Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

Oral solid dosage forms require processes such as disintegration and dissolution to release the drug before it can be absorbed and utilized by the body. In this manuscript, imaging technology was used to continuously visualize and characterize the in vitro static drug release process of gliclazide modified release tablets from 15 manufacturers, combined with the traditional method of in vitro dissolution testing, to determine the release profile of gliclazide modified release tablets, to evaluate the similarity of the release profiles by using the similarity factor (f₂) method and based on the analysis of the release profiles fitted with a variety of mathematical models. The results indicate that the gliclazide modified release tablets produced by 14 companies are hydrophilic gel matrix tablets. Compared to the reference listed drug, the release profiles of formulations from 11 companies show high similarity (f₂ > 50) to the reference. Among these, formulations with visual characteristics similar to the reference exhibit similar release curves. This study provides an alternative method for the in vitro consistency evaluation of gliclazide modified release tablets, aiming to assess the in vitro release behaviour of generic formulations more accurately and comprehensively.

The chemical constituents from the n-butanol fraction of ethanol extract of safflower (Carthamus tinctorius L.) were isolated and purified using chromatographic process including MCI Gel CHP-20, ODS, Sephadex LH-20 column chromatography, and semi-preparative HPLC method, and one alkyne and two phenylpropanoid derivants were obtained. Their structures were identified as (5R,E)-tetradecane-12-ene-8,10-diyne-1,5,14-triol (1), (E)-8-O-β-D-glucopyranosyl n-butyl cinnamate (2), and (7S,8S)-7-(4-hydroxy-3-methoxybenzene)-7-butyl-8,9-diol (3) by modern spectroscopy methods (1D NMR, 2D NMR, UV, IR and MS). 1-3 are all new compounds. Compounds 1-3 were screened for their anti-renal fibrosis activities in vitro, and none of them showed obvious effect.

ObjectiveJunctophilin-2 (JPH2) is an essential structural protein that maintains junctional membrane complexes (JMCs) in cardiomyocytes by tethering the plasma membrane to the sarcoplasmic reticulum, thereby facilitating excitation-contraction (E-C) coupling. Mutations in JPH2 have been associated with hypertrophic cardiomyopathy (HCM), but the molecular mechanisms governing its membrane-binding properties and the functional relevance of its membrane occupation and recognition nexus (MORN) repeat motifs remain incompletely understood. This study aimed to elucidate the structural basis of JPH2 membrane association and its implications for HCM pathogenesis. MethodsA recombinant N-terminal fragment of mouse JPH2 (residues1-440), encompassing the MORN repeats and an adjacent helical region, was purified under near-physiological buffer conditions.X-ray crystallography was employed to determine the structure of the JPH2 MORN-Helix domain. Sequence conservation analysis across species and junctophilin isoforms was performed to assess the evolutionary conservation of key structural features. Functional membrane-binding assays were conducted using liposome co-sedimentation and cell-based localization studies in COS7 and HeLa cells. In addition, site-directed mutagenesis targeting positively charged residues and known HCM-associated mutations, including R347C, was used to evaluate their effects on membrane interaction and subcellular localization. ResultsThe crystal structure of the mouse JPH2 MORN-Helix domain was resolved at 2.6 Å, revealing a compact, elongated architecture consisting of multiple tandem MORN motifs arranged in a curved configuration, forming a continuous hydrophobic core stabilized by alternating aromatic residues. A C-terminal α-helix further reinforced structural integrity. Conservation analysis identified the inner groove of the MORN array as a highly conserved surface, suggesting its role as a protein-binding interface. A flexible linker segment enriched in positively charged residues, located adjacent to the MORN motifs, was found to mediate direct electrostatic interactions with negatively charged phospholipid membranes. Functional assays demonstrated that mutation of these basic residues impaired membrane association, while the HCM-linked R347C mutation completely abolished membrane localization in cellular assays, despite preserving the overall MORN-Helix fold in structural modeling. ConclusionThis study provides structural insight into the membrane-binding mechanism of the cardiomyocyte-specific protein JPH2, highlighting the dual roles of its MORN-Helix domain in membrane anchoring and protein interactions. The findings clarify the structural basis for membrane targeting via a positively charged linker and demonstrate that disruption of this interaction—such as that caused by the R347C mutation—likely contributes to HCM pathogenesis. These results not only enhance current understanding of JPH2 function in cardiac E-C coupling but also offer a structural framework for future investigations into the assembly and regulation of JMCs in both physiological and disease contexts.

ObjectiveIn nature, objects cast shadows due to illumination, forming the basis for stereoscopic perception. Birds need to adapt to changes in lighting (meaning they can recognize stereoscopic shapes even when shadows look different) to accurately perceive different three-dimensional forms. However, how neurons in the key visual brain area in birds handle these lighting changes remains largely unreported. In this study, pigeons (Columba livia) were used as subjects to investigate how neurons in pigeon’s ventrolateral mesopallium (MVL) represent stereoscopic shapes consistently, regardless of changes in lighting. MethodsVisual cognitive training combined with neuronal recording was employed. Pigeons were first trained to discriminate different stereoscopic shapes (concave/convex). We then tested whether and how light luminance angle and surface appearance of the stereoscopic shapes affect their recognition accuracy, and further verify whether the results rely on specify luminance color. Simultaneously, neuronal firing activity of neurons was recorded with multiple electrode array implanted from the MVL during the presentation of difference shapes. The response was finally analyzed how selectively they responded to different stereoscopic shapes and whether their selectivity was affected by the changes of luminance condition (like lighting angle) or surface look. Support vector machine (SVM) models were trained on neuronal population responses recorded under one condition (light luminance angle of 45°) and used to decode responses under other conditions (light luminance angle of 135°, 225°, 315°) to verify the invariance of responses to different luminance conditions. ResultsBehavioral results from 6 pigeons consistently showed that the pigeons could reliably identify the core 3D shape (over 80% accuracy), and this ability wasn’t affected by changes in light angle or surface appearance. Statistical analysis of 88 recorded neurons from 6 pigeons revealed that 83% (73/88) showed strong selectivity for specific 3D shapes (selectivity index>0.3), and responses to convex shapes were consistently stronger than to concave shapes. These shape-selective responses remained stable across changes in light angle and surface appearance. Neural patterns were consistent under both blue and orange lighting. The decoding accuracy achieves above 70%, suggesting stable responses under different conditions (e.g., different lighting angles or surface appearance). ConclusionNeurons in the pigeon MVL maintain a consistent neural encoding pattern for different stereoscopic shapes, unaffected by illumination or surface appearance. This ensures stable object recognition by pigeons in changing visual environments. Our findings provide new physiological evidence for understanding how birds achieve stable perception (“invariant neural representations”) while coping with variations in the visual field.

Aim To design the pyrimidoindole deriva-tive N-butyl-9H-pyrimido[4,5-b]indole-2-carboxamide(BFPI)and synthesize it to investigate whether it in-hibits macrophage pyroptosis and foaming effects through the NLRP3/Caspase-1 pathway.Methods BFPI was synthesized using 2,4,6-triethoxycarbonyl-l,3,5-triazine and 2-aminoindole as starting materials and structurally characterized by 1H NMR,13C NMR,and ESI-MS.The in vitro cultured mouse monocyte macro-phage cell line RAW264.7 was divided into blank,model(PA)and therapeutic(BFPI)groups,and the cells in each group were treated with the corresponding culture medium for 24 h.The proliferative viability was detected by MTT assay,and the formation of intracel-lular lipid droplets was detected by oil red O staining,and NLRP3 was detected by Western-blot and RT-qPCR,caspase-1 and MCP-1 mRNA and protein ex-pression levels by Western blot and RT-qPCR.Results Compared with the blank group,the proliferation vi-ability of cells in the model group significantly de-creased and the formation of lipid droplets significantly increased;compared with the model group,the prolif-eration viability of cells in the treatment group signifi-cantly increased and the formation of lipid droplets sig-nificantly decreased,and the differences were statisti-cally significant(P＜0.01);compared with the blank group,the cellular NLRP3,caspase-1 and MCP-1 mR-NA and protein expression levels of cells in the model group significantly increased;compared with the model group,the expression levels of the above indexes of the cells in the treatment group significantly decreased,and the difference was statistically significant(P＜0.01).Conclusions BFPI contributes to delaying macrophage-derived foam cell formation during athero-genesis by inhibiting macrophage NLRP3,caspase-1,and MCP-1 expression and thereby promoting their pro-liferation and inhibiting lipid phagocytosis.

Aim To investigate the mechanism of icar-itin(ICT)on D-galactose(D-gal)-induced TM4 ser-toli cell junctional function damage in vitro.Methods TM4 cells were divided into the normal control group and D-gal treatment group with different concentra-tions.The expression changes of TM 4 cell junction function-related proteins(ZO-1,Occludin,β-catenin and Cx43)and ERα/FAK signaling pathway-related proteins(ERα,FAK and pY397-FAK)were detected by Western blot.The concentration of ICT was screened by MTT method.TM4 cells were divided into normal control group,D-gal treatment group,and D-gal treatment+different concentrations of ICT group.The expression levels of the above proteins were detected by Western blot.Molecular docking was used to study the interaction between ERα and ICT,meanwhile predict the affinity between them.Finally,TM4 cells were di-vided into normal control group,D-gal treatment group,ERα inhibitor group,D-gal+ICT group,and ERα inhibitor+ICT group.The expression levels of the above proteins were detected by Western blot.Re-sults Compared with the normal control group,the ex-pression of junctional function-related proteins(ZO-1,Occludin,β-catenin and Cx43)and ERα/FAK signa-ling pathway-related proteins(ERα,FAK and pY397-FAK)were significantly down-regulated.After treat-ment with ICT,the expression of above proteins were significantly up-regulated.The docking results of ERα and ICT molecules revealed the formation of two hydro-gen bonds between Asp351 amino acid residue of ERα and ICT,with bond distances measuring 3.4? and 2.4?.Additionally,the docking binding energy be-tween them was found to be lower than-7 kcal·mol-1.After TM4 cells were treated with ERα inhibi-tor,the expression of above proteins and ERα/FAK signaling pathway-related proteins were significantly down-regulated,while the expression levels of the a-bove proteins did not change significantly after being given ICT protected group.Conclusions D-gal can cause damage to the junctional function of TM4 cells,and ICT can improve this damage,which may be related to the up-regulation of ERα/FAK signaling pathway.

The purpose of this study was to investigate the regulatory effects of biofilm associated non-coding small RNA(sRNA)00085 on the survival and environmental fitness of Listeria monocytogenes.Homologous recombination technology was used to construct a deletion mutant strain(△sRNA 00085)and a complementary strain(C △sRNA 00085)of the sRNA00085 target gene.The differences in biological characteristics were compared among the standard strain,△sRNA 00085,and C△sRNA 00085.The deletion of sRNA00085 led to a significant decrease in biofilm formation capacity and sensitivity to several antibiotics,including penicillin,piperacillin,doxycycline,tetracycline,vancomycin,and cotrimoxazole.However,only the minimum inhibitory concentration(MIC)of tetracycline exhibited a significant decrease in △sRNA00085.Meanwhile,the decreased biofilm formation and antibiotic resistance of the sRNA00085 mutant were restored in the C△sRNA00085 strain.Furthermore,we investigated the transcription levels of tetracycline resistance-related genes in L.monocytogenes.Down-regu-lated transcription of the tetS gene but no significant difference in transcription of the tetA gene were observed in △sRNA 00085 compared with the standard strain and C△sRNA00085.Moreover,the elimination of sRNA00085 did not affect bacterial growth ability or sensitivity to disinfectants.These findings highlight that sRNA00085 plays an important role in the environ-mental adaptability of L.monocytogenes by affecting bacterial biofilm formation and resistance.

Objective:To investigate the safety and efficacy of mitoxantrone liposome in the treatment of children with high-risk acute myeloid leukemia(AML).Methods:The children with high-risk AML who received the mitoxantrone liposome regimen at Wuhan Children's Hospital from January 2022 to February 2023 were collected as the observation group,and the children with high-risk AML who received idarubicin regimen were enrolled as controls,and their clinical data were analyzed.Time to bone marrow recovery,the complete remission rate of bone marrow cytology,the clearance rate of minimal residual disease,and treatment-related adverse reactions were compared between the two groups.Results:The patients treated with mitoxantrone liposome showed shorter time to recovery of leukocytes(17 vs 21 day),granulocytes(18 vs 24 day),platelets(17 vs 24 day),and hemoglobin(20 vs 26 day)compared with those treated with idarubicin,there were statistical differences(P＜0.05).The effective rate and MRD turning negative rate in the observation group were 90.9％and 72.7％,respectively,while those in the control group were 94.1％and 76.4％,with no statistical difference(P＞0.05).The overall response rate of the two groups of patients was similar.Conclusion:The efficacy of mitoxantrone liposome is not inferior to that of idarubicin in children with high-risk AML,but mitoxantrone liposome allows a significantly shorter duration of bone marrow suppression and the safety is better.

Objective:To investigate the mechanism of DNA damage and repair in MLL-rearranged acute myeloid leukemia(MLL-r AML)cells by the combination of Chidamide and the BRD4 inhibitor(+)-JQ-1.Methods:MLL-r AML cell lines Molm-13,MV4-11 and non-MLL-r AML cell line Kasumi were divided into control group(contr),Chidamide group(chida),(+)-JQ-1 group and Combination group(combi),respectively.Cell viability of Molm-13 was measured by CCK-8 to determine optimal the concentrations of Chidamide and(+)-JQ-1.The cell cycle was detected by flow cytometry,and apoptosis-related factors Bcl-2,Bax and caspase-3 were detected by Western blot.DNA damage marker γH2AX was detected by immunofluorescence.The protein expressions of DNA damage factor γH2AX,DNA damage checkpoint kinases p-ATR,p-CHK1,p-ATM,p-CHK2 and DNA damage repair factors Rad51 and 53BP1 were detected by Western blot.The expression of DNA damage repair factors Rad51 and 53BP1 mRNA was detected by qRT-PCR.Results:Under the treatment of Chidamide(300 nmol/L)and(+)-JQ-1(400 nmol/L),the proportion of G1 phase cells in MLL-r AML cell lines Molm-13 and MV4-11 was increased in combination group compared with control group.In non-MLL-r AML cell line Kasumi,compared with control group,the proportion of G1 phase cells in combination group was increased(P＜0.05).In Molm-13 and MV4-11 cell lines,compared with control group,the expression level of DNA damage marker γH2AX in combination group was increased(P＜0.05).The expression levels of DNA damage checkpoint and damage repair factors p-ATR,p-CHK1,p-ATM,p-CHK2,Rad51,53BP1 were decreased(P＜0.05).In Kasumi cell line,compared with control group,there was no significant change in the expression of some of the above factors in combination group(P＞0.05),but the expression trend of some factors was opposite.In MLL-r AML cell lines Molm-13 and MV4-11,compared with control group,the expression levels of Bax and caspase-3 protein were increased in combination group,while the expression levels of Bcl-2 protein were decreased(P＜0.05).In non-MLL-r AML cell line Kasumi,there was no significant change in apoptotic factor protein expression in combination group compared with control group(P＞0.05).Conclusion:Chidamide combined with(+)-JQ-1 can inhibit the proliferation of MLL-r AML cells,inhibit the initiation of protective self-repair of these leukemia cells by inhibiting the DNA damage response pathway,and ultimately increase the apoptosis of these cells,but non-MLL-r AML cells have no similar results.