ObjectiveTo compare and evaluate the improvement degree of spermatogenic dysfunction mice at different recovery periods after cyclophosphamide modeling. MethodsForty-eight male ICR mice aged 4-5 weeks with the body weight of approximately 18-20 g were randomly divided into three control groups and three model groups, with 8 mice in each group. Each mouse of three model groups was intraperitoneally injected with 60 mg/kg cyclophosphamide continuously from the 1^st to 7^th day of the experiment, while each mouse of three control groups was intraperitoneally injected with the corresponding volume of normal saline. Then these mice were continued to be fed for another 7, 14 and 21 days after cyclophosphamide injection, respectively. A corresponding control group was set for each model group. The mice in each group were sacrificed after blood collection through orbital veins at corresponding time points. Testis, epididymis and seminal vesicle were taken and weighed, and their reproductive organ indexes were calculated. Histopathological changes of testis and epididymis were compared after HE staining.Sperm quality analysis was used to determine sperm-related indexes. Serum reproductive hormone content, testicular oxidative stress level and testicular signature enzyme activity were detected by ELISA and related kits.Results Compared with the control group, on the 7^th, 14^th and 21^st day after cyclophosphamide treatment, the testicular index of mice in the model group decreased significantly (P<0.01). The epididymis index decreased significantly on the 7^th and 14^th day, and the seminal vesicle index decreased obviously on the 7^th and 21^st day (P<0.05). And the histopathological damage of testis and epididymis of the model group gradually alleviated over time. On the 7^th and 14^th day after cyclophosphamide treatment, the sperm count of the model group declined remarkably (P<0.01), the serum testosterone (T) level reduced (P<0.05), the malonaldehyde (MDA) content of testis increased significantly (P<0.01), the content of reduced glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (P<0.05),the lactic dehydrogenase (LDH) activity of testis reduced obviously (P<0.05), the gamma-glutamyl transpeptidase (γ-GT) activity increased significantly (P<0.05), the latter two of which are important testicular signature enzymes. Therein on the 7^th day after cyclophosphamide treatment, the sperm motility decreased significantly (P<0.001), the rate of sperm malformation increased obviously (P<0.05), the serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increased notably (P<0.01). Nevertheless on the 21^st day after cyclophosphamide treatment, the sperm-related indexes, the content of serum reproductive hormone, the level of testicular oxidative stress and the activity of testicular signature enzyme did not change significantly (P＞0.05). ConclusionThe reproductive toxicity in mice was more apparent on the 7^th day after intraperitoneal injection with 60 mg/kg cyclophosphamide for seven days, at which time the more desirable spermatogenic dysfunction model of mice could be established. However, with the prolongation of the recovery period, the indexes of spermatogenic dysfunction in mice gradually recovered and approached the normal level on the 21^st day after cyclophosphamide treatment.

Endophytic fungi are promising producers of bioactive small molecules. Bioinformatic analysis of the genome of an endophytic fungus

The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs. FLZ, a novel squamosamide derivative, has been shown to have neuroprotective effects on experimental Parkinson's disease (PD) models. FLZ is under phase Ⅰ clinical trial now, while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated. Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice, we focused on the gut microbiota to address how FLZ was metabolized and absorbed.

Objective:To investigate the acute and long-term toxicity of GJ-4 extracted from Gardenia jasminoides J.Ellis, and to provide safety basis for its development as a new drug for the treatment of dementia. Methods:In the acute toxicity experiment, 30 ICR mice were randomly divided into control group, gardenia extract 2.5 g/kg group and gardenia extract 5.0 g/kg group, 10 mice in each group. The mice in the 2.5 g/kg and 5.0 g/kg gardenia extract groups were administrated with GJ-4 suspension. The control group was given 0.5% sodium carboxymethyl cellulose (CMC-Na) by gavage. The mice were given continuous gavage for 7 days. The mortality, body weight and general condition of mice were recorded. The levels of ALT, ALP, BUN and creatinine (CRE) in serum were measured by automatic biochemical detector. In the long-term toxicity experiment, 75 ICR mice were divided into control group and gardenia extract 100, 250, 500, 1 000 mg/kg group according to the random number table method, 15 mice in each group. The GJ-4 suspension of Gardenia extract 100, 250, 500 and 1 000 mg/kg were administrated to the stomach respectively in the gardenia extract 100, 250, 500 and 1 000 mg/kg groups, and 0.5% CMC-Na of the same volume was administrated to the stomach in the control group once a day for 30 days. The mortality, weight and mental state of mice were recorded. The organ index and the levels of ALT, ALP and BUN in serum were observed.Results:In the acute toxicity experiment, the mental state and diet of mice in each group were good, and there was no death within 7 days. Compared with the control group, there was no significant differences in body weight, heart index, liver index and kidney index between the two groups ( P>0.05). Compared with the control group, the level of BUN (10.17 ± 0.82 mmol/L vs. 11.25 ± 0.47 mmol/L) in the gardenia extract 2.5 g/kg group significantly decreased ( P<0.05), and the level of ALP (116.0 ± 10.75 U/L vs. 148.0 ± 25.73 U/L) in the gardenia extract 5.0 g/kg group significantly decreased ( P<0.05). In the long-term toxicity experiment, the mice were in good mental state and had good diet, and no death occurred. Compared with the control group, there was no significant differences in body weight, heart index, kidney index, spleen index and serum ALT, ALP and BUN levels between the two groups ( P>0.05). The liver index (4.9 ± 0.56 vs. 4.38 ± 0.49) in the 250 mg/kg gardenia extract group significantly increased ( P<0.01), and the thymus index (0.09 ± 0.02 vs. 0.14 ± 0.04) significantly decreased ( P<0.05). Conclusions:The Gardenia jasminoides extract GJ-4 has no obvious toxicity in acute and long-term toxicity experiment, indicating that GJ-4 is safe.

To establish an animal model of acute-on-chronic liver failure (ACLF) that would replicate the pathological process of ACLF in humans, rats were administered porcine serum (PS) for 11 weeks. Liver fibrosis was determined by pathological and biochemical assessments. The animals then were injected with d-galactosamine (d-gal) and lipopolysaccharide (LPS). The survival times of animals with cirrhosis and ACLF were determined over 48 h. Other animals were killed at 0, 4, 8 and 12 h after administration of d-gal/LPS. Liver injury was assessed by histopathological analysis and biochemical indices, and apoptosis was detected by Western blot and TUNEL analysis. After PS administration for 11 weeks the serum levels of hyaluronic acid and N-procollagen type III peptide increased significantly, and serious fibrosis and cirrhosis was observed at weeks 10 and 11. Cirrhotic rats were injected with d-gal/LPS to induced ACLF; the rate of mortality over 48 h was 80%. ALT and AST levels increased markedly at 4 h, but decreased significantly at 8 and 12 h post-treatment. The total bilirubin, direct bilirubin, and total bile acids levels increased markedly at 8 and 12 h. Clotting times, TNF-and IL-6 levels increased significantly, except for 12 h post-treatment. Apoptosis, inflammation and necrosis were elevated as determined by hematoxylin-eosin staining and TUNEL assays. BCL-2 levels decreased significantly, While BAX levels increased significantly. Cytochromeexpression peaked at 8 h post-d-gal/LPS treatment. In conclusion, an ACLF model induced by PS and d-gal/LPS was established and the underlying mechanisms of ACLF development were explored.

Purpose To investigate the value of T2WI mild-moderate signal and restricted diffusion in the context of liver imaging reporting and data system (LI-RADS) (2014 edition) in the diagnosis of hepatocellular carcinoma (HCC) with cirrhosis caused by hepatitis B virus.Materials and Methods A total of 77 lesions (LI-RADS 3-5,size of 1.1 cm×0.7 cm-12.7 cm×9.1 cm) of 69 HCC patients in Beijing Friendship Hospital from January 2012 to November 2016 were retrospectively analyzed.All these patients underwent MRI scan and multiphase dynamic enhanced scan.The images were analyzed by two radiologists.If a disagreement occurred,liver accelerated volume acquisition and multiphase dynamic enhanced scan were combined to reach a consensus.The contrast noise ratio (CNR) and apparent diffusion coefficient (ADC) of T2WI and diffusion weighted imaging (DWI) sequences were compared,as well as the identification of the two signs.Results There was no statistically significant difference between T2WI mild-moderate signal and restricted diffusion in the identification of lesions (LI-RADS 3-5) (P＞0.05),while the sensitivity with DWI b=0 (61.0％) was significantly lower than DWI b=600 s/mm2 (70.1％) (P＜0.05).The CNR of all DWI sequences (b=0,600 s/mm2) were larger than those of T2WI (P＜0.01).The ADC of small lesions (diameter ＜2 cm) were larger than those of larger lesions (diameter ＞2 cm) [(1.57+0.37)×10-3 mm2/s vs.(1.37+0.51)×10 3 mm2/s,P＜0.05].Conclusion There is no significant difference in sensitivity of lesions between T2WI mild-moderate signal and restricted diffusion.However,due to different CNRs,DWI with b=600 s/mm2 is more obvious for the lesions,and can be first investigated in practice.

Aim To investigate the anti-neuroinflam-matory activities of dehydromiltirone and the underlying mechanisms in LPS-stimulated microglial cell line BV2 cells. Methods BV2 cells were pre-treated with de-hydromiltirone, then stimulated by LPS. The levels of nitric oxide( NO) were measured by Griess assay, and the concentrations of pro-inflammatory cytokines were measured by ELISA assay. Confocal fluorescence mi-croscopy was used to measure the expression of MAC-1, the biomarker of activated BV2 cells. The levels of-inducible nitric oxide synthase ( iNOS ) , cyclooxygen-ase-2 ( COX-2 ) , NF-κB and PI3 K/Akt were deter-mined by Western blot analysis. Results The treat-ment of dehydromiltirone significantly inhibited the pro-duction of NO, TNF-α and IL-6, attenuated the ex-pression of iNOS and COX-2 protein, and dampened the microglial activation in LPS-stimulated BV2 cells. The mechanistic study revealed that dehydromiltirone inhibited the phosphorylation of PI3 K and Akt in LPS-stimulated BV2 cells, and decreased NF-κB activation by suppressing the degradation of IκB. Conclusion dehydromiltirone shows significant anti-neuroinflamma-tory effects through inhibiting PI3 K/Akt phosphoryla-tion and then inhibiting NF-κB signaling pathway.

Danshen is one of the traditional Chinese herbal medicines and nas a long history or being used clinically in the treatment of cardiovascular and cerebrovascular conditions such as coronary heart disease and angina pectoris. Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen. It has been reported to be the major bioactive compound of Danshen and has diverse biological effects. Recent studies demonstrated that tanshinone IIA had neuroprotective effects on experimental ischemic stroke through its antiinflammatory, anti-oxidant, anti-apoptosis effects and its inhibitory effect on excitatory amino acid toxicity. In this review, we summarized all the recent progresses on the protective effect of tanshinone IIA on cerebral ischemic stroke. Hopefully, this article will throw some light on further study and application of tanshinone IIA.

Neurodegenerative disease is characterized by progressive loss of neurons in specific brain regions that results in neuronal dysfunction of the central nervous system. Although the pathological mechanism is not fully established, the activation of glial cells mediated neuroinflammation appears to be involved. Heat shock protein 70 (HSP70) is originally described as intracellular chaperone, which plays an important role in protein quality control in cells. However, recent study showed that up-regulation of HSP70 had anti-inflammatory effects in the brain. HSP70 protected neurons from damage and improved neurological function by decreasing inflammatory response as indicated by inactivation of glial cells and inhibition of pro-inflammatory cytokine release. So it is of great significance to find new compounds targeting at HSP70 as neuroprotective agents to delay the progress of neurodegenerative disease. This review will focus on the role of HSP70 in neuroinflammation and the recent advances in using HSP70 as a target for the treatment of neurodegenerative disease.

Sphingolipids, especially ceramide and S1P, are structural components of biological membranes and bioactive molecules which participate in diverse cellular activities such as cell division, differentiation, gene expression and apoptosis. Emerging evidence demonstrates the role of sphingolipids in hepatocellular death, which contributes to the progression of several liver diseases including ischaemia-reperfusion liver injury, steatohepatitis or hepatocarcinogenesis. Furthermore, some data indicate that the accumulation of some sphingolipids contributes to the hepatic dysfunctions. Hence, understanding of sphingolipid may open up a novel therapeutic avenue to liver diseases. This review focuses on the progress in the sphingolipid metabolic pathway with a focus on hepatic diseases and drugs targeting the sphingolipid pathway.