ObjectiveThe malaria parasites remodel the host erythrocyte structure by exporting parasite proteins that interact with the membrane skeleton proteins of red blood cells (RBCs), facilitating their intracellular survival and pathogenicity. Skeleton-binding protein 1 (SBP1) is a conserved exported protein across Plasmodium species. In Plasmodium falciparum, SBP1 has been reported to interact with erythrocyte membrane skeleton proteins 4.1R and spectrin, while its contribution to erythrocyte remodeling and parasite virulence in Plasmodium berghei (Pb) remains unclear. This study aims to determine whether PbSBP1 associates with the host cytoskeletal protein 4.1R and to investigate its role in the remodeling of host RBCs and the pathogenicity of Plasmodium berghei. MethodsIn Plasmodium berghei, the relationship between PbSBP1 and the erythrocyte cytoskeletal protein 4.1R was examined using co-immunoprecipitation. A Pbsbp1 gene knockout mutant of Plasmodium berghei (Pbsbp1∆) was generated based on the principle of double crossover homologous recombination. The deformability of erythrocytes infected with Pbsbp1∆ parasites was assessed using microfluidic methods. Microchannels with an array of cylindrical pillars were used to detect modifications in infected RBC deformability. The infected RBCs were squashed between the rows and recovered between the columns and the transit velocity (μm/s) of infected RBCs travelling through the microchannel was recorded. The component of the erythrocyte membrane skeleton junctional complex, tropomodulin (TMOD), was fluorescently labeled, and the cytoskeletal network of infected erythrocytes was imaged using super-resolution stochastic optical reconstruction microscopy (STORM) to analyze ultrastructural changes in the cytoskeleton of wild-type (WT) and Pbsbp1∆-infected erythrocytes. Actin-based junctional complexes were displayed as individual clusters by the labeled TMOD in the STORM images, and the cluster densities and distances between adjacent clusters of infected RBCs were calculated. Additionally, rodent malaria models (BALB/c mice) and experimental cerebral malaria models (C57BL/6 mice) were employed to monitor the growth of Pbsbp1∆ and WT parasites during the intraerythrocytic stage and their capacity to induce cerebral malaria in mice. ResultsPbSBP1 may participate in the remodeling of infected erythrocytes through direct or indirect interaction with the erythrocyte cytoskeletal protein 4.1R. Microfluidic assays revealed that the deformability of erythrocytes infected with Pbsbp1∆ parasites was significantly enhanced compared to those infected with WT parasites. STORM imaging further demonstrated that the ultrastructure of the erythrocyte cytoskeleton in Pbsbp1∆-infected cells was altered relative to that in WT-infected erythrocytes. The distances between nearest neighbors of clusters had a tendency to increase while the cluster densities were decreased in Pbsbp1∆-infected RBCs compared to WT-infected RBCs. Subsequent phenotypic analysis indicated that the growth rate of Pbsbp1∆ parasites during the intraerythrocytic stage was significantly slower than that of WT parasites, and their ability to induce cerebral malaria in mice was also attenuated. These findings suggest that PbSBP1 is involved in the remodeling of the erythrocyte membrane skeleton, likely through its direct or indirect interaction with protein 4.1R, thereby regulating the deformability of infected erythrocytes and influencing the pathogenicity of the blood-stage parasites. ConclusionThis study establishes a role for PbSBP1 in host erythrocyte remodeling and parasite virulence, providing new research strategies for the prevention and treatment of malaria.

Objective:To evaluate the efficacy and safety of sintilimab combined with bevacizumab in the second-line treatment of malignant pleural mesothelioma(MPM).Methods:This was a longitudinal study. Patients with MPM who had progressed after first-line treatment and were admitted to the Day-Care Outpatient Department of Medical Oncology, Ningguo People′s Hospital from February 2019 to February 2022 were included. General clinical data of the patients were collected at baseline. The patients were treated with the second-line treatment regimen of sintilimab (200 mg)+bevacizumab (15 mg/kg) on a 21-day cycle. Enhanced CT scans were performed every 3 cycles to evaluate the efficacy until tumor progression or death. Follow-up period ended in December 2023. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Efficacy was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and the best response of each patient was recorded. The objective response rate (ORR) and disease control rate (DCR) were calculated. Adverse reactions were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), ranging from grade Ⅰto Ⅳ. Kaplan-Meier survival curves were used to analyze PFS and OS, and survival times were expressed as median values.Results:A total of 23 MPM patients were included, with the mean age of (55.04±13.27)years, 15 males, 8 females, 19 cases of epithelial type and 4 cases of non-epithelial type. The Eastern Cooperative Oncology Group (ECOG) performance status scores were 0-1 in 12 patients and 2 in 11 patients. There were 17 smokers and 6 non-smokers, 12 cases with PD-L1 positive and 11 cases with PD-L1 negative, and 6 cases with anti-angiogenic drugs and 17 cases without using anti-angiogenic drugs in the first-line treatment. Of the 23 patients, 1 achieved complete response (CR), 9 achieved partial response (PR), 7 had stable disease (SD), and 6 had progressive disease (PD). The ORR and DCR of the enrolled patients were 43.5% (10/23) and 73.9% (17/23), respectively. Kaplan-Meier survival analysis showed that the PFS of the enrolled patients was 7.50 (95% CI: 5.47-9.54) months, and the OS was 12.50 (95% CI: 1.07-23.93) months. The most common adverse reactions related to the treatment of sintilimab combined with bevacizumab were hypertension (14 cases (60.9%)), fatigue (10 cases (43.5%)), decreased appetite (8 cases (34.8%)), proteinuria (6 cases (26.1%)), pruritus (5 cases (21.7%)), constipation (4 cases (17.4%)) and nausea (3 cases (13.0%)), etc. Only 9 patients had grade Ⅲ adverse reactions (8 cases of hypertension and 1 case of nausea), and only 1 patient had grade Ⅳ adverse reaction (hypertension). Conclusion:Sintilimab combined with bevacizumab has some therapeutic effects on progressive MPM, and the adverse reactions are relatively mild.

OBJECTIVE: Treating peripheral nerve injury (PNI) presents a clinical challenge due to limited axon regeneration. Strychni Semen, a traditional Chinese medicine, is clinically used for numbness and hemiplegia. However, its role in promoting functional recovery after PNI and the related mechanisms have not yet been systematically studied. METHODS: A mouse model of sciatic nerve crush (SNC) injury was established and the mice received drug treatment via intragastric gavage, followed by behavioral assessments (adhesive removal test, hot-plate test and Von Frey test). Transcriptomic analyses were performed to examine gene expression in the dorsal root ganglia (DRGs) from the third to the sixth lumbar vertebrae, so as to identify the significantly differentially expressed genes. Immunofluorescence staining was used to assess the expression levels of superior cervical ganglia neural-specific 10 protein (SCG10). The ultra-trace protein detection technique was used to evaluate changes in gene expression levels. RESULTS: Strychni Semen and its active compounds (brucine and strychnine) improved functional recovery in mice following SNC injury. Transcriptomic data indicated that Strychni Semen and its active compounds initiated transcriptional reprogramming that impacted cellular morphology and extracellular matrix remodeling in DRGs after SNC, suggesting potential roles in promoting axon regeneration. Imaging data further confirmed that Strychni Semen and its active compounds facilitated axon regrowth in SNC-injured mice. By integrating protein-protein interaction predictions, ultra-trace protein detection, and molecular docking analysis, we identified myeloperoxidase as a potentially critical factor in the axon regenerative effects conferred by Strychni Semen and its active compounds. CONCLUSION Strychni Semen and its active compounds enhance sensory function by promoting axonal regeneration after PNI. These findings establish a foundation for the future applications of Strychni Semen and highlight novel therapeutic strategies and drug targets for axon regeneration. Please cite this article as: Zhang Y, Zhao XY, Liu MT, Zhou ZC, Cheng HB, Jiang XH, Zheng YR, Chen Z. Strychni Semen and its active compounds promote axon regeneration following peripheral nerve injury by suppressing myeloperoxidase in the dorsal root ganglia. J Integr Med. 2025; 23(2): 169-181.
Animals ; Nerve Regeneration/drug effects* ; Mice ; Peripheral Nerve Injuries/physiopathology* ; Male ; Ganglia, Spinal/enzymology* ; Axons/physiology* ; Peroxidase/antagonists & inhibitors* ; Mice, Inbred C57BL ; Drugs, Chinese Herbal/pharmacology* ; Disease Models, Animal ; Strychnine/pharmacology*

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

Bacillus velezensis DJ1 exhibits broad-spectrum antagonistic activity against diverse phytopathogenic fungi, while its biocontrol mechanisms against Fusarium graminearum, the causal agent of maize stalk rot, remain poorly characterized. In this study, we integrated genomics and transcriptomics to elucidate the antifungal mechanisms of strain DJ1. The results demonstrated that DJ1 inhibited F. graminearum with the efficacy of 64.4%, while its polyketide crude extract achieved the control efficacy of 55% in pot experiments against this disease. Whole-genome sequencing revealed a single circular chromosome (3 929 792 bp, GC content of 47%) harboring 12 biosynthetic gene clusters for secondary metabolites, six of which encoded known antimicrobial compounds (macrolactin H, bacillaene, difficidin, surfactin, fengycin, and bacilysin). Transcriptomic analysis identified 243 differentially expressed genes (152 upregulated and 91 downregulated, P < 0.05), which were potentially associated with the antagonistic activity against F. graminearum. KEGG enrichment analysis highlighted activation (P < 0.05) of cysteine/methionine metabolism, pentose phosphate pathway, and polyketide biosynthesis pathways, indicating that DJ1 employed synergistic strategies involving antimicrobial compound synthesis, energy metabolism enhancement, and nutrient competition to suppress pathogens. This study provides a theoretical foundation for developing novel microbial resources and application technologies to combat phytopathogenic fungi.
Fusarium/drug effects* ; Bacillus/metabolism* ; Plant Diseases/prevention & control* ; Antifungal Agents/pharmacology* ; Genomics ; Zea mays/microbiology* ; Transcriptome ; Gene Expression Profiling ; Antibiosis ; Multigene Family ; Multiomics

Iodine speciations in aquatic environments are affected by dissolved oxygen,redox potential,microbial activity,organic matter decomposition,light reaction,etc.Accurate quantification of iodine speciation can not only help to understand the geochemical cycle of iodine,but also help to trace and study environmental processes.Based on the combination of ion chromatography(IC)and inductively coupled plasma mass spectrometry(ICP-MS),a rapid and sensitive method was established for determining the speciations of iodine in environmental water samples including seawater,river water,lake water,rainwater,groundwater,etc.The results presented here showed that IO3?and I?in seawater were quickly separated and measured within 120 s when using guard column AG22 and 8 mmol/L(NH4)2CO3 as the mobile phase.While for lake water,river water and precipitation samples with high soluble organically bond iodine(SOI),an AS22 separation column(250 mm×4 mm)connected with a guard column and using 50 mmol/L(NH4)2CO3 as mobile phase could effectively separate unknown SOI from IO3? to achieve accurate quantification of IO3?.For accurate correction of iodine measurement signal fluctuations,133Cs was directly added to the(NH4)2CO3 mobile phase as an internal standard.The SOI content was calculated by the total iodine concentrations minus the sum of IO3?and I?.The precision of the established iodine speciation analytical method was better than 3.5%,and the standard addition experiment showed that the analytical method was accurate.When the injection volume was 25 μL,the detection limits were 0.011?0.025 μg/L for IO3? and 0.023?0.031 μg/L for I?,respectively.The method was successfully used to analyze IO3?,SOI and I? in environmental water samples,such as seawater,river water,rainwater and groundwater.

Objective : To explore the relationship between the nodes of anxiety and depression symptoms in preg- nant women , and to analyze the interaction between these symptoms . Methods : A convenient sampling method was used to evaluate the level of anxiety and depression among pregnant women who underwent antenatal check-up in the obstetric examination in a Grade Ⅲ A hospital . Data were collected using the General Data Questionnaire , the Generalized Anxiety Disorder Scale (GAD-7) , and the Patient Health Questionnaire Depression Scale (PHQ-9) . Based on the relationship between anxiety and depressive symptoms in pregnant women , a network was constructed and analyzed . Results : mong the 1 742 subjects , 476 (27 . 3% ) had anxiety , 290 (16. 6% ) had depression , and 218 (12. 5% ) had anxiety and depression comorbidities . The univariate analysis revealed statistically significant differences in various factors such as age , education level , occupation , gestational week , sleep status during pregnancy , exercise status during pregnancy , drinking , knowledge of pregnancy , planned pregnancy , living envi- ronment , husband-wife relationship , parent-in-law relationship and parental relationship had statistically significant differences in whether they had CAD (all P < 0. 05) . In the network of anxiety and depression symptoms , the edge weight between node PHQ2 (feeling down , depressed , or hopeless) and GAD6 (becoming easily annoyed or irrita- ble) , PHQ8 (slowed speech or movement , or becoming more restless and fidgety than usual) , as well as GAD5 (being so restless that it is difficult to sit still) was 0. 27 . The centrality measures of PHQ2 were as follows : be- tweenness (Bet ) = 2. 648 , closeness ( Clo) = 1 . 785 , strength ( Str) = 1 . 439 , and expected influence ( Exp) = 1 . 439 . Conclusion Node PHQ2 has the strongest correlation with GAD6 , PHQ8 , and GAD5 , with an edge weight of 0. 27 . PHQ2 has a significant impact on other symptoms within the network , making it the core symptom of the network . It is more involved in symptom interactions and plays a role in predicting other symptoms . Targeting PHQ2 as an intervention point can help develop effective treatment strategies , providing new insights into the asso- ciation between perinatal anxiety and depressive symptoms , as well as their clinical significance .

Objective To explore the effects of dodecanoylcarnitine(DA)and myristoleic acid(MA)on the function of mouse alveolar epithelial cell line MLE-12 and their underlying mechanisms.Methods An inflammatory model was established by stimulating MLE-12 cells with IL-4.The expression levels of DA,MA,and sphingosine-1-phosphate(S1P)in the cell supernatant were detected by ELISA.MLE-12 cells were separately intervened with DA and MA.RT-PCR and flow cytometry were used to detect the expression changes of inflammatory factors IL-6 and tumor necrosis factor-α(TNF-α)and the level of intracellular reactive oxygen species(ROS).Additionally,Western blot was performed to detect the expression of key proteins such as p38 mitogen-activated protein kinase(p-38 MAPK)and src homology 2 domain-containing phosphatase 1(SHP-1).To explore the role of S1PR2 in the effects of DA and MA,MLE-12 cells were pretreated with the S1PR2 inhibitor JTE-013,and the above experiments were repeated.Results IL-4 stimulation significantly upregulated the levels of DA,MA,and S1P in MLE-12 cells(P<0.05).DA/MA treatment groups exhibited significantly increased expression of IL-6 and TNF-α compared with the control group(P<0.05),along with elevated ROS levels(P<0.05).Western blot analysis revealed that DA/MA promoted SHP-1 dephosphorylation and phosphorylated p38 MAPK activation in MLE-12 cells.Notably,JTE-013 pre-treatment completely reversed these effects(P<0.05).Conclusion Asthma-related metabolites DA and MA exacerbate the inflammatory and oxidative stress responses of MLE-12 cells by activating the S1PR2 receptor,promoting the dephosphorylation of SHP-1 and the activation of the p-p38 MAPK pathway.This study reveals the core regulatory role of S1PR2 in this pathway as well.

Objective To explore the effects of dodecanoylcarnitine(DA)and myristoleic acid(MA)on the function of mouse alveolar epithelial cell line MLE-12 and their underlying mechanisms.Methods An inflammatory model was established by stimulating MLE-12 cells with IL-4.The expression levels of DA,MA,and sphingosine-1-phosphate(S1P)in the cell supernatant were detected by ELISA.MLE-12 cells were separately intervened with DA and MA.RT-PCR and flow cytometry were used to detect the expression changes of inflammatory factors IL-6 and tumor necrosis factor-α(TNF-α)and the level of intracellular reactive oxygen species(ROS).Additionally,Western blot was performed to detect the expression of key proteins such as p38 mitogen-activated protein kinase(p-38 MAPK)and src homology 2 domain-containing phosphatase 1(SHP-1).To explore the role of S1PR2 in the effects of DA and MA,MLE-12 cells were pretreated with the S1PR2 inhibitor JTE-013,and the above experiments were repeated.Results IL-4 stimulation significantly upregulated the levels of DA,MA,and S1P in MLE-12 cells(P<0.05).DA/MA treatment groups exhibited significantly increased expression of IL-6 and TNF-α compared with the control group(P<0.05),along with elevated ROS levels(P<0.05).Western blot analysis revealed that DA/MA promoted SHP-1 dephosphorylation and phosphorylated p38 MAPK activation in MLE-12 cells.Notably,JTE-013 pre-treatment completely reversed these effects(P<0.05).Conclusion Asthma-related metabolites DA and MA exacerbate the inflammatory and oxidative stress responses of MLE-12 cells by activating the S1PR2 receptor,promoting the dephosphorylation of SHP-1 and the activation of the p-p38 MAPK pathway.This study reveals the core regulatory role of S1PR2 in this pathway as well.

Objective:To evaluate the efficacy and safety of sintilimab combined with bevacizumab in the second-line treatment of malignant pleural mesothelioma(MPM).Methods:This was a longitudinal study. Patients with MPM who had progressed after first-line treatment and were admitted to the Day-Care Outpatient Department of Medical Oncology, Ningguo People′s Hospital from February 2019 to February 2022 were included. General clinical data of the patients were collected at baseline. The patients were treated with the second-line treatment regimen of sintilimab (200 mg)+bevacizumab (15 mg/kg) on a 21-day cycle. Enhanced CT scans were performed every 3 cycles to evaluate the efficacy until tumor progression or death. Follow-up period ended in December 2023. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Efficacy was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and the best response of each patient was recorded. The objective response rate (ORR) and disease control rate (DCR) were calculated. Adverse reactions were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), ranging from grade Ⅰto Ⅳ. Kaplan-Meier survival curves were used to analyze PFS and OS, and survival times were expressed as median values.Results:A total of 23 MPM patients were included, with the mean age of (55.04±13.27)years, 15 males, 8 females, 19 cases of epithelial type and 4 cases of non-epithelial type. The Eastern Cooperative Oncology Group (ECOG) performance status scores were 0-1 in 12 patients and 2 in 11 patients. There were 17 smokers and 6 non-smokers, 12 cases with PD-L1 positive and 11 cases with PD-L1 negative, and 6 cases with anti-angiogenic drugs and 17 cases without using anti-angiogenic drugs in the first-line treatment. Of the 23 patients, 1 achieved complete response (CR), 9 achieved partial response (PR), 7 had stable disease (SD), and 6 had progressive disease (PD). The ORR and DCR of the enrolled patients were 43.5% (10/23) and 73.9% (17/23), respectively. Kaplan-Meier survival analysis showed that the PFS of the enrolled patients was 7.50 (95% CI: 5.47-9.54) months, and the OS was 12.50 (95% CI: 1.07-23.93) months. The most common adverse reactions related to the treatment of sintilimab combined with bevacizumab were hypertension (14 cases (60.9%)), fatigue (10 cases (43.5%)), decreased appetite (8 cases (34.8%)), proteinuria (6 cases (26.1%)), pruritus (5 cases (21.7%)), constipation (4 cases (17.4%)) and nausea (3 cases (13.0%)), etc. Only 9 patients had grade Ⅲ adverse reactions (8 cases of hypertension and 1 case of nausea), and only 1 patient had grade Ⅳ adverse reaction (hypertension). Conclusion:Sintilimab combined with bevacizumab has some therapeutic effects on progressive MPM, and the adverse reactions are relatively mild.