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关键词： erlotinib   familial adenomatous polyposis (FAP)   MHC   sulindac   tumor immunomodulation  

摘要： A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-gamma signaling as a key pathway. In this study, we combine intermittent low-dose ERL +/- SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL +/- SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 x 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL +/- SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 x 2 increases tumor-associated Cd4(+) T cells by similar to 2.6-fold (p < 0.05), with no apparent effect on Cd8(+) T cells. The treatment also increases tumor-associated Cd68(+) cells (p < 0.05) and decreases Foxp3(+) (p < 0.01) and Arg1(+) (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-gamma signaling may benefit FAP patients at drug doses below the clinical standard of care.

关键词： Triple-negative breast cancer   KIF20A   The IL-17 signaling pathway   bioinformatic analysis  

摘要： Background: Triple-negative breast cancer (TNBC), the only breast cancer subtype lacking effective targeted therapies, is associated with a poor prognosis. Emerging evidence highlights the oncogenic role of kinesin family member 20A (KIF20A) in human malignancies, though its mechanistic contributions to TNBC progression remain poorly understood. Methods: Candidate target genes were screened via bioinformatic analysis. Following KIF20A knockdown, we utilized cell counting kit-8, 5-Ethynyl-2 '-deoxyuridine staining, transwell, and wound healing assays to assess TNBC cell viability, proliferative capacity, migratory ability, and invasive potential of TNBC cells. In vivo, we measured the volume, weight, and proliferation of solid tumors. Moreover, the downstream pathway of KIF20A was screened by bioinformatic analysis and validated by an agonist and an inhibitor for the interleukin 17 (IL-17) pathway. The expression levels of proteins associated with the IL-17 pathway were assessed via Western blot. Results: KIF20A, highly overexpressed in TNBC, was screened out as a promising target gene. In vitro, KIF20A knockdown significantly impaired TNBC cell viability, proliferation, migration, and invasion. In vivo, KIF20A knockdown suppressed the growth and proliferation of solid tumors in nude mice xenograft models. Mechanistically, the IL-17 signaling pathway was screened out and the expression of proteins in this pathway was suppressed by KIF20A knockdown. The agonist for the IL-17 signaling countered the impact of KIF20A knockdown on TNBC progression. Direct inhibition of IL-17 showed a similar effect as KIF20A silencing on TNBC cells. Conclusion: KIF20A downregulation suppresses TNBC progression via the inactivation of the IL-17 signaling pathway, suggesting KIF20A as a potential therapeutic target for TNBC.

关键词： TNF-alpha modulator   Ulcerative colitis (UC)   Deuteration   Fluorination   Metabolic stability  

摘要： Tumor necrosis factor-alpha (TNF-alpha) is an important target for the treatment of inflammatory diseases. Targeting TNF-alpha inhibition, such as antibody drug infliximab and adalimumab, has emerged as an effective therapeutic strategy for managing the most difficult-to-treat chronic ulcerative colitis (UC). So far, there are no small molecule TNF-alpha inhibitors available on the market for the treatment of UC. Previously, we reported an indanone analogue (R)-STU104 showed considerable inhibitory activity on TNF-alpha production in both acute and chronic mouse models of UC with a favorable safety profile. However, further development potential of this compound was greatly limited due to its poor metabolic stability in human liver microsomes and suboptimal pharmacokinetic profiles in mice. Herein, we discovered a deuterated TNF-alpha small molecule modulator (R)-104-6D-01, which demonstrated promising clinical potential for the treatment of UC. This new compound exhibited enhanced oral bioavailability and exposure in pharmacokinetic studies, as well as superior anti-UC efficacy in a DSS-induced mouse UC model, compared with (R)-STU104 at a dosage of 30 mg/kg/d. Collectively, (R)-104-6D01 proves to be a promising candidate of potential use in treating UC as an oral TNF-alpha small molecule modulator.

关键词： 乙型肝炎   肝硬化   恩替卡韦   干扰素   细胞免疫功能   肝纤维化  

摘要： 目的 探究对乙型肝炎(乙肝)肝硬化患者采用恩替卡韦、干扰素联合治疗对其肝纤维化和细胞免疫功能的影响。方法 选取乙肝肝硬化患者84例,随机分组为观察组(n=42)、对照组(n=42)。对照组的治疗药物选择恩替卡韦,观察组的治疗药物为在恩替卡韦的基础上加用干扰素。比较两组临床疗效、肝纤维化指标[透明质酸(HA)、层粘连蛋白(LN)、Ⅲ型前胶原(PCⅢ)及Ⅳ型胶原(CⅣ)]、细胞免疫功能指标(CD4~+、CD8~+及CD4~+/CD8~+)以及不良反应发生情况。结果 观察组的治疗总有效率(95.24%)高于对照组(76.19%)(P<0.05)。两组治疗前HA、LN、PCⅢ及CⅣ水平比较无差异(P>0.05);治疗后,两组HA、LN、PCⅢ及CⅣ水平均低于治疗前,观察组HA(108.82±18.51)ng/ml、LN(117.32±10.21)ng/ml、PCⅢ(102.25±15.78)ng/ml及CⅣ(108.24±13.37)ng/ml均低于对照组的(162.25±15.43)、(162.57±14.48)、(146.27±16.62)、(139.43±15.86)ng/ml(P<0.05)。两组治疗前CD4~+、CD8~+及CD4~+/CD8~+比较无差异(P>0.05);治疗后,两组CD4~+及CD4~+/CD8~+高于治疗前, CD8~+低于治疗前,观察组CD4~+(45.22±6.05)%及CD4~+/CD8~+(1.35±0.14)比对照组的(38.91±5.87)%、(1.16±0.10)高, CD8~+(32.89±5.05)%比对照组的(37.22±5.32)%低(P<0.05)。两组的不良反应总发生率比较无差异(P>0.05)。结论 恩替卡韦、干扰素联合治疗乙肝肝硬化,可改善患者肝纤维化程度,促使其免疫功能提升,且安全性良好。

关键词： Aging   Microglia   Neuroinflammation   Parkinson's disease   Type-I interferons  

摘要： Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by motor dysfunction. Pathological hallmarks of the disease include selective dopaminergic neuronal death, intraneuronal deposits known as Lewy bodies and extensive neuroinflammation within the central nervous system (CNS). Microglia are the key cellular players in mediating this neuroinflammatory response, propagating this neuropathology to exacerbate the neuronal cell death. Growing evidence suggests a role for the type-I interferons (IFN) in driving the neuroinflammatory response in PD, with increased type-I IFN signatures reported in both PD patients and in animal models of the disease. This review will discuss 1) the key players that modulate the neuroinflammatory response in PD and their implications in the CNS 2) the contribution of the type-I IFNs in driving the neuroinflammatory response in PD, and 3) evidence for therapeutically targeting type-I IFN signalling to slow disease progression. A greater understanding of the underlying mechanisms that lead to the elevated neuroinflammatory response in PD could lead to new advances in therapeutic targets that effectively slow the disease progression. © 2025

关键词： Aplastic anemia   Hematopoietic stem cell transplantation   Haploidentical donor   Matched sibling donor  

摘要： Our study includes 278 patients aged between 40 and 50 years from 29 centers who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched sibling donors (MSDs) (n = 106) and haploidentical donors (HIDs) (n = 172) over the last decade. Univariate analysis revealed that HID recipients was associated with more serious disease severity, a delayed allo-HSCT after diagnosis, a higher pretransplant transfusion burden and poor performance status pre-transplant than MSD recipients in clinical settings. After these pretransplant clinical factors were well balanced following propensity score-matching (PSM), 80 matched pairs were selected for further analysis. Following PSM, the cumulative incidences of neutrophil were comparable between two matched groups (P = 0.14), while the 100-day engraftment rates of platelet were significant lower in HID-HCT (P < 0.001);The HID cohort showed higher cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) compared with MSD group (P = 0.04). In contrast, the incidence of severe (grade III-IV) acute GVHD and chronic GVHD were not statistically significant (severe acute GVHD P = 0.10;chronic GVHD P = 0.28). Our study observed comparable overall survival (OS) (P = 0.14);failure free survival (FFS) (P = 0.23);GVHD-free/relapse-free survival (GRFS) (P = 0.26) between matched HID and MSD recipients. In conclusion, our data indicates that allo-HSCT from an HID could be considered for SAA patients between 40 and 50 years old who do not have an MSD.

关键词： 颅脑损伤   白介素1β   超氧化物歧化酶   还原型谷胱甘肽   预后  

摘要： 目的探讨白介素1β(IL-1β)、超氧化物歧化酶(SOD)、还原型谷胱甘肽(GSH)与创伤性颅脑损伤(TBI)患者肠道屏障功能的关系及其对患者预后不良的预测价值。方法回顾性选取2022年8月—2024年8月南京鼓楼医院集团宿迁医院收治的114例TBI患者为研究对象,收集患者的临床资料,检测肠道屏障功能指标〔二胺氧化酶(DAO)、D-乳酸〕及IL-1β、SOD、GSH。随访6个月根据格拉斯哥预后评分(GOS)将患者分为预后良好组(79例)和预后不良组(35例)。采用Pearson相关分析探讨TBI患者IL-1β、SOD、GSH与DAO、D-乳酸的相关性;采用多因素Logistic回归分析探讨TBI患者预后的影响因素;采用ROC曲线探讨IL-1β、SOD、GSH及三者联合对TBI患者预后不良的预测价值。结果预后不良组与预后良好组严重程度、DAO、D-乳酸、IL-1β、SOD、GSH比较,差异有统计学意义(P<0.05)。Pearson相关分析结果显示,TBI患者IL-1β与DAO、D-乳酸呈正相关,SOD、GSH与DAO、D-乳酸呈负相关(P<0.05)。多因素Logistic回归分析结果显示,严重程度〔OR=4.311,95%CI(1.490~12.472)〕、DAO〔OR=1.281,95%CI(1.084~1.513)〕、D-乳酸〔OR=5.650,95%CI(1.637~19.499)〕、IL-1β〔OR=5.172,95%CI(2.046~13.070)〕、SOD〔OR=0.613,95%CI(0.479~0.783)〕、GSH〔OR=0.104,95%CI(0.032~0.338)〕是TBI患者预后的独立影响因素(P<0.05)。ROC曲线分析结果显示,IL-1β、SOD、GSH及三者联合预测TBI患者预后不良的AUC分别为0.771〔95%CI(0.674~0.869)〕、0.813〔95%CI(0.728~0.899)〕、0.794〔95%CI(0.699~0.889)〕、0.902〔95%CI(0.839~0.965)〕。结论TBI患者IL-1β、SOD、GSH与肠道屏障功能相关。IL-1β、SOD、GSH是TBI患者预后的独立影响因素,且三者联合对TBI患者预后不良有较好的预测价值。

关键词： IL-6 receptor   Curcumin   ADAM10   Shedding   Membrane domain  

摘要： Proteolytic cleavage and release of single-spanning transmembrane receptors, a process called shedding, is vital for normal physiological functions and pathological responses, including inflammation and cancer. Interleukin-6 receptor (IL-6R) is one of the principal single-spanning transmembrane receptors expressed in hepatocytes and subpopulations of leukocytes, including monocytes and macrophages. Soluble IL-6R (sIL-6R) is also present in human plasma. Herein, we report that membrane-modulating agents including curcumin, enhance IL-6R shedding in human monocytes via a mechanism involving a disintegrin and metalloprotease 10 (ADAM10). Furthermore, amphiphilic derivatives of turmeric curcuminoids increased sIL-6R levels in culture supernatants and altered the membrane domains formed on giant vesicles. These findings offer insights into the mechanism underlying the induction of ectodomain cleavage of IL-6R and ascertain the function of liberated sIL-6R. They can provide a novel strategy to develop therapeutic intervention using membrane-active compounds, such as curcuminoids, for diseases such as inflammation and cancer.

关键词： Dexamethasone   Roflumilast   Phosphodiesterase-4   Inflammatory pathway  

摘要： Introduction: High-dose dexamethasone (DEX) is used for management of severe conditions. However, the multisystem adverse effects induced by glucocorticoids represent a hindering stone toward the effective clinical use of such agents. Various initiatives have been taken to ameliorate these complications with limited success. Aim: The present study aims to explore the beneficial effects of roflumilast (ROF), a phosphodiesterase-4 (PDE-4) inhibitor, to combat DEX-induced steatohepatitis, metabolic abnormalities and aortic degeneration. Results: The application of ROF (2.5 and 5 mg/kg) has reverted the hepatic and aortic histopathological abnormalities as well as the rise in serum liver enzymes induced by DEX. Such palliative effect is probably attributed to PDE-4 inhibition (tcAMP) that subsequently regulates multiple effectors. The chemotaxis of inflammatory cells (MCP-1) was inhibited by ROF treatments which was linked to inhibition of extracellular ROS production (MDA and NO) as well as restoration of cellular antioxidant defense (GSH). DEX challenge was associated with activation of the inflammatory pathways including TNF-alpha/NF-kappa B and NLRP3/IL-1(3 that were significantly dampened in the ROF groups. The oxidative stress as well as activation of inflammatory pathways exerted by DEX has contributed to the activation of endoplasmic reticulum stress (CHOP and PERK) posing more threats to the insulted cells, however, fortunately, ROF treatments showed inhibited activation of ER stress sensors and thereby abstaining the cells from inevitable damage. The metabolic abnormalities induced by DEX including elevated fasting insulin and heightened AUC of blood glucose level upon application of oral glucose tolerance test were significantly improved by ROF treatment. Conclusion: The findings of our study depicted the hepatoprotective and metabolic regulating potentials of ROF in a rat model of DEX- induced steatohepatitis. Thereby, enhancing the overall efficacy and safe