The dysfunction of the lysosome and autophagy-lysosome system serves as a driving force for neurodegenerative diseases, metabolic disorders, inflammatory conditions, and other related diseases, closely influencing their onset and progression. Therefore, restoring the function of the lysosome or autophagy-lysosome system has become an increasingly crucial therapeutic strategy in disease management. In this review, we will introduce the lysosomal biogenesis, structure, and function, as well as the biological process of the autophagy-lysosome system. Various diseases closely associated with lysosomal/autophagic dysfunction are also reviewed, emphasizing the significance of targeting the function of the lysosome or autophagy-lysosome system in disease treatment. Finally, we focus on engineered nanomaterials that have the capabilities to restore the function of the lysosome or autophagy-lysosome system, and summarize different strategies and methods for achieving this goal. This review aims to elucidate the latest progress in the field of nanomedicine for lysosomal/autophagic defect-related diseases and inspire the development of innovative and clinically valuable nanomedicines.
Humans ; Lysosomes/physiology* ; Autophagy/physiology* ; Nanomedicine/methods* ; Neurodegenerative Diseases/therapy* ; Animals ; Nanostructures ; Lysosomal Storage Diseases/therapy*

Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors (NETs). Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue (denoted as ¹⁷⁷Lu-EB-TATE) is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs. This study aimed to enhance the in vivo stability, pharmacokinetics, and pharmacodynamics of ¹⁷⁷Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain, resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical, ¹⁷⁷Lu-LNC1010, for PRRT. In preclinical studies, ¹⁷⁷Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts. Thereafter, we presented the first-in-human dose escalation study of ¹⁷⁷Lu-LNC1010 in patients with advanced/metastatic NETs. ¹⁷⁷Lu-LNC1010 was well-tolerated by all patients, with minor adverse effects, and exhibited significant uptake and prolonged retention in tumor lesions, with higher tumor radiation doses than those of ¹⁷⁷Lu-EB-TATE. Preliminary PRRT efficacy results showed an 83% disease control rate and a 42% overall response rate after two ¹⁷⁷Lu-LNC1010 treatment cycles. These encouraging findings warrant further investigations through multicenter, prospective, and randomized controlled trials.

Objective To investigate the nutritional status and dietary structure of tuberculosis patients among dif-ferent populations, analyze the factors influencing the nutritional status of tuberculosis patients, and provide theo-retical basis for improving clinical nutrition and related issues in tuberculosis patients.Methods Tuberculosis pa-tients, non-tuberculosis patients, and healthy individuals were randomly selected for a questionnaire survey.De-scriptive analysis was conducted using SPSS 20.0 software.Statistical description was performed using rates and composition ratios, and qualitative data were described using relative numbers.Chi-square test was used to compare overall rates and composition ratios among different health conditions groups, with a significance level of α=0.05.Independent factors analysis of nutritional status body mass index (BMI) was conducted using multiple Logistic re-gression analysis for variables with statistically significant differences in the univariate analysis.Results There were differences in the nutritional status (x2 =62.184, P<0.05) and dietary diversity score (x2 =64.049, P<0.05) among tuberculosis patients, non-tuberculosis patients, and healthy individuals.Univariate analysis of nutri-tional status BMI showed statistically significant differences in gender, smoking, meat-based diet, vegetable-based diet, moderate diet diversity score, and 6 other variables for tuberculosis patients (P <0.05) , and in gender, age, ethnicity, marital status, occupation, education level, smoking, drinking white wine, drinking beer, meat-based diet, moderate diet, and 11 other variables for healthy individuals (P<0.05) .The variables with statisti-cally significant differences in the univariate analysis were included in the multiple ordinal logistic regression analy-sis model for both tuberculosis patients and healthy individuals.The results showed that the level of education, veg-etable intake, moderate food diversity score (DDS) of 4-6 were independent influencing factors of nutritional sta-tus BMI among tuberculosis patients (P<0.05);marital status was an independent influencing factor of nutritional status BMI among non-tuberculosis patients (P<0.05);while gender and occupation were independent influencing factors of nutritional status BMI among healthy individuals (P<0.05).Conclusion The dietary nutritional status of the three population groups varied.Targeted health education should be conducted, especially for tuberculosis patients, to address the issue of uneven dietary intake and promote good dietary habits among local tuberculosis pa-tients.

Medical device imaging data augmentation is a method of expanding existing datasets by generating new data samples,which is of great significance for improving the performance of artificial intelligence(AI)medical device-related models and clinical application effects.However,traditional data augmentation methods are usually limited by the quality,realism,and diversity of generated samples.Denoising diffusion probabilistic model(DDPM)is a generative model based on the noise diffusion process,and its main idea is to generate samples with high quality by modelling the sampling process of the target distribution as a process of progressive denoising from the noise distribution.The basic principles and working mechanisms of DDPM were reviewed,the application scenarios of this method in AI medical device data augmentation were analyzed,and its advantages,challenges,and future development directions were explored to provide a reference for the field of AI medical device data augmentation.

Objective To explore the changes of serum angiopoietin-like protein 4(ANGPTL4)and NOD-like receptor protein 3(NLRP3)levels after traumatic brain injury(TBI)and their diagnostic value for sec-ondary massive cerebral infarction.Methods A total of 100 TBI patients admitted to the hospital from Au-gust 2019 to August 2021 were enrolled as the TBI group,meantime,100 healthy people in the hospital were enrolled as the control group.The serum levels of ANGPTL4 and NLRP3 were detected by enzyme-linked im-munosorbent assay(ELISA).The clinical characteristics of TBI patients with and without secondary massive cerebral infarction were compared.Receiver operating characteristic(ROC)curve was applied to analyze the serum levels of ANGPTL4 and NLRP3 on their diagnostic value for TBI patients with secondary massive cere-bral infarction.Multivariate Logistic regression analysis was applied to analyze the factors affecting the occur-rence of secondary massive cerebral infarction in TBI patients.Results The serum ANGPTL4 level in TBI group was lower than that in the control group,and the serum NLRP3 level was higher than that in the con-trol group(P<0.05).There were obvious differences in proportion of brain hernia,proportion of subarach-noid hemorrhage,serum levels of ANGPTL4 and NLRP3 between patients with secondary massive cerebral infarction and patients without secondary massive cerebral infarction(P<0.05).ROC curve analysis showed that the area under the curve(AUC)of serum ANGPTL4 and NLRP3 in diagnosing secondary massive cere-bral infarction in TBI patients was 0.792 and 0.812 respectively,with sensitivity of 77.80%and 83.30%re-spectively,and specificity of 86.60%and 64.60%respectively.The sensitivity,the specificity and AUC of the combined detection were 83.30%,82.90%and 0.867 respectively.Multivariate Logistic regression analysis showed that serum NLRP3 level was a risk factor for TBI patients with secondary massive cerebral infarction(P<0.05).After treatment,it was found that serum ANGPTL4 level increased and NLRP3 level decreased in TBI patients(P<0.05).Conclusion The serum level of ANGPTL4 in TBI patients decreases,while the level of NLRP3 increases,and the level of ANGPTL4 in the serum of patients with secondary massive cerebral in-farction decreases and the level of NLRP3 increases,both of them are of great significance in the diagnosis of secondary massive cerebral infarction in TBI patients.

Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.

The 2024 ASCO-GU Annual Meeting focused on precision diagnosis and treatment of metastatic castration-resistant prostate cancer (mCRPC). Studies showed that treatment strategies guided by molecular subtyping significantly prolonged patient survival. Meanwhile, China is actively exploring personalized treatment plans based on genetic testing. In the future, precision treatment based on genetic testing will be a crucial direction in mCRPC therapy.

Objective:To observe the effects of Qifu Lizhong Enema Prescription on ulcerative colitis rats with yang deficiency of spleen and kidney syndrome; To discuss its mechanism.Methods:Totally 70 male SD rats were randomly divided into blank group, model group, mesalazine group, Qifu Lizhong Guanchang Prescription high-, medium- and low-dosage groups; blank group ( n=10), other groups ( n=12). Except for the blank group, the other groups used bitter cold purgative therapy (Dahuang Decoction) by gavage, and combined with trinitrobenzen sulfonic acid (TNBS) +55% ethanol compound method to induce UC rat model. After successful modeling, the blank group and model group were given 1 ml normal saline enema daily, Qifu Lizhong Enema Prescription groups were given Qifu Lizhong Enema Prescription 3.00, 1.50, 0.75 g/kg enema daily, and the mesalazine group was given mesalazine 0.03 g/kg enema daily, once a day for consecutive 14 days. After 14 days, Disease Activity Index (DAI) score was performed, and hematoxylin-eosin staining (HE) was used to observe the pathological tissues of the colon. The expressions of Occludin and adhesion molecules A (JAM-A) protein in colon tissue were detected by immunohistochemistry and Western blot. Results:HE results showed that the mucosal structure was damaged, inflammatory cells were infiltrated, edema and ulcer foci were observed in model group. The mucosal structure of mesalazine group and Qifu Lizhong Enema Prescription groups were intact, and inflammatory infiltration, edema and ulcer of neoepithelial were improved. Compared with model group, the DAI scores of Qifu Lizhong Enema Prescription groups decreased ( P<0.01), the expressions of Occludin and JAM-A in Qifu Lizhong Guanchang Prescription high- and medium-dosage groups significantly increased ( P<0.05). Conclusion:Qifu Lizhong Enema Prescription can significantly relieve the symptoms and pathological morphology of UC rats, and the mechanism of repairing intestinal mucosal barrier may be related to up-regulating the expressions of Occludin and JAM-A proteins.

Gastrointestinal malignant tumors are common worldwide,particularly gastric cancer(GC)and colorectal cancer(CRC),with complex and not fully understood molecular mechanisms behind their occurrence and progression.Treatment typically involves a comprehensive approach centered on surgery,which,despite achieving good outcomes,still faces challenges due to high recurrence rates and low survival rates impacting patient health.N6-methyladenosine(m6A)is the most abundant internal modification in mRNAs and plays a crucial role in regulating RNA post-transcriptional modifications and downstream functions.Fat mass and obesity-associated protein(FTO)was the first identified m6A demethylase capable of removing dynamic,reversible m6A modifications.During the development of gastrointestinal malignancies,FTO regulates the expression of specific genes,affecting tumor cell proliferation and metastasis;modulates the expression of tumor-related cytokines and immune-related molecules,influencing the tumor microenvironment;and plays a significant role in sensitivity and resistance to chemotherapy.FTO is upregulated in most types of GC,indicating poor prognosis.High FTO expression enhances GC cell migration and invasion,increases chemoresistance,promotes tumor stem cell proliferation and differentiation,and inhibits apoptosis,thus facilitating GC progression.In CRC,many studies show that FTO is upregulated in tissues and cells,promoting CRC progression by enhancing cell proliferation,migration,invasion,and resistance to chemotherapy.Low FTO expression can also elevate m6Am levels in CRC cell cytoplasmic mRNA,promoting tumor stem cell proliferation,differentiation,tumor formation,and increasing resistance.In contrast,high FTO expression inhibits tumor stem cell proliferation and differentiation.FTO is also upregulated in other gastrointestinal tumors like pancreatic and esophageal cancers,where high expression promotes progression and indicates poor prognosis.FTO has both promoting and inhibitory effects on liver and biliary malignancies.As research confirms FTO's widespread oncogenic role in the gastrointestinal tract,developing FTO inhibitors and related drugs offers new avenues for treating gastrointestinal malignancies.Currently identified agents like CS1,omeprazole,and mupirocin significantly inhibit CRC and GC progression by directly or indirectly suppressing FTO.Tumors can evade immune surveillance through FTO-mediated mechanisms,suggesting that blocking FTO-mediated immune escape and enhancing the antitumor effects of immune cells could provide treatment options for gastrointestinal malignancies.Targeting FTO in combination with immunotherapy to inhibit GC and CRC growth and metastasis and reduce resistance presents broad therapeutic prospects.

Objective To investigate the predictive value of Rotterdam CT score combined with serum soluble cluster of differentiation antigen 40 ligand (sCD40L) and fibulin-5 for prognosis of patients with severe traumatic brain injury (sTBI). Methods A total of 186 sTBI patients were divided into good prognosis group (n=104) and poor prognosis group (n=82). CT images were analyzed and Rotterdam CT scores were obtained; the enzyme-linked immunosorbent assay (ELISA) was used to detect serum sCD40L and fibulin-5 levels on the 1st, 3rd and 7th day of admission; the Spearman analysis was used to assess the correlations of serum sCD40L and fibulin-5 levels on the first day of admission with the Rotterdam CT score and Glasgow Coma Scale (GCS) score; the Multivariate Logistic regression analysis was conducted to explore the risk factors for poor prognosis in sTBI patients; the receiver operating characteristic (ROC) curve was performed to analyze the predictive value of Rotterdam CT score combined with serum sCD40L and fibulin-5 levels on the first day of admission for prognosis of sTBI patients. Results On the 1st, 3rd and 7th day of admission, compared with the good prognosis group, the serum levels of sCD40L and fibulin-5 in the poor prognosis group were significantly elevated (P < 0.05); serum sCD40L and fibulin-5 levels were negatively correlated with GCS scores (r=-0.505, -0.421, P < 0.05) and positively correlated with Rotterdam CT score (r=0.495, 0.397, P < 0.05); sCD40L (OR=2.768, 95%CI, 1.537 to 4.983) and fibulin-5 (OR=2.539, 95%CI, 1.301 to 4.953) were independent risk factors for poor prognosis in sTBI patients (P < 0.001); the area under the curve (AUC) of Rotterdam CT score combined with serum sCD40L and fibulin-5 levels on the first day of admission for predicting poor prognosis in sTBI patients was 0.969 (95%CI, 0.933 to 0.989), with a sensitivity of 86.59% and a specificity of 94.23%; the diagnostic performance of Rotterdam CT score combined with sCD40L and fibulin-5 was superior to that of each individual indicator (Z=4.233, 4.274, 4.433, P < 0.001); the Bootstrap internal validation results showed that the predictive performance curve of the combined prediction model was consistent with the actual clinical occurrence curve. Conclusion Rotterdam CT score combined with serum sCD40L and fibulin-5 has certain predictive value for poor prognosis in sTBI patients.