HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

OBJECTIVES: To explore the effect of A. muciniphila gavage on intestinal microbiota and gut-brain interaction disorders (DGBIs) in gp120tg transgenic mouse models of HIV-associated neurocognitive disorder (HAND). METHODS: Intestinal microbiota was detected by 16S rRNA gene sequencing in 6-, 9-, and 12-month-old wild-type (WT) mice and gp120tg transgenic mice. The 12-month-old WT and transgenic mice were divided into 2 groups for daily treatment with PBS or A.muciniphila gavage (2×10⁸ CFU/mouse) for 6 weeks. After the treatment, immunohistochemistry, ELISA and qPCR were used to detect changes in colonic expression levels of glycosylated mucins, MBP and IL-1β, eosinophil infiltration, serum lipopolysaccharide (LPS) levels, and colonic expressions of occludin, ZO-1, IL-10, TNF-α and INF-γ mRNA. Morris water maze test and immunofluorescence assay were used to assess learning and spatial memory abilities and neuronal damage of the mice. RESULTS: Compared with WT mice, the transgenic mice exhibited significantly lowered Simpson's diversity of the intestinal microbiota with reduced abundance of Akkermansia genus, increased serum LPS levels and decreased colonic expression of glycosylated mucin. A.muciniphila gavage obviously ameliorated the reduction of glycosylated mucin in the transgenic mice without causing significant changes in body weight. The 12-month-old gp120tg mice had significantly decreased cdonic expressions of Occludin and ZO-1 with increased eosinophil infiltration and TNF-β, INF-γ and IL-1β levels and obviously lowered IL-10 level; all these changes were significantly mitigated by A.muciniphila gavage, which also improved cognitive impairment and neuronal loss in the hippocampus and cortex of the transgenic mice. CONCLUSIONS The gp120tg mice have lower intestinal microbiota richness and diversity than WT mice. The 12-month-old gp120tg mice have significantly reduced Akkermansia abundance with distinct DGBIs-related indexes, and A. muciniphila gavage can reduce intestinal barrier injury, colonic inflammation and eosinophil activation, cognitive impairment and brain neuron injury in these mice.
Animals ; Mice, Transgenic ; Gastrointestinal Microbiome ; Mice ; Brain ; HIV Envelope Protein gp120/genetics* ; Akkermansia ; Disease Models, Animal

OBJECTIVES: To explore the therapeutic mechanism of compound Centella asiatica formula (CCA) for alleviating Schistosoma japonicum (Sj)-induced liver fibrosis in mice. METHODS: The active components and targets of CCA were identified using the TCMSP database with cross-analysis of Sj-related liver fibrosis targets. A "drug-component-target-pathway-disease" network was constructed using Cytoscape 3.9.1. Functional enrichment analysis (GO/KEGG) was performed using DAVID. Molecular docking study was carried out to validate interactions between the core targets and the key compounds. For experimental validation of the results, 36 mice were divided into control group, Sj-infected model group, and CCA-treated groups. In the latter two groups, liver fibrosis was induced via abdominal infection with Sj cercariae for 8 weeks, followed by 8 weeks of daily treatment with CCA decoction or saline. Hepatic pathology of the mice was assessedwith HE and Masson staining, and hepatic expressions of collagen-I and collagen-III were detected using immunohistochemistry; serum IL-6 and TNF-α levels were determined with ELISA. Hepatic expressions of TLR4 and MyD88 proteins were analyzed with Western blotting. RESULTS: We identified a total of 107 bioactive CCA components and 791 targets, including 37 intersection targets linked to Sj-induced fibrosis. The core targets included TNF, TP53, JUN, MMP9, and CXCL8, involving the IL-17 signaling, lipid metabolism, TLR4/MyD88 axis, and cancer pathways. Molecular docking study confirmed strong binding affinity between quercetin (a primary CCA component) and TNF/TP53/JUN/MMP9. In Sj-infected mouse models, CCA treatment significantly attenuated hepatic inflammatory cell infiltration, reduced collagen-I and collagen-III deposition, improved tissue architecture, reduced serum IL-6 and TNF-α levels, and downregulated TLR4 and MyD88 expressions in the liver. CONCLUSIONS CCA mitigates Sj-induced liver fibrosis by targeting TNF, TP53, JUN, and MMP9 to modulate the TLR4/MyD88 pathway, thereby suppressing pro-inflammatory cytokine release, inhibiting hepatic stellate cell activation, reducing collagen deposition, and preventing granuloma formation in the liver.
Animals ; Toll-Like Receptor 4/metabolism* ; Mice ; Myeloid Differentiation Factor 88/metabolism* ; Schistosoma japonicum ; Liver Cirrhosis/parasitology* ; Schistosomiasis japonica ; Signal Transduction ; Molecular Docking Simulation ; Inflammation ; Centella/chemistry* ; Drugs, Chinese Herbal/pharmacology* ; Tumor Necrosis Factor-alpha/metabolism*

The Internet has become an important carrier of medical information.Good electronic health literacy can enhance the public’s ability to obtain correct medical and health information with the help of electronic resources,which is helpful for the public to use health information to prevent diseases,avoid drug abuse,reduce the waste of medical resources and strengthen the self-management of chronic diseases.The improvement of electronic health literacy is of great value to the healthy development of citizens’ health literacy and healthy behavior.In view of the late start and slow development in the field of electronic health literacy in China,by combing the theoretical and practical research experience of electronic health literacy outside the region and combining with the COVID-19,this paper put forward new thinking on electronic health literacy in China,in order to provide useful reference for improving electronic health literacy of Chinese citizens,realizing self-care,self-management and disease prevention.

Objective:To investigate the effects of 3 adhesives on the bond force and durability of polished and glazed zirconia ceram-ics to orthodontic metal brackets respectively.Methods:Universal adhesives,Single Bond Universal(SBU)and Prime&Bond Universal(PBU)were respectively used to bond polished and glazed zirconia to metal braces of maxillary central incisors using TransbondTM MIP(TM)as the control.The shear bond strength(SBS),the fracture morphology and adhesive residual index(ARI)were examed after wa-ter bath or water bath-thermal cycling storage.Results:The adhesive(P＜0.001)and storage conditions(P＜0.001)significantly af-fected the shear bond strength of zirconia to brackets.There was no significant difference between the polished or glazed groups(P=0.09).SBU showed the stronger SBS and lower ABI,there were significant differences in ARI scores among the 3 cements(P＜0.001).Conclusion:SBU may have better bonding performance than PBU and TM in the orthodontic bonding of polished or glazed zir-conia surfaces to the zirconia ceramics.

AIM:To evaluate the effect of astaxanthin(AST)on cognitive function of intestinal ischemia/re-perfusion(I/R)injury in rats and the role of autophagy.METHODS:Eight-week-old SPF-grade male Sprague-Dawley(SD)rats were randomly divided into sham group,I/R group,AST group and AST+3-methyladenine(3-MA)group,with 12 animals in each group.The superior mesenteric artery(SMA)of the rats in sham group was only exposed without clamping.The SMA in other 3 groups was clamped for 90 min,and then the arterial clamp was released to restore blood supply and perform reperfusion,thus establishing the intestinal I/R model.The rats in AST group were intraperitoneally in-jected with AST(45 mg·kg-1·d-1)3 d before modeling,and those in AST+3-MA group were intraperitoneally injected with AST(45 mg·kg-1·d-1)+3-MA(1.5 mg·kg-1·d-1)3 d before modeling.Morris water maze was used to evaluate the cogni-tive function of rats 48 h after surgery.Hematoxylin-eosin(HE)staining was used to evaluate intestinal tissue damage.Nissl staining of the frontal cortex was used to evaluate neuronal damage.The levels of interleukin-6(IL-6),IL-1β and tu-mor necrosis factor-α(TNF-α)in the frontal cortex and hippocampus were measured by ELISA kits.The protein levels of beclin-1,microtubule-associated protein 1 light chain 3(LC3)and P62 in the frontal cortex and hippocampus were detected by Western blot.RESULTS:Compared with sham group,the swimming distance of rats in I/R group was increased,with prolonged latency,elevated Chiu's score and decreased number of neurons(P<0.01),while the levels of IL-6,IL-1β and TNF-α in the frontal cortex and hippocampus were increased(P<0.01).Beclin-1 expression and LC3-II/LC3-I ratio in the frontal cortex and hippocampus were increased(P<0.05 or P<0.01).Compared with I/R group,the swimming distance and latency of rats in AST group were shortened,with decreased Chiu's score,increased neuronal number(P<0.01),de-creased IL-6,IL-1β and TNF-α levels in the frontal cortex and hippocampus(P<0.01),and increased beclin-1 expres-sion and decreased of P62 expression in the frontal cortex and hippocampus(P<0.05 or P<0.01).Compared with AST group,the swimming distance of rats in AST+3-MA group was increased,with prolonged latency,elevated Chiu's score,decreased number of neurons(P<0.05),increased levels of IL-6,IL-1β and TNF-α in the frontal cortex and hippocam-pus,and decreased beclin-1 expression and LC3-II/LC3-I ratio and increased P62 expression in the frontal cortex and hip-pocampus(P<0.01).CONCLUSION:Astaxanthin alleviates intestinal I/R-induced cognitive impairment in rats by pro-moting autophagy and inhibiting neuroinflammation.

AIM:To investigate the possible mech-anisms by observing the effects of sodium butyrate on the blood-brain barrier and cognitive function after intestinal ischemia/reperfusion in rats.METH-ODS:SD rats were randomly divided into 4 groups of 12 rats each,(1)sham-operated group(the Sham group);(2)intestinal ischemia/reperfusion group(the Ⅱ/R group);(3)intestinal ischemia/re-perfusion+sodium butyrate group(the NaB group):gavage of NaB 500 mg·kg-1·d-1 for 1 week before modeling;(4)intestinal ischemia/reperfusion+sodi-um butyrate+ITSA-1 group(the ITSA-1 group):NaB 500 mg·kg-1·d-1 gavage 1 week before modeling+IT-SA-1 0.5 mg/kg intraperitoneal injection in the first 5 d,3 d and 1 d.Intestinal mucosal injury was eval-uated by HE staining.Morris water maze test evalu-ated the cognitive function of rats.The microstruc-ture of the blood-brain barrier was observed by transmission electron microscope.The levels of in-flammatory cytokines IL-1β,IL-6,TNF-α,Claudin5,ZO-1,and MMP-9 in brain tissue were detected by ELISA.Western blotting detected Claudin5,ZO-1,CypA,and MMP-9 levels.RESULTS:Compared with the Sham group,Chiu's score in the Ⅱ/R group was increased(P<0.001).The swimming distance was increased(P<0.05),the proportion of the non-plat-form quadrant was increased(P<0.001),and the in-cubation period was prolonged(P<0.05).The micro-structure of the blood-brain barrier was changed under the transmission electron microscope.The inflammatory cytokines IL-1β,IL-6,and TNF-α were increased(P<0.001),the expressions of CypA and MMP-9 were increased(P<0.01),and the expres-sions of Claudin5 and ZO-1 were decreased(P<0.01,P<0.001).Compared with the Ⅱ/R group,neu-roinflammation,and blood-brain barrier damage were reduced,and cognitive function was im-proved in the Ⅱ/R+NaB group.The above injuries in group Ⅱ/R+NaB+ITSA-1 were similar to those in group Ⅱ/R.CONCLUSION:Sodium butyrate can ameliorate Ⅱ/R-induced neurocognitive dysfunction in rats by alleviating blood-brain barrier damage,possibly related to inhibiting the CypA/MMP-9 pathway.

ObjectiveLipopolysaccharide （LPS）-induced zebrafish inflammation model was used to evaluate the anti-inflammatory activity of different extracts from Lianggesan （LGS） and its component Glycyrrhiza Radix et Rhizoma. MethodDifferent polar fractions of LGS and Glycyrrhiza Radix et Rhizoma were obtained by the principle of similar miscibility. For toxicity observation， the zebrafish （3 day-post-fertilization） was exposed to different concentrations of extracts for 24， 48 and 72 h. The yolk sac of the zebrafish was microinjected with 0.5 g·L^-1 LPS to establish the inflammation model， and then the embryos were soaked with different concentrations of extracts to observe their survival status at 72 h and the aggregation of neutrophils in yolk sac at 12 h after treatment. Hematoxylin-eosin staining was used to analyze the yolk sac of the zebrafish microinjected with LPS. Quantitative Real-time polymerase chain reaction （Real-time PCR） was performed to further investigate the anti-inflammatory effects and mechanisms of LGS and Glycyrrhiza Radix et Rhizoma. ResultThe toxicity of LGS and Glycyrrhiza Radix et Rhizoma was decreased with the increase of polarity， and the descending order was petroleum ether>ethyl acetate>n-butanol>water. Compared with model group， the extracts from different fractions of LGS and Glycyrrhiza Radix et Rhizoma prolonged the survival time of the zebrafish， and inhibited the recruitment and aggregation of neutrophils and decreased the infiltration of inflammatory cells in the yolk sac， among which the water fraction of LGS and the ethyl acetate fraction of Glycyrrhiza Radix et Rhizoma had the most significant effect （P<0.01）. In addition， compared with model group， the water fraction of LGS and the ethyl acetate fraction of Glycyrrhiza Radix et Rhizoma down-regulated the mRNA expression of interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α）， and suppressed the expression of toll like receptor 4 （TLR4） and nuclear factor kappa-B （NF-κB） in LPS-stimulated zebrafish （P<0.01）. ConclusionThe extracts from different fractions of LGS and Glycyrrhiza Radix et Rhizoma exerted protective effects in LPS-induced zebrafish by inhibiting the TLR4 and NF-κB signaling pathways. Moreover， in zebrafish model， the method of administration by soaking was applicable to the high-throughput screening of anti-inflammatory Chinese medicine， which was suitable for the evaluation of anti-LPS activity of Chinese medicine and the different extracts.

Objective:To investigate the patients with hepatocellular carcinoma suitable for transcatheter arterial chemoembolization (TACE) after radical resection who were screened based on microvascular invasion (MVI) and Ki-67 expression.Methods:Of 400 patients with hepatocellular carcinoma who underwent radical resection in the Affiliated Hospital of Qingdao University from January 2013 to December 2019 were included and analyzed retrospectively, including 324 males and 76 females, aged (59.7±9.8) years, ranging from 32 to 87 years. According to whether they received adjuvant TACE treatment after operation, they were divided into simple operation group ( n=210) and TACE + operation group ( n=190). The recurrence in the first year after operation was followed up by outpatient reexamination. Univariate and multivariate Cox regression analysis were used to analyze the influencing factors of recurrence free survival after surgical resection. Subgroup analysis was performed according to Ki-67 and MVI to compare the recurrence free survival. Results:Multivariate Cox regression analysis showed that patients with proportion of Ki-67 positive cells ≥27.5% ( HR=2.073, 95% CI: 1.433-3.000, P<0.001) and MVI positive ( HR=2.339, 95% CI: 1.584-3.456, P<0.001) had increased risk of recurrence after radical resection. The 1-year cumulative recurrence free survival rate in the simple operation group was 70.0%, and there was no significant difference compared with 67.9% in the operation + TACE group( χ 2=0.08, P=0.774). Subgroup analysis: in the low expression of Ki-67 combined with negative MVI group ( n=128), the cumulative recurrence free survival rate of one year after operation in the simple operation group ( n=84) was 91.7%, which was significantly higher than 72.7% in the operation + TACE group ( n=44)( χ 2=8.22, P=0.004). There was no significant difference in the 1-year cumulative recurrence free survival rate between the simple operation group and the operation + TACE group (both P>0.05) in patients of Ki-67 high expression combined with MVI negative or Ki-67 low expression combined with MVI positive. In the Ki-67 high expression combined with MVI positive group ( n=107), the cumulative one-year recurrence free survival rate in the simple operation group ( n=62) was 40.3%, which was significantly lower than 60.0% in the operation + TACE group ( n=45)(χ 2=4.22, P=0.040). Conclusion:High expression of Ki-67 (≥27.5%) combined with positive MVI are the prediction factors for postoperative TACE treatment. Low expression Ki-67 (<27.5%) combined with negative MVI was contraindicated for postoperative TACE treatment.

Objective To explore the effect of continuous nursing intervention on limb function and nursing quality after proximal femoral nail antirotation (PFNA) internal fixation for femoral intertrochanteric fracture in the elderly. Methods From February, 2017 to November, 2018, 100 elderly patients with femoral intertrochanteric fracture who underwent PFNA internal fixation in our hospital were randomly divided into control group (n = 50) and observation group (n = 50), who accepted routine nursing and continuous nursing respectively for three months. They were assessed with Harris score and visual analogue scale for pain (VAS) before and after the intervention. The postoperative nursing effect was compared. Results The Harris score increased in both groups after the intervention (t > 45.98, P < 0.001), and increased more in the observation group than in the control group (t = 15.03, P < 0.001). The VAS score decreased in both groups after the intervention (t > 16.33, P < 0.001), and decreased more in the observation group than in the control group (t = 9.749, P < 0.001). The effect of nursing was better in the observation group than in the control group (Z = -2.272, P = 0.023). Conclusion Continuous nursing intervention can significantly improve the limb function and nursing satisfaction of elderly patients with femoral intertrochanteric fracture after PFNA.