OBJECTIVE To prepare Arg-Gly-Asp（RGD）-modified doxorubicin （DOX）-loaded “core-shell” nanoparticles （RGD@DOX-LPNs）， characterize the nanoparticles， and investigate their antitumor effects. METHODS RGD@DOX-LPNs were prepared using the nanoprecipitation method. Their morphology was examined by visual inspection and electron microscopy. Particle size， polydispersity index （PDI）， and Zeta potential were determined， and differential scanning calorimetry （DSC） and X-ray diffraction （XRD） were employed. Encapsulation efficiency （EE）， drug loading （DL）， and stability were evaluated. The in vitro release kinetics， mucus diffusion， and tumor cell uptake [tracked using coumarin 6 （COU）] were investigated. The in vivo tissue distribution and gastrointestinal retention [labeled with 11-chloro-1， 1′-dipropyl-3， 3， 3′， 3′-tetramethyl-10， 12- trimethyleneindotricarbocyanine iodide （IR780）] were investigated. Using 4T1 tumor-bearing mice as the experimental subjects， the effects of the prepared formulation on tumor volume， tumor weight， and cell apoptosis rate were evaluated. RESULTS RGD@DOX-LPNs presented as orange transparent liquid with uniform and near-spherical particles. The particle size was （159.67± 8.02） nm， PDI was 0.15±0.06， and Zeta potential was （－19.70±0.79） mV. After modification with RGD， the thermal absorption peak and crystalline diffraction peak of DOX disappeared. EE and DL of RGD@DOX-LPNs were （72.65±4.37）% and （4.62± 0.38）% ， respectively. No obvious changes in appearance， particle size， or EE were observed after storage at 4 ℃ and 25 ℃ for 7 days. The cumulative drug release at 4 h was approximately 73%， which was lower than that of free DOX（almost completely released within 1 h）. The amount of COU in the first segmental mucus layer of COU-LPNs was significantly lower than that in the corresponding segment of RGD@COU- LPNs， whereas it was significantly higher in the 2nd to 5th segmental mucus layers compared to RGD@COU-LPNs （P＜0.01）. Cellular uptake of RGD@COU-LPNs was significantly higher than that of COU-LPNs（P＜0.05）. The isolated tissue fluorescence intensity of RGD@IR780-LPNs was stronger than that of IR780-LPNs， indicating better small intestinal retention. Compared with free DOX and unmodified nanoparticles （DOX-LPNs）， RGD@DOX-LPNs exhibited a higher tumor inhibition rate of 65.74%， significantly reduced tumor volume and weight， and increased apoptosis rate（P＜0.01）. CONCLUSIONS RGD@DOX-LPNs are successfully prepared with sustained release properties， which can improve gastrointestinal mucus retention， enhance cellular uptake of DOX， and have potent antitumor activity against breast cancer.

Metastatic dissemination is the major cause of death from breast-cancer (BC). Fusobacterium nucleatum (F.n) is widely enriched in BC and has recently been identified as one of the high-risk factors for promoting BC metastasis. Here, with an experimental model, we demonstrated that intratumoral F.n induced BC aggressiveness by transcriptionally activating Epithelial-mesenchymal transition-associated genes. Therefore, the F.n may be a potential target to prevent metastasis. Given the fact that cancer-associated fibroblasts (CAFs) are abundant in BC and located near blood vessels, we report an optogenetic system that drives CAF to in situ produce human antibacterial peptide LL37, with the characteristics of biosafety and freely intercellular trafficking, for depleting intratumoral F.n, leading to a 72.1% reduction in lung metastatic nodules number without affecting the balance of the systemic flora. Notably, mild photothermal treatment was found that could normalize CAF, contributing to synergistically inhibiting BC metastasis. In addition, the system can also simultaneously encode a gene of TNF-related apoptosis-inducing ligand to suppress the primary tumor. Together, our study highlights the potential of local elimination of tumor pathogenic bacteria to prevent BC metastasis.

Five novel nor-eremophilane-type sesquiterpenoids, peniroqueforins E-H and J (1-4 and 7), two new eremophilane-type sesquiterpenoids, peniroqueforins I and K (5 and 8), and a new eudesmane-type sesquiterpenoid, peniroqueforin L (9), along with four known compounds (6 and 10-12), were isolated and characterized from fungus Penicillium roqueforti (P. roqueforti). The structures and absolute configurations of these compounds were determined through comprehensive spectroscopic analyses, electronic circular dichroism (ECD) data analyses, and single-crystal X-ray diffraction methods. The anti-multi-drug resistance (MDR) cancer activity of these compounds was evaluated using SW620/Ad300 cells. Notably, the half maximal inhibitory concentration (IC₅₀) value of paclitaxel (PTX) combined with 1 in SW620/Ad300 cells was 50.36 nmol·L^-1, which was 65-fold more potent than PTX alone (IC₅₀ 3.26 μmol·L^-1). Subsequent molecular docking studies revealed an affinity between compound 1 and P-glycoprotein (P-gp), suggesting that this nor-eremophilane-type sesquiterpenoid (1) could serve as a potential lead for MDR reversal in cancer cells through P-gp inhibition.
Penicillium/chemistry* ; Humans ; Sesquiterpenes/isolation & purification* ; Cell Line, Tumor ; Molecular Structure ; Drug Resistance, Neoplasm/drug effects* ; Antineoplastic Agents/pharmacology* ; Drug Resistance, Multiple/drug effects* ; Molecular Docking Simulation

OBJECTIVE To investigate the effect and mechanism of Jingangteng capsules in the treatment of non-alcoholic fatty liver disease （NAFLD）. METHODS Thirty-two SD rats were randomly divided into normal group and modeling group. The modeling group was fed a high-fat diet to establish a NAFLD model. The successfully modeled rats were then randomly divided into model group， atorvastatin group[positive control， 2 mg/（kg·d）]， and Jingangteng capsules low- and high-dose groups [0.63 and 2.52 mg/（kg·d）]， with 6 rats in each group. The pathological changes of the liver were observed by hematoxylin-eosin staining and oil red O staining. Enzyme-linked immunosorbent assay was performed to determine the serum levels of triglycerides （TG）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C）， alanine transaminase （ALT）， aspartate transaminase （AST）， tumour necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， IL-6， IL-18. 16S rDNA amplicon sequencing and metabolomics techniques were applied to explore the effects of Jingangteng capsules on gut microbiota and metabolisms in NAFLD rats. Based on the E-mail：591146765@qq.com metabolomics results， Western blot analysis was performed to detect proteins related to the nuclear factor kappa-B （NF-κB）/NOD-like receptor family protein 3 （NLRP3） signaling pathway in the livers of NAFLD rats. RESULTS The experimental results showed that Jingangteng capsules could significantly reduce the serum levels of TG， TC， LDL-C， AST， ALT， TNF-α， IL-1β， IL-6， IL-18， while increased the level of HDL-C， and alleviated the hepatic cellular steatosis and inflammatory infiltration in NAFLD rats. They could regulate the gut microbiota disorders in NAFLD rats， significantly increased the relative abundance of Romboutsia and Oscillospira， and significantly decreased the relative abundance of Blautia （P＜0.05）. They also regulated metabolic disorders primarily by affecting secondary bile acid biosynthesis， fatty acid degradation， O-antigen nucleotide sugar biosynthesis， etc. Results of Western blot assay showed that they significantly reduced the phosphorylation levels of NF-κB p65 and NF-κB inhibitor α， and the protein expression levels of NLRP3， caspase-1 and ASC （P＜0.05 or P＜0.01）. CONCLUSIONS Jingangteng capsules could improve inflammation， lipid accumulation and liver injury in NAFLD rats， regulate the disorders of gut microbiota and metabolisms， and inhibit NF-κB/NLRP3 signaling pathway. Their therapeutic effects against NAFLD are mediated through the inhibition of the NF-κB/NLRP3 signaling pathway.

Objective:To investigate the characteristics of brain functional networks alterations in patients with inflammatory bowel disease (IBD) and explore their correlations with clinical indicators and psycho-psychological scores.Methods:A cross-sectional survey study was conducted. A total of 48 IBD patients diagnosed at the Changzhou Second People′s Hospital from June 2021 to June 2023 were collected, and 32 healthy individuals matched for age, gender, and education level were selected as the healthy control group. Resting-state functional magnetic resonance imaging data were enrolled, and the topological properties of brain networks between the two groups of subjects were compared by using graph theory analysis. Pearson correlation and Spearman′s partial correlation analyses were used to explore the correlations between changes in IBD patients′ brain networks topological properties and clinical indicators and psycho-psychological scores.Results:In the IBD group, 29 patients were males (60.4%) and 19 were females (39.6%) ; the total disease course was 1.0 (0.3, 5.0) years; 34 patients were Crohn′s disease and 14 ulcerative colitis; they were mainly in the active phase (58.84%, 28/48) . The scores of the hospital anxiety and depression scale (HADS-A and HADS-D) in IBD patients were higher than those in the healthy control group (both P<0.01) . In terms of global properties, both the IBD group and the healthy control group had "small-world" properties (both σ>1.1) . Compared with the healthy control group, the IBD group had lower clustering coefficients, global efficiency, and local efficiency, and longer characteristic path lengths, with all differences being statistically significant (all P<0.05) . In terms of local properties, compared with the healthy control group, the IBD group had higher degree centrality and nodal efficiency in the left middle frontal gyrus, higher betweenness centrality in the left thalamus, lower betweenness centrality and degree centrality in the right parahippocampal gyrus, lower nodal clustering coefficients in the bilateral middle temporal gyrus, right anterior cingulate gyrus and paracingulate gyrus, and lower nodal local efficiency in the bilateral caudate nuclei and left middle temporal gyrus, with all differences being statistically significant (all P<0.05) . The degree centrality of the right parahippocampal gyrus in the IBD group was negatively correlated with the HADS-A score ( r = -0.401, P = 0.005) , and the betweenness centrality was also negatively correlated with the HADS-A score ( r = -0.343, P = 0.017) . The nodal clustering coefficient of the right middle temporal gyrus in the IBD group was positively correlated with the total disease course ( rs = 0.589, P<0.001) . Conclusion:IBD patients have decreased overall information transmission capacity in brain networks, reduced limbic system function, and abnormal functions in brain areas related to pain perception, which are correlated to some extent with the disease course and psycho-psychological state.

Objective To investigate the correlation between serum levels of brain natriuretic peptide (BNP), cancer antigen 125 (CA125) and interleukin-6 (IL-6) with the severity of acute myocardial infarction (AMI) and to evaluate their predictive value for major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI). Methods A total of 100 AMI patients who underwent PCI were enrolled in this study. Patients were divided into MACE group (n=36) and non-MACE group (n=64) based on the occurrence of MACE. Clinical data and serum levels of BNP, CA125 and IL-6 were compared between the two groups. The correlations of serum BNP, CA125 and IL-6 levels with the severity of AMI were analyzed. Factors influencing the occurrence of MACE after PCI in AMI patients were examined. Receiver operating characteristic (ROC) curves were used to assess the predictive value of serum BNP, CA125 and IL-6 for MACE after PCI. Conventional predictive scheme combined risk factors served as the conventional prediction model, while a new prediction model was developed by incorporating serum BNP, CA125 and IL-6 into the conventional model. The area under the curve (AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to compare the predictive values of the two models. Results Among the 100 AMI patients, 36 experienced MACE within three months after PCI. The MACE group had significantly higher age, white blood cell (WBC) count, prevalence of prior myocardial infarction and severity of AMI compared to the non-MACE group (P < 0.05). Serum levels of BNP, CA125 and IL-6 were significantly higher in the MACE group than in the non-MACE group (P < 0.05). Serum BNP, CA125 and IL-6 levels were positively correlated with the severity of AMI (r=0.513, 0.406, 0.320; P < 0.05). Age, WBC count, history of myocardial infarction, and serum BNP, CA125 as well as IL-6 were identified as significant predictors for MACE after PCI (P < 0.05). The AUC for the combined prediction for MACE using BNP, CA125 and IL-6 was greater than that of each individual marker (Z=2.134, 2.005, 2.087; P < 0.05). When age, WBC count and history of myocardial infarction were combined as the conventional prediction model, and serum BNP, CA125 and IL-6 were added to form the new prediction model, the AUC of the new model was significantly higher than that of the conventional model (Z=2.321, P < 0.05). Compared with the conventional prediction scheme, the new prediction scheme had both NRI and IDI greater than zero P < 0.05). Conclusion Elevated serum levels of BNP, CA125 and IL-6 in AMI patients are associated with the severity of AMI and have predictive value for MACE after PCI. The new prediction model with BNP, CA125 and IL-6 demonstrates superior predictive performance for MACE after PCI compared to the conventional model.

Objective:To investigate the characteristics of brain functional networks alterations in patients with inflammatory bowel disease (IBD) and explore their correlations with clinical indicators and psycho-psychological scores.Methods:A cross-sectional survey study was conducted. A total of 48 IBD patients diagnosed at the Changzhou Second People′s Hospital from June 2021 to June 2023 were collected, and 32 healthy individuals matched for age, gender, and education level were selected as the healthy control group. Resting-state functional magnetic resonance imaging data were enrolled, and the topological properties of brain networks between the two groups of subjects were compared by using graph theory analysis. Pearson correlation and Spearman′s partial correlation analyses were used to explore the correlations between changes in IBD patients′ brain networks topological properties and clinical indicators and psycho-psychological scores.Results:In the IBD group, 29 patients were males (60.4%) and 19 were females (39.6%) ; the total disease course was 1.0 (0.3, 5.0) years; 34 patients were Crohn′s disease and 14 ulcerative colitis; they were mainly in the active phase (58.84%, 28/48) . The scores of the hospital anxiety and depression scale (HADS-A and HADS-D) in IBD patients were higher than those in the healthy control group (both P<0.01) . In terms of global properties, both the IBD group and the healthy control group had "small-world" properties (both σ>1.1) . Compared with the healthy control group, the IBD group had lower clustering coefficients, global efficiency, and local efficiency, and longer characteristic path lengths, with all differences being statistically significant (all P<0.05) . In terms of local properties, compared with the healthy control group, the IBD group had higher degree centrality and nodal efficiency in the left middle frontal gyrus, higher betweenness centrality in the left thalamus, lower betweenness centrality and degree centrality in the right parahippocampal gyrus, lower nodal clustering coefficients in the bilateral middle temporal gyrus, right anterior cingulate gyrus and paracingulate gyrus, and lower nodal local efficiency in the bilateral caudate nuclei and left middle temporal gyrus, with all differences being statistically significant (all P<0.05) . The degree centrality of the right parahippocampal gyrus in the IBD group was negatively correlated with the HADS-A score ( r = -0.401, P = 0.005) , and the betweenness centrality was also negatively correlated with the HADS-A score ( r = -0.343, P = 0.017) . The nodal clustering coefficient of the right middle temporal gyrus in the IBD group was positively correlated with the total disease course ( rs = 0.589, P<0.001) . Conclusion:IBD patients have decreased overall information transmission capacity in brain networks, reduced limbic system function, and abnormal functions in brain areas related to pain perception, which are correlated to some extent with the disease course and psycho-psychological state.

OBJECTIVE：To inv estigate the effects of 4-hydroxy-2（3H）-benzoxazolone on inflammatory and apoptosis signaling pathways in non-alcoholic fatty liver disease （NAFLD）model rats. METHODS ：SD rats were divided into normal control group（10 rats）and modeling group （50 rats）. Normal control group was given basic diet ，and modeling group were given high-fat diet to induce NAFLD model. After modeling ，the rats were divided into normal control group ，model group ，silibinin group （26.25 mg/kg），and 4-hydroxy-2（3H）-benzoxazolone high-dose ，medium-dose and low-dose groups （100，50，25 mg/kg），with 8 rats in each group. Normal control group and modeling group were given 0.6％ CMC-Na intragastrically ，and other groups were given relevant medicine 10 mL/kg intragastrically ，once a day ，for consecutive 4 weeks. After last medication ，the serum levels of albumin（ALB），total protein （TP），globulin（GLB），ALB/GLB and free fatty acid （FFA）were detected ；TUNEL staining was used to observe the apoptosis of rat hepatocytes. Western blot assay was used to detect the protein expression and phosphorylation level of inflammatory signaling pathway related proteins [Toll-like receptor 4（TLR4），myeloid differentiation factor 88（MyD88）， nuclear factor-κB p65（NF-κB p65），NF-κB inhibitor protein（IκBα）] in liver tissue as well as the expression of apoptosis signaling pathway related proteins [B cell lymphoma 2（Bcl-2），Bax，caspase-3]. RESULTS ：Compared with model group ，serum levels of TP （except for low-dose group ），GLB and FFA ，the protein expression of TLR 4（except for low-dose group ），MyD88 （except for medium-dose group ）and caspase- 3，the phosphorylation levels of NF-κB p65 and IκBα protein were decreased significantly（P＜0.05 or P＜0.01）. The ratio of A LB/GLB in serum and the ratio of Bcl- 2/Bax in liver tissue were significantly increased（P＜0.05 or P＜0.01），and the phenomenon of hepatocyte apoptosis was improved. CONCLUSIONS ：4-hydroxy-2 （3H）-benzoxazolone can ameliorate NAFLD in rats ，and the mechanism may be associated with inhibiting the expression TLR 4/ MyD88/NF-κB signaling pathway-related proteins and apoptosis-related proteins in liver tissues.

ObjectiveTo evaluate the relationship between the level of thoracic complete spinal cord injury(SCI) and ambulatory function wearing Reciprocating Gait Orthosis(RGO) through three dimentional gait analysis, and to explore the quantitative indicators of reconstructing walking capacity of thoracic complete SCI patients.Methods10 patients with thoracic complete spinal cord injury of lesion level from T4 to T12 who had experienced RGO gait training for at least 3 months. Three dimentional gait analysis system of Vicon Nexus 1.2 was used to test and examine the gait speed, cadence, stride length, pelvic angle of rotation, hip range of motion(ROM), crutch force, angular velocity of hip flexion and extension phases, etc. Pearson's product moment correlation coefficient and Spearman rank correlation coefficient were used to examine the relationship between the level of spinal cord injury and the kinematic and kinetic values.ResultsThe mean cadence and stride length were (37.4±2.15) steps/min and (91.6±9.09) cm. The mean hip ROM, angular velocity of hip flexion and extension phases were (42.57 °±5.43 °), (20.88 °±2.18 °)/s and (124.75 °±9.31 °)/s respectively. The gait speed, stride length, peak crutch force, hip ROM, mean crutch force and angular velocity of hip extension phase all had significant pertinence with the level of spinal cord injury.ConclusionThe limitation of hip ROM and excessive load of upper limbs mainly result in ambulatory disorder in higher thoracic complete SCI patients who should be undertaken some rehabilitation training to reduce excessive physiological load in order to improve their ambulatory capacity.

Transposition of simple or composite forearm island flaps with a radial vascular pedicle was performed in repairing tissue defects of the hand and reconstruction of the thumb in 16 patients. It was found to be easy to operate and no suturing of blood vessels was necessary. The postoperative swelling was less marked. The flap was good in texture and sensation after the operation. The overall result wassatisfactory. Anatomic-physiological situdy was also carried out. 16 patients have been operated on, including 2 thumb reconstructions, with satisfactoryresults.