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关键词： Pancreatic cancer   Perineural invasion   Tissue engineering   Glia   Extracellular vesicles  

摘要： PurposePancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths, and perineural invasion (PNI), in which cancer cells infiltrate nerves, enables metastasis in most patients. PNI is largely attributed to Schwann cells (SC) that, when activated, accelerate cancer cell migration towards nerves. However, this cancer-associated reprogramming is generally under-appreciated. Additionally, tumor extracellular vesicle (EV) facilitation of cancer aggravation is well documented, but more investigation is required to better understand their role in PNI. Here, we assessed whether PDAC EVs mediate PNI via SC activation using tissue-engineered in vitro platforms and PANC-1 and HPNE human cell lines as ***, Luminex (R), and proteomic-pathway analyses characterized tumor (PANC-1) and healthy cell (HPNE) EVs. Human Schwann-like cells (sNF96.2) were embedded in decellularized nerve matrix hydrogels and then treated with EVs and a cargo-function-blocking antibody. Immunofluorescence and Luminex (R) multiplex assays assessed Schwann cell activation. Subsequently, sNF96.2 cells were co-cultured with EVs and either PANC-1 or HPNE cells;Transwell (R) invasion assays with SC-conditioned media were also conducted to establish a mechanism of in vitro ***-1 EVs contained higher levels of interleukin-8 (IL-8) signaling-associated proteins than HPNE EVs. Within nerve-mimetic in vitro testbeds, PANC-1 EVs promoted sNF96.2 activation per cytoskeletal marker alterations and secretion of pro-tumorigenic cytokines, e.g., chemokine ligand-2 (CCL2), via IL-8 cargoes. Furthermore, the IL-8/CCL2 axis heightened PANC-1 *** findings highlight the potential role of PDAC EVs in PNI, which necessitates continued preclinical assessments with increased biodiversity to determine the efficacy of targeting IL-8/CCL2 for PNI.

关键词： ILC   Pemphigus vulgaris   Autoimmunity   ILC1   ILC2   ILC3   Cytokines  

摘要： Innate Lymphoid cells (ILCs) are innate counterparts of helper T cells. Although low in number, they have proven to play major roles in many autoimmune diseases. In Pemphigus Vulgaris (PV), the gaps in the knowledge of functional role of ILCs remain. To bridge the gap, our study investigated the phenotype along with the functional determinants of ILCs involved in PV immunopathogenesis. Our data suggested augmentation in overall ILC population in circulation of PV patients. Specifically, ILC1 and ILC3 subtypes were significantly increased in peripheral circulation of PV patients compared to healthy controls. We observed no changes in ILC2 population. mRNAs from ILC enriched population showed significant upregulation in transcription factors- ID2, T bet and ROR gamma t and a downregulation in GATA3 and ROR alpha. The mRNA levels of ILC related cytokines- IFN gamma and IL17 were significantly upregulated while no change was observed in the levels of IL13, IL 22, AHR. The levels of autoantibodies against desmoglein (Dsg) 3 which is the characteristic of PV pathogenesis were also checked in the serum which confirmed significant upregulation in PV patients. The levels of proinflammatory- IFN gamma, IL 17 and IL 15 were elevated and anti-inflammatory cytokines- IL10 was downregulated in the serum of PV patients. The results of this study offer insights into the functional attributes of ILCs and related cytokines, potentially contributing to the development of future therapeutic interventions.

关键词： Newcastle Disease virus   Genotype-matched, DNA vaccine   Interferon lambda-3   IL-28b   Molecular adjuvant  

摘要： Newcastle disease virus (NDV) is an extremely contagious and deadly virus that affects numerous bird species, posing serious threats to poultry production on a global scale. In addition to implementing biosecurity practices in farming systems, vaccination remains the most effective means of controlling Newcastle disease (ND). However, while existing commercial vaccines provide some level of protection, the effectiveness of these vaccines can be questionable, particularly in field settings where the complexity of vaccination program implementation poses significant challenges, especially against virulent genotypes of NDV. A genotype-matched NDV DNA vaccine could potentially offer a more effective vaccination approach than currently available live attenuated vaccines. By being specifically tailored to match circulating strains, such a vaccine might improve efficacy and reduce the risk of vaccine failure due to genotype mismatch. To develop an alternative vaccine approach, two ND DNA vaccines were constructed in this study. Each vaccine developed in this study contains the fusion (F) and haemagglutinin-neuraminidase (HN) genes of a virulent NDV genotype VII isolate from Tanzania. Interferon lambda-3 (IFN lambda 3;IL-28b), which has demonstrated capacity to significantly enhance specific adaptive immune responses and decreased levels of inflammatory cytokines, as well as improved protective responses at a high viral challenge dose, was included in one of the developed vaccines. These plasmids were designated pTwist-F-HN-VII-IL28b and pTwist-F-HN-VII. The two plasmids differed in that pTwist-F-HN-VII-IL28b contained the cytokine adjuvant IL-28b. Transfection of cells and subsequent immunofluorescence assays indicated that both plasmids expressed high levels of NDV F-HN proteins. In vivo immunization demonstrated that chicks intramuscularly immunized with pTwist-F-HN-VII-IL28b exhibited significant immune responses compared to chicks immunized with pTwist-F-HN-VII or the

关键词： IL-21   IL-33   IL-24   IL-19   IBD  

摘要： Interleukins are potential therapeutic targets that can alter the prognosis and progression of inflammatory bowel disease (IBD). The roles of IL-6, IL-10, IL-17, and IL-23 have been extensively studied, setting the stage for the development of novel treatments for patients with IBD. Other cytokines have been less extensively studied. Members of the IL-20 family, mainly IL-19 and IL-24, are involved in the pathogenesis of IBD, but their exact role remains unclear. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of colonic Tregs in animal models of colitis and patients with IBD. IL-21 is involved in the Th1, Th2, and Th17 responses. Data support a promising future use of these interleukins as biomarkers of severe diseases and as potential therapeutic targets for novel monoclonal antibodies. This review aims to summarize the existing studies involving animal models of colitis and patients with IBD to clarify their role in the intestinal mucosa.

关键词： Brazil   HLA   HLA-DQB1   new allele   next-generation sequencing   Rio de Janeiro  

摘要： The novel HLA-DQB1*04:104 allele, first described in an individual from Brazil.

关键词： bergapten   NF-kappa B signaling pathways   phosphorylation   psoriasis  

摘要： Bergapten (BP) is a plant-derived furocoumarin that has a wide range of pharmacological effects. BP serves as a candidate amplifier in phototherapy against skin inflammation, such as psoriasis and atopic dermatitis. However, the anti-inflammatory role of BP remains elusive. We utilized IL-17A-stimulated keratinocyte line and imiquimod-challenged BALB/c mice to imitate psoriasis-like inflammation. Inflammatory phenotypes were determined by expressions of inflammatory genes and cytokines, histopathological changes and activities of nuclear factor-kappa B (NF-kappa B) pathway. An RNA-seq analysis of rodent skin was performed to explore possible mechanism lying behind. SiRNAs and antagonist (TMS) against cytochrome P450 family 1 subfamily B member 1 (CYP1B1) were subsequently used to determine the role of CYP1B1 in psoriasis pathogenesis in vitro and in vivo. Overexpression of CYP1B1 with lentivirus further validate therapeutic effect of BP. BP significantly suppressed activation of the NF-kappa B pathway by inhibiting p65 phosphorylation and improved the inflammatory phenotype both in vitro and in vivo. We revealed the key role of CYP1B1 in regulating the activation of the NF-kappa B signaling pathway. Knock-down with siRNAs significantly reduce the expression of inflammatory genes and cytokines. An intraperitoneal injection of TMS partially remediated IMQ-induced inflammation, mainly in terms of skin thickness. Overexpression of Cyp1b1 led to increased expression of the CYP1B1 protein and rescued the therapeutic effect of BP in vitro. This study revealed that BP suppressed expression of Cyp1b1 in keratinocytes and inhibited the activation of NF-kappa B signaling pathway by blocking the phosphorylation of p65.

关键词： COPD   IL13   Susceptibility   Stratified analyses   SNP-SNP  

摘要： Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation. Interleukin-13 (IL13), associated with T-helper type 2 cells, plays a crucial role in COPD pathophysiology. This study aimed to investigate the relationship of single nucleotide polymorphisms (SNPs) in IL13 to COPD risk. Methods: Five candidate SNPs of IL13 were genotyped using MassARRAY iPLEX platform in a cohort of472 COPD patients and 472 healthy controls. Logistic regression analysis was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs). Additionally, Multifactor dimensionality reduction (MDR) software was utilized to assess the combined impact of SNP-SNP interactions on COPD risk. Results: IL13 rs20541 (OR: 1.24, p: 0.028), rs1295685 (OR: 1.31, p: 0.006), rs848 (OR: 1.27, p: 0.016), and rs847 (OR: 1.30, p: 0.007) were associated with COPD risk. Moreover, IL13 variants were related to the increased COPD risk in females, individuals aged >= 68 year, non-smokers or non-drinkers. The optimal multi-locus model was identified as the combination of rs20541 and rs1295685. Conclusion: Our findings indicated the association between IL13 variants and an elevated risk of developing COPD, especially rs1295685 and rs847. These findings could have implications for understanding the role of IL13 variants in COPD predisposition.

关键词： bulevirtide   entry inhibitor   HDV   Hepcludex   Myrcludex B   pegylated interferon alfa  

摘要： Background and Aim: Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFN alpha-2a), with 24-week follow-up. Methods: Ninety patients were enrolled into six arms of 15 each (A-F);60 patients were included in the main randomisation (arms A-D), and 30 patients (arms E-F) were randomised to the extension phase: (A) Peg-IFN alpha-2a 180 mu g once weekly (QW);(B) BLV 2 mg once daily (QD) + Peg-IFN alpha-2a 180 mu g QW;(C) BLV 5 mg QD + Peg-IFN alpha-2a 180 mu g QW;(D) BLV 2 mg QD;(E) BLV 10 mg QD + Peg-IFN alpha-2a 180 mu g QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72. Results: At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log(10) IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment. Conclusions: BLV combined with Peg-IFN alpha-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment. Trial Registration: NCT02888106

关键词： Shen Ling Bai Zhu San   Flavonoids   IL-22   Type 3 innate lymphoid cells   Period circadian clock 3   Circadian rhythm  

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 IL22+ILC3s in intestine.

关键词： IL-6   Cytokine storm   Suppressive effect   Isofraxidin   MAPK/ERK pathway  

摘要： Interleukin-6 (IL-6) is a pleiotropic cytokine that has many biological activities, including inflammation, hematopoiesis, bone metabolism, embryonic development, and other fundamental processes. Recently, IL-6 has been widely recognized as an important pro-inflammatory cytokine involved in cytokine storm pathogenesis during severe inflammatory diseases, such as coronavirus disease 2019 (COVID-19). Therefore, IL-6 is considered to be a therapeutic target for inhibiting cytokine storm. In the present study, we investigated the suppressive effect of isofraxidin, a major coumarin compound of Acanthopanax senticosus, on the overexpression of IL-6 and its molecular mechanism. The expression of IL-6 mRNA was measured using quantitative real-time PCR, and intracellular signaling molecules were detected using western blotting. When the HuH-7 human hepatocellular carcinoma cell line and HepG2 human hepatoblastoma cell line were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA), a marked induction of IL-6 mRNA expression was observed in HuH-7 cells compared with HepG2 cells. Isofraxidin significantly suppressed TPA-induced IL-6 mRNA expression in HuH-7 cells in a dose-dependent manner. Furthermore, isofraxidin inhibited TPA-induced phosphorylation of ERK1/2 in a dose-dependent manner. Similarly, the MAPK/ERK inhibitor U0126 suppressed TPA-induced IL-6 mRNA expression. However, isofraxidin had no effects on TPA-induced phosphorylation of SAPK/JNK, Akt (Ser473), and STAT3 (Tyr705), nuclear translocation of NF-kappa B p65, and degradation of I kappa B. Taken together, isofraxidin suppresses TPA-induced overexpression of IL-6 mRNA by selectively inhibiting the activation of the MAPK/ERK pathway in HuH-7 cells, indicating that isofraxidin may be an effective anti-inflammatory agent for treating cytokine storm.