Nanomaterials can be used in drug delivery systems to enhance drug targeting and efficacy, and reduce adverse reactions. At the same time, they can also be used in tissue engineering and regenerative medicine to promote bone tissue repair and regeneration. Nanozymes are special nanomaterials with the catalytic activity of biological enzymes, which can mediate efficient biochemical reactions and provide a new strategy for the diagnosis and treatment of orthopaedic diseases. In the treatment of tendon-related diseases, the enzymatic nanohybrid encapsulated by extracellular vesicles can effectively mimic catalase to remove reactive oxygen species, continuously release zinc ions, and induce immune regulation through extracellular vesicles. It can significantly promote functional recovery and matrix reconstruction, restore tendon morphology, and inhibit scar formation and adhesion around the tendon. In the treatment of bone and joint diseases, photothermal nanozymes with bionic characteristics can generate thermal energy under near-infrared radiation, enhance joint lubrication performance, reduce cartilage wear in early osteoarthritis, effectively remove reactive oxygen species and reactive nitrogen species, increase the production of hyaluronic acid inside and outside the cells, and help to restore the lubrication and function of articular cartilage. Hollow Prussian blue nanoenzyme prepared by template-free hydrothermal synthesis can inhibit osteoclast formation and bone resorption, inhibit intracellular reactive oxygen species production and mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways, thereby improving osteoporosis. In the treatment of spinal diseases, Prussian blue nanozymes can not only remove excessive reactive oxygen species, maintain the normal Redox level of nucleus pulposus cells, but also escape lysosomal phagocytosis, achieve more effective mitochondrial targeting, and effectively alleviate intervertebral disc degeneration.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To investigate the mechanism of modified Guizhi Fuling Pills in treating diabetic kidney disease(DKD)through autophagy regulation based on network pharmacology and experimental validation.Methods Active components and action targets of modified Guizhi Fuling Pills were screened via the TCMSP database.DKD-related autophagy targets were obtained from GeneCards,TTD,DrugBank and PharmGKB.A protein-protein interaction network was constructed using STRING,followed by GO functional and KEGG pathway enrichment analyses via DAVID.Molecular docking of key components and core targets was performed using AutoDock Tools 1.5.7.DKD model rats were prepared.The rats were randomly divided into normal group,model group,valsartan group(50 mg/kg),and modified Guizhi Fuling Pills low-,medium-and high-dosage group(9.9,19.8 and 39.6 g/kg).After 8-week interventions,body mass and water intake were recorded;fasting blood glucose,24 h urinary total protein(24 hUTP),urinary albumin-to-creatinine ratio(UACR)were monitored.Renal histopathology was evaluated via HE and Masson staining.Western blot was used to detect protein expressions of AMPK/FOXO1 pathway(p-AMPK,AMPK,FOXO1)and autophagy markers(Beclin-1,p62),while quantitative real-time PCR was used to assess AMPK and FOXO1 mRNA expressions.Results A total of 146 active components of Guizhi Fuling Pills and 33 main targets for treating DKD were screened,with the core targets including FOXO1,BCL2,TP53 and PTEN.KEGG pathway enrichment analysis suggested that AMPK/FOXO1 signaling pathway,AGE-RAGE and insulin signaling pathways may play a core regulatory role.Guizhi Fuling Pills could significantly reduce the body mass of DKD rats,reduce water intake,decrease renal index,decrease fasting blood glucose,24 hUTP and UACR(P<0.05,P<0.01),improve renal tissue pathology,increase AMPK,FOXO1,Beclin-1 protein expressions and AMPK,FOXO1 mRNA expressions(P<0.05),and reduce p62 protein expression(P<0.05).Conclusion Modified Guizhi Fuling Pills may exert therapeutic effects on DKD by regulating the AMPK-FOXO1-autophagy axis.

Nanomaterials can be used in drug delivery systems to enhance drug targeting and efficacy, and reduce adverse reactions. At the same time, they can also be used in tissue engineering and regenerative medicine to promote bone tissue repair and regeneration. Nanozymes are special nanomaterials with the catalytic activity of biological enzymes, which can mediate efficient biochemical reactions and provide a new strategy for the diagnosis and treatment of orthopaedic diseases. In the treatment of tendon-related diseases, the enzymatic nanohybrid encapsulated by extracellular vesicles can effectively mimic catalase to remove reactive oxygen species, continuously release zinc ions, and induce immune regulation through extracellular vesicles. It can significantly promote functional recovery and matrix reconstruction, restore tendon morphology, and inhibit scar formation and adhesion around the tendon. In the treatment of bone and joint diseases, photothermal nanozymes with bionic characteristics can generate thermal energy under near-infrared radiation, enhance joint lubrication performance, reduce cartilage wear in early osteoarthritis, effectively remove reactive oxygen species and reactive nitrogen species, increase the production of hyaluronic acid inside and outside the cells, and help to restore the lubrication and function of articular cartilage. Hollow Prussian blue nanoenzyme prepared by template-free hydrothermal synthesis can inhibit osteoclast formation and bone resorption, inhibit intracellular reactive oxygen species production and mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways, thereby improving osteoporosis. In the treatment of spinal diseases, Prussian blue nanozymes can not only remove excessive reactive oxygen species, maintain the normal Redox level of nucleus pulposus cells, but also escape lysosomal phagocytosis, achieve more effective mitochondrial targeting, and effectively alleviate intervertebral disc degeneration.

Objective To investigate the mechanism of modified Guizhi Fuling Pills in treating diabetic kidney disease(DKD)through autophagy regulation based on network pharmacology and experimental validation.Methods Active components and action targets of modified Guizhi Fuling Pills were screened via the TCMSP database.DKD-related autophagy targets were obtained from GeneCards,TTD,DrugBank and PharmGKB.A protein-protein interaction network was constructed using STRING,followed by GO functional and KEGG pathway enrichment analyses via DAVID.Molecular docking of key components and core targets was performed using AutoDock Tools 1.5.7.DKD model rats were prepared.The rats were randomly divided into normal group,model group,valsartan group(50 mg/kg),and modified Guizhi Fuling Pills low-,medium-and high-dosage group(9.9,19.8 and 39.6 g/kg).After 8-week interventions,body mass and water intake were recorded;fasting blood glucose,24 h urinary total protein(24 hUTP),urinary albumin-to-creatinine ratio(UACR)were monitored.Renal histopathology was evaluated via HE and Masson staining.Western blot was used to detect protein expressions of AMPK/FOXO1 pathway(p-AMPK,AMPK,FOXO1)and autophagy markers(Beclin-1,p62),while quantitative real-time PCR was used to assess AMPK and FOXO1 mRNA expressions.Results A total of 146 active components of Guizhi Fuling Pills and 33 main targets for treating DKD were screened,with the core targets including FOXO1,BCL2,TP53 and PTEN.KEGG pathway enrichment analysis suggested that AMPK/FOXO1 signaling pathway,AGE-RAGE and insulin signaling pathways may play a core regulatory role.Guizhi Fuling Pills could significantly reduce the body mass of DKD rats,reduce water intake,decrease renal index,decrease fasting blood glucose,24 hUTP and UACR(P<0.05,P<0.01),improve renal tissue pathology,increase AMPK,FOXO1,Beclin-1 protein expressions and AMPK,FOXO1 mRNA expressions(P<0.05),and reduce p62 protein expression(P<0.05).Conclusion Modified Guizhi Fuling Pills may exert therapeutic effects on DKD by regulating the AMPK-FOXO1-autophagy axis.

Healthy lifestyles and good living habits are effective strategies and important approaches to prevent chronic non-communicable diseases. With the development of evidence-based medicine, the evidence translation system has made some achievements in clinical practice. There is, however, no comprehensive, professional and efficient system for translating lifestyle evidence globally. Therefore, the Health Lifestyle Evidence (HLSE) Group of Lanzhou University constructed the HLSE Evidence Translation System (https://hlse.cn/), with the aim of synthesizing, evaluating, translating, and applying lifestyle-related evidence resources. This paper aims to introduce the functional module design of the evidence translation system, the system development process and testing, introduce the interface design and function demonstration, and explain the significance of constructing the HLSE.

Healthy lifestyles and good living habits are effective strategies and important approaches to prevent chronic non-communicable diseases. With the development of evidence-based medicine, the evidence translation system has made some achievements in clinical practice. There is, however, no comprehensive, professional and efficient system for translating lifestyle evidence globally. Therefore, the Health Lifestyle Evidence (HLSE) Group of Lanzhou University constructed the HLSE Evidence Translation System (https://hlse.cn/), with the aim of synthesizing, evaluating, translating, and applying lifestyle-related evidence resources. This paper aims to introduce the functional module design of the evidence translation system, the system development process and testing, introduce the interface design and function demonstration, and explain the significance of constructing the HLSE.

ObjectiveTo observe the mechanism of Jiawei Guizhi Fuling decoction （JGFD） in alleviating sciatic nerve injury in painful diabetic peripheral neuropathy （PDPN） rats by regulating mitophagy through the PTEN-induced putative kinase 1 （PINK1）/Parkin signaling pathway. MethodThe PDPN model was established by intraperitoneal injection of streptozotocin （STZ）. After modeling， the rats were randomly divided into JGFD high， medium， and low dose groups （JGFD-H， JGFD-M， JGFD-L； 39.6， 19.8， 9.9 g·kg^-1·d^-1， respectively）， a positive drug group （lipoic acid capsules， LA； 50 mg·kg^-1·d^-1）， and a model group （PDPN）. A blank control group （CON） was established. Drug intervention was administered continuously for 8 weeks after modeling. Measurements included body weight and fasting blood glucose of PDPN rats at weeks 0， 2， 4， and 8， mechanical pain threshold and thermal pain threshold at weeks 0 and 8， and motor nerve conduction velocity at week 8. Hematoxylin-eosin （HE） staining was used to observe the morphology of sciatic nerve tissue. The ultrastructure of mitochondria and autophagosomes was observed by transmission electron microscopy. Western blot was performed to detect the protein expression levels of PINK1， Parkin， p62， Beclin-1， and LC3 in sciatic nerve tissue. Additionally， real-time quantitative PCR （Real-time PCR） was performed to detect the mRNA expression levels of PINK1， Parkin， p62， Beclin-1， and LC3 in sciatic nerve tissue. ResultCompared with the CON group， the PDPN group showed a significant decrease in body weight at all time points， a significant increase in fasting blood glucose， significantly shortened mechanical pain and thermal pain thresholds， and significantly reduced motor nerve conduction velocity. The protein and mRNA expression of PINK1， Parkin， Beclin-1， and microtubule-associated protein light chain 3（LC3） in sciatic nerve tissue was significantly reduced， while p62 protein and mRNA expression was significantly increased （P<0.01）. Pathological changes included edema of sciatic nerve fibers， segmental demyelination， loose and disordered arrangement of the myelin sheath layers， significant swelling of mitochondria， reduced electron density， disappearance of cristae， and absence of typical autophagosome and autolysosome structures. Compared with the PDPN group， each JGFD dose group showed a significant increase in body weight and a significant reduction in fasting blood glucose （P<0.05， P<0.01）. The mechanical pain threshold and thermal pain threshold were significantly prolonged， and motor nerve conduction velocity was significantly increased across all JGFD and LA groups. The expression levels of PINK1， Parkin， Beclin-1， and LC3 proteins and mRNA in sciatic nerve tissue were significantly increased， while p62 protein and mRNA expression levels were significantly decreased （P<0.05， P<0.01）. Pathological damage to the sciatic nerve was alleviated to varying degrees， with a relatively intact myelin sheath morphology and intact or slightly edematous outer mitochondrial membrane. Autophagolysosome structures were observed in the JGFD-M and JGFD-H groups. Compared with the LA group， the JGFD-H group showed a significant increase in body weight， a significant reduction in fasting blood glucose， a significant increase in motor nerve conduction velocity， a significant increase in PINK1 protein expression and PINK1， Parkin， and Beclin-1 mRNA expression in sciatic nerve tissue， and a significant decrease in p62 mRNA expression （P<0.05， P<0.01）. ConclusionJGFD may alleviate sciatic nerve injury in PDPN rats by activating mitophagy through the regulation of the PINK1/Parkin signaling pathway.

【Objective】 To explore a new treatment of primary bilateral macronodular adrenal hyperplasia (PBMAH) and its efficacy. 【Methods】 Clinical data of 20 PBMAH patients treated in our hospital during Mar.2010 and Apr.2021 were retrospectively analyzed. All patients underwent laparoscopic subcutaneous displacement of vascularized adrenal. The clinical symptoms, plasma free cortisol, adrenocorticotrophic hormone (ACTH), and 24 h urinary free cortisol were regularly monitored after surgery. 【Results】 Of all 20 patients, 19 were followed up for 18 to 120 months (median 60 months). Three months after surgery, reexamination showed 1 patient had decreased plasma free cortisol and increased ACTH, but had no symptoms of low corticosteroids. After another 3 months, the plasma free cortisol and ACTH returned to normal. After 4 to 48 months, the parameters recovered in all patients and the clinical symptoms disappeared. 【Conclusion】 Laparoscopic vascularized adrenal displacement is a new and effective method for the treatment of PBMAH. It can alleviate the Cushing syndrome with no obvious adverse reactions.

Objective:To explore the medication law and core Traditional Chinese Medicine (TCM) compounds in the treatment of blood stasis vascular dementia (VD) based on data mining.Methods:The literature about TCM treatment for blood stasis VD was retrieved from the databases of CNKI, Wanfang, VIP, and CBM from January 2000 to November 2021. Microsoft Office Excel 2019, SPSS Modeler 18.0, SPSS Statistics 25.0, R X64 4.1.2, and Origin 2021 were used to perform medication frequency analysis, frequency analysis of four properties and five tastes of TCM, association rules, clustering analysis, factor analysis and data visualization.Results:A total of 196 articles were included, with 196 TCM prescriptions, involving 200 kinds of Chinese materia medica. High-frequency drugs were for Acori Tatarinowii Rhizoma, Chuanxiong Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Polygalae Radix, Carthami Flos. The medicinal properties were mainly warm, mild and cold, the tastes were mainly sweet, bitter and pungent, and the meridians were mainly liver meridian, spleen meridian and heart meridian. A total of 19 association rules were obtained from the analysis of association rules for 2 kinds of Chinese materia medica, and the rules of the representative were Acori Tatarinowii Rhizoma- Polygalae Radix, Chuanxiong Rhizoma- Carthami Flos, Acori Tatarinowii Rhizoma- Curcumae Radix. A total of 4 categories were extracted through clustering analysis. Factor analysis extracted a total of 8 common factors. Conclusion:The core pathogenesis of blood stasis VD is blood stasis blocking brain collaterals, and there were also pathological factors such as qi deficiency, yin deficiency, phlegm turbidity and so on. The basic treatment is promoting blood circulation and removing stasis, and different methods of promoting blood circulation and drugs are selected. The methods of strengthening spleen and reducing phlegm, nourishing yin and blood, inducing resuscitation, tonifying the kidney and spleen, regulating qi, promoting collaterals and so on can also be used based on syndromes and symptoms of the patients.