In light of the burgeoning successes of cancer immunotherapy, glioblastoma (GBM) remains refractory due to an immunosuppressive microenvironment originating from its molecular heterogeneity. Thus, identifying promising therapeutic targets for treating GBM and discovering methodologies to effectively regulate them is still a tremendous challenge. Here we describe photodynamic protein tyrosine phosphatase 1B (PTP1B) proteolysis mediated by a proteolysis-targeting chimera (PROTAC) nanoassembly. The PTP1B-targeting PROTAC is conjugated with a photosensitizer via a cathepsin B (Cat B)-cleavable peptide, which spontaneously forms nanoassemblies due to intermolecular π-π stacking interactions. In GBM models, PROTAC nanoassemblies significantly accumulate in the tumor region across the disrupted blood-brain barrier (BBB), triggering a burst release of the photosensitizer and active PROTAC by Cat B-mediated enzymatic cleavage. Upon laser irradiation, photodynamic therapy (PDT) synergizes with PROTAC-mediated PTP1B proteolysis to induce potent immunogenic cell death (ICD) in tumor cells. Subsequently, persistent PTP1B degradation by nanoassemblies in Cat B-overexpressed intratumoral T cells downregulates exhaustion markers, reinvigorating their functionality. These sequential processes of photodynamic PTP1B proteolysis ultimately augment T cell-mediated antitumor immunity as well as protective immunity, completely eradicating the primary GBM and preventing its recurrence. Overall, our findings underscore the therapeutic potential of combining PDT with PROTAC activity for GBM immunotherapy.

Objective To explore the mechanism of Danggui Sini Decoction in treating knee osteoarthritis(KOA)by using network pharmacology,combined with in vitro experimental verification.Methods The active components of Danggui Sini Decoction were retrieved and screened through TCMSP,CNKI and PubMed databases,and their corresponding targets were predicted using the SwissTarget Prediction platform.KOA related targets were retrieved from GeneCards and OMIM databases.Intersection of drug targets and KOA targets was obtained,and key components,core targets,and their related biological mechanisms were identified through network topology analysis,GO and KEGG pathway enrichment analysis.Molecular docking was used to verify the degree of binding between key components and core targets.Danggui Sini Decoction containing serum was prepared,and an in vitro KOA model was constructed by inducing rat articular chondrocytes with lipopolysaccharide.The CCK-8 method was used to screen for the optimal concentration of drug containing serum intervention,fluorescent probes were used to detect intracellular ROS content,immunofluorescence was used to detect NF-κB p65 nuclear translocation,RT-qPCR was used to detect the expressions of IL-6,IL-1β and TNF-α mRNA,Western blot was used to detect the expression of Toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),NF-κB p65 and p-NF-κB p65 proteins.Results The results of network pharmacology analysis indicated that the treatment of KOA with Danggui Sini Decoction may involve regulating Toll like receptors,MAPK,TNF,apoptosis and other inflammatory and aging signaling pathways,compounds such as quercetin,kaempferol and glycyrrhizin may play important roles.Core targets included IL6,IL1B,TNF,TLR4,NFKB1,JUN,MAPK1,RELA.In vitro experiments showed that compared with the blank group,the ROS content in chondrocytes of the model group significantly increased(P<0.01),NF-κB p65 protein was significantly nuclear translocation(P<0.01),and mRNA expressions of IL-6,IL-1β,TNF-α mRNA and protein expressions of TLR4,MyD88 and p-NF-κB p65 significantly increased(P<0.01);compared with the model group,the intervention of Danggui Sini Decoction containing serum could significantly reduce intracellular ROS content(P<0.05),inhibit NF-κB p65 nuclear translocation(P<0.01),and reduce the expression of inflammatory factor mRNA and related proteins(P<0.05,P<0.01).Conclusion Danggui Sini Decoction can significantly reduce the inflammatory response of rat articular chondrocytes induced by lipopolysaccharide and exert therapeutic effects on KOA.Its mechanism may be related to the inhibition of TLR4/MyD88/NF-κB pathway.

Objective To explore the mechanism of Danggui Sini Decoction in treating knee osteoarthritis(KOA)by using network pharmacology,combined with in vitro experimental verification.Methods The active components of Danggui Sini Decoction were retrieved and screened through TCMSP,CNKI and PubMed databases,and their corresponding targets were predicted using the SwissTarget Prediction platform.KOA related targets were retrieved from GeneCards and OMIM databases.Intersection of drug targets and KOA targets was obtained,and key components,core targets,and their related biological mechanisms were identified through network topology analysis,GO and KEGG pathway enrichment analysis.Molecular docking was used to verify the degree of binding between key components and core targets.Danggui Sini Decoction containing serum was prepared,and an in vitro KOA model was constructed by inducing rat articular chondrocytes with lipopolysaccharide.The CCK-8 method was used to screen for the optimal concentration of drug containing serum intervention,fluorescent probes were used to detect intracellular ROS content,immunofluorescence was used to detect NF-κB p65 nuclear translocation,RT-qPCR was used to detect the expressions of IL-6,IL-1β and TNF-α mRNA,Western blot was used to detect the expression of Toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),NF-κB p65 and p-NF-κB p65 proteins.Results The results of network pharmacology analysis indicated that the treatment of KOA with Danggui Sini Decoction may involve regulating Toll like receptors,MAPK,TNF,apoptosis and other inflammatory and aging signaling pathways,compounds such as quercetin,kaempferol and glycyrrhizin may play important roles.Core targets included IL6,IL1B,TNF,TLR4,NFKB1,JUN,MAPK1,RELA.In vitro experiments showed that compared with the blank group,the ROS content in chondrocytes of the model group significantly increased(P<0.01),NF-κB p65 protein was significantly nuclear translocation(P<0.01),and mRNA expressions of IL-6,IL-1β,TNF-α mRNA and protein expressions of TLR4,MyD88 and p-NF-κB p65 significantly increased(P<0.01);compared with the model group,the intervention of Danggui Sini Decoction containing serum could significantly reduce intracellular ROS content(P<0.05),inhibit NF-κB p65 nuclear translocation(P<0.01),and reduce the expression of inflammatory factor mRNA and related proteins(P<0.05,P<0.01).Conclusion Danggui Sini Decoction can significantly reduce the inflammatory response of rat articular chondrocytes induced by lipopolysaccharide and exert therapeutic effects on KOA.Its mechanism may be related to the inhibition of TLR4/MyD88/NF-κB pathway.

Objective To conduct hazard vulnerability analysis(HVA)in a blood bank,aimed to identify high-risk e-vents and optimize emergency management measures.Methods The risk event evaluation index system was established by referring to the Kaiser model and the situation of Guangzhou Blood Center,and risk events were ranked by risk matrix and Borda count.Results The top five events with the highest risk values identified by Kaiser model were information system e-mergencies(39.61％),extreme weather(38.03％),major public sentiment(37.86％),public health events(37.37％)and policy changes(37.24％).The results of risk matrix and Borda count revealed 1 extremely high-risk indicator as information system emergency,5 high-risk indicators with the highest risk being major public sentiment,11 medium-risk indicators with the highest risk being major medical disputes and 1 low-risk indicator as external fires.Conclusion Conducting HVA in combination with the actual situation of blood banks can effectively identify high-risk events and provide theoretical basis for improving emergency management measures.

Ten-eleven translocation 1 (TET1) protein is an alpha-ketoglutaric acid (α-KG) and Fe²⁺-dependent dioxygenase. It plays a role in the active demethylation of DNA by hydroxylation of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC). Ten-eleven translocation 1 (TET1) protein is involved in maintaining genome methylation homeostasis and epigenetic regulation. Abnormally expressed TET1 and 5-mC oxidative derivatives have become potential markers in various biological and pathological processes and a research focus in the fields of embryonic development and malignant tumors. This paper introduces the structure and demethylation mechanism of TET1, reviews the research status of epigenetic regulation by TET1 in embryonic development, immune responses, stem cell regulation, cancer progression, and nervous system development, and briefs the upstream regulatory mechanism of TET1, hoping to provide new inspirations for further research in related fields.
Proto-Oncogene Proteins/genetics* ; Epigenesis, Genetic ; Humans ; DNA-Binding Proteins/metabolism* ; DNA Methylation ; Mixed Function Oxygenases/metabolism* ; 5-Methylcytosine/analogs & derivatives* ; Animals ; Embryonic Development/genetics* ; Neoplasms/genetics* ; Dioxygenases/metabolism*

Diabetic peripheral neuropathy （DPN） is one of the common complications of diabetes. The disease has a long course with nerve pain and other symptoms， seriously affecting the quality of life of patients. DPN is related to high glucose in vivo， inflammation， oxidative stress， apoptosis， and autophagy， involving phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt）， Janus kinase （JAK）/signal transducer and activator of transcription （STAT）， nuclear factor-κB （NF-κB）， mitogen-activated protein kinase （MAPK）， and other signaling pathways. At present， the treatment of DPN mainly focuses on symptomatic treatments such as blood glucose control and neurotrophic therapy， but the effect is not ideal. Therefore， it is particularly important to select a reasonable and effective drug to prevent and treat DPN. In recent years， Chinese medicine has played an important role in the treatment of DPN. Many studies have explored the mechanism of Chinese medicine in the treatment of DPN， and it has been found that some Chinese medicine monomers and compounds can regulate signaling pathways to prevent and treat DPN. This paper reviewed the research results of signaling pathways involved in DPN and the regulation of related pathways by Chinese medicine， aiming to provide references for the clinical treatment of DPN.

Knee osteoarthritis （KOA） is a common degenerative joint disease in the middle-aged and elderly. The incidence of KOA is rising as the population aging aggravates and the obese population grows. KOA seriously affects the health and daily life of the patients. The commonly used drugs for the symptomatic treatment of KOA include non-steroidal anti-inflammatory drugs， cartilage protective drugs， and opioid analgesics， which have limited therapeutic effects and induce obvious adverse drug reactions. Eucommiae Cortex is one of the commonly used Chinese herbal medicines for the treatment of KOA， while its pharmacological material basis and mechanism remain unclear， which limits its clinical application. The active ingredients of Eucommiae Cortex for treating KOA mainly include iridoids （geniposide， aucubin）， lignans （pinoresinol diglucoside）， flavonoids （quercetin， astragaloside， baicalein， hyperoside， and kaempferol）， phenylpropanoids （chlorogenic acid）， and polysaccharides. These compounds regulate the levels of inflammatory cytokines， inhibit oxidative stress， protect chondrocytes， balance the synthesis and degradation of extracellular matrix， and control the progression of KOA via the mitogen-activated protein kinase， nuclear factor-κB， phosphatidylinositol-3-kinase/protein kinase B， and Janus kinase 1/signal transducer and activator of transcription 3 signaling pathways. This paper introduces the mechanisms of Eucommiae Cortex and its active components in the treatment of KOA， aiming to provide a theoretical basis for the development of new drugs for KOA.

Objective:To prepare 68Ga-2-(4, 7-bis(carboxymethyl)-1, 4, 7-triazonan-1-yl)pentanedioic acid (NODAGA)-YHWYGYTPQNVI (GE11) and evaluate its feasibility of PET imaging for pancreatic cancer. Methods:GE11 peptide was conjugated with NODAGA and then labeled with 68Ga. The labeling yield, radiochemical purity, hydrophilicity, stability and specificity in vitro were determined. Human pancreatic cancer BxPC3 nude mice models ( n=9) were established. MicroPET imaging was then obtained after 30 and 90 min, and mice were sacrificed at 90 min to acquire the radioactivity distribution of main organs and tumors. Pair t test was used to analyze the data. Results:The labeling yield was (73.5±5.4)% and radiochemical purity was more than 98%. After incubation 120 min in mouse serum at 37 ℃, radiochemical purity was more than 92%. The uptake was specific in BxPC3 cell lines. MicroPET images showed that 68Ga-NODAGA-GE11 could accumulate quickly in tumor. Value of tumor uptake was significantly higher than that of normal pancreas at 90 min ((1.38±0.25) vs (0.49±0.07) %ID/g; t=12.67, P<0.05), and the radio-uptake of blood, muscle and bone was lower than that of tumor. Conclusions:68Ga-NODAGA-GE11 is easy to be prepared with high radiochemical purity and good stability, and can specifically target BxPC3 xenograft tumor. However, due to the high uptake in the kidneys and liver, the value of 68Ga-NODAGA-GE11 in PET imaging for pancreatic tumor needs further study.

Objective:To investigate the clinicopathological characteristics and 18F-fluorodeoxyglucose (FDG) PET/CT imaging features of bronchopulmonary neuroendocrine tumors(BP-NETs) with different pathological subtypes. Methods:From January 2013 to May 2018, 280 patients (196 males, 84 females, median age 58 years) with BP-NETs proved by pathology in Henan Provincial People′s Hospital were retrospectively analyzed. Age, gender, smoking history, the location and size of tumor, Ki-67 positive index, thyroid transcription factor-1 (TTF-1), synaptophysin (Syn), chromogranin-A (CgA), CD56, maximum standardized uptake value (SUV max), lymph node metastasis and distant metastasis were compared among 4 pathological subtypes of BP-NETs, including typical carcinoid (TC), atypical carcinoid (AC), small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). One-way analysis of variance, χ2 test, Fisher exact test and Kruskal-Wallis rank sum test were used for data analysis. Results:There were significant differences in age, smoking history, tumor size and location, Ki-67 positive index, CgA, CD56, TTF-1, SUV max and TNM stage among TC( n=59), AC( n=21), SCLC( n=184) and LCNEC ( n=16) groups ( F values: 2.067, 3.358, H values: 17.749-22.351, all P<0.05). SCLC had the largest tumor size (5.5(3.0, 6.8) cm) and the highest proportion of central type (85.3%, 157/184), and were more prone to lymph node metastasis. LCNEC had the oldest age ((66±16) years), the largest proportion of smoking history (14/16) and peripheral type (12/16). CD56 in SCLC (95.7%, 176/184) and LCNEC(15/16) mostly showed positive expression, while the positive expression rates of CgA and TTF-1 were higher in TC and AC (96.6%(57/59), 93.2%(55/59) and 95.2%(20/21), 90.5%(19/21), respectively). The Ki-67 positive index and SUV max of the four subtypes were significantly different, with the highest in SCLC group and the lowest in TC group. Conclusion:Different pathological subtypes of BP-NETs manifest different clinicopathological features and imaging presentation on 18F-FDG PET/CT, which are useful for understanding their characteristics.

Objective:To establish a 10-year comparison table of cerebrovascular function score and first stroke risk, and to provide a new method for screening of high-risk population of stroke.Methods:In the beginning of 2003, a cohort for studing stroke risk factors in those aged 40 years and over was established in a community of Shanghai by cluster sampling. The common risk factors of stroke were investigated with a unified questionnaire, and the cerebrovascular function (cerebral vascular hemodynamic indexes, CVHI) was measured. The baseline study was completed from April to June 2003 and December 2004 to January 2005, respectively. The incident of first stroke and all cause of death were followed up year by year. The follow-up period was up to December 31, 2014. The 10-year incidence of first stroke was calculated according to the baseline score of cerebrovascular function, and the score-risk control table was established to estimate 10-year first stroke risk in each score group. The role of cerebrovascular function score in stroke was also estimated.Results:The follow-up term of 10 565 participants was (10.26±2.00) years, and 350 patients had first stroke during the follow-up. The trend 10-year incidence of first stroke both in men and women was significantly increased with the decrease of the score of cerebrovascular function (trend χ2=296.125, P<0.01). As the 10-year risk of first stroke was higher than 5% and higher than 10%, the corresponding CVHI score was lower than 70 and 40 points in males and lower than 30 and 20 points in females. When the scores of cerebral vascular function were divided by every 25 points, incidence of first stroke in each group from top to bottom was 1.9%, 4.7%, 10.8%, 15.2% in males and 1.6%, 4.4%, 4.8%, 11.4% in females, respectively. As compared to the top, the relative risk (95% CI) of first stroke in the lower groups was 2.61(1.67-4.07), 6.46(4.22-9.89), 9.74(6.53-14.52) for males and 2.82(1.93-4.12), 3.15(1.99-4.99), 8.12(5.65-11.68) for females, respectively. Multivariate analysis showed that the factors being selected into the regression equation were cerebrovascular function score, age, hypertension history, stroke family history and smoking history, among which the role of cerebrovascular function score was the strongest. Conclusion:The risk of first stroke increases significantly with the decrease of cerebrovascular function score, which can be used to assess the 10-year risk of first stroke.