Distinct from the complementary inhibition mechanism through binding to the target with three-dimensional conformation of small molecule inhibitors, targeted protein degradation technology takes tremendous advantage of endogenous protein degradation pathway inside cells to degrade plenty of “undruggable” target proteins, which provides a novel route for the treatment of many serious diseases, mainly including proteolysis-targeting chimeras, lysosome-targeting chimeras, autophagy-targeting chimeras, antibody-based proteolysis-targeting chimeras, etc. Unlike proteolysis-targeting chimeras first found in 2001, which rely on ubiquitin-proteasome system to mainly degrade intracellular proteins of interest, lysosome-targeting chimeras identified in 2020, which was act as the fastly developing technology, utilize cellular lysosomal pathway through endocytosis mediated by lysosome-targeting receptor to degrade both extracellular and membrane proteins. As an emerging biomedical technology, nucleic acid-driven lysosome-targeting chimeras utilize nucleic acids as certain components of chimera molecule to replace with ligand to lysosome-targeting receptor or protein of interest, exhibiting broad application prospects and potential clinical value in disease treatment and drug development. This review mainly introduced present progress of nucleic acid-driven lysosome-targeting chimeras technology, including its basic composition, its advantages compared with antibody or glycopeptide-based lysosome-targeting chimeras, and focused on its chief application, in terms of the type of lysosome-targeting receptors. Most research about the development of nucleic acid-driven lysosome-targeting chimeras focused on those which utilized cation-independent mannose-6-phosphonate receptor as the lysosome-targeting receptor. Both mannose-6-phosphonate-modified glycopeptide and nucleic aptamer targeting cation-independent mannose-6-phosphonate receptor, even double-stranded DNA molecule moiety can be taken advantage as the ligand to lysosome-targeting receptor. The same as classical lysosome-targeting chimeras, asialoglycoprotein receptor can also be used for advance of nucleic acid-driven lysosome-targeting chimeras. Another new-found lysosome-targeting receptor, scavenger receptor, can bind dendritic DNA molecules to mediate cellular internalization of complex and lysosomal degradation of target protein, suggesting the successful application of scavenger receptor-mediated nucleic acid-driven lysosome-targeting chimeras. In addition, this review briefly overviewed the history of lysosome-targeting chimeras, including first-generation and second-generation lysosome-targeting chimeras through cation-independent mannose-6-phosphonate receptor-mediated and asialoglycoprotein receptor-mediated endocytosis respectively, so that a clear timeline can be presented for the advance of chimera technique. Meantime, current deficiency and challenge of lysosome-targeting chimeras was also mentioned to give some direction for deep progress of lysosome-targeting chimeras. Finally, according to faulty lysosomal degradation efficiency, more cellular mechanism where lysosome-targeting chimeras perform degradation of protein of interest need to be deeply explored. In view of current progress and direction of nucleic acid-driven lysosome-targeting chimeras, we discussed its current challenges and development direction in the future. Stability of natural nucleic acid molecule and optimized chimera construction have a great influence on the biological function of lysosome-targeting chimeras. Discovery of novel lysosome-targeting receptors and nucleic aptamer with higher affinity to the target will greatly facilitate profound advance of chimera technique. In summary, nucleic acid-driven lysosome-targeting chimeras have many superiorities, such as lower immunogenicity, expedient synthesis of chimera molecules and so on, in contrast to classical lysosome-targeting chimeras, making it more valuable. Also, the chimera technology provides new ideas and methods for biomedical research, drug development and clinical treatment, and can be used more widely through further research and optimization.

ObjectiveTo explore the material basis of the "interaction of blood stasis and toxin" mechanism in cerebral ischemia-reperfusion injury， as well as the protective role of Huoxue Huayu Jiedu prescription （HXHYJDF） against ferroptosis. MethodsSixty SPF-grade male SD rats were randomly divided into six groups： sham group， model group， deferoxamine （DFO） group （100 mg·kg^-1）， low-dose HXHYJDF group （4.52 g·kg^-1）， medium-dose HXHYJDF group （9.04 g·kg^-1）， and high-dose HXHYJDF group （18.07 g·kg^-1）， with ten rats in each group. Except for the sham group， the other groups were used to replicate the model of focal cerebral ischemia-reperfusion in the middle cerebral artery of rats by the reforming Longa method. Neurological function was assessed at 1^st， 3^rd， 5^th， and 7^th days post-reperfusion using the modified neurological severity scores （m-NSS）. Brain tissue pathology and the morphology of mitochondria were observed using hematoxylin-eosin （HE） staining and transmission electron microscopy. The contents of malondialdehyde （MDA）， glutathione （GSH）， divalent iron ions （Fe²⁺）， and reactive oxygen species （ROS） in the ischemic cerebral tissue were detected using enzyme-linked immunosorbent assay （ELISA）. Immunohistochemistry and Western blot （WB） were used to detect the expression of iron death marker proteins glutathione peroxidase 4 （GPX4）， ferroportin-1 （FPN1）， transferrin receptor protein 1 （TfR1）， and ferritin mitochondrial （FtMt） in brain tissue. ResultsCompared with the sham group， the mNSS score of the model group was significantly increased （P<0.01）. HE staining showed that the number of neurons in the cortex of brain tissue was seriously reduced， and the intercellular space was widened. The nucleus was fragmented， and the cytoplasm was vacuolated. The results of transmission electron microscopy showed that the mitochondria in the cytoplasm contracted and rounded， and the mitochondrial cristae decreased. The matrix was lost and vacuolated， and the density of the mitochondrial bilayer membrane increased. The results of ELISA showed that the content of GSH decreased significantly （P<0.01）， and the contents of MDA， Fe²⁺， and ROS increased significantly （P<0.01）. The results of immunohistochemistry and WB showed that the expression of GPX4 and FPN1 proteins was significantly decreased （P<0.01）， and the expression of FtMt and TfR1 proteins was significantly increased （P<0.01）. Compared with those of the model group， the m-NSS scores of the high-dose and medium-dose HXHYJDF groups began to decrease on the 3^rd and 5^th days， respectively （P<0.05， P<0.01）. The results of HE and transmission electron microscopy showed that the intervention of HXHYJDF improved the pathological changes of neurons and mitochondria. The results of ELISA showed that the content of GSH in the medium-dose and high-dose HXHYJDF groups increased significantly （P<0.01）， and the contents of MDA， Fe²⁺， and ROS decreased significantly （P<0.05， P<0.01）. The content of GSH in the low-dose HXHYJDF group increased significantly （P<0.01）， and the contents of MDA and ROS decreased significantly （P<0.01）. The results of immunohistochemistry showed that the expression of GPX4 and FPN1 in the high-dose HXHYJDF group increased significantly （P<0.01）， and the expression of FtMt and TfR1 decreased significantly （P<0.01）. The expression of GPX4 and FPN1 in the medium-dose HXHYJDF group increased significantly （P<0.05）， and the expression of TfR1 decreased significantly （P<0.01）. WB results showed that the expression levels of FPN1 and GPX4 proteins in the high-dose， medium-dose， and low-dose HXHYJDF groups were significantly up-regulated （P<0.01）， and the expression levels of FtMt and TfR1 proteins were significantly down-regulated （P<0.01）. ConclusionHXHYJDF can significantly improve neurological dysfunction symptoms in rats with cerebral ischemia-reperfusion injury， improve the pathological morphology of the infarcted brain tissue， and protect the brain tissue of rats with cerebral ischemia-reperfusion injury to a certain extent. Neuronal ferroptosis is involved in cerebral ischemia-reperfusion injury， with increased levels of MDA， Fe²⁺， ROS， and TfR1 and decreased levels of FtMt， FPN1， GPX4， and GSH potentially constituting the material basis of the interaction of blood stasis and toxin mechanism in cerebral ischemia-reperfusion injury. HXHYJDF may exert brain-protective effects by regulating iron metabolism-related proteins， promoting the discharge of free iron， reducing brain iron deposition， alleviating oxidative stress， and inhibiting ferroptosis.

ObjectiveTo investigate the quality markers of Xiaoqinglong granules（XQLG） for treating bronchial asthma using the analytic hierarchy process（AHP）-entropy weight method（EWM）， network pharmacology and high performance liquid chromatography（HPLC） content determination. MethodsEffectiveness， testability and peculiarity component data of XQLG in treating bronchial asthma were constructed through database retrieval， literature review， and network pharmacology. Subsequently， AHP-EWM was used to quantitatively identify and weight the control layer and element layer， the relevant compounds were selected as candidate quality markers based on comprehensive scores. Further comparison of reference substances and establishment of HPLC content determination method were used to determine the potential quality markers of XQLG， which were verified by molecular docking with disease targets. ResultsA total of 13 components， including glycyrrhizic acid， paeoniflorin， schisandrol A， isoliquiritigenin， 6-gingerol， ephedrine， liquiritin， albiflorin， liquiritigenin， 6-shogaol， pseudoephedrine， cinnamic acid and cinnamaldehyde， were identified as potential quality markers of XQLG by AHP-EWM. Quantitative analysis indicated that all aforementioned quality markers could be detected in 13 batches of XQLG， indicating that it had stable testability as a quality marker. Among these 13 batches of samples， ephedrine and paeoniflorin exhibited good consistency in content， while pseudoephedrine and cinnamaldehyde showed poor consistency. Molecular docking analysis revealed that the 13 compounds exhibited binding energies with the core targets -2.11 kcal·mol^-1， indicating that the 13 compounds could spontaneously bind to the disease targets， which may be the material basis for the treatment of bronchial asthma with XQLG. ConclusionIn this study， 13 compounds were screened by AHP-EWM combined with network pharmacology and HPLC as quality markers for the treatment of bronchial asthma by XQLG， laying the foundation for enhancing the quality standards of this preparation.

Humans ; Adolescent ; Acne Vulgaris/therapy* ; Skin Care ; Surveys and Questionnaires ; Cognition ; China ; Skin

Purpose::Our previous study in 2009 concluded that glutamine may shorten the length of hospital stay (LOS) in patients with severe burns. Recent large-scale studies have suggested a decline in the effectiveness of glutamine in treating patients with severe burns over the last decade. Therefore, we conducted this systematic review and meta-analysis to update the status of glutamine uses in patients with severe burns.Methods::We retrieved related literature prior to December 2022 from the PubMed, Web of Science, Cochrane Library, Embase, SinoMed, Wanfang, and CNKI databases. Terms such as glutamine, enteral and burn were linked for searching. Adults patients with severe burns were included and non-randomized controlled trials were excluded. Data from studies that compared enteral glutamine for severe burns with a control group were extracted. The primary outcomes of mortality and infectious morbidities were pooled and analyzed. The modified Jadad scale and Cochrane collaboration's tool were used to assess the risk of bias in RCTs, and the Review Manager 5.4 was used to pool and analyze the data.Results::Six randomized controlled trials involving 1398 patients were included in the analysis. There were no significant differences in overall mortality (risk ratio ( RR) =0.37; 95% confidence interval ( CI): 0.06 -2.37; p =0.300) or infectious morbidities ( RR =0.73; 95% CI: 0.41 -1.31; p =0.290). The incidence of multiple organ dysfunction syndrome was similar between the 2 groups ( RR =0.27; 95% CI: 0.03 -2.24; p =0.220). The LOS (mean difference (MD) =-8.97; 95% CI: -15.22 to -2.71; p =0.005) and LOS/total burn surface area (MD =-0.27; 95% CI: -0.54 to 0.00; p =0.050) decreased in the enteral glutamine group. The incidence of wound infection was significantly reduced ( RR =0.42; 95% CI: 0.16 -1.06; p =0.070). Conclusion::Compared to the control group, enteral glutamine administration may not improve the mortality, although it may be associated with a shorter LOS, a lower LOS/total burn surface area ratio, and may reduce the risk of wound infection in patients with severe burns.

Objective To explore the diagnostic value of serum neuronal Per-Arnt-Sim domain protein 4(NPASDP-4)and myelin basic protein(MBP)expression in patients with Parkinson's disease in relation to cognitive impairment(CI)and severity.Methods Selected and 138 Parkinson's disease patients admitted to the 909th Hospital of the Joint Logistics Support Force of the People's Liberation Army of China as the Parkinson's disease group,and 69 healthy people in the physical examination center of the hospital were in the healthy control group.Patients with Parkinson's disease were divided into normal cognitive function group(n=55),mild CI group(n=51)and dementia group(n=32)according to whether CI occurred and its severity.General data of subjects was collected,the serum levels of NPASDP-4 and MBP were detected by ELISA,correlation analysis was adopted by Spearman rank correlation or Pearson linear correlation,diagnostic value was analyzed by ROC curve,and influencing factors were analyzed by multivariate Logistic regression.Results Compared with the healthy control group,the levels of serum NPASDP-4(6.75±0.48 ng/ml vs 2.38±0.31 ng/ml)and MBP(8.34±0.65 μg/L vs 3.54±0.42 μg/L)in the Parkinson's disease group were increased with statistical significance(r=68.751,55.761,all P＜0.05).There were significant differences in H-Y stage among the normal cognitive function group,mild CI group and dementia group(x2=7.788,P＜0.05).Compared with the group with normal cognitive function(47.92±11.63 score),the mild CI group(50.78±13.69 score)and the dementia group(41.95±10.36 score)showed an increase in UPDRS-Ⅲ scores,and the differences were statistically significant(H=6.672,all P＜0.05).In normal cognitive function group,mild CI group and dementia group,the course of disease,and serum NPASDP-4(5.89±0.40,6.83±0.55,8.12±0.54 ng/ml)and MBP(6.65±0.56,8.94±0.69,10.27±0.70μg/L)levels were significantly increased(H=207.950,355.594,allP＜0.05),while MMSE score(28.47±0.94,24.51±1.35,17.09±2.57 score),MoCA score(27.45±1.03,20.18±1.92,11.75±2.53 score)and GPCOG total score(13.47±0.69,10.25±1.04,8.97±0.82 score)were significantly decreased,and the differences were statistically significant(H=515.005,775.933,327.584,all P＜0.05),respectively.The serum levels of NPASDP-4 and MBP in Parkinson's disease patients were significantly positively correlated with the course of disease(r=0.316,0.358),H-Y stage(r=0.345,0.384)and UPDRS-Ⅲ score(r=0.371,0.396),and significantly negatively correlated with MMSE score(r=-0.468,-0.517),MoCA score(r=-0.504,-0.569)and GPCOG total score(r=-0.527,-0.538)(all P＜0.05),respectivey.The areas under the curve(AUC)of the serum levels of NPASDP-4,MBP and their combination in diagnosing of Parkinson's disease were 0.850,0.930 and 0.960,respectively.The AUC of the serum levels of NPASDP-4 and MBP and their combination in diagnosing the severity of CI in patients with Parkinson's disease were 0.866,0.803 and 0.933,respectively.H-Y stage metaphase[OR(95％CI):4.725(1.742～12.814)],H-Y stage advanced[OR(95％CI):5.083(1.919～13.464)],UPDRS-Ⅲ score[OR(95％CI):3.257(1.464～7.246)],NPASDP-4[OR(95％CI):5.324(1.516～18.701)]and MBP[OR(95％CI):5.769(2.459～13.533)]were the influential factors for CI in patients with Parkinson's disease(all P＜0.05).NPASDP-4[OR(95％CI):4.768(2.382～9.543)]and MBP[OR(95％CI);5.846(3.141～10.882)]were the influential factors for the severity of CI in patients with Parkinson's disease(all P＜0.05).Conclusion The serum levels of NPASDP-4 and MBP in patients with Parkinson's disease were high,and they were closely related to CI and its severity,which may have certain clinical diagnostic value.

Neck dissection(ND)is one of the main treatment methods for oral and maxillofacial malignancies.Although ND type is in con-stant improvement,but intraoperative peal-pull-push injury of the accessory nerve,muscle,muscle membrane,fascia and ligament induced shoulder syndrome(SS)is still a common postoperative complication,combined with the influence of radiochemotherapy,not only can cause pain,stiffness,numbness,limited dysfunction of shoulder neck and arm,but also may have serious impact on patient's life quality and phys-ical and mental health.At present,there is still a lack of a systematic evaluation and rehabilitation management program for postoperative SS of oral and maxillofacial malignant tumors.Based on the previous clinical practice and the current available evidence,refer to the relevant lit-erature at home and abroad,the experts in the field of maxillofacial tumor surgery and rehabilitation were invited to discuss,modify and reach a consenusus on the etiology,assessment diagnosis,differential diagnosis,rehabilitation strategy and prevention of SS,in order to provide clinical reference.

Objective To investigate the clinical significance of combined cerebrospinal fluid(CSF)and routine blood parameter analysis in differentiating between multiple cerebral glioma(MCG)and primary central nervous system lymphoma(PCNSL).Methods We Rretrospectively analyzed the clinical data,CSF and routine blood indicators levels of 62 MCG patients and 56 PCNSL patients admitted to Beijing Tiantan Hospital,Capital Medical University from November 2017 to March 2023.Additionally,we assessed the diagnostic value of individual meaningful indicators as well as their combinations in distinguishing between MCG and PCNSL.Results The levels of CSF total cell count,CSF white cell count,CSF:pro,lactate,routine bloodperipheral neutrophil count,and neu-trophil percentage were significantly higher in the MCG group than in the PCNSL group(P<0.05);while the levels of CSF:Glu,CSF:cl,routine blood lymphocyte count,eosinophil,lymphocyte percentage,and eosinophil percent-age were significantly higher in the PCNSL group than in the MCG group(P<0.05).The AUCs of CSF cell count,CSF white cell count,CSF:pro,lactate,routine blood neutrophil count,neutrophil percentage for differentiating MCG from PCNSL were 0.900,0.899,0.797,0.867,0.828 and 0.772 respectively;sensitivities were 72.4%,77.6%,63.8%,67.2%,72.4%,82.8%,77.6%and 81%,with sensitivities of 97.1%,100%,88.2%,91.2%,88.2%,64.7%,100%and 94.1%,respectively.In addition,the combined detection of CSF total cell count,CSF white cell count,CSF:pro,routine blood neutrophil count and neutrophil percentage in CSF had an AUC of 0.919 for differentiating MCG from PCNSL,with a sensitivity and specificity of 77.6%and 100%,respectively.Conclusions Combined detection of CSF indicators including CSF total cell count,CSF white cell count,CSF:pro,along with routine blood markers such as neutrophil count and neutrophil percentage,holds significant clinical utility for differ-entiating between MCG and PCNSL.

The objective of this study was to analyze the effects on cell viability, apoptosis, and cell cycle of non-small cell lung cancer (NSCLC) A549 cells after intervention with Agrimonia pilosa (AP) and investigate Agrimonia pilosa anti-tumor activity in vitro. Meanwhile, liquid chromatography mass spectrometry (LC-MS) metabolomics technology was used to analyze the changes of cellular metabolites and metabolic pathways. The results of this study will provide a theoretical and experimental basis for investigating the mechanism of the effect of Agrimonia pilosa on non-small cell lung cancer A549 cells. The results showed that the cell nucleus of A549 cells crumpled and apoptosis occurred with the increase of drug concentration. The survival rate of the cells decreased, and the inhibition rate reached 21.5% and 91.74% under the low and high dose conditions, respectively. Lactate dehydrogenase (LDH) content increased (P < 0.05). Metabolomics results showed significant differences in metabolism between groups, thirty-three distinct metabolites including LysoPC(24:0/0:0), LysoPC(17:0/0:0) and PC(O-40:5) were deduced. The pathway enrichment showed that the Agrimonia pilosa plays an anti-tumor role mainly by regulating the metabolism of glycerophosphate and purine in A549 cells, in which the effect on glycerophosphate metabolism pathway was most significant. The results of combined pharmacodynamics suggested that Agrimonia pilosa might induce apoptosis and inhibit the growth of A549 cells by regulating LysoPC(24:0/0:0), LysoPC(17:0/0:0) and PC(O-40:5) metabolites in A549 cells.

This study aims to investigate the effect of salvianolic acid B (Sal B), the active ingredient of Salvia miltiorrhiza, on H9C2 cardiomyocytes injured by oxygen and glucose deprivation/reperfusion (OGD/R) through regulating mitochondrial fission and fusion. The process of myocardial ischemia-reperfusion injury was simulated by establishing OGD/R model. The cell proliferation and cytotoxicity detection kit (cell counting kit-8, CCK-8) was used to detect cell viability; the kit method was used to detect intracellular reactive oxygen species (ROS), total glutathione (t-GSH), nitric oxide (NO) content, protein expression levels of mitochondrial fission and fusion, apoptosis-related detection by Western blot. Mitochondrial permeability transition pore (MPTP) detection kit and Hoechst 33342 fluorescence was used to observe the opening level of MPTP, and molecular docking technology was used to determine the molecular target of Sal B. The results showed that relative to control group, OGD/R injury reduced cell viability, increased the content of ROS, decreased the content of t-GSH and NO. Furthermore, OGD/R injury increased the protein expression levels of dynamin-related protein 1 (Drp1), mitofusions 2 (Mfn2), Bcl-2 associated X protein (Bax) and cysteinyl aspartate specific proteinase 3 (caspase 3), and decreased the protein expression levels of Mfn1, increased MPTP opening level. Compared with the OGD/R group, it was observed that Sal B had a protective effect at concentrations ranging from 6.25 to 100 μmol·L^-1. Sal B decreased the content of ROS, increased the content of t-GSH and NO, and Western blot showed that Sal B decreased the protein expression levels of Drp1, Mfn2, Bax and caspase 3, increased the protein expression level of Mfn1, and decreased the opening level of MPTP. In summary, Sal B may inhibit the opening of MPTP, reduce cell apoptosis and reduce OGD/R damage in H9C2 cells by regulating the balance of oxidation and anti-oxidation, mitochondrial fission and fusion, thereby providing a scientific basis for the use of Sal B in the treatment of myocardial ischemia reperfusion injury.