19 cinnamamide/ester-triazole compounds were designed, synthesized and evaluated for their anti-Alzheimer's disease (AD) activity. Among them, compound 4f displayed excellent anti-β-amyloid protein (Aβ)-mediated cytotoxicity (EC₅₀ = 2.03 ± 2.45 μmol·L^-1) in APPswe cells and acetylcholinesterase inhibiton (IC₅₀ = 4.88 ± 4.70 μmol·L^-1). Further study indicated that, at dosages of (1, 5 and 25 mg·kg^-1), compound 4f was effective in improving spatial learning and memory deficits in Aβ_1-42-impaired mice, which was achieved by promoting the nonamyloidogenic signaling and inhibiting the amyloidogenic pathway, along with the suppression of Aβ-induced Tau phosphorylation. All animal experiments in this study were approved by the Experimental Animal Care and Use Committee of the Institute of Medicinal Biotechnology (IMB-20220908D701). In conclusion, compound 4f holds promise as a lead candidate for AD treatment, and the present study lays the foundation for its subsequent development.

In recent years, with the endless emergence of meibomian gland dysfunction(MGD)diagnostic equipment, rich treatment methods, and in-depth clinical and basic research on MGD at home and abroad, the understanding of MGD has entered a new stage. MGD-related dry eye is considered to be the main cause of lipid abnormal dry eye, and its occurrence and development is a chronic and multi-factorial pathological process. This article reviews the pathogenesis, imaging analysis and clinical treatment progress of MGD-related dry eye, in order to provide scientific evidence and ideas for clinical diagnosis and therapy of MGD-related dry eye.

OBJECTIVE To investigate the potential mechanism of berberine improving diabetes mellitus type 2 （T2DM） combined with metabolic-associated fatty liver disease （MAFLD） by regulating ceramide. METHODS Thirty-two db/db mice with blood glucose levels＞11.1 mmol/L （T2DM model） were divided into four groups： model group， berberine low- and high-dose groups [100， 200 mg/（kg·d）] and metformin group [300 mg/（kg·d）]， with 8 mice in each group. Additionally， 8 wt/wt mice were selected as the normal control group. Mice in each group were administered the corresponding drug solution or water by gavage once daily for a continuous period of 6 weeks. During the experiment， the body weight of the mice was monitored， and the differences in final body weight were analyzed. After the last administration， the body shape of the mice in each group was observed， and their fasting blood glucose （FBG） and the lipid indicators [total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）] were measured. Fasting serum insulin （FINS） levels were also measured， and the insulin resistance index HOMA-IR） and insulin sensitivity index （ISI） were calculated. Liver weight， liver index and serum liver function indicators [alanine transaminase （ALT）， aspartate transaminase（AST）] were assessed， and hepatic histopathological changes were observed. Additionally， the expression of fatty acid synthesis-related proteins [sterol regulatory element-binding protein 1 （SREBP1）， fatty acid synthase （FASN）， acetyl-CoA carboxylase 1 （ACC1）] in liver tissue was examined. Serum samples from the normal control group， model group， and berberine high-dose group were collected for non-targeted lipidomics analysis and validation. RESULTS Compared with the model group， the pathological changes， including disordered liver tissue cell arrangement and lipid vacuoles， were significantly improved in the berberine low- and high-dose groups. The significant decreases or down-regulations were observed in body weight in the last week， as well as FBG， TC， TG， and LDL-C levels， HOMA-IR （except for the berberine low-dose group）， liver weight， liver index， AST and ALT levels， and protein expressions of SREBP1， FASN and ACC1. Additionally， HDL-C levels， FINS （except for the berberine high-dose group）， and ISI （except for the berberine low-dose group） were significantly increased （P＜0.05）. A total of 21 potential differential metabolites， including multiple types of ceramides， were identified； these metabolites were primarily enriched in sphingolipid metabolism and glycerophospholipid metabolism pathways. Verification experiments confirmed that high-dose berberine significantly reduced the serum content of ceramide in model mice （P＜0.05）. CONCLUSIONS Berberine reduces insulin resistance， improves liver damage and lipid accumulation in the T2DM combined with MAFLD mice， and these effects may be related to the reduction of ceramide content.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, functional impairment, and neuropsychiatric symptoms. It represents the most prevalent form of dementia among the elderly population. Accumulating evidence indicates that oxidative stress plays a pivotal role in the pathogenesis of AD. Notably, elevated levels of oxidative stress have been observed in the brains of AD patients, where excessive reactive oxygen species (ROS) can cause extensive damage to lipids, proteins, and DNA, ultimately compromising neuronal structure and function. Amyloid β‑protein (Aβ) has been shown to induce mitochondrial dysfunction and calcium overload, thereby promoting the generation of ROS. This, in turn, exacerbates Aβ aggregation and enhances tau phosphorylation, leading to the formation of two pathological features of AD: extracellular Aβ plaque deposition and intracellular neurofibrillary tangles (NFTs). These events ultimately culminate in neuronal death, forming a vicious cycle. The interplay between oxidative stress and these pathological processes constitutes a core link in the pathogenesis of AD. The signaling pathways mediating oxidative stress in AD include Nrf2, RCAN1, PP2A, CREB, Notch1, NF‑κB, ApoE, and ferroptosis. Nrf2 signaling pathway serves as a key regulator of cellular redox homeostasis, exerts important antioxidant capacity and protective effects in AD. RCAN1 signaling pathway, as a calcineurin inhibitor, and modulates AD progression through multiple mechanisms. PP2A signaling pathway is involved in regulating tau phosphorylation and neuroinflammation processes. CREB signaling pathway contributes to neuroplasticity and memory formation; activation of CREB improves cognitive function and reduce oxidative stress. Notch1 signaling pathway regulates neuronal development and memory, participates in modulation of Aβ production, and interacts with Nrf2 toco-regulate antioxidant activity. NF‑κB signaling pathway governs immune and inflammatory responses; sustained activation of this pathway forms “inflammatory memory”, thereby exacerbating AD pathology. ApoE signaling pathway is associated with lipid metabolism; among its isoforms, ApoE-ε4 significantly increases the risk of AD, leading to elevated oxidative stress, abnormal lipid metabolism, and neuroinflammation. The ferroptosis signaling pathway is driven by iron-dependent lipid peroxidation, and the subsequent release of lipid peroxidation products and ROS exacerbate oxidative stress and neuronal damage. These interconnected pathways form a complex regulatory network that regulates the progression of AD through oxidative stress and related pathological cascades. In terms of therapeutic strategies targeting oxidative stress, among the drugs currently used in clinical practice for AD treatment, memantine and donepezil demonstrate significant therapeutic efficacy and can improve the level of oxidative stress in AD patients. Some compounds with antioxidant effects (such asα-lipoic acid and melatonin) have shown certain potential in AD treatment research and can be used as dietary supplements to ameliorate AD symptoms. In addition, non-drug interventions such as calorie restriction and exercise have been proven to exerted neuroprotective effects and have a positive effect on the treatment of AD. By comprehensively utilizing the therapeutic characteristics of different signaling pathways, it is expected that more comprehensive multi-target combination therapy regimens and combined nanomolecular delivery systems will be developed in the future to bypass the blood-brain barrier, providing more effective therapeutic strategies for AD.

ObjectiveTo explore the mechanism of Bushen Huoxue enema in treating the rat model of kidney deficiency and blood stasis-thin endometrium （KDBS-TE） by transcriptome sequencing. MethodThe rat model of KDBS-TE was established by administration of tripterygium polyglycosides tablets combined with subcutaneous injection of adrenaline. The pathological changes of rat endometrium in each group were then observed. Three uterine tissue specimens from each of the blank group， model group， and Bushen Huoxue enema group were randomly selected for transcriptome sequencing. The differentially expressed circRNAs， lncRNAs， and miRNAs were screened， and the disease-related specific competitive endogenous RNA （ceRNA） regulatory network was constructed. Furthermore， the gene ontology （GO） functional annotation and the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment were performed for the mRNAs in the network. ResultCompared with the blank group， the model group showed endometrial dysplasia， decreased endometrial thickness and endometrial/total uterine wall thickness ratio （P<0.01）， and differential expression of 18 circRNAs， 410 lncRNAs， and 7 miRNAs. Compared with the model group， the enema and estradiol valerate groups showed improved endometrial morphology and increased endometrial thickness and ratio of endometrial to total uterine wall thickness （P<0.05）. In addition， 21 circRNAs， 518 lncRNAs， and 17 miRNAs were differentially expressed in the enema group. The disease-related specific circRNA-miRNA-mRNA regulatory network composed of 629 nodes and 664 edges contained 2 circRNAs， 34 miRNAs， and 593 mRNAs. The lncRNA-miRNA-mRNA regulatory network composed of 180 nodes and 212 edges contained 5 lncRNAs， 10 miRNAs， and 164 mRNAs. The mNRAs were mainly enriched in Hippo signaling pathway， autophagy-animal， axon guidance， etc. ConclusionBushen Huoxue enema can treat KDBS-TE in rats by regulating specific circRNAs， lncRNAs， and miRNAs in the uterus and the ceRNA network.

This study investigated the effect of different carrier materials on the in vitro properties of progesterone solid dispersions. The solid dispersions of the insoluble drug progesterone were prepared by hot melt extrusion technique using rheological properties as the index of investigation, and the in vitro properties of the solid dispersions were characterized. Scanning electron microscope revealed solid dispersions with rough surfaces and agglomerated microstructures into irregular lumpy particles. Differential scanning calorimetry and powder X-ray diffraction showed the change of progesterone crystalline form in solid dispersions from crystalline to amorphous state. In vitro dissolution studies showed that solid dispersions prepared with different carrier materials can effectively improve the dissolution rate of drugs. The results of the study showed that the type of carrier material had a significant effect on the in vitro properties of solid dispersions, providing a reference for the study of solid dispersions in the controlled release of insoluble drugs.

Needle-free injection technology (NFIT) refers to the drug delivery systems in which drugs are propelled as high-speed jet streams using any of the pressure source to penetrate the skin to the required depth. NFIT is a promising drug delivery system as it enables the injection of liquids, powders, and depot/projectiles, and has the advantages of preventing needle stick accidents, improving drug bioavailability, eliminating needle-phobia, increasing vaccine immunity, simplifying operations and is convenient for patients to use. NFIT and its research background, the structure and classification of needle-free jet injectors (NFJI), drugs that can be delivered using NFJI and the factors affecting the injection effect are comprehensively reviewed in this paper. The limitations and potential development directions are summarized to provide a theoretical basis for the application and development of NFIT.

BACKGROUND:Diabetic osteoporosis is gaining public attention.However,few studies have reported the effect of a high-glucose environment on the osteogenic differentiation of human umbilical cord mesenchymal stem cells and the corresponding therapeutic strategies. OBJECTIVE:To investigate whether vitamin D3 can restore the osteogenic differentiation potential of human umbilical cord mesenchymal stem cells in a high-glucose environment. METHODS:The viability of human umbilical cord mesenchymal stem cells was detected by CCK-8 assay to screen the appropriate vitamin D3 intervention concentration.Under the high-glucose environment,RT-qPCR,western blot assay,immunofluorescence,JC-1 mitochondrial membrane potential,alizarin red staining,and β-galactosidase staining were used to evaluate the osteogenic differentiation potential,intracellular reactive oxygen species accumulation,mitochondrial membrane potential alteration,and cell senescence of human umbilical cord mesenchymal stem cells after vitamin D3 intervention.The underlying mechanism was also discussed. RESULTS AND CONCLUSION:(1)Vitamin D3 significantly promoted the proliferation of human umbilical cord mesenchymal stem cells in the range of 0.1 μmol/L to 1 mmol/L.(2)High-glucose environment down-regulated the mRNA and protein level expressions of osteogenic-related genes α1-I collagen,alkaline phosphatase,Runt-associated transcription factor 2,and osteocalcin in human umbilical cord mesenchymal stem cells,which induced oxidative stress and cellular senescence.(3)Vitamin D3 at an intervention concentration of 10 μmol/L significantly restored the osteogenic phenotype of human umbilical cord mesenchymal stem cells under high-glucose conditions and attenuated intracellular oxidative stress and cellular senescence by activating the Nrf2/HO-1 signaling pathway.(4)These findings suggested that the osteogenic differentiation ability of human umbilical cord mesenchymal stem cells was reduced in the high-glucose environment,and vitamin D3 could partially improve their osteogenic differentiation ability and reduce cell damage.

BACKGROUND:Osteoporosis has a high incidence,leading to fracture and other complications.However,existing drugs have great side effects and are difficult to meet the clinical application. OBJECTIVE:To explore the effect and potential mechanism of fucoxanthin on osteoporosis induced by glucocorticoid. METHODS:Primary rat osteoblasts were inoculated in 6-well plates.When the cell fusion reached 80%,the cells were divided into four groups:the control group was cultured alone for 24 hours,the glucocorticoid group was intervened with dexamethasone for 24 hours,the fucoxanthin group was intervened with fucoxanthin for 24 hours,and the glucocorticoid + fucoxanthin group was intervened with dexamethasone and fucoxanthin at the same time for 24 hours.After intervention,cell proliferation,apoptosis,intracellular reactive oxygen species level,and protein expression of apoptosis-related proteins,bone formation-related proteins,and nuclear factor erythroid-2-related factor 2 were detected. RESULTS AND CONCLUSION:Cell counting kit-8 results showed that the cell viability was decreased in the glucocorticoid group compared with the control group(P＜0.05)but increased in the glucocorticoid+fucoxanthin group compared with the glucocorticoid group(P＜0.05).JC-1 mitochondrial membrane potential staining and flow cytometry assay showed that the percentage of apoptosis increased in the glucocorticoid group compared with the control group(P＜0.05)but decreased in the glucocorticoid+fucoxanthin group compared with the glucocorticoid group(P＜0.05).Western blot assay showed that compared with the control group,the protein expression of BAX and cleaved poly(ADP-ribose)polymerase was elevated in the glucocorticoid group(P＜0.05),and the protein expression of BCL2,type Ⅰ collagen α1 peptide chain,alkaline phosphatase,osteocalcin,and RUNX2 was decreased in the glucocorticoid group(P＜0.05).Compared with the glucocorticoid group,the protein expression of BAX and cleaved poly(ADP-ribose)polymerase was decreased(P＜0.05),and the protein expression of BCL2,type Ⅰ collagen α1 peptide chain,alkaline phosphatase,osteocalcin,and RUNX2 was elevated(P＜0.05)in the glucocorticoid+fucoxanthin group.Fluorescent probe assay showed an increase in reactive oxygen species level in the glucocorticoid group compared with the control group(P＜0.05)and a decrease in reactive oxygen species level in the glucocorticoid+fucoxanthin group compared with the glucocorticoid group(P＜0.05).Immunofluorescence staining and western blot assay showed that the protein expression of nuclear factor erythroid-2-related factor 2 in the glucocorticoid group was decreased compared with that in the control group(P＜0.05);and the protein expression of nuclear factor erythroid-2-related factor 2 in the glucocorticoid+fucoxanthin group was elevated compared with that in the glucocorticoid group(P＜0.05).To conclude,fucoxanthin can improve glucocorticoid-induced osteoblast apoptosis and the expression of bone formation-related molecules by activating nuclear factor erythroid-2-related factor 2.

Objective To study the brain functional connectivity(FC)changes in patients with normal tension glau-coma(NTG)and healthy volunteers using FC technique of resting-state functional magnetic resonance imaging(rs-fMRI)based on V1 region seed point(ROI),so as to explore the pathogenesis and early diagnosis of NTG.Methods Fourteen NTG patients(NTG group)who met the inclusion criteria and 14 healthy controls(HCs group)were enrolled.The clinical data of all subjects were collected,and rs-fMRI was performed in both groups.The magnetic resonance data was pre-pro-cessed by software,and bilateral A1 regions were taken as the ROI to analyze their correction with the whole brain voxel time series and obtain the FC value between the ROI and the whole brain by comparison of FC values in resting state be-tween the groups.Pearson correlation analysis was used to explore the relationship between FC value in the brain regions with significant differences with the ROI and clinical variables in the NTG group.Results Compared with the subjects in the HCs group,there were no statistically significant differences in age,gender,body weight,cup-disc ratio and 24 h mean intraocular pressure of patients in the NTG group(all P＞0.05),and there were statistically significant differences in the best corrected visual acuity(BCVA)of both eyes and peripapillary retinal nerve fiber layer thickness(RNFLT)(all P＜0.05).The Pearson correlation analysis showed that FC value of the brain regions with abnormal FC to V1 region were cor-related with RNFLT in the NTG group(P＜0.05).ROI1-left superior frontal gyrus,ROI1-right superior frontal gyrus,ROI2-left cingulate gyrus and ROI2-right middle frontal gyrus were significantly positively correlated with RNFLT(all P＜0.05).Compared with the HCs group,the brain regions with reduced FC to the right ROI in the NTG group were the left superior frontal gyrus and right superior frontal gyrus;the brain regions with reduced FC to the left ROI were the left cingulate gyrus and right middle frontal gyrus.Conclusion Compared to healthy individuals,NTG patients have significant changes in the functional connections between certain specific brain regions and V1 region,including bilateral superior frontal gyrus,left cingulate gyrus,and middle frontal gyrus.The changes in brain functional activity may be caused by visual dysfunction caused by NTG,leading to functional impairment of the visual and cognitive emotion processing brain regions,which may be one of the potential neuropathological mechanisms in NTG patients.