Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC50 = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE-/- mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.

Relationship between promoting effect of Zuogui Pills on angiogenesis of reproductive organs and mobilization factors GM-CSF, SDF-1, and their receptors of EPCs in early-aging rats / 中国中药杂志

This study aimed to investigate the relationship between the promoting effect of Zuogui Pills on ovarian and vaginal angiogenesis in early-aging rats and mobilization factors granulocyte-macrophage colony-stimulating factor(GM-CSF), stromal cell-derived factor-1(SDF-1), and their receptors of endothelial progenitor cells(EPCs) and explore the mechanism of Zuogui Pills in improving reproductive hypofunction in early-aging rats. Ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) was used to analyze the chemical components of the extract of Zuogui Pills. Forty 14-month-old female early-aging rats with estrous cycle disorder were randomly divided into a blank group, a conjugated estrogen group(conjugated estrogen suspension, 65 μg·kg~(-1)), and low-(11 g·kg~(-1)) and high-dose(33 g·kg~(-1)) Zuogui Pills groups, with 10 rats in each group. In addition, 10 4-month-old female rats were assigned to the youth control group. The rats in the blank group and the youth control group were treated with 20 g·kg~(-1) distilled water by gavage, while those in the groups with drug intervention were treated with corresponding drugs by gavage, once a day for 15 days. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of SDF-1 and GM-CSF in the mobilization of EPCs in serum. Hematoxylin-eosin(HE) staining was used to observe the changes in the number of ovarian follicles at all levels and corpus luteum, the number of vaginal epithelial layers, the number of vaginal folds, and the blood vessels of ovarian and vaginal tissues in the groups with drug intervention. Western blot was used to detect the expression of ER, GM-CSFR, CXCR4, and CXCR7 proteins in ovarian and vaginal tissues. As revealed by the results, the blank group showed decreased number of corpus luteum, gro-wing follicles at all levels, and blood vessels(P<0.05), decreased thickness of vaginal mucosa, the number of epithelial layers, the number of vaginal folds, and the number of vessels in the lamina propria(P<0.05), reduced content of SDF-1 and GM-CSF in the peripheral blood(P<0.05), and down-regulated levels of ER, CXCR4, CXCR7, and GM-CSFR proteins in ovarian and vaginal tissues(P<0.05). The groups with drug intervention showed increased number of growing follicles at all levels, corpus luteum, and blood vessels(P<0.05), decreased number of atresia follicles(P<0.05), increased thickness of vaginal mucosa, the number of epithelial layers, the number of vaginal mucosal folds, and the number of blood vessels in the lamina propria(P<0.05), increased content of SDF-1 and GM-CSF in the peripheral blood(P<0.05), and up-regulated levels of ER, CXCR4, CXCR7, and GM-CSFR proteins in ovarian and vaginal tissues(P<0.05). This experiment suggests that Zuogui Pills may promote ovarian and vaginal angiogenesis and improve the reproductive function of early-aging rats by up-regulating the levels of mobilization factors SDF-1, GM-CSF, and their receptors of EPCs.

The role of Toll-like receptor 4-mediated immune inflammation in inorganic arsenic-induced liver fibrosis in rats / 中华地方病学杂志

Objective:To observe the expression levels of Toll-like receptor 4 (TLR4) signaling pathway-related proteins and their phosphorylation in the liver tissues of rats with inorganic arsenic poisoning, and to explore the role of TLR4-mediated inflammatory signaling pathway in arsenic-induced liver fibrosis injury.Methods:Eighteen healthy weanling SD rats were divided into 3 groups according to their body weight (80 - 100 g) using a random number table (6 rats in each group, half males and half females). The control group was given 10 ml/kg of normal saline by gavage. The sodium arsenite (NaAsO 2) exposure group was given 10 mg/kg of NaAsO 2 by gavage. The TAK-242 intervention group was given 10 mg/kg of NaAsO 2 by gavage, and 0.5 mg/kg of TAK-242 was also administered intraperitoneally to inhibit TLR4 after 12 weeks. All rats were administered 6 days a week for 36 weeks. At the end of the treatment, the liver tissues and serum of the rats in each group were collected. HE and Masson staining were used to observe the pathological and fibrotic changes of the liver tissues. Automatic biochemical analyzer was used to detect serum liver function indexes of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Western blot was used to detect the expression changes of rat liver fibrosis protein α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), Vimentin and TLR4 signaling pathway-related proteins TLR4, nuclear factor κB (NF-κB)-p65 subunit (p65), NF-κB-p50 subunit (p50) and their phosphorylation p-p65 and p-p50 expression levels. Enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion levels of inflammatory related factors interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-10. Results:HE and Masson staining results showed that compared with the control group, the NaAsO 2 exposure group showed significant inflammatory cell infiltration, hepatocyte necrosis and collagen fibrous deposition, while the TAK-242 intervention group showed improvement of the inflammatory cell infiltration and reduction of collagen fibrous deposition compared with the NaAsO 2 exposure group. The results of serum liver function indexes showed that ALT, AST and ALP in NaAsO 2 exposure group were increased compared with the control group, but the TAK-242 intervention group was significantly decreased compared with the NaAsO 2 exposure group ( P < 0.05). Western bolt results showed that in NaAsO 2 exposure group, the expression levels of fibrosis protein α-SMA, TGF-β1 and Vimentin (1.04 ± 0.19, 0.92 ± 0.14, 1.20 ± 0.21) and TLR4 signaling pathway-related proteins and their phosphorylation TLR4, p50, p-p50 and p-p65 (1.16 ± 0.21, 0.95 ± 0.16, 1.24 ± 0.23, 1.56 ± 0.25) were higher than the control group (0.44 ± 0.08, 0.42 ± 0.08, 0.72 ± 0.07, 0.69 ± 0.15, 0.71 ± 0.11, 0.46 ± 0.07, 0.54 ± 0.11, P < 0.05), and the TAK-242 intervention group (0.60 ± 0.13, 0.59 ± 0.16, 0.49 ± 0.11, 0.47 ± 0.08, 0.86 ± 0.09, 0.79 ± 0.14, 1.02 ± 0.17) were lower than the NaAsO 2 exposure group ( P < 0.05). There was no significant difference in the expression level of TLR4 signal pathway-related protein p65 among the three groups ( F = 14.29, P = 0.053). ELISA results showed that the secretion levels of IL-6 and TNF-α [(98.89 ± 4.58), (83.25 ± 4.57) ng/g] in rats liver tissues of the NaAsO 2 exposure group were higher than the control group [(27.30 ± 3.92), (27.77 ± 1.83) ng/g, P < 0.05], while the secretion level of IL-10 [(36.88 ± 3.86) ng/g] was lower than the control group [(77.96 ± 7.87) ng/g, P < 0.05]. In TAK-242 intervention group, IL-6 and TNF-α secretion levels [(44.32 ± 3.60), (36.51 ± 2.93) ng/g] were lower and IL-10 secretion level [(60.40 ± 4.94) ng/g] was higher compared with the NaAsO 2 exposure group ( P < 0.05). Conclusion:TLR4-mediated inflammatory signaling pathway-related proteins and their phosphorylation are highly expressed in the liver tissues of rats with inorganic arsenic poisoning, and inhibition of TLR4 signaling pathway could significantly reduce the degree of liver fibrosis injury caused by inorganic arsenic in rats.

Youguiwan Regulates CXCL8/CXCR1/2 Signaling Pathway and Ang-1 and Ang-2 Expression to Promote Ovarian Angiogenesis in Rats / 中国实验方剂学杂志

ObjectiveTo study the effects of Chinese herbal compound Youguiwan on angiogenesis of rats with ovarian dysfunction caused by natural aging and its relationship with chemokine interleukin 8 （CXCL8）/CXC chemokine receptor 1/2 （CXCR1/2） signaling pathway， angiopoietin 1 （Ang-1）， and angiopoietin 2 （Ang-2）， so as to explore its mechanism in improving the ovarian function. MethodFifty six female SD rats were randomly divided into the young control group （n=8） and modeling group （n=48， ovarian dysfunction caused by natural aging）. Rats in both the young control and modeling groups were routinely fed， during which the ones in the modeling group underwent exfoliative cytology of vaginal smears for five to seven days. The ones presented with prolonged estrous cycle， followed by continuous estrus and repeated pseudopregnancy revealed by vaginal cytology during four consecutive estrous cycles indicated early aging， and the young rats with keratinocyte proliferation index higher than 50% for 10 consecutive days were classified into the young control group. The successfully modeled rats were randomly divided into the early-aged group， estrogen （65 μg·kg-1·d-1） group， Zuoguiwan （33 g·kg-1·d-1） group， as well as the low-， medium-， and high-dose （1.2， 2.4， 4.8 g·kg-1·d-1） Youguiwan groups. Rats in the young control group and the early-aged group were gavaged with the same volume of normal saline for 30 days. After the experiment， the morphological changes in rat ovary were observed by hematoxylin-eosin （HE） staining. The protein expression levels of chemokines CXCL8， CXCR1， CXCR2， Ang-1， and Ang-2 in rat ovary were detected by Western blotting and immunohistochemistry， and the mRNA expression levels of CXCL8， CXCR1， CXCR2， Ang-1， and Ang-2 by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultCompared with the young control group， the early-aged group exhibited reduced number of growing follicles， corpus luteum， and blood vessels at all levels， elevated atretic follicles （P<0.01）， up-regulated protein and mRNA expression of CXCL8， CXCR1， and CXCR2 in the ovarian tissue （P<0.01）， and down-regulated Ang-1 and Ang-2 protein and mRNA expression （P<0.05）. Compared with the early-aged group， each medication remarkably increased the number of growing follicles， corpus luteum， and blood vessels （P<0.05）， lowered the number of atretic follicles （P<0.05）， down-regulated the protein and mRNA expression levels of CXCL8， CXCR1， and CXCR2 in the ovarian tissue （P<0.05）， and up-regulated the protein and mRNA expression levels of Ang-1 and Ang-2 （P<0.05）. ConclusionYouguiwan down-regulates the levels of CXCL8， CXCR1， and CXCR2 in rat ovary and up-regulates the levels of Ang-1 and Ang-2 to promote ovarian angiogenesis and improve rat ovarian function.

Upper left lung cancer with congenital complete left pericardial defect: A case report / 中国胸心血管外科临床杂志

@#A 54-year-old asymptomatic man underwent a video-assisted thoracoscopic left pneumonectomy for squamous-cell carcinoma. During the surgery, a complete left pericardial defect was unexpectedly discovered, but no special intervention was made. The preoperative chest CT was reciewed, which showed the heart extended unusually to the left, but the left pericardial defect was not evident. The operation time was 204 min and the patient was discharged from hospital upon recovery 9 days after the surgery. The pathological result indicated moderately differentiated squamous-cell carcinoma (T2N1M0, stage ⅡB), and metastasis was found in the parabronchial lymph nodes (3/5). The patient did not receive chemotherapy after the surgery, and there was no signs of recurrence 6 months after the surgery. Complete pericardial defects usually do not endanger the lives of patients, and if the patient is asymptomatic, pneumonectomy is feasible.

Role of mitogen-inducible gene 6 in the activation of human hepatic stellate cells and deposition of extracellular matrix induced by sodium arsenite / 环境与职业医学

Background Arsenic is a well-known environmental toxicant. Hepatic fibrosis could occur dueto excessive or long-term exposure to arsenic, while associated molecular mechanisms remain undefined. Mitogen-inducible gene 6 (Mig-6) exhibits a protective effect on numerous diseases or cancers. However, the specific role of Mig-6 in the mechanisms of arsenite-induced hepatic fibrosis remains indistinct. Objective To investigate the specific role of Mig-6 in the activation of hepatic stellate cells (HSC) and the deposition of extracellular matrix (ECM) induced by sodium arsenite (NaAsO2). Methods Human hepatic stellate cells (Lx-2) were treated with 0, 1.875, 3.75, 7.5, and 15 μmol·L−1 of NaAsO2 for 24 h, or with 7.5 μmol·L−1 NaAsO2 for 0, 12, 24, 48, and 72 h. Additionally, Lx-2 cells were transfected by pcDNA3.1(+)/Mig-6, then treated with 7.5 μmol·L−1 NaAsO2 for 24 h; a blank control group, a pcDNA3.1(+)-control group, a pcDNA3.1(+)/Mig-6 group, and an arsenic (7.5 μmol·L−1 NaAsO2) group were also set up. After transfection, the cells and culture supernatants were collected, and the protein levels of Mig-6, α-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1) in Lx-2 cells were identified by Western blotting analysis; moreover, the secretion levels of main ECM components in supernatants such as hyaluronic acid (HA), laminin (LN), collagens IV (COL-IV), and procollagen-III (PIIINP) were tested by ELISA. Results The Mig-6 expression decreased in the 3.75, 7.5, and 15 μmol·L−1 NaAsO2 groups (0.561±0.095, 0.695±0.048, and 0.401±0.030) compared to the control group (1.000±0.000) in Lx-2 cells (P<0.05). After administration with 7.5 μmol·L−1 of NaAsO2 for 24, 48, and 72 h, the Mig-6 expression (0.856±0.036, 0.515±0.077, 0.491±0.060) decreased compared with the 0 h group (1.000±0.000) (P<0.05). After over-expression of Mig-6, the results of Lx-2 activation related protein levels showed that compared to the control group, the α-SMA and TGF-β1 expression were up-regulated in the arsenic group (P<0.05); meanwhile, the α-SMA and TGF-β1 in the Mig-6 over-expression combined arsenic exposure group reduced compared to the arsenic (7.5 μmol·L−1) group (P<0.05). The results of ELISA showed that compared with the control group, the HA, LN, PIIINP, COL-IV in the arsenic group were up-regulated (P<0.05); while compared to the arsenic group, the HA, LN, PIIINP, and COL-IV in the Mig-6 over-expression combined with arsenic exposure group were decreased (P<0.05). Conclusion Arsenic down-regulates Mig-6 expression in HSC, and over-expression of Mig-6 can reverse the activation of HSC and ECM deposition induced by arsenic exposure. It suggests that Mig-6 plays a protective role in arsenic-induced HSC activation and ECM deposition.

Effects of sodium arsenite on liver fibrosis and expression of epithelial-mesenchymal transformation-related proteins in SD rats / 环境与职业医学

Background Long-term exposure to sodium arsenite leads to its accumulation in the liver and liver injury as a result. Previous studies showed that mesenchymal cells play an important role in hepatic fibrosis, and epithelial-mesenchymal transformation (EMT) is considered to be a main source of mesenchymal cells. Objective To investigate the effects of sodium arsenite at different doses on liver fibrosis and EMT-related protein expressions in SD rats. Methods Twenty-four healthy weaned SD rats, half male and half female, were randomly divided into four groups according to body weight, with 6 rats in each group. The four groups were control group (gavage with 10.0 mL·kg−1 physiological saline), 2.5 mg·kg−1 sodium arsenite group, 5.0 mg·kg−1 sodium arsenite group, and 10.0 mg·kg−1 sodium arsenite group. All rats were gavaged 6 d per week for 36 weeks and weighed once a week, the serum and liver tissues of rats were collected and weighed, then the organ coefficient was calculated. Hematoxylin-eosin staining and Masson's trichrome staining were used to determine the pathological changes of hepatic fibrosis in rats. The serum secretion levels of hyaluronic acid (HA), laminin (LN), procollagen Ⅲ N-terminal propeptide (PⅢNP), and collagen Ⅳ (COL-Ⅳ) in rats were detected by enzyme-linked immunosorbent assay (ELISA). The protein expressions of HSCs activation-related proteins, such as α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1), as well as EMT-related markers, such as E-cadherin, N-cadherin, Vimentin, and Snail, were detected by Western blotting. Results Compared with the control group, the 10.0 mg·kg−1 sodium arsenite group showed decreased body weight (P<0.05) and increased liver coefficient (P<0.05) of female and male rats. The pathological staining showed that, compared with the control group, a large number of inflammatory cells were observed in liver tissue of rats exposed to sodium arsenite, liver parenchymal cells were also liquefied, necrotic, and denatured, and the collagen positive staining area of liver tissue showed an upward trend along with the increase of arsenic exposure dose (P<0.05). The results of ELISA and Western blotting showed that the serum secretion levels of HA, LN, PⅢNP, and COL-Ⅳ in the 5.0 and 10.0 mg·kg−1 sodium arsenite groups were higher than those in the control group and the 2.5 mg·kg−1 sodium arsenite group (P<0.05). Compared with the control group, the expressions of α-SMA and TGF-β1 proteins in liver tissue were increased in each sodium arsenite exposure group (P<0.05), the expression levels of E-cadherin protein were decreased (P<0.05), and the expression levels of N-cadherin, Vimentin, and Snail were increased (P<0.05). Conclusion Sodium arsenite exposure can induce HSCs activation and liver fibrosis injury in SD rats, resulting in increased extracellular matrix secretion levels, accompanied by EMT in liver tissue, suggesting that EMT is closely related to the process of liver fibrosis caused by arsenic.

Role of intestinal flora and 5-HT in depression- and anxiety-like behaviors in mice exposed to PM2.5 / 环境与职业医学

Background Some studies have shown that PM2.5 exposure is closely related to central nervous system diseases that lead to cognitive dysfunction and change the composition of intestinal flora. However, there are few studies on the role of intestinal flora in PM2.5-induced depression- and anxiety-like behaviors in mice. Objective To observe the effects of PM2.5 exposure on depression- and anxiety-like behaviors and the composition of intestinal flora in mice, and to explore the role of intestinal flora in regulating 5-hydroxytryptamine (5-HT) in depression- and anxiety-like behaviors in mice exposed to PM2.5. Methods Eight-week-old male SPF C57BL/6J mice were randomly divided into control group (NS group), probiotic group (LGG group), PM2.5 group (PM group), and combined exposure group (PML group), 6 mice in each group. Mice in the PM group and the PML group were exposed to PM2.5 in a dynamic exposure cabinet for 6 h per day, 6 d a week for 7 consecutive weeks, and the PM2.5 concentrations were approximately 8 times higher than the outdoor concentration. The LGG group and the PML group were orally administered with Lactobacillus rhamnosus while the NS group and the PM group were orally administered with the same amount of saline. Elevated plus maze test and open field test were used to detect depression and anxiety in mice. Fecal samples of mice were collected to evaluate intestinal flora abundance, diversity, and structure between groups using high-throughput sequencing of 16S rRNA. ELISA was employed to detect the levels of 5-HT in serum and hippocampus. Spearman correlation was used to analyze the correlations of differential intestinal flora with 5-HT level in hippocampus and depression- and anxiety-like behavior indicators in mice. Results The percentage of open-arm entry [M(P25, P75)] in the PM group was 0.0% (0.0%, 33.3%), lower than those in the NS group [47.7% (25.0%, 50.8%) ] and the PML group [46.9% (40.0%, 50.0%)], and the differences were statistically significant (P<0.05). The total travelled distance and the time spent in central area (\begin{document}$\bar x \pm s $\end{document}) in the PM group were (2.01±0.90) m and (10.31±1.99) s respectively, shorter than those of the NS group [(3.80±0.89) m, (14.47±3.07) s], the total travelled distance in the PML group [(2.73±1.12) m] was shorter than those of the NS group and the LGG group [(4.21±1.08) m], and the differences were statistically significant (P<0.05). Compared to the NS group, the Simpson index of the PM group significantly increased (P<0.05). Compared to the LGG group, the Simpson index of the PML group significantly decreased (P<0.05). The results of Beta diversity analysis showed that there were differences in the composition of intestinal flora among the four groups of mice. Compared with the NS group and the LGG group, the abundances of Erysipelotrichaceae and Dubosiella in the PM group and the PML group increased, while the abundances of Prevotellaceae_UCG-001 decreased, and the differences were statistically significant (P<0.05). In hippocampus, the level of 5-HT in the PM group [(135.02±10.31) μg·g−1] was lower than those in the NS group [(178.77±43.15) μg·g−1] and the LGG group [(224.85±22.98) μg·g−1], and the level of 5-HT in the PML group [(161.27±15.81) μg·g−1] was lower than that in the LGG group (P<0.05). 5-HT level in hippocampus was significantly positively correlated with the relative abundance of Prevotellaceae_UCG-001 (r=0.6090, P=0.012). The percentage of open-arm entry was significantly negatively correlated with the relative abundance of Dubosiella (r=−0.4630, P=0.023). Conclusion Atmospheric PM2.5 exposure may cause depression- and anxiety-like behaviors in mice. The observed behavior dysfunction may be associated with the changes in diversity and relative abundance of intestinal flora as well as the decrease of 5-HT level. Such depression- and anxiety-like behaviors are alleviated after adding probiotics.

Efficacy of posterior atlantoaxial joint release in treating craniovertebral junction deformity combined with atlantoaxial instability / 西安交通大学学报(医学版)

【Objective】 To evaluate the curative effect of posterior atlantoaxial joint release and internal fixation in treating unstable craniocervical junction malformation （UCVJM）. 【Methods】 This study retrospectively enrolled 31 patients with UCVJM， who received posterior atlantoaxial joint release and internal fixation between January 2015 and December 2018. The pre- and postoperative changes of the Japanese Orthopaedic Association （JOA） scores， the cervicomedullary angle （CMA）， the atlantodental interval （ADI） and the height above the Chamberlain line of the odontoid （H） were traced to evaluate whether clinical symptoms， compression of spinal cord， horizontal and vertical dislocation of atlantoaxial were improved postoperatively. 【Results】 The average operation duration， bleeding during operation and the average days of hospitalization were （168.38±38.21）min， （147.09±59.84）mL， and （9.54±2.81） days， respectively. None of the patients had vertebral artery or spinal cord injury during operation. JOA score， ADI， H， and CMA were （11.94±1.37） points， （2.72±1.08）mm， （3.03±0.78）mm， and （145.35±8.00）° respectively on the 6th days after operation compared with the preoperative （9.94±1.26） points， （4.96±1.60）mm， （6.89±1.36） mm and （122.16±9.58）°， with statistical differences， which indicated all indexes were improved （all P<0.001）. During 6-25 months’ follow-up， there was no internal fixation looseness or displacement and JOA score was increased to （13.16±1.19） for all the patients in the last follow-up （all P<0.001）. 【Conclusion】 The posterior atlantoaxial joint release combined with internal fixation is safe and effective for patients with UCVJM.

Comparison of Relative Molecular Weight Distribution and Immune Activity of Polysaccharides in Polygonati Rhizoma Before and After Processing / 中国实验方剂学杂志

Objective:To study the relative molecular weight and distribution of polysaccharides in Polygonati Rhizoma （PR） before and after processing， as well as the effects of different polysaccharide fractions on immune function and inflammatory response of mouse peritoneal macrophages. Method:High-performance gel permeation chromatography （HPGPC） was used to determine the relative molecular weight and distribution of polysaccharides in PR （named SC） and polysaccharides in PR processed with wine （named JC）， and polysaccharide fractions with different relative molecular weights were obtained by dialysis. Different polysaccharide fractions were applied to mouse peritoneal macrophages， which was normal or induced by lipopolysaccharide （LPS）. Cell counting kit-8 （CCK-8） method was used to select the optimal administration concentration. Enzyme linked immunosorbent assay （ELISA） was used to determine the concentrations of tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>） and interleukin-1<italic>β</italic> （IL-1<italic>β</italic>） in the cell supernatant. The Griess method was used to detect the concentration of nitric oxide （NO）. Result:SC and JC could be divided into four parts according to relative molecular weight and its distribution range， including part Ⅰ（14 800-2 273 kDa）， part Ⅱ（2 148-296 kDa）， part Ⅲ（12-1 kDa） and part Ⅳ（818-362 Da）. Based on the differences of part Ⅰ and part Ⅲ after processing， the SC and JC were divided into two-part according to the weight-average relative molecular weight （<italic>M</italic>_W）. For normal mouse peritoneal macrophages， JC could significantly promote the secretion of TNF-<italic>α</italic> （<italic>P</italic><0.01）， while SC had no significant effect. Four polysaccharide fractions， named SD （SC fraction with <italic>M</italic>_W>50 kDa）， JD （JC fraction with <italic>M</italic>_W>50 kDa）， SX （SC fraction with <italic>M</italic>_W<50 kDa） and JX （JC fraction with <italic>M</italic>_W<50 kDa）， also could<italic> </italic>significantly promote the secretion of TNF-<italic>α</italic> （<italic>P</italic><0.01）， but only JX could significantly promote the secretion of NO （<italic>P</italic><0.05）. In addition， the effect of JX group stimulated secretion of TNF-<italic>α</italic> was better than the JD group （<italic>P</italic><0.01）. For the LPS-induced macrophage model， JC and SC group could<italic> </italic>significantly inhibit the secretion of TNF-<italic>α</italic> and IL-1<italic>β</italic> （<italic>P</italic><0.01）， and the effect of JC was stronger. To compare different polysaccharide fractions， the impact of JX on inhibiting the secretion of TNF-<italic>α</italic> and IL-1<italic>β</italic> was<italic> </italic>significantly stronger than JD （<italic>P</italic><0.01）， and SX inhibited the secretion of TNF-<italic>α</italic> was significantly stronger than SD （<italic>P</italic><0.01）. Conclusion:The relative molecular weight and distribution of polysaccharides in PR before and after processing have changed. JC and SC improve the immune regulation mainly by inhibiting the inflammatory response， the fraction of <italic>M</italic>_W<50 kDa is the main effective part， and the effect of PR polysaccharides in inhibiting the inflammatory is enhanced after processing with wine.

Effect of Rhein on AQP4 and Microglia Mediated Inflammatory Response in Cerebral Ischemia Rats / 中国实验方剂学杂志

Objective:To investigate the effect of rhein on aquaporin 4 （AQP4） and brain edema after cerebral ischemia and the role of microglia-mediated inflammation in this process. Method:The modified thread embolization method was selected to establish the cerebral ischemia model of the right middle cerebral artery embolism （MCAO） in rats. The rats were divided into sham operation group， model group， minocycline group， and high， medium and low-dose rhein groups （3.46，1.73，0.865 mg·kg^-1）. The neurobehavioral function was measured by a modified neurobehavioral score. Wet and dry weight methods were used to measure the changes of water content in brain tissue of rats with cerebral ischemic injury. Western blot was used to detect the expressions of interferon-<italic>γ</italic> （IFN-<italic>γ</italic>） and interleukin-2 （IL-2） in the peripheral ischemic area of rats in each group. Immunofluorescence double labeling method was used to detect the expressions and localization of microglia fine markers Iba-1 and AQP4. Result:Compared with the sham operation group， neurological function score and water content on the side of brain tissue injury of the model group were significantly increased （<italic>P</italic><0.05）. Compared with the model group， the neurological function score and the water content of the brain tissue of each drug group were reduced （<italic>P</italic><0.05， <italic>P</italic><0.01）. Compared with sham operation group， the protein expressions of IFN-<italic>γ</italic> and IL-2 in the model group increased significantly （<italic>P</italic><0.05）. Compared with the model group， the protein expressions of IFN-<italic>γ</italic> and IL-2 in the peripheral area of cerebral ischemia of each drug group were significantly improved （<italic>P</italic><0.05， <italic>P</italic><0.01）. Immunofluorescence double staining results showed that compared with the sham operation group， the model group showed significant increase in the fluorescence expression of AQP4 protein on activated microglia， while each drug group could reduce the fluorescence expression of AQP4 protein on activated microglia， different levels of activated microglia markers Iba-1 and AQP4 were co-localized in the peripheral area of cerebral ischemia in each group. Conclusion:Rhein could reduce the degree of brain edema caused by cerebral ischemic injury， and its mechanism may be related to the inhibition of microglia-mediated neuroinflammation and the down-regulation of AQP4 expression.

Comparative study on modified selective posterior rhiotomy and traditional selective posterior rhiotomy in the treatment of spastic cerebral palsy / 西安交通大学学报(医学版)

【Objective】 To compare the application of modified selective posterior rhiotomy of spinal nerve with traditional rhiotomy in the treatment of spastic cerebral palsy and to evaluate the efficacy and complications of the two surgical methods. 【Methods】 The clinical data of 52 patients with spastic cerebral palsy were analyzed retrospectively. Among them 23 cases were treated with traditional selective posterior rhiotomy and the remaining 29 cases with modified selective posterior rhiotomy. Operation time, amount of blood loss, proportion of root after spinal nerve amputation, postoperative complications, spasm index, ankle clonus, and Holden walking ability at 1 year after operation were compared between the two groups. 【Results】 The operation time of modified selective posterior rhiotomy was longer than that of conventional surgery (P0.05). The proportion of root was smaller in the modified group than in the traditional group (P<0.05). The improved group was superior to the traditional group in the disappearance of ankle clonus (P<0.05). 【Conclusion】 Modified selective posterior rhiotomy has more advantages in eliminating ankle clonus. It is a safe and effective surgical improvement method to evaluate the changes of muscle tension and ankle clonus to quantitatively cut the posterior root of spinal nerve during the operation. This can reduce the proportion of the posterior root of spinal nerve during the operation, and keep the anatomical and functional basis for reducing the occurrence of surgical complications.

Clinical study of 80 patients with spasmodic cerebral palsy undergoing microsurgery / 西安交通大学学报(医学版)

【Objective】 To discuss and summarize the choice of the operation plan and evaluation of curative effect of spasmodic cerebral palsy. 【Methods】 Clinical data of 80 patients with spastic cerebral palsy treated by neurosurgery in The First Affiliated Hospital of Xi’an Jiaotong University were collected retrospectively and analyzed statistically. Eighty patients were followed up for 12 to 52 months, with an average follow-up of 21.3 months. The muscle tension grading, spasm index, range of motion, Holden walking ability and postoperative complications were compared one year after surgery. 【Results】 Totally 64 cases received selective posterior rhizotomy (SPR) combined muscle strength muscle tension adjustment method (MMA) and 16 cases selective peripheral neurotomy combined muscle strength muscle tension adjustment method. The grade and spasm index of muscle tension decreased significantly one year after operation (P<0.001). The range of joint motion and Holden walking ability were significantly improved (P<0.001). Transient urination disorder occurred in two cases (2.5%), and limb sensation disorder in two cases (2.5%), all of which were improved within three months. Weakness of dorsiflexion of foot in one case (1.25%). 【Conclusion】 Selective partial neurotomy and muscle tension adjustment is a safe and effective surgical method to treat spasmodic cerebral palsy. Real-time evaluation of muscle tension and ankle clonus changes during the operation is an important factor to ensure the postoperative efficacy.

Surgical freedom of odontoidectomy via endoscopic endonasal approach / 西安交通大学学报(医学版)

【Objective】 To quantitatively analyze the surgical freedom of odontioectomy via endoscopic endonasal approach. 【Methods】 Seven adult head specimens were dissected by the endoscopic transnasal approach to the sellar region and craniocervical junction. The center of sellar floor (CenSF), opticocarotid recess (LOCR), foramen magnum, atlas, atlas-occipital joint and tip of odontoid process (TOP) were exposed. The surgical freedom of TOP was calculated by using the spatial coordinate positioning system of neuronavigation, and compared with that of LOCR and CenSF. 【Results】 CenSF and LOCR were common landmarks in the endonasal endoscopic approach. When the surgical freedom between TOP and CenSF and LOCR was compared, it indicated that ① The angle of attack on axial plane (AAAP):There was a significant difference among TOP, LOCR and CenSF (5.7 ° vs. 6.9 ° vs. 8.5 °, P=0.004). The comparison between the two groups showed that TOP was less than CenSF (P=0.003). ② The angle of attack on sagittal plane (AASP): There was a significant difference among TOP, LOCR and CenSF (6.3° vs. 7.0° vs. 9.5°, P=0.009). The TOP was less than CenSF (P=0.008). ③ There was no statistical significance between TOP and LOCR in surgical freedom (P=0.604, P=0.688). 【Conclusion】 Endoscopic transnasal approach can provide sufficient surgical freedom for odontoidectomy.

Efficacy of modified posterior fossa decompression in the treatment of Chiari type Ⅰ malformation with the neuroendoscope / 西安交通大学学报(医学版)

【Objective】 To investigate the clinical efficacy of modified posterior fossa decompression in treating Chiari type I malformation under the neuroendoscope. 【Methods】 We made a retrospective analysis of the clinical data of 63 patients with Chiari type I malformation treated at the Neurosurgery Department of The First Affiliated Hospital of Xi’an Jiaotong University from January 2015 to December 2019. Of the patients, 28 ones underwent modified posterior fossa decompression assisted with neuroendoscopy (observation group) while 35 received posterior fossa decompression with duraplasty (control group). Tator grading, syringomyelia improvement and complications were compared between the two groups to evaluate the postoperative efficacy. 【Results】 The operations were successful in all the 63 patients and no death or severe neurological dysfunction was observed. The efficacy rate was 78.6% in the observation group and 54.3% in the control group, with significant difference (P0.05). 【Conclusion】 Modified posterior fossa decompression assisted with neuroendoscope is a safe and effective treatment for Chiari type Ⅰ malformation. Intraoperative dural watertight suture and dural-muscle suspension can help reduce the occurrence of subcutaneous effusion.

Effect of Huangqin Qingre Chubi Capsules containing serum on oxidative stress and protein expression of AMPK and FoxO3a in rheumatoid arthritis patients / 中国中药杂志

To study the effect of Huangqin Qingre Chubi Capsules containing serum on the protein expressions of AMPK and FoxO3 a in peripheral blood mononuclear cells of patients with rheumatoid arthritis(RA), in order to explore the mechanism of anti-oxidation. Peripheral anticoagulant was collected from patients and normal people. Monocytes(PBMC) were isolated through density gradient centrifugation, and the logarithmic phase cells were cultured. Drug containing serum was prepared through intragastric admini-stration to SD rats. The rats were divided into five groups, namely normal group, model group, AMPK blocker group(compound C 10 μmol·L~(-1)), medium-dose HQC+AMPK blocker group, and middle-dose HQC group. The cell inhibition rate was calculated by MTT method. The levels of IL-1β, IL-4, LPO, MDA, SOD and TAOC were detected by ELISA. The expressions of AMPK, p-AMPK, p-FoxO3 a and FoxO3 a were detected by Western blot. The HQC containing serum had an inhibitory effect on human monocytes in peripheral blood. The best concentration was observed in middle-dose HQC, and the best time was 24 hours. Middle-dose HQC group was better than model group, AMPK blocker group and middle-dose HQC + AMPK blocker group in terms of increase of SOD, p-AMPK, p-FoxO3 a and decrease of LPO. It was better than model group and AMPK blocker group in terms of increase of IL-4, TAOC, AMPK, FoxO3 a and decrease of IL-1β, MDA. The differences were statistically significant(P<0.05 or P<0.01). The HQC containing serum may increase the levels of TAOC and SOD, decrease the level of MDA and LPO, activate AMPK, directly phosphorylate FOXO3 a, enhance its transcriptional activity, and improve the state of oxidative stress in RA patients.

Research on Textual Research and Methods of Chinese Herbs in Famous Classical Formulas / 中国实验方剂学杂志

As the essential part of tratidional Chinese medicine(TCM), the research and development of classic formula have become a hot spot in TCM industry. However, with the change of the age, the species, medical part and origin of TCM have more or less changed. It is of great significance for the safety and effectiveness of the classical prescription to clarify the varieties and medicinal parts of TCM. In this paper, based on the discussion of the methods of textual research on the Chinese herbs, the species and medical parts, origin of Chinese herbs in a list of 100 famous classical formulas which promulgated by the state administration of TCM were analyzed. The textual research of Chinese herbs shows that most of the herbs involved in the classical formula have the problems of species, medical part, and origin. Therefore, it is of great significance for the selection of the species and medical parts, origin of the Chinese herbs in the research and development process of the classical formula.

Comparison of Total Daily Doses of 16 Active Components in Three Dosage Forms of Fuzi Lizhongwan / 中国实验方剂学杂志

Objective:To compare the total daily doses of 16 active components in big honeyed pills, concentrated pills and tablets of Fuzi Lizhongwan. Method:Three dosage forms of Fuzi Lizhongwan were prepared according to the process described in the literature. RRLC-QqQ-MS was employed to analyze the contents of 16 active ingredients with mobile phase of 0.1%formic acid aqueous solution-0.1%formic acid acetonitrile solution for gradient elution,the separation was performed on a Accucore RP-MS column(2.1 mm×100 mm, 2.6 μm) with a flow rate of 0.3 mL·min-1 and the column temperature at 30℃, the mass spectrometry condition was electrospray ion source, positive and negative ion switching mode for detection, multi-reaction monitoring mode(MRM) for scanning. The contents of 16 active ingredients were calculated, and the normalization arithmetic method was used for comparing the total daily doses of these active ingredients in three dosage forms of Fuzi Lizhongwan. Result:Processed products of Aconiti Lateralis Radix Praeparata were used as raw powder in preparation process of the three dosage forms, so there was no significant difference in the contents of six alkaloids in the three dosage forms, while the contents of other 10 active ingredients from Zingiberis Rhizoma, Codonopsis Radix, Atractylodis Macrocephalae Rhizoma and Glycyrrhizae Radix et Rhizoma Praeparata cum Melle were significantly higher in big honeyed pills than those in concentrated pills or tablets(PConclusion:The total daily doses of 16 active ingredients in the three dosage forms of Fuzi Lizhongwan are significantly different caused by preparation process, prescription and dosage.

Mental health and its related factors in patients with cardiac rehabilitation after coronary artery bypass grafting / 中华全科医师杂志

The mental health status of 237 patients with coronary heart disease who participated in cardiac rehabilitation (CR) after coronary artery bypass grafting and 148 non-participating patients(control group) in three hospitals was evaluated,and the related factors for mental health of patients with CR were analyzed.The results showed that the anxiety,depression,and quality of life scores of patients after 2 months of participation in CR were significantly lower than those before CR (P＜0.05),and the incidence of anxiety and depressive symptoms was significantly lower than that in control group (18.5％ vs.31.1％ and 14.8 vs.25.0％,respectively,P＜0.05).The risk of anxiety and depressive symptoms was higher in CR participants with lower monthly income [OR=0.335(0.150-0.751),P=0.008],unemployment [OR=0.427(0.244-0.749),P=0.003] and knowing their own disease [OR=3.243(1.427-7.371),P=0.005].This study shows that CR can effectively improve the state of depression and anxiety and improve the quality of life.The implementation of CR shoμld fully consider a variety of influencing factors and develop a targeted rehabilitation program.

Simultaneous determination of gallic acid，methyl gallate and ellagic acid in mouth rinse residues and the effect of residue-drying methods on their content / 国际药学研究杂志

Objective: To establish a method for the simultaneous determination of gallic acid(GA),methyl gal- late(MG)and ellagic acid(EA)in the residue of a gingival consolidation liquid(a mouth rinse preparation),and inves- tigate the effect of different residue-drying methods on the GA,MG and EA content in the residues. Methods: High per- formance liquid chromatography(HPLC)switching walvelength method was used to determine the GA,MG and EA con- tents. The column was Agilent Zorbax SB-C18(250 mm×4.6 mm,5 μm). The mobile phase was methanol(A)-0.05% phosphoric acid aqueous solution(B)in a gradient elution. The detection wavelength was 272 nm for GA/MG and 255 nm for EA. The flow rate was 1 ml/min,and the injection volume was 3 μl. Meanwhile,the residues were dried with the methods of sun drying,blast drying,vacuum drying and microwave vacuum drying,respectively and the GA,MG and EA contents in the residues were determined by the established HPLC method. Results: The linear ranges for GA,MG and EA were 1.280-4.608(r=0.9998),0.560-2.016(r=0.9998),0.1145-0.4122 μg(r=0.9997),respectively. The aver- age recoveries for GA,MG and EA were 99.97%,99.93% and 100.20%,with the RSD of 0.34%,2.30% and 0.93%,re- spectively. The contents of GA,MG and EA varied in quite a large range in the residues dried by different methods. Con- clusion: The established method is fast,simple and practicable,which could be used for the determination of GA,MG and EA in the residue of a gingival consolidation liquid. The drying methods could significantly affect the contents of GA, MG and EA in the residues,and the related results provide a reference for future studies.