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*

Objective 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.Conclusion 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.

Objective:To observe the effects of Yiyuan moxibustion on bladder function and antioxidant level of spinal cord tissues in rats with urinary retention after spinal cord injury (SCI); To explore the mechanism of inhibition of ferroptosis in spinal cord neurons after SCI by Yiyuan moxibustion.Methods:Wistar female rats were divided into sham-operation group, model group, and Yiyuan moxibustion group according to random number table method, with 12 rats in each group. The modified Allen′s vertical percussion method was used to construct the model of urinary retention after SCI in T10 segment. The rats in the Yiyuan moxibustion group were moxibued at the Zhongji acupoint, Guanyuan acupoint, and Shenque acupoint for 20 min per day, and the intervention was continued for 2 weeks. Urodynamic test was used to observe the degree of urinary retention in rats; HE staining was used to observe the morphological changes of the injured spinal cord tissues; transmission electron microscopy was used to observe the mitochondrial ultrastructure of the spinal cord tissues; ferric ion kit was used to detect the ferric ion content of the spinal cord tissues; ELISA was used to detect the GSH and MDA contents of the spinal cord tissues of the rats; Western blot was used to measure the relative expressions of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) proteins in rat spinal cord tissue.Results:Compared with the model group, the basal and leakage point pressures of the bladder, and bladder compliance were significantly reduced in the Yiyuan moxibustion group ( P<0.05); the spinal cord tissue structure was restored and mitochondrial morphology improved; the levels of iron ions and MDA in spinal cord tissue decreased ( P<0.05), while the level of GSH increased ( P<0.05), and the relative expressions of GPX4 and SLC7A11 proteins increased ( P<0.05). Conclusion:Yiyuan moxibustion can improve bladder function in rats with urinary retention after SCI, and the mechanism may involve the initiation of antioxidant defense and reduction of lipid peroxidation in spinal cord neuronal cells, thus preventing the occurrence of ferroptosis and achieving the protection of neuronal cells.

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.

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.

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 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.