The Type III Secretion System (T3SS) serves as a pivotal virulence apparatus for numerous Gram-negative bacterial pathogens, enabling them to infect both animal and plant hosts. Functioning as a molecular syringe, the T3SS directly translocates bacterial effector proteins from the bacterial cytoplasm into the interior of eukaryotic host cells. These effectors are central weapons that precisely manipulate a wide spectrum of host cellular physiological processes, ranging from cytoskeletal dynamics to immune signaling, to establish a favorable niche for bacterial survival and proliferation. Among the diverse arsenal of T3SS effectors, the YopJ family constitutes a critical group of virulence factors. Members of this family are characterized by a conserved catalytic triad structure—a hallmark of the CE clan of cysteine proteases that has been evolutionarily repurposed to confer acetyltransferase activity. A defining and intriguing feature of these enzymes is their stringent dependence on a host-derived eukaryotic cofactor, inositol hexakisphosphate (IP₆), for allosteric activation. This requirement acts as a sophisticated molecular safeguard, ensuring enzymatic activity only within the appropriate host environment, thereby preventing detrimental effects on the bacterium itself. While seminal studies on individual members such as Yersinia’s YopJ and Salmonella’s AvrA have provided deep mechanistic insights, a systematic and integrative understanding of the structure-function relationships across the entire family remains fragmented. Key questions persist regarding how a conserved catalytic core has diverged to recognize distinct host substrates in different kingdoms of life. To address this gap, this article provides a systematic review of the YopJ family, focusing on three interconnected aspects: their structural features, their catalytic mechanism, and their divergent immunosuppressive strategies in animal versus plant hosts. By conducting a comparative analysis of the sequences and resolved three-dimensional structures of three representative members (e.g., HopZ1a, PopP2, AvrA), we elucidate regions of significant variation embedded within the conserved core catalytic architecture. These variable regions, often involving surface loops and substrate-binding interfaces, are crucial determinants of target specificity and functional specialization. The functional divergence of this effector family is most apparent when comparing their modes of action in different hosts. In animal hosts, YopJ-family effectors primarily sabotage innate immune signaling pathways. They achieve this by acetylating key serine and threonine residues within the activation loops of critical kinases in the MAPK and NF‑κB pathways. This post-translational modification blocks the phosphorylation and subsequent activation of these kinases, leading to potent suppression of inflammatory cytokine production. Conversely, in plant hosts, the strategy broadens to dismantle the two-tiered plant immune system. YopJ homologs target a more diverse set of substrates, including immune-associated receptor-like cytoplasmic kinases (RLCKs), microtubule networks via tubulin acetylation (which disrupts cellular trafficking and signaling), and transcription factors central to defense gene regulation. This multi-target approach effectively suppresses both Pattern-Triggered Immunity (PTI) and Effector-Triggered Immunity (ETI). In conclusion, this synthesis aims to deepen the mechanistic understanding of YopJ family-mediated pathogenesis by integrating structural biology with cellular function across host kingdoms. Elucidating the precise molecular basis for substrate selection—how conserved platforms achieve target diversity—is a major frontier. Furthermore, this knowledge provides a vital theoretical foundation for developing novel anti-virulence strategies. Targeting the conserved IP₆-binding pocket or the catalytic acetyltransferase activity itself represents a promising avenue for designing broad-spectrum inhibitors that could disarm this critical family of bacterial effectors, potentially offering new therapeutic approaches against a range of pathogenic bacteria.

[摘 要] 目的：探讨复发/转移性鼻咽癌（NPC）接受含PD-1单抗免疫治疗的临床特征和预后影响因素。方法：回顾性分析2019年3月至2024年7月期间南部战区总医院确诊的95例NPC患者的临床资料和外周血生化及免疫学指标。预后分析采用Kaplan-Meier曲线，组间比较使用Log-rank检验，采用Cox比例风险模型进行单因素和多因素分析。结果：95例患者中男性81例，女性14例，中位年龄49.72岁（16~74岁），Ⅳ期91例（95.79%），所有患者均采用免疫治疗，联合或不联合化疗方案治疗，中位无进展生存期（mPFS）为10.5个月，客观缓解率（ORR）70.53%，疾病控制率（DCR）89.47%，接受含铂治疗方案患者PFS相对更长，且差异有统计学意义。紫杉醇 + 顺铂 + 氟尿嘧啶（TPF）对比吉西他滨 + 顺铂（GP）和紫杉醇 + 顺铂（TP）显示出更长的PFS，但差异无统计学意义。不同PD-1单抗治疗组间的PFS未显示出有统计学意义的差异。单因素及多因素Cox回归分析结果显示，肿瘤复发状态、初始血浆EBV感染状态、治疗周期数、基线外周血SII是复发/转移性NPC患者接受PD-1抑制剂治疗疗效预测的独立相关因素（均P < 0.05），并且非复发患者、初始血浆EBV DNA阳性、接受 ≥ 4治疗周期、基线外周血SII < 772.81的患者接受PD-1抑制剂治疗预后相对更好。结论：在接受PD-1抑制剂治疗的复发/转移性NPC患者中，非复发患者、初始血浆EBV DNA阳性、≥ 4治疗周期且外周血SII < 772.81者PFS相对更长，可早期识别免疫治疗效果不佳患者并精准干预。

ObjectiveTo compare the clinical features of patients with hepatitis B virus （HBV）-related early-onset liver cancer and those with late-onset liver cancer， to assess the severity of the disease， and to provide a theoretical basis for the early diagnosis and treatment of liver cancer. MethodsA retrospective analysis was performed for 695 patients who were diagnosed with HBV-related liver cancer for the first time in Guangzhou Eighth People’s Hospital， Guangzhou Medical University， from January 2019 to August 2023， among whom 93 had early-onset liver cancer （defined as an age of50 years for female patients and40 years for male patients） and 602 had late-onset liver cancer （defined as an age of ≥50 years for female patients and ≥40 years for male patients）. Related clinical data were collected， including demographic data， clinical symptoms at initial diagnosis， comorbidities， smoking history， drinking history， family history， routine blood test results， biochemical parameters of liver function， serum alpha-fetoprotein（AFP）， virological indicators， coagulation function， and imaging findings. The pan-inflammatory indices neutrophil-to-lymphocyte ratio （NLR）， platelet-to-lymphocyte ratio （PLR）， and lymphocyte-to-monocyte ratio （LMR） were calculated， as well as FIB-4 index， aspartate aminotransferase-to-platelet ratio index （APRI）， S index， Model for End-Stage Liver Disease （MELD） score， Child-Turcotte-Pugh （CTP） score， albumin-bilirubin （AIBL） grade， and Barcelona Clinic Liver Cancer （BCLC） stage. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test or Fisher’s exact test were used for comparison of categorical data between two groups. ResultsThere were significant differences between the two groups in the proportion of male patients and the incidence rates of diabetes， hypertension， and fatty liver disease （χ²=6.357， 15.230， 11.467， and 14.204， all P0.05）， and compared with the late-onset liver cancer group， the early-onset liver cancer group had a significantly higher proportion of patients progressing to liver cancer without underlying cirrhosis （χ²=24.657， P0.001） and a significantly higher proportion of patients with advanced BCLC stage （χ²=6.172， P=0.046）. For the overall population， the most common clinical symptoms included abdominal distension， abdominal pain， poor appetite， weakness， a reduction in body weight， edema of both lower limbs， jaundice， yellow urine， and nausea， and 55 patients （7.9%） had no obvious symptoms at the time of diagnosis and were found to have liver cancer by routine reexamination， physical examination suggesting an increase in AFP， or radiological examination indicating hepatic space-occupying lesion； compared with the late-onset liver cancer group， the patients in the early-onset liver cancer group were more likely to have the symptoms of abdominal distension， abdominal pain， and jaundice （all P0.05）. Compared with the late-onset liver cancer group， the early-onset liver cancer group had a significantly larger tumor diameter （Z=2.845， P=0.034）， with higher prevalence rates of multiple tumors and intrahepatic， perihepatic， or distant metastasis （χ²=5.889 and 4.079， both P0.05）， and there were significant differences between the two groups in tumor location and size （χ²=3.948 and 11.317， both P0.05）. Compared with the late-onset liver cancer group， the early-onset liver cancer group had significantly lower FIB-4 index， proportion of patients with HBsAg ≤1 500 IU/mL， and levels of LMR and Cr （all P0.05）， as well as significantly higher positive rate of HBeAg and levels of log₁₀ HBV DNA， AFP， WBC， Hb， PLT， NLR， PLR， TBil， ALT， Alb， and TC （all P0.05）. ConclusionCompared with late-onset liver cancer， patients with early-onset liver cancer tend to develop liver cancer without liver cirrhosis and have multiple tumors， obvious clinical symptoms， and advanced BCLC stage， which indicates a poor prognosis.

Objective To construct a targeted drug delivery system, Ang-BEVs@Dox, based on Angiopep-2 peptide-modified bacterial extracellular vesicles （BEVs） loaded with doxorubicin （Dox）, overcome the challenges of blood-brain barrier （BBB） penetration and systemic toxicity in chemotherapy for glioblastoma （GBM）, enhance drug targeting to brain tumors and reduce its toxic side effects. Methods BEVs derived from Escherichia coli were isolated using ultracentrifugation. The targeting ligand Angiopep-2, specific for the LRP-1 receptor, was conjugated onto the surface of BEVs to construct the targeted carrier （Ang-BEVs）. Dox was loaded into Ang-BEVs using low-frequency sonication to form Ang-BEVs@Dox. The physicochemical properties （morphology and size） of the carriers were characterized by transmission electron microscopy （TEM） and dynamic light scattering （DLS）. The BBB-penetrating capability, in vitro/in vivo anti-tumor efficacy, and biosafety of the system were evaluated using cellular uptake assays, 3D tumor spheroid models, and orthotopic tumor-bearing mouse models. Results ① Carrier characterization and in vitro efficacy: Ang-BEVs@Dox exhibited a particle size of approximately 100 nm and maintained structural stability after Dox loading. It significantly enhanced cellular uptake efficiency in U87MG cells and achieved deep penetration within 3D tumor spheroids. Cytotoxicity assays demonstrated synergistic anti-tumor effects between the BEVs and Dox in the Ang-BEVs@Dox system. ② In vivo targeting and anti-tumor efficacy: In orthotopic tumor-bearing mouse models, Ang-BEVs@Dox effectively penetrated the BBB and significantly inhibited tumor growth, extending the median survival time of tumor-bearing mice to 33.5 days （compared to 23.5 days in the blank control group, P<0.001）. Immunohistochemical analysis revealed significant suppression of the tumor cell proliferation marker Ki-67 and enhancement of the apoptosis marker TUNEL staining signals. ③ Biosafety: Major organs from mice in the Ang-BEVs@Dox treatment group showed no observable pathological damage, indicating good biosafety. Conclusion This study successfully constructed an Angiopep-2 peptide-modified engineered BEVs delivery system （Ang-BEVs@Dox）. Through Angiopep-2-mediated BBB penetration and tumor targeting, it significantly enhanced the accumulation and therapeutic efficacy of BEVs at the GBM site. This method combined efficient delivery, low systemic toxicity, and clinical translation potential, which provided an innovative solution to overcome the therapeutic bottleneck in GBM treatment.

This study aims to investigate the therapeutic effect and mechanism of Daotan Xixin Decoction on APP/PS1 mice. Twelve APP/PS1 male mice were randomized into four groups: APP/PS1 and low-, medium-, and high-dose Daotan Xixin Decoction. Three C57BL/6 wild-type mice were used as the control group. The learning and memory abilities of mice in each group were examined by the Morris water maze test. The pathological changes of hippocampal nerve cells were observed by hematoxylin-eosin staining and Nissl staining. Immunohistochemistry was employed to detect the expression of β-amyloid(Aβ)_(1-42) in the hippocampal tissue. The high-dose Daotan Xixin Decoction group with significant therapeutic effects and the model group were selected for high-throughput sequencing. The differentially expressed gene(DEG) analysis, Gene Ontology(GO) analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and Gene Set Variation Analysis(GSVA) were performed on the sequencing results. RT-qPCR and Western blot were conducted to determine the mRNA and protein levels, respectively, of some DEGs. Compared with the APP/PS1 group, Daotan Xixin Decoction at different doses significantly improved the learning and memory abilities of APP/PS1 mice, ameliorated the neuropathological damage in the CA1 region of the hippocampus, increased the number of neurons, and decreased the deposition of Aβ_(1-42) in the brain. A total of 1 240 DEGs were screened out, including 634 genes with up-regulated expression and 606 genes with down-regulated expression. The GO analysis predicted the biological processes including RNA splicing and protein folding, the cellular components including spliceosome complexes and nuclear spots, and the molecular functions including unfolded protein binding and heat shock protein binding. The KEGG pathway enrichment analysis revealed the involvement of neurodegenerative disease pathways, amyotrophic lateral sclerosis, and splicing complexes. Further GSVA pathway enrichment analysis showed that the down-regulated pathways involved nuclear factor-κB(NF-κB)-mediated tumor necrosis factor-α(TNF-α) signaling pathway, UV response, and unfolded protein response, while the up-regulated pathways involved the Wnt/β-catenin signaling pathway. The results of RT-qPCR and Western blot showed that compared with the APP/PS1 group, Daotan Xixin Decoction at different doses down-regulated the mRNA and protein levels of signal transducer and activator of transcription 3(STAT3), NF-κB, and interleukin-6(IL-6) in the hippocampus. In conclusion, Daotan Xixin Decoction can improve the learning and memory abilities of APP/PS1 mice by regulating the STAT3/NF-κB/IL-6 signaling pathway.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Male ; Alzheimer Disease/metabolism* ; Computational Biology ; Mice, Inbred C57BL ; High-Throughput Nucleotide Sequencing ; Amyloid beta-Protein Precursor/metabolism* ; Hippocampus/metabolism* ; Mice, Transgenic ; Presenilin-1/metabolism* ; Humans ; Memory/drug effects* ; Maze Learning/drug effects* ; Amyloid beta-Peptides/genetics* ; Disease Models, Animal

Based on the pharmacokinetics theory, this study investigated the pharmacokinetic characteristics of albiflorin, paeoniflorin, wogonoside, and wogonin in normal and febrile rats and summarized absorption and elimination rules of Dayuanyin in them to provide reference for further development and clinical application of Dayuanyin. Blood samples were taken from the fundus venous plexus of normal and model rats after intragastric administration of Dayuanyin at different time points. The concentration of each substance in blood was determined by ultra performance liquid chromatography-triple quadrupole mass spectrometry(UPLC-MS/MS) technique at different time points. DAS 2.0, a piece of pharmacokinetics software, was used to calculate the pharmacokinetic parameters of each component. The results show that the 4 components had good linear relationship in their respective ranges, and the results of methodological investigation met the requirements. The pharmacokinetic parameters of C_(max), T_(max), t_(1/2), AUC_(0-t), AUC_(0-∞), and MRT_(0-t) were calculated by the DAS 2.0 non-compartmental model. Compared with those in the normal group, C_(max) and AUC_(0-t) of the 4 components in the model group were significantly increased. There were significant differences in the pharmacokinetic characteristics between the normal and model groups, suggesting that the absorption and elimination of Dayuanyin may be affected by the changes of internal environment of the body in different physiological states.
Animals ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Rats, Sprague-Dawley ; Fever/metabolism* ; Tandem Mass Spectrometry ; Chromatography, High Pressure Liquid ; Glucosides/pharmacokinetics* ; Monoterpenes

Lung cancer is one of the most common and deadliest cancers globally, with its incidence and mortality rates rising each year. Therefore, finding new, safe, and effective alternative therapies poses a significant research challenge in this field. Programmed cell death refers to the process by which cells actively self-destruct in response to specific stimuli, regulated by genetic mechanisms. Modern research indicates that dysregulation of programmed cell death is widespread in the occurrence and progression of lung cancer, allowing cancer cells to evade death while continuing to proliferate and metastasize. Thus, inducing the death of lung cancer cells can be considered a novel therapeutic strategy for treating the disease. In recent years, research on traditional Chinese medicine(TCM) in the field of oncology has gained widespread attention, becoming a focal point. An increasing number of studies have demonstrated that TCM can inhibit the progression of lung cancer and exert anti-cancer effects by inducing apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis. This paper provided a comprehensive review of the molecular mechanisms of programmed cell death in lung cancer, along with the potential mechanisms and research advancements related to the regulation of these processes by TCM, so as to establish a theoretical foundation and direction for future basic and clinical research on lung cancer.
Humans ; Lung Neoplasms/pathology* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use* ; Apoptosis/drug effects* ; Animals ; Autophagy/drug effects*

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal

Colorectal cancer(CRC) is one of the most common malignant tumors worldwide, primarily originating from recurrent inflammatory bowel disease(IBD). Therefore, blocking the inflammation-cancer transformation in the colon has become a focus in the early prevention and treatment of CRC. The inflammation-cancer transformation in the colon involves multiple types of cells and complex pathological processes, including inflammatory responses and tumorigenesis. In this complex pathological process, immune cells(including non-specific and specific immune cells) and non-immune cells(such as tumor cells and fibroblasts) interact with each other, collectively promoting the progression of the disease. In traditional Chinese medicine(TCM), inflammation-cancer transformation in the colon belongs to the categories of dysentery and diarrhea, with the main pathogenesis being cold and heat in complexity. This paper first elaborates on the complex molecular mechanisms involved in the inflammation-cancer transformation process in the colon from the perspectives of inflammation, cancer, and their mutual influences. Subsequently, by comparing the pathogenic characteristics and clinical manifestations between inflammation-cancer transformation and the TCM pathogenesis of cold and heat in complexity, this paper explores the intrinsic connections between the two. Furthermore, based on the correlation between inflammation-cancer transformation in the colon and the TCM pathogenesis, this paper delves into the importance of the interaction between inflammation and cancer. Finally, it summarizes and discusses the clinical and basic research progress in the TCM intervention in the inflammation-cancer transformation process, providing a theoretical basis and treatment strategy for the treatment of CRC with integrated traditional Chinese and Western medicine.
Humans ; Colon/pathology* ; Integrative Medicine ; Animals ; Cold Temperature ; Cell Transformation, Neoplastic/drug effects* ; Medicine, Chinese Traditional ; Hot Temperature ; Inflammation ; Drugs, Chinese Herbal/therapeutic use* ; Colonic Neoplasms/drug therapy*

OBJECTIVE: To explore the effect of nano-hydroxyapatite/collagen composite (nHAC) on bone graft fusion after anterior cervical discectomy and fusion (ACDF) in patients with cervical spondylosis and low bone mass. METHODS: A retrospective analysis was conducted on 47 patients with low bone mass who underwent ACDF from 2017 to 2021. They were divided into the nHAC group and the allogeneic bone group according to different bone graft materials. The nHAC group included 26 cases, with 8 males and 18 females;aged 50 to 78 years old with an average of (62.81±7.79) years old;the CT value of C₂-C₇ vertebrae was (264.16±36.33) HU. The allogeneic bone group included 21 cases, with 9 males and 12 females;aged 54 to 75 years old with an average of (65.95±6.58) years old;the CT value of C₂-C₇ vertebrae was (272.39±40.44) HU. The visual analogue scale (VAS), neck disability index (NDI), and Japanese Orthopaedic Association (JOA) spinal cord function score were compared before surgery, 1 week after surgery, and at the last follow-up to evaluate the clinical efficacy. Imaging assessment included C₂-C₇ Cobb angle, surgical segment height, intervertebral fusion, and whether the cage subsidence occurred at 1 week after surgery and the last follow-up. RESULTS: The follow-up duration ranged from 26 to 39 months with an average of (33.27±3.34) months in the nHAC group and 26 to 41 months with an average of (31.86±3.57) months in the allogeneic bone group. At 1 week after surgery and the last follow-up, the VAS, NDI scores, and JOA scores in both groups were significantly improved compared with those before surgery, with statistically significant differences (P<0.05). At 1 week after surgery, the C₂-C₇ Cobb angles in the nHAC group and the allogeneic bone group were (14.26±10.32)° and (14.28±8.20)° respectively, which were significantly different from those before surgery (P<0.05). At the last follow-up, the C₂-C₇ Cobb angles in both groups were smaller than those at 1 week after surgery, with statistically significant differences (P<0.05). At 1 week after surgery, the height of the surgical segment in the nHAC group was (31.65±2.55) mm, and that in the allogeneic bone group was (33.63±3.26) mm, which were significantly different from those before surgery (P<0.05). At the last follow-up, the height of the surgical segment in both groups decreased compared with that at 1 week after surgery, with statistically significant differences (P<0.05). At the last follow-up, 39 surgical segments were fused and 6 cages subsided in the nHAC group;40 surgical segments were fused and 7 cages subsided in the allogeneic bone group;there was no statistically significant difference between the two groups (P>0.05). Compared with the CT value of vertebrae without cage subsidence, the CT value of vertebrae with cage subsidence in both groups was significantly lower, with a statistically significant difference (P<0.05). CONCLUSION The application of nHAC in ACDF for patients with low bone mass can achieve effective fusion of the surgical segment. There is no significant difference in improving clinical efficacy, intervertebral fusion, and cage subsidence compared with the allogeneic bone group. With the extension of follow-up time, the C₂-C₇ Cobb angle decreases, the height of the surgical segment is lost, and the cage subsides in both the nHAC group and the allogeneic bone group, which may be related to low bone mass. Low bone mass may be one of the risk factors for cervical spine sequence changes, surgical segment height loss, and cage subsidence after ACDF.
Humans ; Male ; Female ; Middle Aged ; Spondylosis/physiopathology* ; Spinal Fusion/methods* ; Cervical Vertebrae/surgery* ; Aged ; Diskectomy ; Durapatite ; Retrospective Studies ; Collagen/chemistry*