total of 10461 (7331 men and 3130 women) current and former petrochemical employees attended for screening. The overall prevalence of post-cholecystectomy, gallstones and PLGs was 0.9%, 5.2% and 7.4%, respectively. Compared with the increased prevalence of either gallstones or post-cholecystectomy in older persons, PLGs were more common in the middle-aged, peaking in those aged 40-59 years. Excluding the patients with gallstones, gallstones mixed with PLGs, or those who had undergone cholecystectomy, in the remaining 9828 participants, the prevalence of PLGs in men (8.9%) was significantly higher than that in women (5.5%, P < 0.001). The analyzed risk factors with increased OR for the development of PLGs were male gender (OR = 1.799, P < 0.001), age ≥ 30 years (OR = 2.699, P < 0.001) and hepatitis B surface antigen (HBsAg) positivity (OR = 1.374, P = 0.006). CONCLUSION: PLGs are not rare among Chinese petrochemical employees. Male gender, HBsAg positivity, and middle age are risk factors for developing PLGs.

Lead, cadmium, arsenic, mercury and copper levels in Chinese Yunnan Pu'er tea.

The Yunnan region of China produces a distinctive variety of Pu'er tea, which is consequently labeled as a Chinese geographic indication product. In this study, the safety of Chinese Yunnan Pu'er tea with regard to heavy metal content was evaluated in 30 different brands of Pu'er tea, including 150 commercial samples. Metal levels in the Pu'er tea samples followed the order: copper (12-22 µg/g) > lead (0.26-3.2 µg/g) > arsenic (0.035-0.24 µg/g) > cadmium (0.0059-0.085 µg/g) > mercury (<0.010 µg/g). Mercury was not detected in 17 of the brands of Pu'er tea. Metal-to-metal correlation studies showed that there were no significant correlation between metal pairs. Based on current safety standards, the low levels of metals detected in these Pu'er tea samples mean they are safe for human consumption.

[Analysis of rare earth elements in pu'er tea of Yunnan by ICP-AES].

The 150 samples of pu'er tea collected from the main producing area of Yunnan were detected by ICP-AES method, to investigate the current safety status of pu'er tea rare earth elements. The rare earth elements contents were found to be in the range 0.26-4.07 mg x kg(-1) in all detected samples, with the 43.0% samples exceeding the maximum levels of contaminants of 2 mg x kg(-1) set by GB 2762-2005 "Maximum levels of contaminants in foods". There was a significant difference between ripened tea rare earth elements and raw tea's from the same sources, which affected some ripened tea quality at last. There was a significant difference among the rare earth elements contents of the pu'er tea main producing areas, and the condition of pu'er tea quality and safety controlling was not optimistic at individual producing areas.