Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

OBJECTIVES: To investigate the effects of early life intervention with Bifidobacterium bifidum BD-1 (B. bifidum BD-1) on hyperactivity in a female mouse model of attention deficit hyperactivity disorder (ADHD) and explore the underlying mechanisms. METHODS: Eight newborn female Wistar-Kyoto (WKY) rats and 6 spontaneous hypertensive rats (SHRs) were gavaged with saline and another 6 SHRs were gavaged with B. bifidum BD-1 (10⁹ CFU) daily for 3 weeks. Open field test of the rats was conducted at 7 weeks, and fecal samples were collected at weaning (3 weeks) and at 7 weeks for 16S rRNA sequencing. Immunofluorescent staining was used to detect dopamine transporter (DAT) and tyrosine hydroxylase (Th) levels in the striatum and activated microglia in the prefrontal cortex. Treg cells in the mesenteric lymph nodes, spleen and blood were analyzed using flow cytometry. RESULTS: The SHRs traveled a significantly greater distance in open fields test than WKY rats, and this behavior was significantly attenuated by B. bifidum BD-1 intervention. The expression of DAT and Th in the striatum was significantly lower in the SHRs than in WKY rats, while B. bifidum BD-1 treatment obviously increased Th levels in the SHRs. B. bifidum BD-1 intervention significantly deceased the number of activated microglia and increased Treg cell counts in the spleen of SHRs. The treatment also enhanced α diversity in gut microbiota of the SHRs and resulted in a decreased Firmicutes/Bacteroidota ratio, more active Muribaculaceae growth, and suppression of Clostridia_UCG-014 proliferation. CONCLUSIONS Early life intervention with B. bifidum BD-1 alleviates hyperactivity in female SHRs by modulating the gut microbiota and peripheral immune response, suppressing neuroinflammation and improving dopaminergic system function. These findings provide evidence for early prevention strategies and support the development and application of psychobiotics for ADHD.
Animals ; Female ; Rats ; Rats, Inbred WKY ; Rats, Inbred SHR ; Attention Deficit Disorder with Hyperactivity/therapy* ; Bifidobacterium bifidum ; Probiotics/therapeutic use* ; Dopamine Plasma Membrane Transport Proteins/metabolism* ; Tyrosine 3-Monooxygenase/metabolism* ; Gastrointestinal Microbiome ; Disease Models, Animal

Exosomes, as crucial mediators of intercellular communication, exhibit a wide range of biological functions in the onset and treatment of atherosclerosis (AS). Recent studies have indicated that exosomes can carry various active substances, including miRNA, lncRNA, proteins, and lipids. By regulating inflammatory responses, lipid metabolism, vascular endothelial function, and the immune microenvironment, they mediate the formation, progression, and reversal of AS at multiple levels. Specifically, miRNAs within exosomes can target and regulate the expression of inflammatory factors, inhibiting macrophage activation and foam cell formation. Meanwhile, exosomes derived from endothelial cells (EC) or stem cells can enhance vascular endothelial integrity and suppress endothelial dysfunction (ED). Furthermore, exosomes have been extensively explored as natural carriers for delivering drugs and nucleic acid molecules. Their membrane structure possesses excellent biocompatibility and targeting capabilities, showcasing significant potential as a novel therapeutic tool. Starting from basic mechanistic studies, this article summarizes the molecular pathways and key biological effects of exosomes in AS intervention, and further explores their current clinical application and multiple challenges they face, aiming to provide theoretical support and research directions for novel cardiovascular disease intervention strategies.

Objective To investigate the role and mechanism of urate in chronic kidney disease complicated with renal interstitial fibrosis(CKD-RIF).Methods Mice were continuously fed with a diet containing 0.2％adenine for a duration of 9 weeks to establish mice models with CKD-RIF.By the end of the 9-week experimental periods,collected blood samples from the posterior orbital venous plexus of mice to measure renal functions and serum urate concentrations prior to euthanizing the mice.Hematoxylin-eosin(HE)staining and periodic acid-Schiff staining(PAS)were used to investigate the pathological alternations in kidney tissues.Masson's trichrome staining was used to observe the extent of renal fibrosis.Urate staining was used to detect urate deposition in renal tissues.Western blot and immunohistochemistry were used to detect the expression of target molecules.Scratch tests were used to ex-amine the migration abilities of cells treated with different concentrations of uric acid.Results The kidney function analysis showed that a significant increase in the levels of serum urea nitrogen(P=0.006 4),creatinine(P=0.008 0)and urate(P=0.000 7)in the CKD-RIF mice compared with the normal control group.The results of HE staining and PAS staining showed a significance of renal tubule injury and infiltration of inflammatory cells in the model group.Masson's trichrome staining showed that a marked increase in collagen deposition in the model group.The results of urate staining showed a significant presence of urate crystals in kidney tissue of the model group when compared to the control group.Animal tissue immunoblotting and immunohistochemistry analysis showed a significant increase in the expression levels of vimentin,α-SMA and TGF-β1 in the model group in comparison to the control group.Conversely,in the model group,E-cadherin levels exhibited a dramatic reduction compared to the control group.The findings from the scratching tests showed that uric acid significantly enhanced cell migration.Western blot analysis showed a dramatic increase in the expression levels of vimentin and α-SMA,while E-cadherin exhibited significant decrease in the cells subjected to uric acid treatment.Conclusion Urate stimulates the secre-tion of TGF-β1 by renal tubule epithelial cells and induces epithelial-mesenchymal transdifferentiation,thereby ex-acerbating renal interstitial fibrosis in CKD.

Objective: To investigate the effect of G protein-coupled receptor 108(GPR108) gene knockout on systemic inflammation in lipopolysaccharide(LPS)-induced sepsis mice. Methods: Male C57BL/6 mice and GPR108 gene knockout mice were randomly divided into 4 groups: WT group, WT-LPS group, KO group, KO-LPS group. The physiological characteristics of mice in different groups were observed, and the morphological changes of liver and lung tissues were observed. Macrophages were extracted from bone marrow and subjected to flow cytometry to detect their M1 polarization status. The expression levels of IL-6 in liver and lung tissues, macrophages, and serum were also measured. Results: KO-LPS group mice showed significant liver and lung tissue damage, with a significantly greater number of bone marrow-derived macrophages polarizing towards M1 in the KO-LPS group compared to the WT-LPS group. Additionally, at the tissue, cellular, and serum levels, the expression of IL-6 in the KO-LPS group mice was significantly higher than that in the WT-LPS group mice(P<0.05). Conclusion During the systemic inflammatory infection induced by LPS in mice, the lack of GPR108 exacerbates the systemic inflammatory response. GPR108 has an inhibitory effect on the inflammatory response in mice with LPS-induced sepsis.

Objective To compare the difference between sperm floating plate and density gradient centrifugation combined with swim-up in human sperm preparation.Methods The semen samples were obtained from 50 infertile men in the clinic of Reproductive Medi-cine of Northwest Women's and Children's Hospital excluding azoospermia,severe oligoasthenozoospermia and semen volume less than 2 mL.After semen liquefaction,the differences of sperm concentration,total progressively motile sperm count(TMSC),percentages of progressively motile sperm and normal morphology sperm,recovery rate and DNA fragmentation index(DFI)were measured by both the methods of sperm floating plate and density gradient centrifugation combined with swim-up,and the results were compared.Results Compared with the pre-sorting samples,sperm concentrations[(16.08±13.39)x 106/mL,(8.88±8.06)x 106/mL vs(60.05± 27.21)×106/mL],TMSC[(7.41±6.14)×106,(3.98±3.57)×106vs(22.24±13.74)×106]and DFI[(2.20±3.44)％,(5.20± 10.79)％vs(26.38±13.92)％]in the sorting groups by sperm floating plate and density gradient centrifugation combined with swim-up were decreased significantly,and the percentages of progressive motile sperm[(91.67±4.75)％,(87.86±7.90)％vs(40.21± 16.83)％]and normal morphology sperm[(9.58±5.08)％,(7.72±4.01)％vs(3.58±2.06)％]were increased significantly.Com-pared with the density gradient centrifugation combined with swim-up,the results of sperm floating plate were higher in sperm concen-tration,percentages of progressively motile sperm and normal morphology sperm,TMSC and sperm recovery rate[(30.74±13.70)％vs(17.09±9.20)％],but DFI was lower,time-consuming was shorter[(32.38±1.01)min vs(60.08±2.06)min],and the difference between the two groups was statistically significant(P＜0.05).Conclusion The sperm floating plate may have certain clinical applica-tion prospects in the future due to better parameters of sperm preparation than those of density gradient centrifugation combined with swim-up in simple operation and shorter time-consuming.

Objective To investigate the metabolic characteristics,body composition and dietary intake in elderly sarcopenia patients with type 2 diabetes(T2DM).Methods A total of 652 T2DM patients(327 males and 325 females)aged over 60 years were selected from endocrinology department of nine different hospitals in Beijing.Body composition was measured by bioimpedance analysis,and the appendicular skeletal mass index(ASMI)was calculated.Sarcopenia was defined as body height-adjusted skeletal muscle mass (ASMI)below the lower quintile of the young reference group.The diagnostic cutoff points for sarcopenia were 7.18 kg/m2 for men and 5.73 kg/m2 for women.All patients were divided into the sarcopenia group versus the control group(below vs.not below 7.18 kg/m2 for men and 5.73 kg/m2 for women).The anthropometric parameters,body composition,biochemical laboratory results and dietary intake were compared between the two groups.The blood glucose target levels were less than 7 mmol/L of fasting plasma glucose(FPG)or less than 7％ of haemoglobin A1c(HbA1c).The obesity ratio was calculated according to body fat percentage more than 25％ in men and more than 30％ in women as obesity.Results There were 116 (17.8％)patients in the sarcopenia group (men/women,82/34),and 536 (82.2 ％) patients in the control group (men/women,245/291).Age was higher in the sarcopenia group than in the control group(t =4.385,P =0.000),and body mass index and waist hip ratio(WHR)were lower in the sarcopenia group than in the control group(t =11.724 and 4.173,P=0.000 and 0.000).FPG[(7.5±2.4) mmol/L vs.(8.5±2.5)mmol/L,t =-3.450,P=0.001]and HbA1c[(7.0±1.6) ％ vs.(8.2± 1.7) ％,t =-5.745,P =0.000] were higher in male sarcopenia group than in male control group.The control rate of FPG (127.0％ or 51.8％ vs.27.0％ or 32.9％,x2=8.817,P=0.003)and HbA1c(131.0％ or 53.5％ vs.23.0％ or 28.0％,x2 =15.934,P=0.000)were lower in the sarcopenia group than in the control group.The red blood cell counts,hemoglobin and serum albumin levels,estimated glomerular filtr ationrate(eGFR)were lower in male sarcopenia group than in the male control group(P＜0.05).eGFR was lower in female sarcopenia group than in female control group(t =4.090,P =0.000).Both in men and women,ASMI,grip power,fatless circumference on upper arm,bone mineral content and basal metabolic rate were lower in the sarcopenia group than in the control group(P＜0.05).The total daily intake of energy,carbohydrate,protein and fat were lower in male sarcopenia group than in male control group(P＜ 0.05).Conclusions Compared with the control group,sarcopenia patients are older with worse glycemic control and lower levels of BMI,WHR,renal function,muscle mass and muscle strength.Sarcopenia patients are more prone to osteoporosis.Furthermore,they have poorer nutritional status with an imbalance of dietary intake.Appropriate increase of protein especially high quality protein intake should be recommended to sarcopenia patients with T2DM.

AIM:To investigate the effects of celecoxib,a selective cyclooxygenase-2 inhibitor,on antioxidative capability and apoptosis of cardiac myocytes after myocardial infarction.METHODS:24 New Zealand rabbits were divided into three groups randomly(8 in each group):sham-operated group(sham group),myocardial infarction group(MI group),celecoxib group(Cele group,10 mg kg-1?d-1,qd,with the drugs gastric gavage for six weeks).The NO concentration,total antioxidative capability(T-AOC),the activity of constitutive nitric oxide synthase(cNOS)and inducible NOS(iNOS)in cardiac tissue homogenate,adjacent to the infracted area,were detected.The pathological changes were observed by light microscope and electron microscopy.The expressions of Bcl-2 and Bax protein in myocytes were observed using immunohistochemistry,and the degree of apoptosis were examined by TUNEL.RESULTS:Cardiac tissue in MI group presented interstitial edema,fibroplastic proliferation,inflammatory cellular infiltration,and vacuolar degeneration in cardiac myocytes.The results of electron microscopy showed that myocytes presented more changes caused by ischemic injury:widened interspace of myofibril,disordered myofibrillae,focal lysis of myofilament,ectasia of sarcoplasmic reticulum.In Cele group,the pathological changes were light,the NO-_2/NO-_3 concentration,the activity of iNOS were lower(P