Plant-derived extracellular vesicles (PDEVs), describe a group of nanoparticles released by plants. These particles are characterized by a lipid bilayer structure containing various proteins, lipids, nucleic acids, and unique metabolites. Although the study on PDEVs is relatively new, having only been around for ten years, they have shown promising development prospects in both basic research and clinical transformation areas. Evidence suggests that PDEVs have excellent application prospects in regulating inflammation and treating tumors. Their distinctive, vesicle-mimicking architecture and stellar biocompatibility render them prime candidates for ferrying various anti-cancer agents, including RNA, proteins, and conventional chemotherapy drugs. Increasingly, studies have shown that PDEVs can be engineered as an innovative platform for combination cancer immunotherapy. Consequently, this paper provides an extensive summary of current developments in engineering methods and strategies for PDEVs in cancer treatment and combined cancer immune therapeutics. The essential characteristics of PDEVs, including the biogenesis process and components, as well as their anti-tumor activity and mechanism, are summarized. Finally, the in vivo safety of PDEVs as delivery vectors and the challenges of scale-up production and clinical transformation are discussed.

Osteoporosis is a prevalent skeletal condition characterized by reduced bone mass and strength, leading to increased fragility. Buqi-Tongluo (BQTL) decoction, a traditional Chinese medicine (TCM) prescription, has yet to be fully evaluated for its potential in treating bone diseases such as osteoporosis. To investigate the mechanism by which BQTL decoction inhibits osteoclast differentiation in vitro and validate these findings through in vivo experiments. We employed MTS assays to assess the potential proliferative or toxic effects of BQTL on bone marrow macrophages (BMMs) at various concentrations. TRAcP experiments were conducted to examine BQTL's impact on osteoclast differentiation. RT-PCR and Western blot analyses were utilized to evaluate the relative expression levels of osteoclast-specific genes and proteins under BQTL stimulation. Finally, in vivo experiments were performed using an osteoporosis model to further validate the in vitro findings. This study revealed that BQTL suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and osteoclast resorption activity in vitro in a dose-dependent manner without observable cytotoxicity. The inhibitory effects of BQTL on osteoclast formation and function were attributed to the downregulation of NFATc1 and c-fos activity, primarily through attenuation of the MAPK, NF-κB, and Calcineurin signaling pathways. BQTL's inhibitory capacity was further examined in vivo using an ovariectomized (OVX) rat model, demonstrating a strong protective effect against bone loss. BQTL may serve as an effective therapeutic TCM for the treatment of postmenopausal osteoporosis and the alleviation of bone loss induced by estrogen deficiency and related conditions.
Animals ; NFATC Transcription Factors/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Ovariectomy ; Osteoclasts/metabolism* ; Female ; Osteogenesis/drug effects* ; Rats, Sprague-Dawley ; Rats ; NF-kappa B/genetics* ; Osteoporosis/genetics* ; Signal Transduction/drug effects* ; Bone Resorption/genetics* ; Cell Differentiation/drug effects* ; Humans ; RANK Ligand/metabolism* ; Mitogen-Activated Protein Kinases/genetics* ; Transcription Factors

Background and aims:Metabolic dysfunction-associated fatty liver disease(MAFLD)is a common chronic condition that can lead to cancer due to its complex pathogenesis.Therapeutic agents targeting AMP-activated protein kinase(AMPK)activation have been suggested as potential treatments for metabolic disorders such as metabolic dysfunction-associated steatohepatitis(MASH).Rhizoma Atractylodis Mac-rocephalae(RAM)has been clinically used to treat obesity-related health problems,but its therapeutic effects on MAFLD and the underlying mechanism remain unclear.Therefore,this study was conducted to evaluate the function and underlying mechanism of RAM in the treatment of MAFLD.Methods:The effect of RAM decoction on MAFLD was evaluated using a high-fat diet(HFD)-induced MAFLD mouse model.In vitro studies were conducted using a palmitic acid/oleic acid-induced lipid accumulation model in the alpha mouse liver 12 cells and RAM-containing serum.The underlying mechanisms were elucidated through a combination of network pharmacology analysis,immunohis-tochemistry,western blotting,and polymerase chain reaction analysis.Results:Administration of RAM decoction significantly reduced body weight gain in MAFLD mice without changing food intake.The weights of the liver and inguinal adipose tissues were also reduced after RAM treatment.Additionally,RAM administration decreased serum levels of alanine aminotrans-ferase,aspartate transaminase,total cholesterol,triglyceride,low-density lipoprotein cholesterol,and glucose,while reducing lipid droplet accumulation in the liver tissues of MAFLD mice.The underlying mechanisms included the activation of the phosphorylation of AMPK and acetyl-CoA carboxylase(ACC),and inhibition of the expression of sterol regulatory element binding protein 1(SREBP1).However,RAM did not alter the protein expression levels of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1α.Furthermore,the RAM-induced upregulation of phosphorylated AMPK,phos-phorylated ACC,and SREBP1 expression,as well as the downregulation of fatty acid synthase expression,were reversed by using an AMPK inhibitor.Conclusions:Through a combination of network pharmacology and experimental validation,we demonstrated that RAM may exert therapeutic effects on MAFLD by inhibiting lipid synthesis and activating phosphorylated AMPK pathways.

Objective To explore the effects of acceptance and commitment therapy(ACT)on anxiety,depression and self-management abilities of patients with maintenance hemodialysis(MHD).Methods A total of 140 MHD patients from June 2021 to December 2023 were selected as research subjects,and were randomly divided into control group and study group,with 70 cases in each group.The control group received routine nursing,while the study group received ACT intervention based on routine nursing care.Score of Self-rating Anxiety Scale(SAS),score of Self-rating Depression Scale(SDS),and score of self-management ability were compared before and after intervention in both groups.Results After intervention,the SAS and SDS scores in both groups decreased significantly,with the study group having significantly lower SAS and SDS scores than the control group(P＜0.05).After intervention,the self-management ability scores of all dimensions in both groups were sig-nificantly higher than those before intervention,with the study group having significantly higher scores in all dimensions than the control group(P＜0.05).Conclusion ACT can improve anxiety and de-pression in MHD patients,enhance their self-management abilities,and improve their quality of life.

Objective There are 6 leads of limb lead ECG,and the cardiac electrical axis can be estimated by any combination of two leads.In this paper,the estimation accuracy of all 15 pairs of limb-lead combinations was compared.Methods Using the open database of 12-lead electrocardiograms(at a sampling frequency of 500 Hz with duration of 10 seconds during resting state)from PhysioNet,totally 21 306 ECG records were extracted with age≥18 years which labeled as single sinus type(axis normal),including 6 153 records with Sinus Rhythm,10 916 records with Sinus Bradycardia,3 466 records with Sinus Tachycardia,and 771 records with Sinus Irregularity.Moreover,totally 2 323 axis deflection recordings with age≥18 years were extracted,including 1 526 records with Axis left shift,and 797 records with Axis right shift.Cardiac electrical axis was estimated with the net amplitude(or area)of QRS complex(algebraic sum of positive and negative amplitude or area)by any pair of leads from{Ⅰ,Ⅱ},{Ⅰ,Ⅲ},{Ⅰ,aVR},{Ⅰ,aVL},{Ⅰ,aVF},{Ⅱ,Ⅲ},{Ⅱ,aVR},{Ⅱ,aVL},{Ⅱ,aVF},{Ⅲ,aVR},{Ⅲ,aVL},{Ⅲ,aVF},{aVR,aVL},{aVR,aVF},{aVL,aVF},respectively.Results For the amplitude-based method,the recognition accuracy for the normal,left and right axes from{Ⅰ,Ⅱ}and{Ⅱ,aVL}is 93.56%and 93.50%,respectively,which is better than that of the traditional classical method{I,aVF}(92.93%).For the area-based method,the recognition accuracy from{Ⅲ,aVR},{Ⅰ,aVR},{Ⅰ,Ⅱ},{aVR,aVF},{Ⅱ,aVL}and{Ⅱ Ⅲ}is 92.66%,92.53%,92.29%,92.19%,92.10%and 91.91%,respectively,which is better than the traditional classical method{Ⅰ,aVF}(91.82%).Conclusion The accuracy of amplitude-based method is higher than that of area-based method.Lead pair{Ⅰ,Ⅱ}and{Ⅱ,aVL}have higher accuracy than traditional classical{Ⅰ,aVF}in automatic estimation of cardiac electrical axis for both amplitude and area method.

Objective:To survey the status quo and influencing factors of contracted family doctor pay services in urban communities of Suzhou city.Methods:This study was a cross-sectional study. A questionnaire survey on the status quo and influencing factors of contracted family doctor pay services was conducted from July to October 2022 among 750 residents from 40 communities of 4 subdistricts in Suzhou Gusu District, selected by stratified random sampling method. A self-designed questionnaire was used for the survey, which included demographic information, status quo of pay services among residents and factors influencing the service contracting. Chi-square test and binary logistic regression were used to analyze the influencing factors of contracted family doctor pay services.Results:A total of 750 questionnaires were distributed, with 720 valid ones returned at a recovery rate of 96.0%. Among the 720 residents, 370 (51.4%) were female, and 300 (41.7%) were between the age of 35 and 60 years old. There were 71 residents who had contracted pay services with a contracting rate of 9.9% (71/720), and the renewal rate was 80.3% (57/71). The top 3 reasons for signing the contract were health guidance (67.6%, 48/71), medical counselling (63.4%, 45/71) and 3 free consultations (57.7%, 41/71). The top 3 reasons for not signing a contract were not needing services (49.9%, 324/649), not knowing about contracted services (41.9%, 272/649) and rarely visiting the community health service center (25.6%, 166/649). Age ( χ2=21.072), marital status ( χ2=10.969), knowing the family doctor team ( χ2=145.954), knowing the family doctor contract system ( χ2=133.981), knowing the content and the rights of the contracted services ( χ2=132.905), using primary medical institutions as first choice for common and chronic diseases ( χ2=13.532), multiple comorbid chronic diseases ( χ2=30.024), being agreed by family members ( χ2=46.258), signing contract in family members ( χ2=108.833) or relatives and friends ( χ2=47.492), and experience in community health service centers ( χ2=26.116) were significantly associated with the contract signing (all P<0.05). Logistic regression analysis showed that knowing family doctor team well ( OR=23.13,95% CI:5.05-105.97) or very well( OR=95.28,95% CI: 10.71-847.68); having ≥3 chronic diseases compared to no chronic diseases ( OR=5.60, 95% CI: 1.88-16.75, P<0.05); contracting agreed by family members compared to not agreed ( OR=2.66, 95% CI: 1.03-6.84, P<0.05); signing contract in family members compared to not signing ( OR=4.42, 95% CI:2.05-9.55, P<0.05) were independent influencing factors of signing contract of family doctor pay services. Conclusions:The rate of contracted of family doctor pay services in Gusu District of Suzhou City is relatively low. Knowing the family doctor team, having multiple comorbid chronic diseases, agreement among family members, and signing contract in family members are influencing factors of contracted family doctor pay services.

Tumor microenvironment(TME)is a complex cellular environment where tumor cells reside,along with various types of cells and extracellular components surrounding the tumor cells.Immune cells are key components of TME,including tumor-associated macrophages(TAMs),myeloid-derived suppressor cells(MDSCs),lymphocytes,regulatory T cells(Tregs),natural killer cells(NK cells),dendritic cells(DCs),and many others.It is worth noting that drug resistance is currently a major factor limiting the efficacy of cancer treatment methods such as chemotherapy,radiotherapy,targeted therapy,and immunotherapy,and a leading cause of treatment failure.Research has found that the development of drug resistance in tumor cells is the result of interactions between tumor cells and TME.Consequently,overcoming drug resistance in tumors caused by TME is considered a significant challenge in cancer treatment.In recent years,with in-depth research into immune cells within TME,significant progress has been made in understanding the specific mechanisms by which immune cells regulate drug resistance in tumor cells.Furthermore,therapeutic strategies that target these immune cells,signaling pathways,or cytokines have been shown to effectively combat tumor drug resistance and enhance the therapeutic outcomes of cancer treatment.This article reviews the research advancements regarding the roles of TAMs,MDSCs,Tregs,and NK cells in tumor drug resistance within TME and discusses the development of targeting strategies to overcome this resistance.Additionally,we explore the relationship of tumor-associated neutrophils(TANs)and B regulatory cells(Bregs)with tumor drug resistance.It is hoped that this review will offer insights and serve as reference for reducing tumor drug resistance and improving the efficacy of anti-tumor therapies.

Objective: To explore whether Lycium barbarum polysaccharide (LBP) can reduce the apoptosis of retinal photoreceptor cells in retinitis pigmentosa (RP) mice by inhibiting nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway. Methods: (i) In vitro experiments, mouse retinal ganglion cells (661W cells) were divided into normal, model, LBP low-dose (LBP-L, 40 mg/L), LBP middle-dose (LBP-M, 80 mg/L), LBP high-dose (LBP-H, 160 mg/L), and positive drug control (NLRP3 inhibitor, 160 mg/L) groups. And the 661W cells were exposed to varying concentrations of H2O2 ranging from 50 to 400 μmol/L to determine the optimal concentration for inducing apoptosis (200 μmol/L). Then the cell viability was assessed using Cell Counting Kit-8 (CCK-8), while the apoptosis rate was detected by flow cytometry; the expression of NLRP3 was detected by immunofluorescence; and the expression of apoptosis markers was detected by enzyme-linked immunosorbent assay (ELISA) and Western blot (WB). (ii) In vivo assays were carried out with the use of C57/BL6 and Rd10 mice. The animal experimental groups were divided into normal, model, LBP-L, LBP-M, LBP-H, and NLRP3 inhibitor groups, in which the normal group was C57/BL6 mice and the other groups were Rd10 mice. Ten mice were included in each group, and the corresponding drugs were administered intragastrically for a duration of four weeks. NF-κB/NLRP3 pathway and the expression of apoptosis markers were observed by electroretinogram, histopathological examination, and WB to assess the effects of LBP on retinal photoreceptor cell apoptosis. Results: (i) In vitro experiments, compared with the normal group, the apoptosis rate of 661W cells in model group was significantly increased (P < 0.01), and the expression levels of key proteins of NF-κB/NLRP pathway, such as NLRP3, NF-κB, p-NF-κB, and pro-apoptotic protein caspase-3, were up-regulated (P < 0.01). The rate of Bax/Bcl-2 was increased (P < 0.01), and the concentrations of interleukin (IL)-1β and tumor necrosis factor (TNF)-α were significantly increased (P < 0.01). Compared with the model group, high dose of LBP decreased the apoptosis rate of 661W cells (P < 0.01), and down-regulated the expression levelsof the key proteins of NF-κB/NLRP3 pathway, including NF-κB, NLRP3, p-NF-κB, and caspase-3 (P < 0.01). The rate of Bax/Bcl-2 was decreased (P < 0.01), and the concentrations of IL-1β and TNF-α were decreased (P < 0.01). (ii) In vivo experiments, high dose of LBP significantly increased morphological changes in the outer nuclear layer (ONL) thickness of Rd10 mice, as well as functional changes in the amplitudes of the a-wave and b-wave (P < 0.01), which also down-regulated the expression levels of NF-κB (P < 0.05), NLRP3, p-NF-κB, and caspase-3 (P < 0.01), reduced the Bax/Bcl-2 rate (P < 0.01), and decreased the concentrations of IL-1β (P < 0.01) and TNF-α (P < 0.05). Conclusion LBP could improve both retinal morphology and function, providing protection to photoreceptors from apoptosis through the inhibition of the NF-κB/NLRP3 pathway.

Objective To investigate the intervention effect of Xuanfuhua decoction on mice with nonalcoholic steatohepatitis (NASH) induced by high-fat, high-fructose, and high-cholesterol diet. Methods A total of 32 male C57/BL6J mice were randomly divided into normal group, model group, Xuanfuhua decoction group, and obeticholic acid group, with 8 mice in each group. Since week 24 of modeling using high-fat, high-fructose, and high-cholesterol diet, each group was given the corresponding drug for intervention at a dose of 14.19 g/kg by gavage for the Xuanfuhua decoction group and 10 mg/kg by gavage for the obeticholic acid group and a volume of 20 mL/kg for gavage, once a day for 6 consecutive weeks. HE staining, oil red O staining, Sirius Red staining, and Masson staining were used to observe the pathological changes, lipid deposition, and collagen deposition of liver tissue; related kits were used to measure the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and glucose, as well as the content of TG and hydroxyproline (Hyp) in liver tissue; quantitative real-time PCR was used to measure the expression of genes associated with lipid metabolism, inflammation, and fibrosis in liver tissue; immunohistochemical staining was used to observe the positive expression of F4/80 and α-SMA in liver tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. Results Compared with the normal group, the model group had significant increases in body weight, liver wet weight, and serum levels of AST, ALT, TC, TG, LDL-C and glucose (all P < 0.01). HE staining showed hepatocyte steatosis, a large number of fat vacuoles, hepatocyte ballooning degeneration, and inflammatory cell infiltration in liver tissue of the mice in the model group, and the model group had a significant increase in NAFLD activity score (NAS) compared with the normal group ( P < 0.01). Oil red O staining showed the deposition of a large number of red lipid droplets with different sizes in hepatocytes of the mice in the model group, and compared with the normal group, the model group had significant increases in the area percentage of oil red O staining and the content of TG in the liver ( P < 0.01). Sirius Red staining and Masson staining showed significant collagen fiber hyperplasia in the perisinusoidal area, the central vein, and the portal area in the model group, and the model group had a significant increase in the content of Hyp in liver tissue compared with the normal group ( P < 0.05). Compared with the model group, the Xuanfuhua decoction group had significant reductions in the serum levels of AST, ALT, TC, TG, LDL-C, and glucose (all P < 0.05), significant improvements in hepatic steatosis, inflammatory infiltration, lipid droplet deposition, and collagen fiber hyperplasia, and significant reductions in NAS score, area percentage of oil red O staining, and content of TG and Hyp in the liver (all P < 0.05). Compared with the normal group, the model group had significant increases in the mRNA expression levels of lipid metabolism-related genes (SREBP-1c, FASN, SCD-1, PPAR-γ, and CD36), inflammation-related genes (F4/80, TNF-α, CCL2, and CD11b), and the fibrosis-related gene α-SMA (all P < 0.05), and immunohistochemical staining showed significant increases in the positive expression of F4/80 and α-SMA ( P < 0.01). Compared with the model group, the Xuanfuhua decoction group had significant reductions in the mRNA expression levels of SREBP-1c, FASN, SCD-1, PPAR-γ, CD36, F4/80, TNF-α, CCL2, CD11b, and α-SMA in liver tissue (all P < 0.05), and immunohistochemical staining showed significant reductions in the positive expression of F4/80 and α-SMA ( P < 0.01). Conclusion Xuanfuhua decoction has a good intervention effect on mice with NASH induced by high fat, high fructose, and high-cholesterol diet and can significantly inhibit hepatic lipid deposition, inflammatory response, and liver fibrosis.

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a. Also, the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of 4a, especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate 5f, with a potent IC₅₀ value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.