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关键词： 妊娠糖尿病   山柰酚   白细胞介素-6   信号转导与转录激活子3   炎症   胰岛素抵抗  

摘要： 目的探讨山柰酚(kaempferol,Kpf)调节白细胞介素-6(interleukin-6,IL-6)/信号转导与转录激活子3(signal transducer and activator of transcription 3,STAT3)信号通路对妊娠糖尿病(gestational dia-betes mellitus,GDM)大鼠炎症反应的影响。方法雌雄同笼与高脂高糖喂养联合腹腔注射链脲佐菌素(streptozotocin,STZ)构建GDM大鼠模型,将造模成功大鼠按照随机数字表达分为Model组、Kpf低、中、高剂量组、激活剂组(IL-6/STAT3通路激活剂rIL-6),每组12只,同批12只妊娠大鼠作为control组,各组腹腔注射相应药物,每天1次,直到妊娠19 d。罗氏血糖仪测量大鼠空腹血糖(fasting blood glucose,FBG);分析各组大鼠妊娠结局;ELISA法测定大鼠血清空腹胰岛素(fasting insulin,FINS)及胎盘中白细胞介素(interleukin,IL)-6、IL-1β、肿瘤坏死因子(tumor necrosis factor-α,TNF-α)水平;苏木精伊红(hematoxylin-eosin,HE)染色观察大鼠胎盘组织中病理损伤;TUNEL染色检测胎盘组织细胞凋亡;蛋白质印迹测定胎盘中IL-6/STAT3通路蛋白表达。结果与control组比较,Model组大鼠FBG、FINS、HOMA-IR、胎鼠质量、IL-6、IL-1β、TNF-α水平、胎盘组织IL-6、p-STAT3/STAT3水平及细胞凋亡率增加,活胎率、窝产子数下降(P<0.05);相较于Model组,Kpf低、中、高剂量组大鼠FBG、FINS、HOMA-IR、胎鼠质量、IL-6、IL-1β、TNF-α水平、胎盘组织IL-6、p-STAT3/STAT3水平及细胞凋亡率下降,活胎率、窝产子数增加(P<0.05);相较于Kpf高剂量组,激活剂组上述指标变化均显著逆转(P<0.05)。结论Kpf可能通过抑制IL-6/STAT3信号通路降低GDM大鼠胎盘炎症,减轻胰岛素抵抗。

关键词： Keywords   Diabetic cardiomyopathy   Interleukin-1   Inflammation   Cytokines  

摘要： Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with diabetes and is characterised by contractile dysfunction and left ventricular hypertrophy. The complex pathological and physiological mechanisms underlying DCM have contributed to a limited number of available treatment options. A substantial body of evidence has established that DCM is a low-grade inflammatory cardiovascular disorder, with the interleukin-1 (IL-1) family of cytokines playing crucial roles in initiating inflammatory responses and shaping innate and adaptive immunity. In this review, we aim to provide an overview of the underlying mechanisms of the IL-1 family and their relevance in DCM of various aetiologies. Furthermore, we highlighted potential therapeutic targets within the IL-1 family for the management of DCM.

关键词： Mammals  

摘要： Type 3 Innate lymphoid cells (ILC3s) functions bear complex response during Inflammatory bowel diseases (IBD). Here, our study first analyzed the main pharmacological components in Shen Ling Bai Zhu San n-butanol extracts (S-Nb), and then explored whether S-Nb administrated immune response of ILC3s, and how it regulates ILC3s. Shen Ling Bai Zhu San (SLBZS) or S-Nb were administrated for 7 days to analyze the frequency of ILC3s and their produced cytokine. Using siRNA technology to knock down the expression of period circadian clock 2 (Per2) and period circadian clock 3 (Per3) and Anti-IL-22 antibody was supplied to mice, then detecting the moderator effect of S-Nb on colitis. The most class of S-Nb is flavonoids, with a content of approximately 48%. Oral administration of S-Nb enhanced the production of NCR+ILC3s and IL-22 produced by ILC3s, but did not alter IL-17A. Surprisingly, knocking down the expression of Per3 instead of Per2 inhibited the modulation effect of S-Nb on colitis and reduced IL-22 production, whether originating from NCR+ILC3s or NCR−ILC3s. After neutralizing the expression of IL-22 in mice, S-Nb was deprived of ability to alleviate colitis. The reason why S-Nb alleviates colitis is by enhancing the expression of Per3 via flavonoids, which in turn promotes the secretion of IL-22+ILC3s in intestine. © 2024 Elsevier B.V.

关键词： Malaria   Collagen-induced arthritis   Interleukin-10   Autoimmunity   Plasmodium yoelii 17XNL  

摘要： We previously reported that Plasmodium yoelii 17XNL (Py), a non-lethal rodent malarial parasite, could suppress collagen-induced arthritis (CIA) and increase the production of T cell-derived interleukin (IL)-10. However, it remained unclear whether IL-10 is essential for the Py-induced suppression of CIA. Male IL-10 knockout (KO) DBA/1 J mice were immunized with bovine type II collagen (CII) and subsequently infected with Py at one week post-immunization. The development of arthritis was evaluated by an arthritis score up to 6 weeks postimmunization. At 3 weeks post-immunization, cytokine production from splenocytes and serum anti-CII IgG/ IgG1/IgG2a levels were compared between non-infected control mice and Py-infected mice. Py infection inhibited the development of CIA in IL-10KO mice until 4 weeks post-immunization, after which the arthritis score reached levels comparable with the control mice. Both pro-arthritic (IL-17 and TNF-alpha) and anti-arthritic (IFN-gamma and IL-4) cytokines were down-regulated during the periods of parasitemia, while no significant differences were observed in levels of anti-CII IgG antibodies. Our findings indicate that Py alleviates CIA via IL-10independent mechanisms.

关键词： Lead   Mice   Hippocampus   TNF-R1-RIPK1/RIPK3   Necroptosis  

摘要： Lead (Pb), a dense, soft, blue-gray metal, is widely used in metallurgy, cables, storage batteries, pigments, and other industrial applications. Pb has been shown to cause degenerative changes in the nervous system. Necroptosis, a form of non-apoptotic programmed cell death modality, is closely associated with neurodegenerative diseases. Whether the TNF-R1-RIPK1/RIPK3 pathway is involved in the neurodegeneration induced by Pb has yet to be determined. Here, we explored the role of the TNF-R1-RIPK1/RIPK3 signaling pathway in the Pb-induced necroptosis by using HT-22 cells, primary mouse hippocampal neurons, and C57BL/6 mice models, demonstrating that Pb exposure elevated lead levels in murine whole blood and hippocampal tissue in a dose-response relationship. Protein expression levels of PARP, c-PARP, RIPK1, p-RIPK1, RIPK3, MLKL, and p-MLKL in the hippocampal tissues were elevated, while the protein expression of caspase-8 was decreased. Furthermore, Pb exposure reduced the survival rates in HT-22 cells and primary mouse hippocampal neurons, while increasing the protein expressions of RIPK1 and p-MLKL. Collectively, these novel findings suggest that the TNF-R1/RIPK1/RIPK3 signaling pathway is associated with Pb-induced neurotoxicity in hippocampal neurons in mice.

关键词： Cytomegalovirus   Inflammation   Cytokines   Atherosclerosis   Myocardial infarction  

摘要： Background: Efforts to understand atherosclerosis, a major cause of ischemic heart disease, have linked several lifestyle factors to increased risk for developing cardiovascular disease. Some studies suggest that cytomegalovirus (CMV), a widely prevalent herpesvirus, is reactivated in atherosclerotic plaques and associated with higher cardiovascular mortality risk. We aimed to explore whether CMV seropositivity and CMV-IgG antibody levels correlate with relevant biomarkers in a cohort of patients with myocardial infarction (MI) and matched controls.
Methods and results: We analyzed a dataset from 324 survivors of MI treated in Stockholm between 1996 and 2001. Blood samples collected three months after MI were used to measure protective Apo B100 autoantibodies, metabolic, and inflammatory biomarkers. CMV serology was performed on stored serum samples. Correlation analyses were conducted between biomarkers and CMV serostatus in 324 patients and age- and sex-matched controls. While CMV seroprevalence was equal, the CMV-IgG levels were higher in controls. Among various factors examined, CMV seropositive MI patients had elevated levels of plasminogen activator inhibitor-1 (PAI-1) and interleukin-6, along with lower levels of MMP-3, than CMV seronegative MI patients. CMV-IgG levels correlated positively with PAI-1 levels in patients. Although CMV seropositivity was associated with increased proinsulin levels, there was no correlation with diabetes diagnosis.
Conclusions: Our findings suggest an enhanced inflammatory and prothrombotic state in CMV seropositive patients after MI. Notably, patients had lower levels of CMV IgG than controls.

关键词： PF   IL   ECM   AECs  

摘要： Pulmonary fibrosis (PF) is a progressive, irreversible disease characterized by heterogeneous interstitial lung tissue damage. It originates from persistent or repeated lung epithelial injury and leads to the activation and differentiation of fibroblasts into myofibroblasts. Interleukins (ILs) are a group of lymphokines crucial for immunomodulation that are implicated in the pathogenesis of PF. However, different types of ILs exert disparate effects on PF. In the present review, based on the effect on PF, ILs are classified into three categories: i) Promotors of PF;ii) inhibitors of PF;and iii) those that exert dual effects on PF. Several types of ILs can promote PF by provoking inflammation, initiating proliferation and transdifferentiation of epithelial cells, exacerbating lung injury, while other ILs can inhibit PF through suppressing expression of inflammatory factors, modulating the Th1/Th2 balance and autophagy. The present review summarizes the association of ILs and PF, focusing on the roles and mechanisms of ILs underlying PF.

关键词： miR-128-3p   IL-8   Hypoxia   HIF-1 alpha   Temozolomide (TMZ)   Glioblastoma multiforme (GBM)  

摘要： Glioblastoma multiforme (GBM) is an aggressive type of brain tumor known for its hypoxic microenvironment. Understanding the dysregulated mechanisms in hypoxic GBM is crucial for its effective treatment. Through data mining of The Cancer Genome Atlas (TCGA) with hypoxia enrichment scores and in vitro experiments, miR-1283p was negatively correlated with hypoxia signaling and the epithelial-mesenchymal transition (EMT). Additionally, lower miR-128-3p levels existed in hypoxic GBM, leading to desensitizing temozolomide (TMZ)'s efficacy, a first-line therapeutic drug for GBM. Overexpressing miR-128-3p enhanced both the in vitro and in vivo sensitivity of hypoxic gliomas to TMZ treatment. Mechanistically, HIF-1 alpha suppressed miR-128-3p expression in hypoxic GBM. Through establishing miR-128-3p-mediated transcriptomic profiles and data mining, interleukin (IL)-8 was selected. IL-8 respectively showed positive and negative correlations with hypoxia and miR-128-3p, and was associated with poor TMZ therapeutic results in GBM. Elevated miR-128-3p, which targets both the 3 '-untranslated region (UTR) and 5 ' UTR of IL-8, resulted in suppression of IL-8 expression. Moreover, IL-8 was validated to be involved in HIF-1 alpha/miR-128-3p-regulated TMZ sensitivity and the EMT in hypoxic GBM cells. Collectively, the HIF-1 alpha/miR-128-3p/IL-8 signaling pathway plays a critical role in promoting the progression of hypoxic GBM. Targeting this signaling pathway holds promise as a potential therapeutic strategy.

关键词： ciliary neurotrophic factor   astrocytes   IL-6/IL-6R   neuroinflammation   neuron  

摘要： The occurrence of epilepsy is a spontaneous and recurring process due to abnormal neuronal firing in the brain. Epilepsy is understood to be caused by an imbalance between excitatory and inhibitory neurotransmitters in the neural network. The close association between astrocytes and synapses can regulate the excitability of neurons through the clearance of neurotransmitters. Therefore, the abnormal function of astrocytes can lead to the onset and development of epilepsy. The onset of epilepsy can produce a large number of inflammatory mediators, which can aggravate epileptic seizures, leading to a vicious cycle. Neurons and glial cells interact to promote the onset and maintenance of epilepsy, but the specific underlying molecular mechanisms need to be further studied. Ciliary neurotrophic factor (CNTF) belongs to the IL-6 cytokine family and is mainly secreted by astrocytes and Schwann cells. In the normal physiological state, CNTF levels are low, but in an epileptic state, CNTF levels in the serum and tears of patients are elevated. Astrocyte activation plays an important role in epileptic seizures. CNTF activates astrocytes to produce a variety of secreted proteins, which are secreted into the astrocyte culture medium (ACM), thus forming a distinct culture medium (CNTF-ACM) that can be used to study the effect of astrocytes on neurons in vitro. CNTF-activated astrocytes increase the secretion of the pro-inflammatory factor IL-6. In the present study, CNTF-ACM was applied to primary cerebral cortical neurons to observe the specific effects of IL-6 in CNTF-ACM on neuronal activity and excitability. The results suggested that CNTF-ACM can reduce neuronal activity via the IL-6/IL-6R pathway, promote neuronal apoptosis, increase Ca2+ inflow, activate the large conductance calcium-activated potassium channel and enhance neuronal excitability. The results of the present study further revealed the functional changes of astrocytes after CNTF activated astrocytes and the e

关键词： ESKAPE   HLA   Hypothetical proteins   Multi-epitope   P. aeruginosa  

摘要： ObjectivesPseudomonas aeruginosa, identified as an ESKAPE pathogen, contributes to severe clinical diseases worldwide and despite its prevalence an effective vaccine or treatment remains elusive. Numerous computational methods are being employed to target hypothetical proteins (HPs). Presently, no studies have predicted multi-epitope vaccines for these ***, 877 HPs from P. aeruginosa were included in the study and the data showcased here illustrate a methodical approach to prioritize the proteome by employing diverse comparative proteomics. The study employed physicochemical property assessment and conserved domain analysis to identify stable and immunologically pertinent proteins for epitope prediction. The VaxiJen2.0 antigenicity assessment aided in epitope selection, contributing to the foundational steps in vaccine development by predicting T-cell and B-cell epitopes. Potential T and B cell epitopes with high antigenicity, non-toxic categorization, and robust binding affinities were identified in the investigation. The periplasmic HP WP_132813935.1 was predicted as conserved, stable, and soluble. The T-cell peptide RTSMRALAY and the B-cell peptide MPVYLYLM were predicted to be probable non-allergen and demonstrated strong binding with MHC class I allele HLA-C*03:*** research provides a comprehensive approach to predict T and B cell epitopes for conditions associated with P. aeruginosa, offering a candidate pool for tailored vaccine development. However, the efficacy of these epitopes in vaccine development necessitates clinical validation and testing for confirmation.