Esophageal cancer （EC） is a highly prevalent malignant tumor in China. The phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， as one of the key oncogenic pathways， can promote the cell cycle progression， proliferation， migration， and invasion， induce chemoresistance， and inhibit apoptosis and autophagy of EC cells. Traditional Chinese medicine （TCM）， with the advantages of targeting multiple points with multiple components to delay cancer progression， can target the PI3K/Akt signaling pathway for EC treatment. This article preliminarily discusses the molecular mechanism and role of the PI3K/Akt signaling pathway in EC and elaborates on the specific targets and efficacy of TCM in treating EC through intervention in the PI3K/Akt signaling pathway in the past five years. TCM materials and extracts inhibiting the PI3K/Akt signaling pathway in EC include Borneolum， spore powder of Ganoderma lucidum without spore coat， extract of Celastrus orbiculatus， root extract of Taraxacum， and Bruceae Fructus oil emulsion. TCM active ingredients exerting the effect include flavonoids， terpenoids， saponins， phenols， polysaccharides， alkaloids， and other compounds. TCM compound prescriptions with such effect include Qige San， Huqi San， Xuanfu Daizhetang， Tongyoutang and its decomposed prescriptions， Liujunzi Tang， and Xishenzhi Formula. In addition， TCM injections such as Compound Kushen Injection and Kang'ai injection also inhibit the PI3K/Akt signaling pathway in EC. This paper summarizes the role of the PI3K/Akt signaling pathway in EC and the TCM interventions， aiming to provide reference for the research and clinical application of new drugs for EC.

Plant-derived extracellular vesicles (PDEVs), describe a group of nanoparticles released by plants. These particles are characterized by a lipid bilayer structure containing various proteins, lipids, nucleic acids, and unique metabolites. Although the study on PDEVs is relatively new, having only been around for ten years, they have shown promising development prospects in both basic research and clinical transformation areas. Evidence suggests that PDEVs have excellent application prospects in regulating inflammation and treating tumors. Their distinctive, vesicle-mimicking architecture and stellar biocompatibility render them prime candidates for ferrying various anti-cancer agents, including RNA, proteins, and conventional chemotherapy drugs. Increasingly, studies have shown that PDEVs can be engineered as an innovative platform for combination cancer immunotherapy. Consequently, this paper provides an extensive summary of current developments in engineering methods and strategies for PDEVs in cancer treatment and combined cancer immune therapeutics. The essential characteristics of PDEVs, including the biogenesis process and components, as well as their anti-tumor activity and mechanism, are summarized. Finally, the in vivo safety of PDEVs as delivery vectors and the challenges of scale-up production and clinical transformation are discussed.

Hypoxic-ischemic (HI) brain damage poses a high risk of death or lifelong disability, yet effective treatments remain elusive. Here, we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice. Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery, through inhibiting the cleaved-caspase-3 level, microglia activation, and the release of proinflammation cytokines following HI injury. Engineered extracellular vesicles (EVs) containing neuron-targeting rabies virus glycoprotein (RVG) and miR-100-5p antagonists (RVG-EVs-Antagomir) selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery. Both pre- and post-HI administration showed therapeutic benefits. Mechanistically, we identified protein phosphatase 3 catalytic subunit alpha (Ppp3ca) as a novel candidate target gene of miR-100-5p, inhibiting c-Fos expression and neuronal apoptosis following HI insult. In conclusion, our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.
Animals ; MicroRNAs/metabolism* ; Extracellular Vesicles/metabolism* ; Mice ; Recovery of Function/physiology* ; Hypoxia-Ischemia, Brain/therapy* ; Mice, Inbred C57BL ; Antagomirs/administration & dosage* ; Male ; Animals, Newborn ; Apoptosis/drug effects* ; Brain Injuries/metabolism* ; Glycoproteins ; Peptide Fragments ; Viral Proteins

Osteoporosis is a prevalent skeletal condition characterized by reduced bone mass and strength, leading to increased fragility. Buqi-Tongluo (BQTL) decoction, a traditional Chinese medicine (TCM) prescription, has yet to be fully evaluated for its potential in treating bone diseases such as osteoporosis. To investigate the mechanism by which BQTL decoction inhibits osteoclast differentiation in vitro and validate these findings through in vivo experiments. We employed MTS assays to assess the potential proliferative or toxic effects of BQTL on bone marrow macrophages (BMMs) at various concentrations. TRAcP experiments were conducted to examine BQTL's impact on osteoclast differentiation. RT-PCR and Western blot analyses were utilized to evaluate the relative expression levels of osteoclast-specific genes and proteins under BQTL stimulation. Finally, in vivo experiments were performed using an osteoporosis model to further validate the in vitro findings. This study revealed that BQTL suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and osteoclast resorption activity in vitro in a dose-dependent manner without observable cytotoxicity. The inhibitory effects of BQTL on osteoclast formation and function were attributed to the downregulation of NFATc1 and c-fos activity, primarily through attenuation of the MAPK, NF-κB, and Calcineurin signaling pathways. BQTL's inhibitory capacity was further examined in vivo using an ovariectomized (OVX) rat model, demonstrating a strong protective effect against bone loss. BQTL may serve as an effective therapeutic TCM for the treatment of postmenopausal osteoporosis and the alleviation of bone loss induced by estrogen deficiency and related conditions.
Animals ; NFATC Transcription Factors/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Ovariectomy ; Osteoclasts/metabolism* ; Female ; Osteogenesis/drug effects* ; Rats, Sprague-Dawley ; Rats ; NF-kappa B/genetics* ; Osteoporosis/genetics* ; Signal Transduction/drug effects* ; Bone Resorption/genetics* ; Cell Differentiation/drug effects* ; Humans ; RANK Ligand/metabolism* ; Mitogen-Activated Protein Kinases/genetics* ; Transcription Factors

Background Heavy metal exposure may be associated with the risk of metabolic syndrome (MetS) and serum uric acid. The role of serum uric acid in the relationship between heavy metal exposure and MetS is currently unclear. Objective To evaluate the relationships of heavy metal exposure with MetS and serum uric acid, and to quantify the role of serum uric acid in the relationship. Methods In 2021, convenience sampling was used to select 571 local adults in Liuzhou, Guangxi. Demographic characteristics, lifestyle habits, and physiological and biochemical indicators were collected through questionnaire surveys and physical examinations. Fasting blood and mid-stream morning urine were also collected. The concentrations of 16 heavy metals in urine were measured using inductively coupled plasma mass spectrometry. Least absolute shrinkage and selection operator (LASSO) regression was employed to identify heavy metals associated with MetS. Logistic regression and linear regression models were employed to evaluate the association between the selected heavy metals and MetS as well as serum uric acid. Bayesian kernel machine regression (BKMR) model was utilized to assess the impact of combined exposures to multiple metals on the risk of MetS and identify the main effect metals. Generalized structural equation model was used to evaluate potential mediating effect of serum uric acid on the relationship between heavy metal exposure and MetS. Results The LASSO regression identified a total of 9 heavy metals that were associated with MetS. The logistic regression revealed a positive correlation between zinc and copper in urine and MetS (P _trend<0.05), while vanadium showed a negative correlation with MetS (P _trend<0.05). Compared to the low concentration groups, the high concentration groups of zinc (OR=2.37, 95%CI: 1.33, 4.20) and copper (OR=2.29, 95%CI: 1.26, 4.18) had an increased risk of MetS, while the high concentration group of vanadium showed a decreased risk of MetS (OR=0.47, 95%CI: 0.27, 0.84). The main effect metals identified by the BKMR model were consistent with the results of logistic regression. The linear regression analysis demonstrated an association between urinary zinc and vanadium concentrations and serum uric acid levels (P _trend<0.05). Compared to the low concentration group, the high concentration group of zinc showed an increase in serum uric acid level (β=0.07, 95%CI: 0.03, 0.11), while the high concentration group of vanadium showed a decrease in serum uric acid level (β=-0.06, 95%CI: -0.09, -0.02). The mediation analysis revealed that serum uric acid played a mediating role in the relationship between urinary zinc and vanadium concentrations and MetS, with mediation proportions of 8.33% and 16.67%, respectively. Conclusion Exposure to heavy metals zinc, copper, and vanadium are closely associated with MetS. Zinc and vanadium exposures are correlated with serum uric acid levels, and serum uric acid plays a partial mediating role in the relationship between zinc and vanadium exposures and MetS.

OBJECTIVE To explore the detoxification mechanism of Terminalia chebula Retz(TCR)soup-processed Euphorbia fischeriana Steud.(EFS)based on LC-MS and simulation processing.METHODS The changes of chemical composition of TCR soup-processed EFS,and dichloromethane extracts of crude EFS after simulation processing with TCR soup were analyzed by LC-MS.Mice were orally administered with alcoholic extracts of crude EFS,alcoholic extracts of water-processed EFS,alcoholic extracts of TCR soup,alcoholic extracts of TCR soup-processed EFS,dichloromethane extracts of crude EFS,dichloromethane extracts of TCR soup-processed EFS,and dichloromethane extracts of crude EFS after simulation processing with TCR soup,respectively.Toxicity changes in TCR soup-processed EFS and dichloromethane extracts of crude EFS after simulation processing with TCR soup were evalu-ated by fecal water contents,release levels of TNF-α and IL-1β,and intestinal pathology.RESULTS A total of 115 and 53 com-pounds were identified in EFS and TCR soup,respectively.The contents of 58 and 12 compounds significantly decreased and signifi-cantly increased respectively in EFS after processing with TCR soup.Compared to the blank control group,the fecal water contents and the release levels of TNF-α and IL-1β significantly increased in both the crude and water-processed EFS groups(P<0.01),and no-table intestinal injury was observed.Compared to the crude EFS group,the fecal water contents and the release levels of TNF-α and IL-1β significantly decreased in both the TCR soup group and the TCR soup-processed EFS group(P<0.01),and repaired intestinal injury was observed.After simulation processing for the dichloromethane extracts of crude EFS with TCR soup,the ion intensity change rates for diterpenoids and tannin phenolic acid compounds ranged from-6.75%to 8.09%and 66.06%to 100.00%,respectively.The ion intensity change rates of diterpenoids in the dichloromethane extracts of TCR soup-processed EFS ranged from-9.92%to 54.72%with almost no tannin phenolic acid compounds.Compared to the blank control group,the fecal water contents and the release levels of TNF-α and IL-1β significantly increased in both the dichloromethane extracts of crude and TCR soup-processed EFS groups(P<0.01),and severe intestinal injury was observed.Compared to the dichloromethane extracts of crude EFS group,the fecal water contents and the release levels of TNF-α and IL-1β significantly decreased in the group of the dichloromethane extracts of crude EFS after simulation processing with TCR soup(P<0.01),with no apparent intestinal injury.CONCLUSION TCR soup pro-cessing can alleviate the intestinal toxicity of EFS.The detoxification mechanism may involve the introduction of a large number of tan-nin phenolic acid compounds in TCR soup during the processing of EFS,which plays a pharmacological antagonistic role in the animal body.

Purpose To study the expression of of mono-clonal and polyclonal TRPS1 antibodies in synovial sarcoma,and to explore the value of TRPS1 in the diagnosis and differen-tial diagnosis of synovial sarcoma and the sensitivity and speci-ficity of polyclonal TRPS1 for the diagnosis of synovial sarcoma.Methods Immunohistochemical EnVision method was used to detect the expression of monoclonal and polyclonal TRPS1 anti-bodies in the synovial sarcomas and its mimickers.Results A-mong 31 cases of synovial sarcoma,the positive rates of poly-clonal and monoclonal TRPS1 antibodies were 54.8％and 93.5％,respectively.Of 30 synovial sarcoma mimicking le-sions,2 were positive for TRPS1(polyclonal antibody),which was 6.67％,and TRPS1 was more frequently expressed in syno-vial sarcoma than in non-synovial sarcoma(P＜0.05).The sensitivity of polyclonal TRPS1 antibody for the diagnosis of syn-ovial sarcoma was 93.5％,and the specificity was 93.3％.Conclusion Polyclonal TRPS1 antibody has a higher sensitivity and specificity for the diagnosis of synovial sarcoma and it there-fore is recommended in routine pathologic diagnosis.

Tumor microenvironment(TME)is a complex cellular environment where tumor cells reside,along with various types of cells and extracellular components surrounding the tumor cells.Immune cells are key components of TME,including tumor-associated macrophages(TAMs),myeloid-derived suppressor cells(MDSCs),lymphocytes,regulatory T cells(Tregs),natural killer cells(NK cells),dendritic cells(DCs),and many others.It is worth noting that drug resistance is currently a major factor limiting the efficacy of cancer treatment methods such as chemotherapy,radiotherapy,targeted therapy,and immunotherapy,and a leading cause of treatment failure.Research has found that the development of drug resistance in tumor cells is the result of interactions between tumor cells and TME.Consequently,overcoming drug resistance in tumors caused by TME is considered a significant challenge in cancer treatment.In recent years,with in-depth research into immune cells within TME,significant progress has been made in understanding the specific mechanisms by which immune cells regulate drug resistance in tumor cells.Furthermore,therapeutic strategies that target these immune cells,signaling pathways,or cytokines have been shown to effectively combat tumor drug resistance and enhance the therapeutic outcomes of cancer treatment.This article reviews the research advancements regarding the roles of TAMs,MDSCs,Tregs,and NK cells in tumor drug resistance within TME and discusses the development of targeting strategies to overcome this resistance.Additionally,we explore the relationship of tumor-associated neutrophils(TANs)and B regulatory cells(Bregs)with tumor drug resistance.It is hoped that this review will offer insights and serve as reference for reducing tumor drug resistance and improving the efficacy of anti-tumor therapies.

Objective:To establish a polymerase chain reaction(PCR)method to accurately discriminate the crude materials and aqueous extract of Zaocys dhumnades,Elaphe carinata,Elaphe meollendorff and Ptyas korros.Methods:Specific primers were designed using mitochondrial Cytb gene(CO1)as a target gene,and annealing temperature,number of cycles and the type of DNA polymerases were optimized.The mixed samples were detected by this method.Results:By this multiplex allele-specific PCR identification method,135,182,246 and 197 bp of specific fragments were amplified from DNA templates of Zaocys dhumnades,Elaphe carinata,Elaphe meollendorffi and Ptyas korros,respectively,following the conditions:cycle number of 35,annealing temperature of 62 ℃.The adulterants and the blank control showed no bands.The method could simultaneously and accurately identify the snake-derived components in the mixed samples.Conclusion:The method can be used to identify the samples of Zaocys dhumnades,Elaphe carinata,Elaphe meollendorffi and Ptyas korros simultaneously,accurately and rapidly,and is suitable for the identification of standard decoctiond and formula granules samples.

Objective:To observe the change of retinal artery angle in eyes with idiopathic epiretinal membrane (ERM) and to analyze the relationship between retinal artery angle, ERM classification based on optical coherence tomography (OCT), and visual acuity.Methods:A retrospective cross-sectional clinical study. A total of 187 eyes in 187 patients diagnosed with monocular idiopathic ERM (IERM group) in Department of Ophthalmology of Zhejiang Provincial People's Hospital and the Affiliated Eye Hospital of Wenzhou Medical University at Hangzhou from November 2018 to January 2023 were included in the study. The contralateral healthy eyes were included as the control group. All patients underwent best corrected visual acuity (BCVA), fundus photography, spectral-domain OCT, OCT angiography (OCTA) and axial length (AL) measurement. BCVA examination was performed using the standard logarithmic visual acuity chart, which was converted to the logarithm of the minimum angle of resolution (logMAR) visual acuity. The foveal avascular zone (FAZ) area was measured by OCTA. The central macular thickness (CMT) was measured by spectral domain OCTaccording to the grading criteria of ectopic inner foveal layer (EIFL) was divided into stages 1 to 4 with 42, 45, 62, and 38 eyes, and the IERM group was subdivided into stage 1, stage 2, stage 3, and stage 4 groups accordingly. Image J was used to measure the retinal artery angle and the 1/2 retinal artery angle on fundus images. Multiple linear regression analysis was used to analyze the correlation between BCVA and artery angle, 1/2 artery Angle, CMT, FAZ area and AL.Results:Compared with the control group, eyes in IERM group had worse BCVA ( t=9.727), thicker CMT ( t=12.452), smaller FAZ area ( t=-14.329), smaller artery angle ( t=-9.165) and smaller 1/2 artery angle ( t=-9.549). The differences were statistically significant ( P<0.001). With the increase of IERM stage, the artery angle and 1/2 artery angle decreased significantly ( F=21.763, 12.515; P<0.001). There was no significant difference in artery angle and 1/2 artery angle between stage 1 group and stage 2 group, and 1/2 arterial angle between stage 2 group and stage 3 group ( P>0.05). There were significant differences in artery angle and 1/2 artery angle between the other groups ( P<0.05). There were significant differences in CMT and logMAR BCVA among different classification subgroups in IERM groups ( P<0.05). There was no significant difference in FAZ area between grade 3 group and grade 4 group ( P>0.05). There were significant differences in FAZ area between the other groups ( P<0.05). Correlation analysis showed that decreased artery angle ( P=0.013) and increased CMT ( P<0.001) were associated with decreased BCVA. Conclusions:Compared with healthy eyes, the artery angle decreases significantly with the increase of ERM stage. Decreased retinal artery angle is associated with decreased visual acuity in IERM eyes.