Vascular cognitive impairment (VCI), caused by cerebrovascular dysfunction, severely impacts the quality of life in the elderly population, yet effective therapeutic approaches remain limited. Mitophagy, a selective mitochondrial quality-control mechanism, has emerged as a critical focus in neurological disease research. Accumulating evidence indicates that mitophagy modulates oxidative stress, neuroinflammation, and neuronal apoptosis. Key signaling pathways associated with mitophagy—including PINK1/Parkin, BNIP3/Nix, FUNDC1, PI3K/Akt/mTOR, and AMPK—have been identified as potential therapeutic targets for VCI. This review summarizes the mechanistic roles of mitophagy in VCI pathogenesis and explores emerging therapeutic strategies targeting these pathways, aiming to provide novel insights for clinical intervention and advance the development of effective treatments for VCI.

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Increasing evidence showed that histone deacetylase 6 (HDAC6) dysfunction is directly associated with the onset and progression of various diseases, especially cancers, making the development of HDAC6-targeted anti-tumor agents a research hotspot. In this study, artificial intelligence (AI) technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline, which combined Voting strategy based on compound-protein interaction (CPI) prediction models, cascade molecular docking, and molecular dynamic (MD) simulations. The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays. Among the identified compounds, Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity (IC₅₀ = 5.41 nM) than that of tubastatin A (TubA) (IC₅₀ = 15.11 nM), along with a favorable subtype selectivity profile (selectivity index ≈ 117.23 for HDAC1), which was further verified by the Western blot analysis. Additionally, Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells, exerting desirable antiproliferative activity (IC₅₀ = 2.59 μM). Furthermore, based on long-term MD simulation trajectory, the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis, thereby elucidating its binding mechanism. Moreover, the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation, thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.

Objective:To prepare the bacterial outer membrane vesicles(OMV)that can express programmed death ligand 1(PD-L1)nanobody on surface,and to discuss its structural characteristics,cell compatibility,intracellular distribution,and its blocking effect on the programmed cell death protein-1(PD-1)/PD-L1 signaling axis.Methods:The pET28a-ClyA-PD-L1nb prokaryotic expression vector was constructed and transformed into Escherichia coli BL21(DE3)competent cells;the OMV was isolated from the BL21(DE3)monoclonal colonies transformed with the PD-L1nb expression vector by ultracentrifugation;the protein purification was performed using the histidine(His)tag;transmission electron microscope and nanoparticle size analyzer were used to analyze and identify the OMV;the OMV isolated from the BL21(DE3)monoclonal colonies transformed with the PD-L1nb expression vector was used as experimental group;the OMV isolated from the untransformed BL21(DE3)monoclonal colonies was used as control group;Western blotting method was used to detect the expression levels of ClyA-PD-L1nb fusion protein in the OMV in two groups;cell counting kit-8(CCK-8)assay was used to detect the activities of mouse macrophage RAW 264.7 cells,mouse triple-negative breast cancer 4T1 cells,and human embryonic kidney HEK293T cells after treated with OMV;fluorescence imaging technology was used to observe the tumor cell endocytosis of OMV;flow cytometry was used to detect the binding effect of OMV to the PD-L1 on surface of the tumor cells in PBS group,OMV-PD-L1nb group,and aPD-L1+OMV-PD-L1nb group.Results:The sodium dodecyl sulfate-polyacrylamide gel electrophoresis(SDS-PAGE)results showed that after induction of Escherichia coli,significantly thickened protein bands appeared near the predicted relative molecular mass(about 49 000),and after purification,no obvious impurity proteins existed in the lanes;the OMV-PD-L1nb with a size of about 120 nm was isolated by ultracentrifugation,and it presented a uniform spherical structure under transmission electron microscope;the Western blotting results showed that the specific band of ClyA-PD-L1nb was detected in the OMV in experimental group;the CCK-8 assay results showed that after treated with different concentrations of OMV,the viabilities of the RAW 264.7 cells,4T1 cells,and HEK293T cells were all close to 100％;the fluorescence imaging results showed that OMV-PD-L1nb was endocytosed by 4T1 cells and dispersed in the cytoplasm;compared with OMV-PD-L1nb group,the average fluorescence intensity in the cells in aPD-L1+OMV-PD-L1nb group was significantly decreased(P＜0.001).Conclusion:The OMV surface-displaying PD-L1nb,OMV-PD-L1nb,is successfully prepared and isolated;OMV-PD-L1nb shows good compatibility on mouse macrophage cells,tumor cells,and human embryonic kidney cells,can be endocytosed by tumor cells,and successfully blocks the PD-1/PD-L1 signaling pathway.

Objective:To discuss their effects of PLA(polylactic acid)/PTMC(polytrimethylene carbonate)and PLA/PTMC-calcium phosphate[Ca3(PO4)2]composite porous scaffolds prepared by 3D printing technology on bone marrow mesenchymal stem cells(BMSCs)of the rabbits,and to clarify their application values in bone defect repairment.Methods:After mixing the materials,PLA/PTMC and PLA/PTMC-Ca3(PO4)2 filaments were prepared by desktop filament extruder.The scaffolds were designed by CATIA V5-6R2019 modeling software and fabricated using CreatBot F430 3D printer.The chemical structure of the PLA/PTMC-Ca3(PO4)2 scaffold was detected by infrared spectroscopy.In vitro degradation experiments were used to detect the degradation weight loss rates and pH values of the two scaffolds.A contact angle measuring instrument was used to detect the hydrophilicities of the two scaffolds.The BMSCs were extracted from three newborn New Zealand white rabbits(2-5-day-old);CCK-8 method was used to detect the proliferation activities of the cells co-cultured with two scaffolds,and Alizarin red staining was used to observe the osteogenic differentiation of the cells co-cultured with two scaffolds.Results:Infrared spectroscopy confirmed the successful preparation of composite scaffolds containing PLA,PTMC,and β-Ca3(PO4)2.During degradation for 6-14 weeks,compared with PLA/PTMC scaffold,the degradation rates of the PLA/PTMC-Ca3(PO4)2 scaffold in lipase solution and phosphate-buffered saline(PBS)were significantly increased(P<0.05 or P<0.01).During degradation for 8-14 weeks,compared with PLA/PTMC scaffold,the pH value of the PLA/PTMC-Ca3(PO4)2scaffold in lipase solution was significantly increased(P<0.01).Compared with PLA/PTMC scaffold,the contact angle of the PLA/PTMC-Ca3(PO4)2 scaffold was significantly decreased(P<0.01).On days 5 and 7 of cell co-culture,compared with PLA/PTMC scaffold,the proliferation activity of the cells co-cultured with PLA/PTMC-Ca3(PO4)2 scaffold was significantly increased(P<0.05 or P<0.01).After 21 d of co-culture,both scaffolds overlapped with BMSCs and locally formed calcified nodules,which were stained orange by Alizarin red.Compared with PLA/PTMC scaffold,the number of mineralized calcium nodules in the cells co-cultured with PLA/PTMC-Ca3(PO4)2 scaffold was increased,with greater density and deeper color.Conclusion:The PLA/PTMC-Ca3(PO4)2 composite porous scaffolds containing PLA,PTMC,and β-Ca3(PO4)2 are successfully prepared by 3D printing technology.These scaffolds exhibit good degradation properties and show advantages in biocompatibility,hydrophilicity,and osteogenic induction;they are excellent materials for the bone defect repairment.

Objective:To investigate the clinicopathological characteristics of rashes in monkeypox patients through a series of skin biopsies, and examine their pathological features and the most effective tests.Methods:Patients with monkeypox virus infection admitted to Beijing Ditan Hospital from June to August 2023 were identified. Among them, 24 patients underwent skin biopsies for clinical pathological study that were included in this study. Clinical information, rash pictures, and nucleic acid test results were analyzed using histopathology, immunohistochemistry, RNAscope ? hybridization and electron microscopy. Results:All 24 patients were male, including 14 patients with concurrent human immunodeficiency virus infection. Their average age was (32.3±5.4) years. The nucleic acid test confirmed monkeypox virus infection. The clinical feature of monkeypox rashes was solitary rather than clustered distribution, with rashes occurring in similar phase, distinguishing it from herpesvirus. The rashes in these patients were mostly scattered, with an average of (13.0±11.8) rashes, and most commonly present in the perineum, face, limbs, and trunk. The three main pathological features of these rashes were ballooning degeneration of the epidermal spinous cell layer, the characteristic intra-cytoplasmic Guarnieri′s bodies and significant infiltration of inflammatory cells in whole dermal layer. Immunohistochemistry, RNAscope ? hybridization, and electron microscopy can all effectively detect the monkeypox virus. Electron microscopy showed viral replication in various types of skin cells. Conclusions:The study describes the pathological features of monkeypox virus rashes. Pathological examination of skin biopsy samples is helpful to diagnose these rashes. The study suggests that the monkeypox virus has a unique epitheliotropic affinity and can infect various types of cells in the skin.

Objective:To explore the abnormalities of functional brain networks and their relationship with behavioral scale scores in patients with spinal cerebellar ataxia (SCA) type 3 using MRI.Methods:The study was a cross-sectional study. Clinical and imaging data of 52 patients with SCA type 3 (SCA type 3 group) and 55 normal control group admitted to the First Affiliated Hospital of Army Medical University from May 2017 to May 2023 were prospectively analyzed. All participants underwent structural and resting-state functional MRI. Graph theory analysis assessed global and nodal properties of brain network connectivity, including clustering coefficient (Cp), characteristic path length (Lp), normalized clustering coefficient (γ), normalized characteristic path length (λ), small-world index (σ), global efficiency (Eglob), local efficiency (Eloc), assortativity, and nodal efficiency. The area under the curve (AUC) for global attribute parameters was calculated and a two-sample t-test was used to compare the AUC values of the global attribute parameters between the 2 groups, and corrected for false discovery rate correction (FDR). A two-sample t-test was used to compare the node efficiencies of the 2 groups, corrected for network-based statistics (NBS), and the brain regions with significant differences in node efficiencies between the 2 groups were selected as the brain regions of interest, and a two-sample t-test was used to compare the differences in resting state functional connectivity (rsFC) values between the brain regions of interest and other brain regions in the SCA type 3 group and the normal control group, corrected for NBS. Spearman test was used to correlate significantly different rsFC values ( P<0.01) between the 2 groups and their clinical behavioral scores. Results:Compared with the normal control group, the AUC value of Cp for brain network connectivity was significantly increased in the SCA type 3 group ( Z=2.05, P=0.043), whereas the differences in γ, λ, σ, Eglob, Eloc, Lp, and homozygosity were not statistically significant between the 2 groups (all P>0.05). The SCA type 3 group had significantly lower nodal efficiency in the left precuneus ( t=-2.16, NBS corrected P=0.033) and left inferotemporal gyrus ( t=-2.25, NBS corrected P=0.027), and significantly higher nodal efficiency in the right lentiform nucleus ( t=2.05, NBS corrected P=0.043) and left middle temporal gyrus ( t=2.25, NBS corrected P=0.027) compared to normal control group. Significant alterations in rsFC values were found between multiple brain regions in SCA type 3 patients, correlating with clinical data and behavioral assessment scores. Conclusions:SCA type 3 patients exhibit specific alterations in brain functional networks, including changes in clustering coefficient and nodal efficiency. Furthermore, rsFC between brain regions correlates with behavioral abnormalities.

Femoral head fracture combined with posterior hip dislocation is a serious traumatic condition. Conservative treatment has a long time of bed rest, and may cause muscle apraxia atrophy, hypostatic pneumonia, deep vein thrombosis of the lower limbs, or pulmonary embolism, which has poor clinical efficacy. Therefore, surgical treatment is the first choice for femoral head fracture combined with posterior hip dislocation. The direct anterior approach of the hip can better expose Pipkin type I and type II femoral head fractures without the need to dislocate the hip completely. However, the disadvantage is that it destroys the structural integrity of the anterior hip joint, which increases the risk of femoral head necrosis and heterotopic ossification to a certain extent. The medial approach can also be chosen for Pipkin type I and II fractures, but it is important to avoid damaging the integrity of the fascial layer, some small vascular branches can be ligated, and injury to the medial rotary femoral artery should be avoided. The lateral approach is considered to be an effective treatment for Pipkin type III fractures, but there is limited exposure of the posterior acetabular injury and a risk of injury to the superior gluteal vessels and nerves, which may be secondary to adductor weakness postoperatively. The posterior approach is the main surgical approach for type IV Pipkin fracture. The classic posterior lateral approaches mainly include the Kocher - Langenbeck approach and the Ganz surgical dislocation approach. The Kocher - Langenbeck approach does not destroy the abductors and is particularly suitable for patients with posterior hip dislocation and difficult to reposition. Ganz surgical approach protects the blood supply of the medial femoral circumcator artery, so the incidence of femoral head necrosis is low. It can achieve all-round visualization of the femoral head and acetabulum, comprehensively evaluate the lesions of the femoral head and acetabulum, and find the occult injuries missed in imaging examinations..

The human immune system plays a key role in maintaining tissue homeostasis and disease progression. The development of biomaterials that can regulate the innate immune system and adapt to the immune system has great application prospects in the field of tissue engineering. This paper discusses how to design the surface interface topographies or the physicochemical properties of biomaterials, to regulate the fate of macrophages, such as activation, polarization, adhesion, migration, proliferation, and secretion. At the same time, the application of these biomaterials with immunoregulation function in the field of wound healing is discussed. In addition, this paper also put forward the limitations of biomaterials in immunoregulation applications and prospected the future development directions.