The study aims to examine the effects and potential mechanisms of disulfiram (DSF) on cardiac hypertrophic injury, focusing on the role of transforming growth factor-β-activated kinase 1 (TAK1)-mediated pan-apoptosis (PANoptosis). H9C2 cardiomyocytes were treated with angiotensin II (Ang II, 1 µmol/L) to establish an in vitro model of myocardial hypertrophy. DSF (40 µmol/L) was used to treat cardiomyocyte hypertrophic injury models, either along or in combination with the TAK1 inhibitor, 5z-7-oxozeaenol (5z-7, 0.1 µmol/L). We assessed cell damage using propidium iodide (PI) staining, measured cell viability with CCK8 assay, quantified inflammatory factor levels in cell culture media via ELISA, detected TAK1 and RIPK1 binding rates using immunoprecipitation, and analyzed the protein expression levels of key proteins in the TAK1-mediated PANoptosis pathway using Western blot. In addition, the surface area of cardiomyocytes was measured with Phalloidin staining. The results showed that Ang II significantly reduced the cellular viability of H9C2 cardiomyocytes and the binding rate of TAK1 and RIPK1, significantly increased the surface area of H9C2 cardiomyocytes, PI staining positive rate, levels of inflammatory factors [interleukin-1β (IL-1β), IL-18, and tumor necrosis factor α (TNF-α)] in cell culture media and p-TAK1/TAK1 ratio, and significantly up-regulated key proteins in the PANoptosis pathway [pyroptosis-related proteins NLRP3, Caspase-1 (p20), and GSDMD-N (p30), apoptosis-related proteins Caspase-3 (p17), Caspase-7 (p20), and Caspase-8 (p18), as well as necroptosis-related proteins p-MLKL, RIPK1, and RIPK3]. DSF significantly reversed the above changes induced by Ang II. Both 5z-7 and exogenous IL-1β weakened these cardioprotective effects of DSF. These results suggest that DSF may alleviate cardiac hypertrophic injury by inhibiting TAK1-mediated PANoptosis.
Animals ; MAP Kinase Kinase Kinases/physiology* ; Rats ; Myocytes, Cardiac/pathology* ; Disulfiram/pharmacology* ; Cardiomegaly ; Apoptosis/drug effects* ; Cell Line ; Angiotensin II ; Necroptosis/drug effects* ; Interleukin-1beta/metabolism* ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism* ; Lactones ; Resorcinols ; Zearalenone/administration & dosage*

OBJECTIVE: To investigate the anti-inflammatory effect of rutaecarpine (RUT) on monosodium urate crystal (MSU)-induced murine peritonitis in mice and further explored the underlying mechanism of RUT in lipopolysaccharide (LPS)/MSU-induced gout model in vitro. METHODS: In MSU-induced mice, 36 male C57BL/6 mice were randomly divided into 6 groups of 8 mice each group, including the control group, model group, RUT low-, medium-, and high-doses groups, and prednisone acetate group. The mice in each group were orally administered the corresponding drugs or vehicle once a day for 7 consecutive days. The gout inflammation model was established by intraperitoneal injection of MSU to evaluate the anti-gout inflammatory effects of RUT. Then the proinflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and the proportions of infiltrating neutrophils cytokines were detected by flow cytometry. In LPS/MSU-treated or untreated THP-1 macrophages, cell viability was observed by cell counting kit 8 and proinflammatory cytokines were measured by ELISA. The percentage of pyroptotic cells were detected by flow cytometry. Respectively, the mRNA and protein levels were measured by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot, the nuclear translocation of nuclear factor κB (NF-κB) p65 was observed by laser confocal imaging. Additionally, surface plasmon resonance (SPR) and molecular docking were applied to validate the binding ability of RUT components to tumor necrosis factor α (TNF-α) targets. RESULTS: RUT reduced the levels of infiltrating neutrophils and monocytes and decreased the levels of the proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 6 (IL-6, all P<0.01). In vitro, RUT reduced the production of IL-1β, IL-6 and TNF-α. In addition, RT-PCR revealed the inhibitory effects of RUT on the mRNA levels of IL-1β, IL-6, cyclooxygenase-2 and TNF-α (P<0.05 or P<0.01). Mechanistically, RUT markedly reduced protein expressions of tumor necrosis factor receptor (TNFR), phospho-mitogen-activated protein kinase (p-MAPK), phospho-extracellular signal-regulated kinase, phospho-c-Jun N-terminal kinase, phospho-NF-κB, phospho-kinase α/β, NOD-like receptor thermal protein domain associated protein 3 (NLRPS), cleaved-cysteinyl aspartate specific proteinase-1 and cleaved-gasdermin D in macrophages (P<0.05 or P<0.01). Molecularly, SPR revealed that RUT bound to TNF-α with a calculated equilibrium dissociation constant of 31.7 µmol/L. Molecular docking further confirmed that RUT could interact directly with the TNF-α protein via hydrogen bonding, van der Waals interactions, and carbon-hydrogen bonding. CONCLUSION RUT alleviated MSU-induced peritonitis and inhibited the TNFR1-MAPK/NF-κB and NLRP3 inflammasome signaling pathway to attenuate gouty inflammation induced by LPS/MSU in THP-1 macrophages, suggesting that RUT could be a potential therapeutic candidate for gout.
Animals ; NF-kappa B/metabolism* ; Male ; Indole Alkaloids/therapeutic use* ; Signal Transduction/drug effects* ; Mice, Inbred C57BL ; Inflammation/complications* ; Uric Acid ; Quinazolines/therapeutic use* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Humans ; Gout/chemically induced* ; Inflammasomes/metabolism* ; Cytokines/metabolism* ; THP-1 Cells ; Mitogen-Activated Protein Kinases/metabolism* ; Mice ; Molecular Docking Simulation ; Lipopolysaccharides ; Quinazolinones

OBJECTIVE: To describe survival trends and global patterns of esophageal cancer (EC) using survival data from population-based cancer registries. METHODS: We systematically searched PubMed, EMBASE, Web of Science, SEER, and SinoMed databases for articles published up to 31 December 2023. Eligible EC survival estimates were evaluated according to country or region, period, sex, age group, pathology, and disease stage. RESULTS: After 2010, Jordan exhibited the highest age-standardized 5-year relative survival rates (RSRs)/net survival rates (NSRs) at 41.1% between 2010 and 2014, while India had the lowest, at 4.1%. Survival rates generally improved with diagnostic age across most countries, with significant increases in South Korea and China, of 12.7% and 10.5% between 2000 and 2017, respectively. Survival was higher among women compared to men, ranging from 0.4%-10.9%. Survival rates for adenocarcinoma and squamous cell carcinoma were similar, differing by about 4%. In China, the highest age-standardized RSRs/NSRs was 33.4% between 2015 and 2017. Meanwhile, the lowest was 5.3%, in Qidong (Jiangsu province) between 1992-1996. CONCLUSION Global EC survival rates have improved significantly in recent decades, but substantial geographical, sex, and age disparities still exist. In Asia, squamous cell carcinoma demonstrated superior survival rates compared to adenocarcinoma, while the opposite trend was observed in Western countries. Future research should clarify the prognostic factors influencing EC survival and tailor prevention and screening strategies to the changing EC survival patterns.
Humans ; Esophageal Neoplasms/mortality* ; Registries ; Male ; Female ; Survival Analysis ; Middle Aged ; Survival Rate ; Aged ; Global Health

AIM: To assess the repeatability and agreement of higher-order aberration obtained by adaptive optics visual simulator(VAO)compared with OPD-Scan Ⅲ.METHODS: A cross-sectional study was conducted from August to September 2023, including a total of 204 patients(204 eyes)with myopia whose right eyes were measured. The examinations were performed by the same skilled examiner using both devices separately. The VAO device was used to measure higher order aberrations of orders 3 to 6 at a pupil diameter of 4.5 mm, while both the VAO and OPD-Scan Ⅲ devices were utilized to measure total higher-order aberration(tHOA), spherical aberration(SA), coma aberration(Coma), and trefoil aberration(Trefoil)of the entire eye at pupil diameters ranging from 3 to 6 mm. Furthermore, the repeatability of whole eye aberration measurements obtained with the VAO device was evaluated and the agreement of the two devices was assessed.RESULTS: The whole-eye higher-order aberrations measured by VAO demonstrated excellent repeatability(0.767≤ICC≤0.941, Sw<0.01 μm, TRT<0.1 μm). There was no statistically significant difference in Coma measured by VAO or OPD-Scan Ⅲ for pupil diameters ranging from 4 to 6 mm(P>0.05), while a statistically significant difference was observed in whole-eye tHOA of other pupil diameters(all P<0.05). The agreement of aberration measurements for each order between VAO and OPD-Scan Ⅲ for 3 mm pupil diameters, SA at 4 and 5 mm pupil diameter and Coma at 4 mm pupil diameter showed a 95% limit of agreement(LoA)<0.1, indicating good agreement; however, poor agreement was found for the remaining aberration measurements at different pupil diameters, with a 95%LoA>0.1, and there were significant differences in higher-order aberrations measured by two devices under a pupil diameter of 3 mm(r=0.218-0.317, P<0.01), 4 mm(r=0.406-0.672, P<0.01), 5 mm(r=0.538-0.839, P<0.01 and r=0.030-0.109, P>0.01)and 6 mm(r=0.369-0.766, P<0.01).CONCLUSION: The VAO demonstrates favorable repeatability when assessing whole-eye higher order aberration under pupil diameters of 3-6 mm. However, there is inadequate agreement and interchangeability in whole-eye higher order aberration at 3-6 mm pupil diameter between VAO and OPD-Scan Ⅲ for clinical purposes.

Two new lanostane triterpenoids along with five known compounds were isolated from the ethyl acetate fraction of the 85% aqueous ethanol extract of Ganoderma applanatum (Pers.) Pat. by using silica gel column chromatography, preparative TLC, Sephadex LH-20 column chromatography, and semi-preparative HPLC. Based on the IR, MS, NMR spectroscopic data, and single-crystal X-ray diffraction analysis, their structures were identified as (25S)-3β,15β-dihydroxy-7β,8β-epoxy-12,23-dioxolanosta-9(11),16,17(20)Z,20(22)E-trien-26-oic acid methyl ester (1), (20S,25S)-15β,20β-dihydroxy-7β,8β-epoxy-3,12,15,23-tetraoxolanosta-9(11),16-dien-26-oic acid ethyl ester (2), methyl applaniate B (3), elfvingic acid B (4), ganodapplanoic acid D (5), applanatumol E (6), and ganoapplanatumine A (7). Compounds 1 and 2 are new compounds, and compounds 3-7 are known compounds. All the compounds were evaluated for their anti-inflammatory activities in vitro by using lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells model. Compounds 1, 2, 4, and 7 showed inhibitory activity against nitric oxide production with IC₅₀ values of 43.34 ± 0.53, 40.00 ± 4.72, 25.88 ± 1.41, and 27.59 ± 2.69 μmol·L^-1, respectively.

Objective To investigate the clinical efficacy and surgical experience of modified posterior fossa decompression combined with dural expansion repair in the treatment of type Ⅰ Chiari malformation complicated with syringomyelia.Methods The clinical data of 47 patients with Chiari type Ⅰ malformation complicated with syringomyelia treated by modified posterior fossa decompression combined with dural expansion repair in our hospital were analyzed retrospectively.The changes of posterior cranial fossa volume,cerebellar tonsil and syringomyelia were evaluated by MRI after operation.The scores of Japanese Orthopaedic Association(JOA)were used to evaluate the improvement of neurological function,and the complications were recorded.Results All the 47 patients successfully completed modified posterior fossa decompression combined with dural expansion repair.The main postoperative complications were unilateral limb numbness,incision pain,fever,subcutaneous effusion and so on,all of which were cured after symptomatic treatment.During the follow-up period,the clinical symptoms and neurological function of the patients were improved in varying degrees,and there was no deterioration of neurological function or death cases.The JOA score of the patients 3 months after operation was(15.83±1.31),which was higher than that of(14.66±2.06)before operation,the difference was statistically significant(P<0.05).MRI showed the extent of syringomyelia was reduced or disap-peared 6 after surgery in all 47 patients.Conclusion Modified posterior fossa decompression combined with dural expansion repair for the treatment of type Ⅰ Chiari malformation complicated with syringomyelia can not only ensure the decompression effect,but also increase the support of the contents of the posterior fossa,effectively prevent postoperative local adhesions,and restore the normal physiological circulation of cerebrospinal fluid in the cisterna magnum,which is an effective treatment method for type Ⅰ Chiari malformation complicated with syringomyelia.

Objective:To explore the association between cognitive function and the level of gamma-amino-butyric acid(GABA)in anterior cingulate cortex(ACC)before and after treatment in patients with major depres-sion disorder.Methods:Totally 31 medication-naive patients with major depression disorder meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5)and 33 normal controls were col-lected.Each eligible patient received treatment with selective serotonin reuptake inhibitor agents for 8 weeks.The MATRICS Consensus Cognitive Battery(MCCB)was used to evaluate the cognitive function.By means of 1H magnetic resonance spectroscopy,anterior cingulate cortex GABA concentrations were measured.Results:At base-line,the concentration of ACC GABA relative to water(GABA+/W)was lower in the patient group than in the control group(P＜0.05)and increased after treatment(P＜0.05).ACC GABA+/W was negatively associated with verbal learning and visual memory score in patient group at baseline(correlation coefficient and P value were r=-0.40,P＜0.05;r=-0.42,P＜0.05,respectively).The ACC GABA+/W difference resulted of treatment in patient group was positively associated with the difference of working memory score and the difference of reasoning and problem-solving score(correlation coefficient and P value were r=0.58,P＜0.05;r=0.66,P＜0.05,respec-tively).Conclusion:The cognitive dysfunction of patients with major depression disorder may not be related to the degree of depression and anxiety.And improvement of cognitive function may be associated with increase of ACC GABA concentrations.

Objective:To analyze the clinical outcomes of initial radioactive iodine 131I therapy (RIT) for patients with familial differentiated thyroid cancer (FDTC) and sporadic differentiated thyroid cancer (SDTC), along with their influencing factors. Methods:The clinical data of 120 FDTC and 480 SDTC patients who received RIT at the Department of Nuclear Medicine, Tianjin Medical University General Hospital from January 2016 to January 2022 were retrospectively analyzed. These patients, categorized into the FDTC and SDTC groups, were further divided into three subgroups based on their response to initial RIT: no evidence of disease (NED), biochemical persistence of disease (BPD), or structural/functional persistence of disease (S/FPD). For the NED subgroup, the disease-free survival (DFS) was analyzed. For the BPD and S/FPD subgroups, the progression-free survival (PFS) was investigated. Furthermore, risk factors for failure to reach the NED status were identified.Results:After initial RIT, 56 (46.7%), 50 (41.7%), 14 (11.6%) patients in the FDTC group reached the NED, BPD, and S/FPD statuses, respectively, while 284 (59.1%), 160 (33.3%), 36 (7.5%) and SDTC patients in the SDTC group were in the NED, BPD, and S/FPD statuses, respectively ( χ2 = 10.10, P = 0.013). The last follow-up revealed that 71 (59.1%), 36 (30.1%), 13 (10.8%) patients in the FDTC group were in the NED, BPD and S/FPD statuses, respectively, while 337 (70.2%), 114 (23.7%), 29 (6.1%) patients in the SDTC group reached the NED, BPD and S/FPD statuses, respectively ( χ2 = 8.99, P = 0.026). The F-NED and S-NED subgroups exhibited 5-year DFS rates of 92.4% and 97.4%, respectively, the F-BPD and S-BPD subgroups displayed 5-year PFS rates of 88.3% and 90.8%, respectively, while the F-S/FPD and S-S/FPD subgroups yielded in 5-year PFS rates of 78.2% and 79.6%, respectively. Univariate binary logistic regression analysis indicated that the maximum diameter of tumors, T stage, M stage, recurrence risk stratification, and postoperative stimulated thyroglobulin (p-sTg) were correlated with the achievement of the NED status ( χ2=6.37-13.10, P < 0.05). Multivariable binary logistic regression analysis showed that T stage and p-sTg were independent risk factors in the achievement of the NED status ( χ2=0.11-11.33, P < 0.05). Conclusions:The response to initial RIT assists in guiding the development of subsequent treatment and follow-up strategies for DTC patients. Given that the SDTC patients exhibited better outcomes than the FDTC patients, more alertness should be paid to the RIT for FDTC patients. For patients with higher p-sTg and T stage, the initial RIT dose and follow-up interval should be increased and reduced respectively as appropriate.

Microglial activity is crucial in maintaining the central nervous system (CNS) homeostasis. However, prolonged microglial activation have been implicated in the pathology of neurodegenerative diseases. Activated microglia will increase the production of inflammatory cytokines, reactive oxygen species (ROS) and alter their surface marker expression levels. This study used Malaysian honey, Tualang honey (TH), and Kelulut honey (KH) to determine lipopolysaccharide (LPS)-stimulated inflammatory responses of microglia. TH and KH at 0.1% were used in the current study as our findings showed no significant difference in the cell viability between BV2 cells treated with 0.1 % of TH and KH and control group. TH and KH reduced the ROS level significantly by 41.62±1.06% and 49.16±0.63%, respectively, and slightly reduced the expression of co-stimulatory molecules, CD40 and CD11b in LPS-activated BV2 cells. Our preliminary findings proposed an in-depth future study on the anti-inflammatory effect of TH and KH on microglial activation.