ObjectiveTo investigate the effect of 1，25（OH）₂D₃ on the level of peroxisome proliferator-activated receptor-γ （PPAR-γ） in the liver， the phenotype of hepatic macrophages， and liver inflammation in a rat model of nonalcoholic steatohepatitis （NASH）， as well as the mechanism of 1，25（OH）₂D₃ improving liver inflammation. MethodsAfter 1 week of adaptive feeding， 24 specific pathogen-free Wistar rats were randomly divided into normal group ［choline-supplemented L-amino acid-defined （CSAA） diet］， normal+1，25（OH）₂D₃ group ［CSAA diet+1，25（OH）₂D₃］， model group ［choline-deficient L-amino acid-defined diet （CDAA） diet］， and model+1，25（OH）₂D₃ group ［CDAA diet+1，25（OH）₂D₃］， with 6 rats in each group. The dose of 1，25（OH）₂D₃ was 5 μg/kg for intraperitoneal injection twice a week for 12 weeks. The serum levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT） were measured， liver histopathology was observed， and SAF score was assessed. M1 hepatic macrophages and M2 hepatic macrophages were measured to analyze in the change in the phenotype of hepatic macrophages， and ELISA was used to measure the levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， interleukin-4 （IL-4）， and interleukin-10 （IL-10） in liver tissue， and qPCR was used to measure the mRNA level of PPAR-γ. The two-factor analysis of variance was use for comparison between groups， and the least significant difference t-test was used for further comparison； the Pearson method was used for correlation analysis. ResultsCompared with the normal group， the model rats with CDAA diet-induced NASH had significant increases in the serum levels of AST and ALT （P=0.019 and P<0.001）， the SAF score of liver histopathology （P<0.001）， the level of M1 hepatic macrophages （P<0.001）， and the ratio of M1 and M2 hepatic macrophages （P<0.001）， as well as a significant increase in the level of TNF-α （P<0.001） and a significant reduction in the level of IL-4 in liver tissue （P=0.025）. The 1，25（OH）₂D₃ group had significant reductions in the serum levels of ALT （P<0.001）， the SAF score of liver histopathology （P<0.001）， the level of M1 hepatic macrophages （P<0.001）， and the ratio of M1 and M2 hepatic macrophages （P=0.001）， the level of IL-1β （P<0.001） and a significant increase in the level of M2 hepatic macrophages （P=0.017）， the level of IL-10 （P=0.039）， the level of IL-4 （P<0.001）， the level of PPAR-γ （P=0.016）. There were significant interactions between CDAA diet-induced NASH model and 1，25（OH）₂D₃ in serum the levels of AST and ALT （P=0.007 and P=0.008）， the SAF scores of liver histopathology （P<0.001）， the level of M1 hepatic macrophages （P<0.001）， the level of M2 hepatic macrophages （P=0.008）， the ratio of M1 and M2 of hepatic macrophages （P=0.005）， the level of TNF-α （P<0.001）， the level of IL-10 （P=0.038）， the level of IL-4 （P<0.001） and the level of PPAR-γ （P=0.009）. The correlation analysis showed that PPAR-γ was negatively correlated with the ratio of M1 and M2 hepatic macrophages （r=-0.415， P=0.044） and was positively correlated with M2 hepatic macrophages （r=0.435， P=0.033）， IL-10 （r=0.433， P=0.035）， and IL-4 （r=0.532， P=0.007）. ConclusionThis study shows that 1，25（OH）₂D₃ improves liver inflammation in NASH by activating PPAR-γ to regulate the phenotypic transformation of hepatic macrophages.

The nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome is an inflammatory protein complex, and can participate into the inflammatory response. Upon activation, these inflammasomes can lead to Caspase-1 activation, thereby inducing a cascade of inflammatory factor activation and further cell pyroptosis. Excessive activation of inflammasomes will induce the overexpression of inflammatory factors, persistently triggering immune dysregulation and inflammatory chain reactions, even causing severe damage. The recent studies have confirmed a close association between retinal diseases, such as diabetic retinopathy(DR), retinal ischemia-reperfusion injury(RIRI), and proliferative vitreoretinopathy(PVR)with immune dysregulation and inflammatory responses, which is serving as crucial factors in the progression of retinal diseases. This article reviews the NLRP3 inflammasome signaling pathway and its role in the occurrence and development of retinal diseases, in order to provide new ideas for the pathogenesis and prevention of retinal diseases.

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

Objective: To study the relationship between the single nucleotide polymorphism of HLA⁃A rs3132682 and the risk of liver cancer. Methods: The author selected 291 cases of liver cancer patients in Yanbian area as the experimental group and 272 healthy people as the control group. The genotypes and allele frequencies of the two loci were detected by MassARRAY SNPS mass spectrometry. Odds ratio (OR) and 95% confidence interval (CI) were calculated by unconditional logistic regression to evaluate the risk of liver cancer in patients with different genotypes. Results: There were G and C alleles in HLA⁃A rs3132682 locus , GG , GC and CC genotype. After adjusting for confounding factors in HLA⁃A rs3132682 locus , there was correlation between CC genotype and the risk of liver cancer compared with GG genotype (P < 0. 05) . Stratification analysis showed that compared with the population with CG + GG genotype , the Korean population with CC genotype increased the risk of liver cancer by 3. 331 times. Conclusion The single nucleotide polymorphism of HLA⁃A rs3132682 is correlated with the risk of liver cancer in Yanbian area.

Tinnitus and anxiety disorder are common clinical symptoms. Comorbidity between tinnitus and anxiety state is increasing year by year. The relationship between tinnitus and anxiety state has always been a hot topic, and this paper reviews the literature on the relationship between chronic subjective tinnitus and anxiety state in recent years.
Humans ; Tinnitus/diagnosis* ; Anxiety ; Anxiety Disorders/epidemiology* ; Comorbidity

Ethanol is one of the most widely used and abused psychoactive substances in the world. Long-term and excessive intake of alcohol can damage the central nervous system and lead to impairment of its function. As an important component of the central nervous system, cerebellum is one of the main target organs damaged by ethanol. Acute and chronic ethanol intake can damage human motor coordination, motor learning and some cognitive functions. Its damage mechanism is generally believed to be caused by the abnormal function of cerebellar cortical neural circuit caused by ethanol intake. Combined with recent studies on the mouse model of long-term ethanol intake, this article reviews the cerebellar neural network mechanism of long-term ethanol intake from various aspects, with a view to providing research and development in behavioral movement, motor coordination, cognitive function, depression, and offers new ideas with the rise of precision medicine for treatment. People are increasingly interested in exploring the mechanism of long-term ethanol intake on the cerebellar neural network. How to improve or block the corresponding mechanism based on the mechanism of action found in existing research is an important proposition in future research.

WNT signaling plays an important role in cardiac development, but abnormal activity is often associated with cardiac hypertrophy, myocardial infarction, remodeling, and heart failure. The effect of WNT signaling on regulation of atrial natriuretic peptide (ANP) secretion is unclear. Therefore, the purpose of this study was to investigate the effect of Wnt agonist 1 (Wnta1) on ANP secretion and mechanical dynamics in beating rat atria. Wnta1 treatment significantly increased atrial ANP secretion and pulse pressure; these effects were blocked by U73122, an antagonist of phospholipase C. U73122 also abolished the effects of Wnta1-mediated upregulation of protein kinase C (PKC) β and γ expression, and the PKC antagonist Go 6983 eliminated Wnta1-induced secretion of ANP. In addition, Wnta1 upregulated levels of phospho-transforming growth factor-β activated kinase 1 (p-TAK1), TAK1 banding 1 (TAB1) and phospho-activating transcription factor 2 (p-ATF2); these effects were blocked by both U73122 and Go 6983. Wnta1-induced ATF2 was abrogated by inhibition of TAK1. Furthermore, Wnta1 upregulated the expression of T cell factor (TCF) 3, TCF4, and lymphoid enhancer factor 1 (LEF1), and these effects were blocked by U73122 and Go 6983. Tak1 inhibition abolished the Wnta1-induced expression of TCF3, TCF4, and LEF1 and Wnta1-mediated ANP secretion and changes in mechanical dynamics. These results suggest that Wnta1 increased the secretion of ANP and mechanical dynamics in beating rat atria by activation of PKC–TAK1–ATF2–TCF3/LEF1 and TCF4/LEF1 signaling mainly via the WNT/Ca2+ pathway. It is also suggested that WNT–ANP signaling is implicated in cardiac physiology and pathophysiology.

Objective:To investigate the effect of long-term alcohol intake on sensory information synaptic transmission of mossy fiber-granular cells in the cerebellar cortex of mice.Methods:Twenty healthy male ICR mice aged 6 to 8 weeks were divided into normal saline group(control group) and alcohol intake group(alcohol group) according to random number table, with 10 mice in each group. The mice in alcohol group were injected intraperitoneally with 20% alcohol and the mice in control group were injected with the same amount of saline for 28 days.After the injection, the scalp, muscle tissue and skull were removed in turn, and the dura mater was removed to fully expose the crus II area of cerebellum. The mice were stimulated by air blowing at 30 mm of the ipsilateral tentacle pad with a gas jet device.When the the maximal response site was determined, the NMDA receptor antagonist (D-APV), metabolic glutamate receptor 1 antagonist (JNJ16259685) and N-methyl-D-aspartic acid (NMDA) were perfused on the brain surface of mice. Each drug was perfused for 20 minutes and ACSF was used between the two drugs until the waveform was recovered. Patch clamp amplifier was used to record the changes of potential waveform in mouse cerebellar granule layer. The data were analyzed by the softwares of Clampfit 10.3 and SPSS 22.0.Results:After exposure to wind stimulation, the latency of field potential response in granular layer of mice in alcohol group (11.8±0.7)ms was significantly longer than that in the control group (10.1±0.2)ms ( t=-8.041, P<0.05), and the amplitude of N1 (1.2±0.1) MV was significantly lower than that in the control group (0.6±0.1) MV ( t=-12.728, P<0.05). Compared with the control group, the rise time of P1 waveform((4.4±0.2)ms, (3.2±0.2)ms), duration ((12.1±0.5)ms, (10.3±0.2)ms), extinction time((7.8±0.2)ms, (6.9± 0.2)ms), volume under waveform ((7.3±0.2)ms, (4.3±0.2)ms) were significantly increased in the alcohol group ( t=16.100, - 11.840, -11.673, -35.576, all P<0.05). There were no significant differences in the amplitude, half width, rise time and decay time of Roff wave between the two groups ( t=-1.909, -0.910, -0.789, 1.462, all P>0.05). When JNJ16259685 was perfused on the brain surface of mice in alcohol group, the amplitude of field potential evoked by five blowing stimuli had no significant difference compared with that before administration (all P>0.05). When D-APV was perfused into the brain surface of mice in the alcohol group, the amplitude of P1 ((42.3±1.5) Mv)was significantly lower than that before administration ((101.1±0.9)mV) and after elution ((100.1±2.2) mV) ( t=106.762, - 69.605, both P<0.05), and the area under waveform of P1 ((42.6±1.3)%) was also significantly lower than that before administration ((100.6±1.6)%) and after elution ((97.6±2.2)%) ( t=88.862, -67.791, both P<0.05).The ratio of N2 / N1 (0.3±0.1) was significantly lower than that before administration (0.4±0.1) and after elution (0.3±0.1) ( t=2.242, 2.121, both P<0.05). When NMDA was perfused on the brain surface of mice in the control group, compared with before administration and after elution, the amplitude of P1 ((110.7±3.2) mV, (100.1±0.9) mV, (102.0±1.7) mV, t=-10.173, 7.669, both P<0.05), the area under the waveform of P1 ((127.9±3.5)%, (100.0±3.1)%, (115.0±5.3)%, t=-18.698, 6.447, both P<0.05), the ratio of N2 / N1 ((0.5±0.1), (0.3±0.1), (0.3±0.1), t=-5.669, 5.669, both P<0.05) were all significantly increased. When D-APV was perfused on the brain surface of mice in control group, the field potential evoked by blowing stimuli had no significant difference compared with that before administration and after elution (all P>0.05). Conclusion:Long-term alcohol intake significantly suppresses the synaptic transmission of excitatory glutamate in MF-GC, and enhances the inhibitory response mediated by GABAA receptor in cerebellar cortex. The inhibitory component is enhanced by NMDA receptor, but not by type 1 metabolic glutamate receptor.

Background: The accessory tendon of the extensor hallucis longus (ATEHL) muscle is a common abnormal structure, and its clinical significance remains debatable. In this study, we provide the incidence of the ATEHL and characterize its morphological types in Asian cadavers and investigate its clinical applications. Methods: The tendons from 50 adult cadaveric feet, fixed in 10% formalin, were analyzed. We measured the length and width of both the ATEHL and the extensor hallucis brevis (EHB). Results: All dissected specimens had an ATEHL. The first metatarsophalangeal joint was surrounded by an accessory tendon that inserted onto the joint capsule and the dorsal base of the proximal phalanx. We classified the ATEHL into 3 types based on their directions. Differences in ATEHL type based on sex were not statistically significant. Conclusions We found an ATEHL in all cadaveric specimens in this study. We surmise that the ATEHL acts as an antagonist with the EHB when the toe is extending, which might help prevent the occurrence of hallux valgus deformity.

OBJECTIVE: To investigate the biological function of Cysteine rich (CysR) domain of a disintegrin and metalloprotease with thrombospondin type 1 repeats-13 (ADAMTS13) on cleavage of von Willebrand factor (vWF) and provide experimental evidence for exploring the pathogenesis of thrombotic thrombocytopenic purpura (TTP). METHODS: The six amino acids (EDGTLS) in ADAMTS13 CysR domain were point mutated one by one, and the mutant ADAMTS13 proteins were expressed and purified. The cleavage products of vWF polymer by wild-type or mutant ADAMTS13 under denaturing condition or shear stress were separated by 1% SeaKem HGT agarose gel and detected by Western blot. RESULTS: The mutant ADAMTS13 plasmids (M1: Glu515Ala; M2: Asp516Ala; M3: Gly517Ala; M4: Thr518Ala; M5: Leu519Ala; M6: Ser520Ala) were successfully constructed and the proteins of wild-type and mutant ADAMTS13 were purified. Wild-type ADAMTS13 almost completely cleaved the vWF polymer under denaturing condition, while the cleavage activity of M1 mutant was significantly reduced in the same condition (P<0.01). The cleavage activity of M1 mutant of ADAMTS13 was also significantly reduced compared with that of the wild-type under shear stress (P<0.01). The activity of M1 mutant to cleave the FRETS-vWF73 was dramatically reduced compared with that of wild-type ADAMTS13. However, the binding ability of M1 mutant to vWF was similar with that of wild-type ADAMTS13. CONCLUSION The CysR domain of ADAMTS13 plays an important role in the digestion of vWF under denaturing condition and shear stress. The Glu515 amino acid residue might be an important site for substrate recognition.
ADAM Proteins ; ADAMTS13 Protein/genetics* ; Humans ; Purpura, Thrombotic Thrombocytopenic/genetics* ; von Willebrand Factor/genetics*