Two new sesterterpenoids from Atractylodes japonica Koidz. ex Kitam.

Two new sesterterpenoids, atractylodes japonica terpenoid acid I (1) and atractylodes japonica terpenoid aldehyde I (2), were isolated from the rhizomes of Atractylodes japonica Koidz. ex Kitam together with ten known compounds (3-12). Their structures were elucidated on the basis of comprehensive spectroscopic analysis (1D/2D NMR, HRESIMS and IR). In addition, all of these isolated compounds were evaluated for their cytotoxic activities against human gastric cancer cell MGC-803 and human hepatocellular cancer cell HepG-2. Most of them exhibited moderate to weak inhibitory effects with IC50 values in the range of 25.15-88.85 µM except for 9-12.

Phosphorus fertiliser application mitigates the negative effects of microplastic on soil microbes and rice growth.

Soil microplastics (MPs) have attracted widespread attention recently. Most studies have explored how soil MPs affect the soil's physicochemical parameters, matter circulation, and soil microbial community assembly. Similarly, a key concern in agricultural development has been the use of phosphorus (P) fertiliser, which is essential for plant health and development. However, the relationship between MPs and phosphate fertilisers and their effects on the soil environment and plant growth remains elusive. This study assessed the influence of adding low-density polyethylene MPs (1%) with different phosphate fertiliser application rates on microbial communities and rice biomass. Our results showed that MPs changed the structure of soil bacterial and phoD-harbouring microbial communities in the treatment with P fertiliser at the same level and suppressed the interactions of phoD-harbouring microorganisms. In addition, we found that MPs contamination inhibited rice growth; however, the inclusion of P fertiliser in MP-contaminated soils reduced the inhibitory action of MPs on rice growth, probably because the presence with P fertiliser promoted the uptake of NO3--N by rice in MP-contaminated soils. Our results provide further insights into guiding agricultural production, improving agricultural management, and rationally applying phosphate fertilisers in the context of widespread MPs pollution and global P resource constraints.

[Mechanism of Xuebijing Injection in treatment of sepsis-associated ARDS based on network pharmacology and in vitro experiment].

The aim of this study was to investigate the effect and molecular mechanism of Xuebijing Injection in the treatment of sepsis-associated acute respiratory distress syndrome(ARDS) based on network pharmacology and in vitro experiment. The active components of Xuebijing Injection were screened and the targets were predicted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). The targets of sepsis-associated ARDS were searched against GeneCards, DisGeNet, OMIM, and TTD. Weishengxin platform was used to map the targets of the main active components in Xuebijing Injection and the targets of sepsis-associated ARDS, and Venn diagram was established to identify the common targets. Cytoscape 3.9.1 was used to build the "drug-active components-common targets-disease" network. The common targets were imported into STRING for the building of the protein-protein interaction(PPI) network, which was then imported into Cytoscape 3.9.1 for visualization. DAVID 6.8 was used for Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment of the common targets, and then Weishe-ngxin platform was used for visualization of the enrichment results. The top 20 KEGG signaling pathways were selected and imported into Cytoscape 3.9.1 to establish the KEGG network. Finally, molecular docking and in vitro cell experiment were performed to verify the prediction results. A total of 115 active components and 217 targets of Xuebijing Injection and 360 targets of sepsis-associated ARDS were obtained, among which 63 common targets were shared by Xuebijing Injection and the disease. The core targets included interleukin-1 beta(IL-1ß), IL-6, albumin(ALB), serine/threonine-protein kinase(AKT1), and vascular endothelial growth factor A(VEGFA). A total of 453 GO terms were annotated, including 361 terms of biological processes(BP), 33 terms of cellular components(CC), and 59 terms of molecular functions(MF). The terms mainly involved cellular response to lipopolysaccharide, negative regulation of apoptotic process, lipopolysaccharide-mediated signaling pathway, positive regulation of transcription from RNA polyme-rase Ⅱ promoter, response to hypoxia, and inflammatory response. The KEGG enrichment revealed 85 pathways. After diseases and generalized pathways were eliminated, hypoxia-inducible factor-1(HIF-1), tumor necrosis factor(TNF), nuclear factor-kappa B(NF-κB), Toll-like receptor, and NOD-like receptor signaling pathways were screened out. Molecular docking showed that the main active components of Xuebijing Injection had good binding activity with the core targets. The in vitro experiment confirmed that Xuebijing Injection suppressed the HIF-1, TNF, NF-κB, Toll-like receptor, and NOD-like receptor signaling pathways, inhibited cell apoptosis and reactive oxygen species generation, and down-regulated the expression of TNF-α, IL-1ß, and IL-6 in cells. In conclusion, Xuebijing Injection can regulate apoptosis and response to inflammation and oxidative stress by acting on HIF-1, TNF, NF-κB, Toll-like receptor, and NOD-like receptor signaling pathways to treat sepsis-associated ARDS.

Evaluation of physicochemical properties, bacterial community, and product fertility during rice straw composting supplemented with different nitrogen-rich wastes.

This study evaluated the compostability of rice straw as the main feedstock (75 % in dry weight), supplemented with three different nitrogen-rich wastes, namely food waste (FW), dairy manure (DM), and sewage sludge (SS). Organic matter (OM) degradation, maturity and fertility of the end-product, and bacterial community structure during the composting processes were compared. All composting processes generated mature end-product within 51 days. Notably, FW addition was more effective to accelerate rice straw OM degradation and significantly improved end-product fertility with a high yield of Chinese cabbage. The succession of the bacterial community was accelerated with FW supplementation. Genera Geobacillus, Chryseolinea, and Blastocatella were significantly enriched during the composting of rice straw with FW supplementation. Finally, temperature, total nitrogen, moisture, pH, and total carbon were the key factors affecting microorganisms. This study provides a promising alternative method to enhance the disposal of larger amounts of rice straw in a shorter time.

Abietane-Type Diterpenoids From Nepeta bracteata Benth. and Their Anti-Inflammatory Activity.

Terpenes possess a wide range of structural features and pharmaceutical activities and are promising for drug candidates. With the aim to find bioactive terpene molecules, eight new compounds were isolated from the medicinal plant Nepeta bracteata Benth., including seven new abietane-type diterpenoids (1-7), along with a new ursane-type triterpenoid (8). The structures of compounds 1-8 were elucidated through the detailed spectroscopic analyses of their 1D and 2D NMR and MS data, and the absolute configurations of compounds 1-7 were determined by comparing their experimental and calculated ECD spectra. Compound 1 was a novel degraded carbon diterpene with the disappearing of methyl signal at C-19, while compound 7 possessed a new norabietane-type diterpenoid carbon skeleton with the presence of five-membered lactone arising from ring rearrangement. The anti-inflammatory of all obtained isolates were evaluated on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the results of anti-inflammatory activity screening showed that compared with the LPS model group, all compounds were significantly down-regulation the TNF-α inflammatory factor at the specific concentration, except for compound 6.

Microbial communities in crude oil phase and filter-graded aqueous phase from a Daqing oilfield after polymer flooding.

AIMS: The aim was to characterize indigenous micro-organisms in oil reservoirs after polymer flooding (RAPF). METHODS: The microbial communities in the crude oil phase (Oil) and in the filter-graded aqueous phases Aqu0.22 (>0.22 µm) and Aqu0.1 (0.1-0.22 µm) were investigated by 16S rRNA gene high-throughput sequencing. RESULTS: Indigenous micro-organisms related to hydrocarbon degradation prevailed in the three phases of each well. However, obvious differences in bacterial compositions were observed amongst the three phases of the same well and amongst the same phase of different wells. The crude oil and Aqu0.22 shared many dominant bacteria. Aqu0.1 contained a unique bacterial community in each well. Most bacteria in Aqu0.1 were affiliated to culturable genera, suggesting that they may adapt to the oil reservoir environment by reduction of cell size. Contrary to the bacterial genera, archaeal genera were similar in the three phases but varied in relative abundances. The observed microbial differences may be driven by specific environmental factors in each oil well. CONCLUSIONS: The results suggest an application potential of microbial enhanced oil recovery (MEOR) technology in RAPF. The crude oil and Aqu0.1 contain many different functional micro-organisms related to hydrocarbon degradation. Both should not be overlooked when investing and exploring the indigenous micro-organisms for MEOR. SIGNIFICANCE AND IMPACT OF THE STUDY: This work facilitates the understanding of microbial community structures in RAPF and provides information for microbial control in oil fields.

[Mechanism of modified Liangge San in treatment of acute respiratory distress syndrome based on network pharmacology and experimental validation].

A network pharmacology-based strategy combined with molecular docking and in vitro validation was employed to investigate potential targets and molecular mechanisms of modified Liangge San(MLGS) against acute respiratory distress syndrome(ARDS). Active ingredients and corresponding targets of MLGS were screened out on the Traditional Chinese Medicines Systems Pharmacology(TCMSP) database, and the disease targets of ARDS were obtained by integrating GeneCards and DisGeNET database. The two were intersected to obtain the potential targets of MLGS against ARDS. Cytoscape 3.7.2 was used to construct a "Chinese medicine-active ingredient-target network" of MLGS and a "regulatory network of MLGS against ARDS". The protein-protein interaction(PPI) network was created on the STRING database platform, and the Metascape database was used to carry out Gene Ontology(GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. Subsequently, molecular docking and in vitro experiments were performed to further verify the above findings. A total of 211 active ingredients of MLGS and 54 key targets were obtained. The GO enrichment analysis obtained 709 GO entries(P<0.05), including 457 biological processes(BP), 50 cell components(CC), and 98 molecular functions(MF), mainly involved in lipopolysaccharides, response to reactive oxygen species, and apoptosis signal pathways. KEGG pathway enrichment analysis obtained 266 pathways, mainly involved in the cancer signaling pathways, advanced glycation end-products and their receptors(AGE-RAGE) signaling pathways, fluid shear stress, atherosclerosis, proteoglycan pathway in cancer, nuclear and factor kappa B(NF-κB) signaling pathway. Molecular docking showed that the main active ingredients bound steadily with the targets. The experiments proved that MLGS inhibited the generation of reactive oxygen species and the activation of NF-κB signaling pathway, thereby reducing apoptosis. The study shows that MLGS, through its multiple active ingredients including wogonin and luteolin, can treat ARDS by intervening in various signaling pathways such as NF-κB, inhibiting the inflammatory response and oxidative stress, and reducing apoptosis.

[Visual analysis of literature knowledge structure and acupoint matching rules of acupuncture for depression].

OBJECTIVE: To analyze the literature knowledge structure and acupoint matching rules of acupuncture for depression. METHODS: The articles regarding acupuncture for depression published from January 1 of 1984 to October 19 of 2020 were searched in CNKI database. CiteSpace5.7.R2 software was used to import the literature data, and the keyword cluster analysis, emergence analysis and time-zone analysis of articles and acupoints were conducted, and the map of scientific knowledge was draw. RESULTS: A total of 3524 articles were included to the knowledge structure analysis, while 601 articles into the acupoint matching rules analysis. There were 13 keyword clusters of acupuncture for depression, with "post-stroke depression" and "electroacupuncture treatment" as high-frequency keywords, and "electroacupuncture treatment" and "Hamilton depression scale" had high centrality, and "electroacupuncture treatment" had the highest emergence intensity. The keywords such as "electroacupuncture treatment" and "Hamilton depression scale", etc. appeared the earliest, followed by "post-stroke depression", "fluoxetine" and "auricular point therapy", etc. According to traditional Chinese medicine theory, acupoint keywords were divided into four clusters: ①core acupoint, ②replenishing-spleen and dispelling phlegm, dispersing-liver and relieving depression, reinforcing qi and nourishing blood, ③back-shu points, five-zhi points, ④inducing-resuscitation and opening-closes. CONCLUSION: The main knowledge structure of acupuncture for depression includes five parts: treatment method, depression type, TCM-related diseases, literature type and curative effect index. Clinical acupoint matching should adhere to the principle of "focusing the disease before syndrome" and "combination of disease and syndrome", and treatment should be modified for the syndromes of phlegm stagnation blocking, liver-stagnation and qi-stagnation, and deficiency of both qi and blood.

[Effect of acupuncture on pain-emotion related brain regions in patients with cervical spondylosis of cervical type: a fMRI study].

OBJECTIVE: To observe the changes of functional connectivity of brain pain-emotion regulation region in patients with cervical spondylosis of cervical type by functional magnetic resonance imaging (fMRI). METHODS: Thirty-two subjects were selected. Of them, 16 patients with cervical spondylosis of cervical type were divided into an observation group and 16 healthy subjects into a control group. The patients in the observation group were treated with acupuncture at Tianzhu (BL 10), Jingbailao (EX-HN 15), Jianzhongshu (SI 15) and ashi points for 30 min. The rest-state fMRI data was collected before and after acupuncture in the observation group. The subjects in the control group received no treatment, and the rest-state fMRI data was collected once. The visual analogue scale (VAS) score before and after treatment and the pain catastrophizing scale (PCS) score before treatment in the observation group were recorded. The resting-state brain functional imaging characteristics between the observation group and control group before treatment, between the observation group before and after treatment, were compared. Based on the brain functional connectivity of region of interest (ROI) the changes of functional connectivity in insula and ventral tegmental area (VTA) in emotional regulation brain region were observed, and the correlation between functional connectivity changes and VAS、PCS scores in patients of the observation group was analyzed. RESULTS: In the observation group, the VAS score was (1.94±1.12) after the treatment, which was lower than (5.62±1.20) before treatment (P<0.05). The PCS score before treatment was (19.18±8.42) in the observation group. Compared with the control group, the areas with increased functional connectivity with insula in the observation group before acupuncture included bilateral dorsolateral prefrontal lobe and right middle cingulate gyrus, and the areas with increased functional connectivity with VTA included right central posterior gyrus and right insula. In the observation group, the connectivity coefficient of left insula and left dorsolateral prefrontal lobe (r=0.438, P<0.05), the connectivity coefficient of right insula and right dorsolateral prefrontal lobe (r=0.483, P<0.05) were positively associated with the VAS score. In the observation group, the connectivity coefficient between the right insula and the right middle cingulate gyrus (r=-0.560, P<0.05), the connectivity coefficient between the right VTA and the right insula (r=-0.525, P<0.05) were negatively associated with the PCS score. After acupuncture, the areas with decreased functional connectivity with insula included bilateral posterior central gyrus, right anterior central gyrus, middle cingulate gyrus and left corpus callosum, while the bilateral suboccipital gyrus and left cerebellum showed increased functional connectivity with right insula. The areas with decreased functional connectivity with VTA included bilateral dorsomedial prefrontal cortex, left anterior cingulate gyrus, right middle temporal gyrus and left anterior cingulate gyrus. After acupuncture in the observation group, the functional connectivity of left VTA left dorsomedial prefrontal cortex and left anterior cingulate cortex (r=-0.548, P<0.05), the functional connectivity of right VTA-bilateral dorsomedial prefrontal cortex and left anterior cingulate cortex (r=-0.547, P<0.05) were negatively associated with the PCS score. CONCLUSION: Pain involves the formation and expression of "pain-emotion-cognition". Acupuncture can systematically regulate the brain functional connections between cognitive regions such as dorsal prefrontal lobe and anterior cingulate gyrus and emotional regions such as insula and VTA in patients with cervical spondylosis of cervical type, suggesting that acupuncture has a multi-dimensional and comprehensive regulation effect on pain.

Effects of calcitriol on peripheral endothelial progenitor cells and renal renovation in rats with chronic renal failure.

BACKGROUND: The role of calcitriol (1,25-dihydroxyvitamin D3 or 1,25-(OH)2D3) in physiological processes, such as anti-fibrosis, anti-inflammation, and immunoregulation is known; however, its role in the remodeling of the glomerular capillary endothelium in rats with chronic renal failure (CRF) remains unclear. METHODS: Here, we analyzed the role/number of endothelial progenitor cells (EPCs), renal function, and pathological alterations in rats with CRF, and compared the results before and after supplementation with calcitriol in vivo. RESULTS: Amongst the three experimental groups (sham group, CRF group, and calcitriol-treated group (0.03 µg/kg/d), we observed substantially elevated cell adhesion and vasculogenesis in vivo in the calcitriol-treated group. Additionally, lower levels of serum creatinine (Scr) and blood urea nitrogen (BUN) was recorded in the calcitriol-treated group than the CRF group (p > 0.05). Calcitriol treatment also resulted in an improvement in renal pathological injury. CONCLUSIONS: Thus, calcitriol could ameliorate the damage of glomerular arterial structural and renal tubules vascular network integrity, maybe through regulating the number and function of EPCs in the peripheral blood of CRF rats. Treatment with it may improve outcomes in patients with renal insufficiency or combined cardiac insufficiency. Calcitriol could ameliorate CRF-induced renal pathological injury and renal dysfunction by remodeling of the glomerular capillary endothelium, thus, improving the function of glomerular endothelial cells.

The cerebral mechanism of acupuncture for chronic insomnia with gastrointestinal disorder: protocol for a randomized controlled trial.

BACKGROUND: Many patients with chronic insomnia disorder (CID) have gastrointestinal (GI) symptoms. First-line insomnia medications do not treat GI problems. Acupuncture has a comprehensive regulative action on both CID and GI disorder and is receiving increasing attention. Recent studies indicate that both CID and GI diseases may cause abnormal brain activity. However, the neurological mechanism underlying the effect of acupuncture on such diseases is still unclear. The aim of this study is to explore the pathological mechanisms of CID with GI discomfort, as well as the main response characteristics of acupuncture treatment from multiple perspectives using multimodal magnetic resonance imaging (MRI). METHODS: A total of 60 participants with CID and GI disorders will be randomly divided into two groups (real acupuncture group and sham acupuncture group; ratio of 1:1). Patients will receive 20 sessions (five sessions per week) of real acupuncture treatment or sham acupuncture treatment. The primary outcome is the aggregate score on the Pittsburgh Sleep Quality Index. Secondary outcomes are scores on the Gastrointestinal Symptom Rating Scale, Self-Rating Anxiety Scale, and Self-Rating Depression Scale. Multimodal MRI scans and clinical assessments will be performed both at baseline and post-treatment. Another 30 age-, sex-, and education-matched healthy subjects will be recruited as controls and will receive MRI scans and clinical evaluations. DISCUSSION: This study aims to provide scientific evidence for the mechanism of acupuncture in treating CID with GI disorder using multimodal MRI imaging data on brain structure, function, and metabolism. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800017092 (URL: http://www.chictr.org.cn/showproj.aspx?proj=27173 ). Registered on July 11, 2018.

Changes of Anti-tuberculosis Herbs Formula During Past Three Decades in Contrast to Ancient Ones.

OBJECTIVE: To investigate the evolution of herbal medicine in treating tuberculosis (TB) and encourage anti-TB drug discovery and development. METHODS: In this study, 477 ancient traditional Chinese medicine formulae were collected from the Dictionary of Traditional Chinese Medicine Prescriptions and 172 modern Chinese medicine formulae (from 1986 to 2016) were collected by searching 4 databases: WanFang Data Knowledge Service Platform, China National Knowledge Infrastructure Database (CNKI), China Science and Technology Journal Database (VIP) and Chinese Bio-medical Literature and Retrieval System (SinoMed) in Chinese. We restricted the search to publications in Chinese. Further data analysis was done using the Traditional Chinese Medicine Inheritance Support System version 2 Software. RESULTS: There were 425 herbs in the 477 ancient formulae and 257 herbs in the 172 modern formulae. Half of the top 30 herbs were shared by both modern and ancient prescriptions. They are Radix Ophiopogonis, Astragalus membranaceus, Fritillaria cirrhosa, Dried rehmannia glutinosa, Poria cocos, Angelica sinensis, Prepared rehmannia glutinosa, Platycodon Root, Radix paeoniae alba, Schisandra chinensis, Bighead atractylodes rhizome, Rhizoma anemarrhenae, Cortex lycii radicis and Radix Scutellariae. Only two groups of herbs with a high correlation coefficient were found in both modern and ancient prescriptions, the Dried rehmannia glutinosa with Radix ophiopogonis, and Radix ophiopogonis with Prepared rehmannia glutinosa. There were 9 and 15 core herb combinations in modern and ancient prescriptions, respectively, but no one was found simutaniously in both modern and ancient prescriptions. CONCLUSIONS: Although there were wide variations in the herb groups and herb combinations in the formulae, half of the top 30 herbs were found in both modern and ancient prescriptions. The core herb combinations in modern and ancient prescriptions could help us to improve the priscription for treatment of TB.

Effect of Electroacupuncture versus Sham Electroacupuncture in Patients with Knee Osteoarthritis: A Pilot Randomized Controlled Trial.

OBJECTIVE: To explore the feasibility of evaluating the effectiveness and safety of electroacupuncture versus sham electroacupuncture for patients with knee osteoarthritis (KOA). METHOD: A pilot randomized controlled trial was conducted at a teaching hospital in Beijing. A total of 30 patients with KOA (Kellgren grade II or III) were randomly allocated to an eight-week treatment of either electroacupuncture or sham electroacupuncture. Patients and outcome assessors were blinded to group allocation. The primary outcome was the proportion of responders achieving at least 1.14 seconds decrease in the Timed Up and Go Test (TUG) at week eight compared with baseline. The secondary outcomes included the knee range of motion, the knee extensor and flexor muscle strength, Lequesne index, 9-step stair-climb test (9-SCT), and TUG. RESULTS: Of 30 patients allocated to two groups, 27 (90%) completed the study. The proportion of responders was 53.3% (8 of 15) for electroacupuncture group and 26.7% (4 of 15) for sham electroacupuncture group by the intention-to-treat analysis (P = 0.264). There was no statistically significant difference in TUG between the two groups at eight weeks (P = 0.856). The compliance rate measured according to patients who conformed to the protocol and had received treatments ≥20 times was 93.3% (28 of 30). The dropout rate was 20% (3 of 15). Adverse effects were not reported in the study. CONCLUSION: Our research demonstrated that further evaluation of the effectiveness of electroacupuncture versus sham electroacupuncture was feasible and safe for patients with KOA. Whether or not the electroacupuncture can improve the physical functions of knee joint, expand the knee range of motion, and increase the extensor and flexor muscle strength more significantly than sham electroacupuncture, future studies can be designed with larger sample size, randomization design and less biases. This trial is registered with NCT03366363.

[Effects of Rg_1 on LPS-induced apoptosis and autophagy of lung epithelial cells].

This paper aimed to study the protective effect of ginsenoside Rg_1 on endotoxin(LPS)-induced apoptosis of lung epithelial cells and its mechanism of action. Mouse lung epithelial cells(MLE-12) were first treated with LPS. The autophagy changes and apoptosis and the relationship with concentration and time of LPS were observed. Then,the level of autophagy in MLE-12 was regulated at a specific concentration and action time of LPS,and the changes of apoptosis were observed. Secondly,ginsenoside Rg_1 and autophagy inhibitor 3-MA were added respectively at the same concentration and action time of LPS. The lung epithelial cells were grouped to observe the effect of ginsenoside Rg_1 on LPS-induced apoptosis of lung epithelial cells and its mechanism. In the animal experiment,the mice were grouped and tested by apoptosis protein,lung injury score and HE staining section to verify whether ginsenoside Rg_1 has a protective effect on LPS-induced lung injury. The results showed that apoptosis and autophagy increased as the rise of concentration after treatment with LPS for 12 h. The apoptosis increased gradually,and the autophagy increased first and then decreased over time at the LPS concentration of 25 g·L-1. The apoptosis of LPS group was higher than that of control group,and LPS+3-MA group increased further,while apoptosis decreased significantly in LPS+RAM(rapamycin,autophagy promoter) group. The autophagy increased in LPS group,decreased in LPS+3-MA group and increased in LPS+RAM group. The apoptosis of LPS group was higher than that of control group,and the apoptosis of LPS+Rg_1 group decreased. The apoptosis of LPS+Rg_1+3-MA group increased again. The autophagy of LPS group further increased after administration of ginsenoside Rg_1,but decreased after administration of 3-MA. In the in vivo experiments in mice,the apoptosis of LPS group increased significantly compared with the control group,while LPS + ginsenoside Rg_1 group decreased. Lung injury score and HE staining also conformed to the above trend. LPS can induce the apoptosis of lung epithelial cells in a time-dependent and concentration-dependent manner. The autophagy of lung epithelial cells increases with the rise of LPS concentration. At the specific concentration of LPS,autophagy increases first and then decreases after 12-16 hours. Proper increase of autophagy in lung epithelial cells within a certain period of time can reduce the apoptosis induced by LPS,while inhibition of autophagy can increase apoptosis. Ginsenoside Rg_1 has a protective effect on lung cancer epithelial cell apoptosis induced by autophagy.

Metabolism, pharmacokinetics, and hepatic disposition of xanthones and saponins on Zhimu treatments for exploratively interpreting the discrepancy between the herbal safety and timosaponin A3-induced hepatotoxicity.

Timosaponin A3, a saponin in Zhimu, elicited hepatotoxicity via oxidative stress. However, the clinical medication of Zhimu has been historically regarded as safe, probably associated with the antioxidants it contains. However, the related information on the in vivo levels of timosaponin A3 and antioxidants remained unclear on Zhimu treatments. Therefore, a combination of the in vitro metabolism, including microbiota-mediated and liver-mediated metabolism, and in vivo pharmacokinetics and hepatic disposition, was conducted for three xanthones (neomangiferin, mangiferin, and norathyriol) and three saponins (timosaponin B2, timosaponin B3, and timosaponin A3) on Zhimu treatments. Consequently, following oral administration of Zhimu decoction to rats, those saponins and xanthones were all observed in the plasma with severe liver first-pass effect, where mangiferin was of the maximum exposure. Despite the ignorable content in the herb, timosaponin A3 elicited sizable hepatic exposure as the microbiota-mediated metabolite of saponins in Zhimu. The similar phenomenon also occurred to norathyriol, the microbiota-mediated metabolite of xanthones. However, the major prototypes in Zhimu were of limited hepatic exposure. We deduced the hepatic collection of norathyriol, maximum circulating levels of mangiferin, and timosaponin B2 and mangiferin interaction may directly or indirectly contribute to the whole anti-oxidation of Zhimu, and then resisted the timosaponin A3-induced hepatotoxicity. Thus, our study exploratively interpreted the discrepancy between herbal safety and timosaponin A3-induced hepatotoxicity. However, given the considerable levels and slow eliminated rate of timosaponin A3 in the liver, more attention should be paid to the safety on the continuous clinical medication of Zhimu in the future.

Bysspectin A, an unusual octaketide dimer and the precursor derivatives from the endophytic fungus Byssochlamys spectabilis IMM0002 and their biological activities.

Bysspectin A (1), a polyketide-derived octaketide dimer with a novel carbon skeleton, and two new precursor derivatives, bysspectins B and C (2 and 3), were obtained from an organic extract of the endophytic fungus Byssochlamys spectabilis that had been isolated from a leaf tissue of the traditional Chinese medicinal plant Edgeworthia chrysantha, together with a known octaketide, paecilocin A (4). Their structures were determined by HRMS, 1D and 2D NMR spectroscopic analysis. A plausible route for their biosynthetic pathway is proposed. Compounds 1-3 were tested for their antimicrobial activities. Only compound 3 was weakly active against Escherichia coli and Staphyloccocus aureus with MIC values of 32 and 64 µg/mL, respectively. Further, the inhibitory effects on human carboxylesterases (hCE1, hCE2) of compounds 1 and 4 were evaluated. The results demonstrated that bysspectin A (1) was a novel and highly selective inhibitor against hCE2 with the IC50 value of 2.01 µM. Docking simulation also demonstrated that active compound 1 created interaction with the Ser-288 (the catalytic amino-acid in the catalytic cavity) of hCE2 via hydrogen bonding, revealing its highly selective inhibition toward hCE2.

Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats via inhibiting MMP2/9, TIMP1/2 and the TGF-ß/Smad signaling pathways.

AIM: Chinese medicine CGA formula consists of polysaccharide from Cordyceps sinensis mycelia (CS-PS), gypenosides and amygdalin, which is derived from Fuzheng Huayu (FZHY) capsule for treating liver fibrosis. In this study we attempted to confirm the therapeutic effects of CGA formula in dimethylnitrosamine (DMN)-induced liver fibrosis in rats, and to identify the mechanisms of anti-fibrotic actions. METHODS: Rats were injected with DMN (10 mg·kg(-1)·d(-1), ip) for 3 consecutive days per week over a 4-week period. The rats then were orally administered with CGA formula (CS-PS 60 mg·kg(-1)·d(-1), gypenosides 50 mg·kg(-1)·d(-1) and amygdalin 80 mg·kg(-1)·d(-1)) daily in the next 2 weeks. CS-PS, gypenosides or amygdalin alone were administered as individual component controls, whereas colchicine and FZHY were used as positive controls. Serum biomarkers were measured. Hepatic injury, collagen deposition and stellate cell activation were examined. The MMP activities, expression of TIMP protein and proteins involved in the TGF-ß1/Smad signaling pathways in liver tissues were assayed. RESULTS: In DMN-treated rats, administration of CGA formula significantly decreased serum ALT, AST and total bilirubin and hepatic hydroxyproline levels, increased serum albumin level, and attenuated liver fibrosis as shown by histological examination. Furthermore, these effects were comparable to those caused by administration of FZHY, and superior to those caused by administration of colchicine or the individual components of CGA formula. Moreover, administration of CGA formula significantly decreased the protein levels of α-SMA, TGF-ß1, TGF-ß1 receptor (TßR-I), p-TßR-I, p-TßR-II, p-Smad2, p-Smad3, TIMP1 and TIMP2, as well as MMP2 and MMP9 activities in liver tissues of DMN-treated rats. CONCLUSION: Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats, and this effect was likely associated with the down-regulation of MMP2/9 activities, TIMP1/2 protein expression and the TGF-ß1/Smad signaling pathways in the liver.

[Effects of lipopolysaccharide and dexamethasone on the expression of Kisspeptin/GPR54 in mouse hypothalamus].

OBJECTIVE: To evaluate the effects of lipopolysaccharide (LPS) and dexamethasone on function of hypothalamus-pituitary-testis axis and to explore the possible underlying mechanisms. METHODS: LPS (100 µg/kg), dexamethasone (DEX, 1 mg/kg) and phosphate buffer saline (PBS) were injected subcutaneously into castrated mice (n=5 in each group) for 4 weeks. The expression of Kisspeptin and its receptor GPR54 in hypothalamus were measured by immunohistochemistry, and plasma luteinizing hormone (LH) were measured by chemiluminescence immunoassay. RESULTS: After LPS and DEX were administered for 4 weeks, the LH level in LPS group and DEX group was (1.79±0.74) U/L and (2.19±0.60) U/L, respectively, which were lower than PBS group (4.87±1.25) U/L (all P<0.01). In LPS group, after treatment, the kisspeptin immunohistochemistry index in hypothalamus was 4.2±1.1, which was lower than the control group (10.2±1.6, P<0.05). The GPR54 immunohistochemistry index in hypothalamus was 3.6±0.5, which was lower than PBS group (6.2±1.8, P<0.05). In DEX group, the expressions of kisspeptin and GPR 54 in hypothalamus did not change after treatment. CONCLUSIONS: LPS may downregulate function of hypothalamus-pituitary-testis axis through Kisspeptin/GPR54 system. Dexamethasone could suppress function of gonadal axis as well, while the underlying mechanism is still unclear.

[Effect of electroacupuncture intervention on neurological function, cerebral blood flow and cerebral cytochrome P 450 2 C 11 mRNA expression in rats with focal cerebral ischemia].

OBJECTIVE: To observe the effect of electroacupuncture(EA) intervention on changes of neurological function and expression of cerebral cytochrome P 450 2 C 11 (CYP 2 0 11) mRNA in focal cerebral ischemia (FCI) rats, so as to explore its mechanism underlying improvement of ischemic cerebral vascular disease. METHODS: Wistar rats were randomly divided into normal, model, EA and EA+ 17-ODYA (17-Octadecynoic acid, an inhibitor for the metabolism of arachidonic acid by cytochrome P 450) groups. Focal cerebral ischemia rats were induced by middle cerebral artery occlusion (MCAO) with thread embolus. EA was applied to bilateral "Neiguan"(PC 6 ) and "Quchi" (LI 11) after MCAO. Zea Longa's score and beam walking test (BWT) score of rats were used to evaluate the neurological impairment. Local cerebral blood flow (LCBF) of the pial tissue was moni- tored using Laser-Doppler Flowmetry. The expression of cerebral CYP 2 C 11 mRNA was examined by Real-time Quantitative PCR (qPCR). RESULTS: In comparison with the normal group, BWT score and LCBF of the model group were significantly decreased (P<0.05), and Zea Longa's score and cerebral CYP 2 C 11 mRNA expression level of the model group were significantly increased (P<0.05). While in comparison with the model group, BWT score, LCBF and cerebral CYP2 C 11 mRNA levels were considerably up-regulated and Zea Longa's score was down-regulated in the EA group (P<0.05) rather than in the EA + 17- ODYA group (P<0.05). H.E. stainshowed that the nerve impairment of the ischemic cerebral tissue including the neuronal degeneration, necrosis, apoptosis, etc. was relatively milder in the EA group. CONCLUSION: EA intervention can improve cerebral blood flow and up-regulate cerebral CYP 2 C 11 mRNA expression in FCI rats, which may contribute to its action in improving neu- rological impairment.

Gefitinib-Integrated Regimen versus Chemotherapy Alone in Heavily Pretreated Patients with Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: A Case-Control Study.

BACKGROUND: The study aimed to compare the tolerability and efficacy of gefitinib combined with chemotherapy agents versus chemotherapy alone for the treatment of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma in heavily pretreated patients. METHODS: The study was designed as a matched-pair case-control investigation to minimize intergroup heterogeneity. Patients were stratified into gefitinib plus chemotherapy and chemotherapy alone groups with matching for sex, age, ECOG performance status, progress-free survival (PFS) from previous EGFR tyrosine kinase inhibitor treatment, EGFR mutation types, and tumor metastasis status. RESULTS: Sixty-six patients were selected from our database using the matched-pair method. The median age was 61 years (95% confidence interval, 57-65 years). During a follow-up period of 14.5 months on average, the overall response rates of the gefitinib-integrated and chemotherapy alone groups were 9.1% and 6.5%, respectively (P > .05), whereas the corresponding disease-control rates were 39.4% and 30.3%, respectively (P > .05). No statistically significant differences in PFS (median, 4.2 vs 3.3 months; P = .06) and overall survival (median, 10.4 vs 7.9 months; P = .44) were observed between two groups. The 6-month survival rates of the gefitinib-integrated and chemotherapy alone groups were 21.2% and 12.1%, respectively (P < .05). Side effects were mild, and all treatments were well tolerated. CONCLUSIONS: Our results indicated that gefitinib-integrated therapy offered a trend to better PFS and an improved 6-month survival rate in heavily pretreated patients with metastatic EGFR-mutated lung adenocarcinoma. All treatments were well tolerated. Future prospective studies are warranted to confirm our findings.