Ischemic stroke is a disease resulting from the cerebral ischemia and hypoxia caused by the blockage of brain vessels in the brain,and is characterized by the focal neurological signs.Pathologically,neuronal necrosis in the infarcted area and the neuronal degeneration or delayed death of neurons in the ischemic penumbra,contribute to the morphological basis of the disease.Ischemic stroke is regulated by multiple processes,including ferroptosis,apoptosis,and autophagy.Ferroptosis,a type of iron-dependent cell death,is closely associated with ischemic stroke.Nuclear factor erythroid 2-related factor 2(Nrf2),a key transcription factor,plays a critical role in maintaining cellular redox balance and regulating inflammatory responses.Nrf2 promotes the expression of solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),thereby activating the Nrf2 signaling pathway to counteract ferroptosis and protect cells from damage.This article reviews and analyzes recent experimental studies on traditional Chinese medicine(TCM)therapy targeting the Nrf2/SLC7A11/GPX4 pathway to suppress ferroptosis.The studies have found that TCM therapy with herbal compounds,Chinese patent medicines,single herbal components and their active ingredients,and acupuncture and moxibustion can inhibit ferroptosis by activating the Nrf2/SLC7A11/GPX4 signaling pathway,which will provide novel strategies for the TCM intervention of ischemic stroke.

Objective To investigate the effects of polybutylene terephthalate(PBT)grafted with various monomers,such as acrylic acid(AA),acrylamide(AM),sodium styrene sulfonate(SSS),AA+AM and AA+SSS on platelet adhesion and function.Methods The AA,AM,SSS,AA+AM,and AA+SSS were grafted onto the surface of PBT by γ-ray irradia-tion,and the grafted PBT was characterized by fourier transform infrared spectrometry(FTIR)and wetting time.Platelet ac-tivation and aggregation of different monomers grafted with PBT were observed by scanning electron microscopy(SEM).Platelet concentration,maximum aggregation ability,positive expression rate of CD62p and hypotonic shock rate(HSR)of PBT grafted with different monomers were tested to study their effect on platelet adhesion and function.Results The char-acteristic absorption peaks of AA,AM and SSS appeared in FTIR,and the hydrophilicity of the grafted material was im-proved obviously,indicating that the monomer was grafted successfully.The results of SEM showed that the degree of platelet activation and aggregation caused by the original PBT was significantly higher than that of modified ones.Compared with the original platelets,the platelet concentration of PBT was(533.00±4.58 vs 672.00±3.61)×109/L,the maximum platelet ag-gregation rate was(48.80±0.96 vs 58.60±1.37)%,the positive expression rate of CD62p was(45.35±0.58 vs 39.90±0.52)%,and the platelet HSR was(48.74±0.46 vs 51.86±0.93)%(P<0.05).Compared with the original PBT,the platelet loss and platelet function damage caused by PBT grafted with different monomers decreased significantly(P<0.05).PBT-(AA+AM)had the least comprehensive effect on platelets[platelet concentration(637.00±2.65)×109/L,maximum plate-let aggregation rate(62.45±0.61)%,positive expression rate of CD62p(37.39±0.42)%,platelet HSR(53.51±0.58)%].Conclusion The comprehensive effect of PBT grafted with AA+AM on platelet adhesion and function is significantly lower than that of PBT grafted with other monomers,so it is anticipated to apply filtering and removing leukocytes in platelet prep-arations.

N1-methyladenosine(m1A)RNA methylation is critical for regulating mRNA translation;however,its role in the development,progression,and immunotherapy response of head and neck squamous cell carcinoma(HNSCC)remains largely unknown.Using Tgfbr1 and Pten conditional knockout(2cKO)mice,we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels.Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis.Mechanistically,TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis,upregulating programmed death-ligand 1(PD-L1)expression.Moreover,m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus(oHSV),contributing to reactive PD-L1 upregulation.Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth,representing a promising strategy to alleviate resistance.These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression,providing a mutually reinforcing combination immunotherapy approach.

Recurrent ulcerative colitis is a difficult point in clinical treatment.Its TCM property is deficiency in nature and excess in superficiality.Deficiency of spleen yang for a long time will affect the kidney;if Taiyang and Shaoyin meridians are attacked for a long time,Jueyin will be involved.San yin diseases will occur,and yang qi will be severely injured;dampness and heat,turbid poison,cold coagulation,food stagnation and other pathogenic factors invade and attack from outside to inside,lie down in the intestinal collaterals,remove heat by stasis,fumigate the lipid membrane and form internal ulcers.Deficiency of healthy qi,weakness and sores are the origin of the disease,stagnation of intestinal collaterals is the superficiality of the disease,and"stasis"as the main pathological factor carries out the disease from beginning to end.According to the idea of supporting sores and removing blood stasis,the self-made Xiaoyong Yukui Decoction can support sores to generate new ones,remove blood stasis and eliminate stagnation,and help regulate cold and heat,so as to strengthen the health and reduce toxin,remove blood stasis and unblock collaterals,so that the pathogenic factors can be removed and health can be restored,and the internal ulcer can heal,achieving good clinical efficacy in treating recurrent ulcerative colitis.

Cancer stem cell-like cells (CSCs) play an integral role in the heterogeneity, metastasis, and treatment resistance of head and neck squamous cell carcinoma (HNSCC) due to their high tumor initiation capacity and plasticity. Here, we identified a candidate gene named LIMP-2 as a novel therapeutic target regulating HNSCC progression and CSC properties. The high expression of LIMP-2 in HNSCC patients suggested a poor prognosis and potential immunotherapy resistance. Functionally, LIMP-2 can facilitate autolysosome formation to promote autophagic flux. LIMP-2 knockdown inhibits autophagic flux and reduces the tumorigenic ability of HNSCC. Further mechanistic studies suggest that enhanced autophagy helps HNSCC maintain stemness and promotes degradation of GSK3β, which in turn facilitates nuclear translocation of β-catenin and transcription of downstream target genes. In conclusion, this study reveals LIMP-2 as a novel prospective therapeutic target for HNSCC and provides evidence for a link between autophagy, CSC, and immunotherapy resistance.
Humans ; Autophagy ; Carcinoma, Squamous Cell/pathology* ; Cell Line, Tumor ; Glycogen Synthase Kinase 3 beta/metabolism* ; Head and Neck Neoplasms/pathology* ; Neoplastic Stem Cells/pathology* ; Squamous Cell Carcinoma of Head and Neck/pathology* ; Lysosome-Associated Membrane Glycoproteins

Objective:To investigate the relationship between cerebrovascular variation and the occurrence and recurrence of cerebral infarction, and provide a theoretical basis for the precise prevention and treatment of cerebral infarction.Methods:Totally 13 939 patients who underwent magnetic resonance imaging(MRI) and magnetic resonance angiography(MRA) examination at the Second Affiliated Hospital of Shandong First Medical University from January 2020 to December 2021 were grouped according to clinical symptoms combined with the imaging report, including 4 412 cases in the cerebral infarction group and 9 527 cases in the control group.2 048 patients in the cerebral infarction group were eventually enrolled in the study according to the inclusion and exclusion criteria, including 1 479 cases of initial cerebral infarction and 569 cases of recurrent cerebral infarction.SPSS 25.0 statistical software was used for data analysis.The χ2 test was used to compare the incidence of cerebral infarction with different cerebrovascular variations.Univariate analysis of suspected risk factors for recurrent cerebral infarction was performed with χ2 test, nonparametric test and t test.The binary logistic regression was used to analyze independent risk factors of recurrent cerebral infarction. Results:The incidence of cerebral infarction in the dual-system cerebrovascular variant patients, the single-system cerebrovascular variant patients, and the non-cerebrovascular variant patients were 40.9%, 30.7% and 31.8% respectively.The incidence of cerebral infarction in the dual-system cerebrovascular variant patients was the highest compared with those in the single-system cerebrovascular variant patients and the non-cerebrovascular variant patients (both P<0.05). The incidence rates of embryonic posterior cerebral artery, vertebral artery dominance, and bilateral common origin anterior cerebral arteries were 14.09%, 10.76% and 5.32%, respectively.The incidence of bilateral common origin anterior cerebral arteries in the cerebral infarction group was significantly higher than that in the control group and the difference was statistically significant.Patients with cerebral infarction who were familial aggregation ( OR=2.207, 95% CI=1.591-3.062), hyperhomocysteinemia ( OR=1.262, 95% CI=1.014-1.570), hypertension ( OR=1.461, 95% CI=1.114-1.918), diabetes mellitus ( OR=1.348, 95% CI=1.072-1.694), coronary heart disease ( OR=1.491, 95% CI=1.196-1.858) were more likely to recurrent cerebral infarction ( P<0.05), and patients with cerebral infarction had a significantly increased risk of recurrent cerebral infarction with age ( OR=1.031, 95% CI=1.020-1.042, P<0.05). Conclusion:Dual-system cerebrovascular variation and bilateral common origin anterior cerebral arteries are risk factors for cerebral infarction.

Objective:To observe the efficacy of apatinib combined with first-line chemotherapy and maintenance therapy of only apatinib in patients with extensive small-cell lung cancer.Methods:The clinical data of 56 newly diagnosed patients with extensive small-cell lung cancer in the Fifth People′s Hospital of Dalian City from January 2018 to June 2019 were retrospectively analyzed. Among them, 27 patients (experimental group) were treated with first-line chemotherapy combined with apatinib, and 29 patients (control group) were treated with first-line chemotherapy alone. In experimental group, the expression levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR)-2 1 day before chemotherapy and 1 day after chemotherapy were detected by enzyme linked immunosorbent assay method. Response evaluation criteria in solid tumor (RECIST) was used to evaluate the efficacy. The occurrence of adverse reaction was recorded. The patients were followed up for 12 to 24 months, and progression-free survival and 1-year survival were recorded.Results:The objective response rate, median progression-free survival time and 1-year survival rate in experimental group were significantly higher than those in control group: 81.5% (22/27) vs. 55.2% (16/29), 10.5 months vs. 8.5 months and 81.5% (22/27) vs. 55.2% (16/29), and there were statistical differences ( P<0.05); there was no statistical difference in disease control rate between 2 groups ( P>0.05). In experimental group, the patients with complete response and partial response after chemotherapy were classified as effective subgroup (22 cases), and the patients with stationary disease and progressive disease were classified as ineffective subgroup (5 cases). There were no statistical difference in VEGF and VEGFR-2 before chemotherapy between 2 subgroups ( P>0.05). The VEGF and VEGFR-2 in effective subgroup were significantly lower than those in ineffective subgroup: (275.34 ± 16.15) ng/L vs. (330.24 ± 23.21) ng/L and (89.35 ± 4.34) ng/L vs. (112.34 ± 5.45) ng/L, and there were statistical differences ( P<0.01). There were no uncontrollable adverse reactions in 2 groups, and there was no statistical difference in the incidence of adverse reactions between 2 groups ( P>0.05). Conclusions:Application of apatinib in first-line therapy and maintenance therapy for patients with extensive small-cell lung cancer can improve clinical efficacy and survival benefit with controllable adverse reactions.

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.