Hepatocellular carcinoma (HCC) develops within a profoundly immunosuppressive tumor immune microenvironment (TIME), which limits the efficacy of immunotherapy. Polarization of tumor-associated macrophages (TAMs) toward a pro-tumorigenic M2 phenotype is a major driver of immune escape. Ferroptosis, an iron-dependent regulated cell death program, intersects with hepatic iron metabolism and immune regulation and thus offers promising points of therapeutic intervention. This review systematically elucidates the mechanistic role of TAM ferroptosis in HCC immune evasion and highlights a “bidirectional regulation” intervention strategy grounded in the Traditional Chinese medicine (TCM) principle of “fortifying healthy qi and eliminating pathogens” (Fuzheng Quxie). This strategy employs “eliminating pathogens” (Quxie) approaches to exploit the metabolic vulnerability of M2-like TAMs and precisely induce their ferroptosis. Moreover, it utilizes “fortifying healthy qi” (Fuzheng) approaches to protect M1-like TAMs and CD8⁺ T cells from oxidative damage. This parallel “induction-protection” paradigm demonstrates the unique advantages of TCM in systemically remodeling TIME through multitarget synergistic actions. Accordingly, precision regulation of TAM ferroptosis based on the Fuzheng Quxie theory represents a promising integrative Chinese-Western medicine strategy for overcoming current bottlenecks in HCC immunotherapy, although its clinical translational potential warrants further validation.

Objective:To explore the predictive value of combined evaluation of neutrophil to lymphocyte ratio(NLR),platelet to lymphocyte ratio(PLR),and lactate dehydrogenase(LDH)on the therapeutic effect and prognosis of ICIs(immune checkpoint inhibitors)in metastatic gastric cancer(MGC)patients.Methods:This study conducted a retrospective analysis of pre-and post-treatment peripheral hematological indicators of 88 MGC patients treated at Nanping First Hospital affiliated to Fujian Medical University.The recent treatment efficacy of the two patient groups was evaluated based on the solid tumor response evaluation criteria.χ2 tests were conducted to analyze and compare differences in disease control rate(DCR)and objective response rate(ORR),as well as differences in PD-L1 expression and clinical characteristics between the two groups.Survival analysis was performed using the Kaplan-Meier method for univariate analysis.Intergroup differences were detected by the Log-Rank test.Univariate analysis was conducted using the Cox proportional hazards regression model.Results:After immunotherapy,NLR3,NLR4,PLR2,PLR3,PLR4,LDH2 and LDH3 decreased significantly compared with those before treatment(all P<0.05).There were significant statistical differences in NLR1 and LDH1 before treatment between the complete-remission(CR)+partial-remission(PR)group and the progress-disease(PD)group(all P<0.05).Patients with higher levels of NLR2,NLR3,NLR4,PLR4,LDH1,LDH3,LDH4,ΔNLR1,ΔNLR2,ΔNLR3 and ΔPLR1 had shorter OS(all P<0.05),and patients with higher levels of NLR2,NLR3,NLR4,PLR1,LDH1,ΔNLR1,ΔNLR2,ΔNLR3,Δ PLR1 and Δ PLR2 had shorter PFS compared with patients in low-level group(all P<0.05).The percentage of PD-L1 negative patients among NLR3-H patients was the highest,and the number of NLR3-H patients in the NLR3-L group was larger than that in the negative group,the combined positive score(CPS)=1-5 group and the CPS≥5 group(all P<0.05).The proportion of women in the NLR3-H and PLR3-H groups was higher(all P<0.05).Conclusion:The evaluation of NLR,PLR,and LDH has certain value in predicting the efficacy and prognosis of immunotherapy for MGC.

OBJECTIVE: To observe the effect of electroacupuncture (EA) pretreatment of "biaoben acupoint combination" on cardiomyocyte mitochondrial fission in the rats with myocardial ischemia-reperfusion injury (MIRI) and explore its mechanism. METHODS: Fifty male SD rats were randomly divided into a sham-operation group, a model group, an EA pretreatment group, an EA pretreatment + Compound C group and an EA pretreatment+ML385 group, 10 rats in each group. In the EA pretreatment, the EA pretreatment + Compound C group and the EA pretreatment+ML385 group, EA was delivered at bilateral "Neiguan" (PC6), "Zusanli" (ST36) and "Guanyuan" (CV4) for 20 min, with continuous wave and 2 Hz of frequency, 1 mA of current, once daily for consecutive 7 days. On day 8, in the EA pretreatment + Compound C group and the EA pretreatment+ML385 group, 30 min before model preparation, the intraperitoneal injection with Compound C (0.3 mg/kg) and ML385 (30 mg/kg) was administered respectively. Except in the sham-operation group, the ligation of the left anterior descending coronary artery was performed to prepare MIRI rat model in the rest groups. In the sham-operation group, the thread was not ligated. After modeling, the content of reactive oxygen species (ROS) in the ischemic area was measured by flow cytometry, superoxide dismutase (SOD) was detected using xanthine oxidase method, and malondialdelyde (MDA) was detected using thiobarbituric acid (TBA) chromatometry. The morphology of myocardial tissue in the ischemic area was observed with HE staining, and the mitochondria ultrastructure of cardiomyocytes observed under transmission electron microscopy. Using immunofluorescence analysis, the positive expression of mitochondrial fission factor (MFF), mitochondrial fission 1 protein antibody (Fis1) and dynamin-related protein 1 (Drp1) was detected; and with immunohistochemical method used, the protein expression of adenosine monophosphate-activated protein kinase (AMPK), nuclear factor E2-associated factor2 (Nrf2) and Drp1 in the ischemic area was detected. RESULTS: Compared with the sham-operation group, the content of ROS and MDA in the myocardial tissue of the ischemic area, and the positive expression of MFF, Fis1 and Drp1 increased in the model group (P<0.01); the content of SOD and the protein expression of AMRK and Nrf2 decreased (P<0.01), and the protein expression of Drp1 elevated (P<0.01). Compared with the model group, the content of ROS and MDA in the myocardial tissue of the ischemic area, and the positive expression of MFF, Fis1 and Drp1 were dropped in the EA pretreatment group (P<0.01); the content of SOD and the protein expression of AMRK and Nrf2 rose (P<0.01), and the protein expression of Drp1 declined (P<0.01); and in the EA pretreatment+Compound C group and the EA pretreatment+ML385 group, the positive expression of MFF, Fis1 and Drp1, and the protein expression of Drp1 were all reduced (P<0.01). When compared with the EA pretreatment + Compound C group and the EA pretreatment+ML385 group, the content of ROS and MDA in the myocardial tissue of the ischemic area, and the positive expression of MFF, Fis1 and Drp1 were dropped in the EA pretreatment group (P<0.01); the content of SOD and the protein expression of AMRK and Nrf2 rose (P<0.01, P<0.05), and the protein expression of Drp1 decreased (P<0.05). In comparison with the model group, the EA pretreatment+Compound C group and the EA pretreatment+ML385 group, the cardiac muscle fiber rupture, cell swelling and mitochondrial disorders were obviously alleviated in the EA pretreatment group. The morphological changes were similar among the model group, the EA pretreatment+Compound C group and the EA pretreatment+ML385 group. CONCLUSION Electroacupuncture pretreatment of "biaoben acupoint combination" attenuates myocardial injury in MIRI rats, probably through promoting the phosphorylation of AMPK and Nrf2, inhibiting the excessive mitochondrial fission induced by Drp1, and reducing mitochondrial dysfunction caused by mitochondrial fragmentation and vacuolation.
Animals ; Electroacupuncture ; Male ; Rats, Sprague-Dawley ; Myocardial Reperfusion Injury/physiopathology* ; Myocytes, Cardiac/cytology* ; Rats ; Acupuncture Points ; Mitochondrial Dynamics ; Humans ; Reactive Oxygen Species/metabolism* ; NF-E2-Related Factor 2/genetics* ; Superoxide Dismutase/metabolism*

A high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS) method was established for simultaneous determination of seven characteristic components from the active fraction of Alpiniae Officinarum Rhizoma in rat plasma, including galangin, kaempferol, kaempferide, pinocembrin, 1,7-diphenyl-4-en-3-heptanone, 5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-phenyl-3-heptanone(DHPA), and 7-(4-hydroxy-3-methoxyphenyl)-1-phenyl-4-en-3-heptanone(DPHB). The new developed HPLC-MS/MS method was applied to study the pharmacokinetics of the 7 characteristic components in rats with Helicobacter pylori gastritis. A Waters Sunfire C_(18) column(2.1 mm×150 mm, 3.5 μm) was used. The acetonitrile-aqueous solution(containing 0.1% formic acid) was adopted as the mobile phase for gradient elution. Seven components and internal standard(chlorogenic acid) were separated within 12 min. Mass spectrometric detection was performed in multiple reaction monitoring(MRM) mode using electrospray ionization(ESI) source with fast switching between positive and negative ions. The method was verified by specificity, linearity, precision, accuracy, recovery, matrix effect, and stability and met the requirements of pharmacokinetic study on the 7 components in rat plasma. Pharmacokinetic results showed that the average peak time(T_(max)) of the 7 components was 0.31-2.19 h, their elimination half-life(t_(1/2)) was 5.26-16.65 h, and the average residence time(MRT) was 6.29-31.03 h after the oral administration of the active fraction of Alpiniae Officinarum Rhizoma to rats with H. pylori gastritis. The plasma exposure levels of galangin and DHPA were higher than those of the other components. The concentration-time curves of four detected flavonoids showed obvious double peaks. This study elucidated the pharmacokinetic characteristics of 7 characteristic components from the active fraction of Alpiniae Officinarum Rhizoma in rats with H. pylori gastritis, providing a scientific basis for the identification of the pharmacodynamic substances of Alpiniae Officinarum Rhizoma for treatment of H. pylori gastritis and the clinical application of Alpiniae Officinarum Rhizoma in the prevention and treatment of H. pylori gastritis.
Animals ; Rats ; Chromatography, High Pressure Liquid/methods* ; Tandem Mass Spectrometry/methods* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Helicobacter pylori/drug effects* ; Alpinia/chemistry* ; Rats, Sprague-Dawley ; Gastritis/metabolism* ; Helicobacter Infections/metabolism* ; Flavonoids/blood* ; Rhizome/chemistry* ; Liquid Chromatography-Mass Spectrometry

Objective:To explore the predictive value of combined evaluation of neutrophil to lymphocyte ratio(NLR),platelet to lymphocyte ratio(PLR),and lactate dehydrogenase(LDH)on the therapeutic effect and prognosis of ICIs(immune checkpoint inhibitors)in metastatic gastric cancer(MGC)patients.Methods:This study conducted a retrospective analysis of pre-and post-treatment peripheral hematological indicators of 88 MGC patients treated at Nanping First Hospital affiliated to Fujian Medical University.The recent treatment efficacy of the two patient groups was evaluated based on the solid tumor response evaluation criteria.χ2 tests were conducted to analyze and compare differences in disease control rate(DCR)and objective response rate(ORR),as well as differences in PD-L1 expression and clinical characteristics between the two groups.Survival analysis was performed using the Kaplan-Meier method for univariate analysis.Intergroup differences were detected by the Log-Rank test.Univariate analysis was conducted using the Cox proportional hazards regression model.Results:After immunotherapy,NLR3,NLR4,PLR2,PLR3,PLR4,LDH2 and LDH3 decreased significantly compared with those before treatment(all P<0.05).There were significant statistical differences in NLR1 and LDH1 before treatment between the complete-remission(CR)+partial-remission(PR)group and the progress-disease(PD)group(all P<0.05).Patients with higher levels of NLR2,NLR3,NLR4,PLR4,LDH1,LDH3,LDH4,ΔNLR1,ΔNLR2,ΔNLR3 and ΔPLR1 had shorter OS(all P<0.05),and patients with higher levels of NLR2,NLR3,NLR4,PLR1,LDH1,ΔNLR1,ΔNLR2,ΔNLR3,Δ PLR1 and Δ PLR2 had shorter PFS compared with patients in low-level group(all P<0.05).The percentage of PD-L1 negative patients among NLR3-H patients was the highest,and the number of NLR3-H patients in the NLR3-L group was larger than that in the negative group,the combined positive score(CPS)=1-5 group and the CPS≥5 group(all P<0.05).The proportion of women in the NLR3-H and PLR3-H groups was higher(all P<0.05).Conclusion:The evaluation of NLR,PLR,and LDH has certain value in predicting the efficacy and prognosis of immunotherapy for MGC.

Objective:To investigate the characteristics of brain functional networks alterations in patients with inflammatory bowel disease (IBD) and explore their correlations with clinical indicators and psycho-psychological scores.Methods:A cross-sectional survey study was conducted. A total of 48 IBD patients diagnosed at the Changzhou Second People′s Hospital from June 2021 to June 2023 were collected, and 32 healthy individuals matched for age, gender, and education level were selected as the healthy control group. Resting-state functional magnetic resonance imaging data were enrolled, and the topological properties of brain networks between the two groups of subjects were compared by using graph theory analysis. Pearson correlation and Spearman′s partial correlation analyses were used to explore the correlations between changes in IBD patients′ brain networks topological properties and clinical indicators and psycho-psychological scores.Results:In the IBD group, 29 patients were males (60.4%) and 19 were females (39.6%) ; the total disease course was 1.0 (0.3, 5.0) years; 34 patients were Crohn′s disease and 14 ulcerative colitis; they were mainly in the active phase (58.84%, 28/48) . The scores of the hospital anxiety and depression scale (HADS-A and HADS-D) in IBD patients were higher than those in the healthy control group (both P<0.01) . In terms of global properties, both the IBD group and the healthy control group had "small-world" properties (both σ>1.1) . Compared with the healthy control group, the IBD group had lower clustering coefficients, global efficiency, and local efficiency, and longer characteristic path lengths, with all differences being statistically significant (all P<0.05) . In terms of local properties, compared with the healthy control group, the IBD group had higher degree centrality and nodal efficiency in the left middle frontal gyrus, higher betweenness centrality in the left thalamus, lower betweenness centrality and degree centrality in the right parahippocampal gyrus, lower nodal clustering coefficients in the bilateral middle temporal gyrus, right anterior cingulate gyrus and paracingulate gyrus, and lower nodal local efficiency in the bilateral caudate nuclei and left middle temporal gyrus, with all differences being statistically significant (all P<0.05) . The degree centrality of the right parahippocampal gyrus in the IBD group was negatively correlated with the HADS-A score ( r = -0.401, P = 0.005) , and the betweenness centrality was also negatively correlated with the HADS-A score ( r = -0.343, P = 0.017) . The nodal clustering coefficient of the right middle temporal gyrus in the IBD group was positively correlated with the total disease course ( rs = 0.589, P<0.001) . Conclusion:IBD patients have decreased overall information transmission capacity in brain networks, reduced limbic system function, and abnormal functions in brain areas related to pain perception, which are correlated to some extent with the disease course and psycho-psychological state.

Objective:To investigate the characteristics of brain functional networks alterations in patients with inflammatory bowel disease (IBD) and explore their correlations with clinical indicators and psycho-psychological scores.Methods:A cross-sectional survey study was conducted. A total of 48 IBD patients diagnosed at the Changzhou Second People′s Hospital from June 2021 to June 2023 were collected, and 32 healthy individuals matched for age, gender, and education level were selected as the healthy control group. Resting-state functional magnetic resonance imaging data were enrolled, and the topological properties of brain networks between the two groups of subjects were compared by using graph theory analysis. Pearson correlation and Spearman′s partial correlation analyses were used to explore the correlations between changes in IBD patients′ brain networks topological properties and clinical indicators and psycho-psychological scores.Results:In the IBD group, 29 patients were males (60.4%) and 19 were females (39.6%) ; the total disease course was 1.0 (0.3, 5.0) years; 34 patients were Crohn′s disease and 14 ulcerative colitis; they were mainly in the active phase (58.84%, 28/48) . The scores of the hospital anxiety and depression scale (HADS-A and HADS-D) in IBD patients were higher than those in the healthy control group (both P<0.01) . In terms of global properties, both the IBD group and the healthy control group had "small-world" properties (both σ>1.1) . Compared with the healthy control group, the IBD group had lower clustering coefficients, global efficiency, and local efficiency, and longer characteristic path lengths, with all differences being statistically significant (all P<0.05) . In terms of local properties, compared with the healthy control group, the IBD group had higher degree centrality and nodal efficiency in the left middle frontal gyrus, higher betweenness centrality in the left thalamus, lower betweenness centrality and degree centrality in the right parahippocampal gyrus, lower nodal clustering coefficients in the bilateral middle temporal gyrus, right anterior cingulate gyrus and paracingulate gyrus, and lower nodal local efficiency in the bilateral caudate nuclei and left middle temporal gyrus, with all differences being statistically significant (all P<0.05) . The degree centrality of the right parahippocampal gyrus in the IBD group was negatively correlated with the HADS-A score ( r = -0.401, P = 0.005) , and the betweenness centrality was also negatively correlated with the HADS-A score ( r = -0.343, P = 0.017) . The nodal clustering coefficient of the right middle temporal gyrus in the IBD group was positively correlated with the total disease course ( rs = 0.589, P<0.001) . Conclusion:IBD patients have decreased overall information transmission capacity in brain networks, reduced limbic system function, and abnormal functions in brain areas related to pain perception, which are correlated to some extent with the disease course and psycho-psychological state.

Humans ; SARS-CoV-2 ; COVID-19 ; Antibodies ; Antibodies, Viral/therapeutic use* ; Antibodies, Neutralizing/therapeutic use*

Objective To analyze the effect of angiopoietin-like protein 4(ANGPTL4) on M2 macrophage differentiation.Methods The frequency of M2 macrophages in spleen of ANGPTL 4-/-mice and the controls was detected by flow cytometry.And the changes of M2 macrophages was measured by LPS stimulation.F4/80 + macrophages was separated by flow cytometry and treated with LPS or recombinant ANGPTL 4 protein.The secretion of IL-4 in CD4 + T cells was observed after purified macrophages after co-culture with CD4 + T cells by the flow-cytometric intracellular staining method.Results There was no significant difference in the frequency of M2 macrophages in ANGPTL 4-/-mice and controls.LPS stimulation did not affect the expression of M2 macrophages from ANGPTL 4-/-mice.The macrophages from ANGPTL 4/-mice did not promote differentiation of CD4 + T cells into Th2 cells.After co-culturing of macrophages and CD4 + T cells for 48 h in vitro,IL-4 secretion of CD4 + T cells was not changed.Conclusions ANGPTL4 has no effects on M2 macrophage differentiation.

Objective To analyze the effect of angiopoietin-like protein 4(ANGPTL4) on M2 macrophage differentiation.Methods The frequency of M2 macrophages in spleen of ANGPTL 4-/-mice and the controls was detected by flow cytometry.And the changes of M2 macrophages was measured by LPS stimulation.F4/80 + macrophages was separated by flow cytometry and treated with LPS or recombinant ANGPTL 4 protein.The secretion of IL-4 in CD4 + T cells was observed after purified macrophages after co-culture with CD4 + T cells by the flow-cytometric intracellular staining method.Results There was no significant difference in the frequency of M2 macrophages in ANGPTL 4-/-mice and controls.LPS stimulation did not affect the expression of M2 macrophages from ANGPTL 4-/-mice.The macrophages from ANGPTL 4/-mice did not promote differentiation of CD4 + T cells into Th2 cells.After co-culturing of macrophages and CD4 + T cells for 48 h in vitro,IL-4 secretion of CD4 + T cells was not changed.Conclusions ANGPTL4 has no effects on M2 macrophage differentiation.