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关键词： Rhizoma Chuanxiong   Radix et Rhizoma Rhei   Transcriptomics   Proteomics   Contras-induced acute kidney injury   Experimental validation  

摘要： Background: Contrast-induced nephropathy (CIN), also known as contrast-induced acute kidney injury (CI-AKI), represents a prevalent form of hospital-acquired renal injury. However, the mechanisms underlying its pathogenesis remain unclear. Based on our previous research findings, the Dahuang Chuanxiong decoction (DCH), composed of Radix et Rhizoma Rhei (DH) and Rhizoma Chuanxiong (CX), has demonstrated efficacy for inhibiting CI-AKI by attenuating oxidative stress and apoptosis in renal tubular epithelial cells. Despite these findings, the detailed mechanisms underlying the renoprotective actions have not been thoroughly clarified. Purpose: The objective of this study was to screen potential targets and signaling pathways involved in inhibition of CI-AKI by DCH using multi-omics analysis and to verify whether the renoprotective mechanism of DCH is related to these identified targets or pathways through in vivo and in vitro experiments. Methods: Initially, we identified the components of DCH using UPLC-Q-TOF-MS. Transcriptomics and proteomics, combined with experimental validation, were used to further elucidate the molecular mechanisms of the herbal pair in CI-AKI treatment. A CI-AKI rat model was established, and the expression levels of proteins related to mitophagy and the IL-17 signaling pathway were detected in renal tissues using immunofluorescence, immunohistochemistry, and western blotting analysis to elucidate the nephroprotective effects of DCH. Additionally, siRNA was used in the HK-2 cell model to investigate the crosstalk between the mitophagy and IL-17 signaling pathways and the impact on apoptosis when these pathways were inhibited. Results: Multi-omics results revealed that the crucial signaling pathways involved were mitophagy, the MAPK signaling pathway, and the IL-17 signaling pathway. In vivo experiments indicated that contrast media (CM) led to an increase in AKI biomarkers, with upregulated expression of Parkin, BNIP3, IL-17, and p-NF-kappa B.

关键词： colorectal cancer   DMH   JAK2   linagliptin   rats   STAT3  

摘要： Colorectal cancer (CRC) is a multicomponent disease and the second most frequent root of cancer-related deaths globally. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It has been repurposed in recent experimental studies due to its marked anti-inflammatory activities. This study aimed to evaluate the ameliorative role of linagliptin in 1,2-dimethylhydrazine (DMH)-induced CRC via modulation of NFAT-mediated IL-6 and JAK2/STAT3/NF-kappa B signaling pathways. CRC model has been successfully established via a dose equal 40 mg/kg two times a week of DMH for 8-week duration. Twenty-four Wistar rats were segregated into three groups of eight rats each;normal control, DMH-induced CRC and DMH + linagliptin (10 mg/kg;p.o). Linagliptin attenuated DMH-induced oxidative stress by restoring the declined levels of some antioxidant enzymes. Linagliptin suppressed the elevated nuclear factor kappa B (NF-kappa B) induced by DMH which is highlighted using immunohistochemistry analysis. The anti-inflammatory role of linagliptin has been fortified by the decline in nuclear factor of activated T-cells (NFAT) mRNA expression level along with the reduction in vascular endothelial growth factor (VEGF), interlukin-6 (IL-6) and cyclooxygenase-2 (COX-2) levels. Linagliptin mitigate the protein expression of DMH-activated oncogenic janus-activated kinase/signal transducers and activators of transcription (JAK2/STAT3). Linagliptin exerted a proapoptotic effect to tumor cells manifested by a remarkable decline in B-cell lymphoma 2 (Bcl-2) and a significant elevation in Bcl-2-associated X protein (Bax) expression levels. The histopathological analysis revealed that linagliptin has inhibitory potential against the DMH induced dysplastic aberrant crypt foci (ACF) and adenocarcinoma. Linagliptin ameliorated CRC by modulating NFAT-mediated IL-6 with JAK2/STAT3/NF-kappa B signaling cascades.

关键词： Interleukins   IL-15   IL-22   IL-37   Caspase 9 gene   Polycystic Ovary Syndrome  

摘要： The study aims to evaluate the significant role of interleukin 15 (IL-15), IL-22, IL-37, and Caspase 9 gene expression in polycystic ovary syndrome (PCOS), focusing on the underlying mechanisms and potential diagnostic or therapeutic implications. Peripheral blood has been collected, and serum was separated for the evaluation of the serum IL-15, IL-22, and IL-37. The ELISA technique has been carried out to determine the serum levels of understudied factors mentioned above in Iraqi women patients diagnosed with PCOS (No. = 90) via a specialized gynecologist and healthy fertile women (No. = 48) as a control group. In addition, a genetic study on the expression of the caspase 9 gene in these patients had been performed. The data reveals statistically significant differences in interleukin levels in PCOS patients versus the control group. Specifically, the PCOS group exhibits significantly higher levels of IL-15 and IL-22 as compared to the control group. Conversely, the PCOS group shows significantly lower levels of IL-37 compared to the control group. The results showed no statistically significant difference in the mean expression of the Caspase 9 gene when comparing these fold graduations. However, it's worth noting that a higher fold frequency was observed in both the PCOS and control groups, with 57.1 % and 60 %, respectively, having folds less than 1. The distribution of folds varied across other categories was also addressed. Additionally, there was a notable difference in the frequency of 11.4 % in the PCOS group compared to 2 % in the control group for folds greater than 9. The findings suggest that interleukins, particularly IL-22 and IL-37, hold promise as diagnostic markers for distinguishing PCOS from healthy conditions. However, the potential diagnostic utility of the Caspase 9 gene expression was not confirmed in this study.

关键词： Rheumatoid arthritis   IL-6 receptor   Janus kinase (JAK)   Signal transducer and activator of transcription   (STAT)   Preferential inhibition  

摘要： Interleukin-6 (IL-6) is a relevant cytokine in rheumatoid arthritis (RA) pathogenesis, potentially activating Janus kinases (JAK)-1, -2, and tyrosine kinase 2 (TYK2), and thus, three signal transducer and activator of transcription (STAT)-1, -3 or - 5 pathways. This pilot study aims to explore differences in phosphorylated (p)STAT3 levels among patients with RA, those not classified as RA (nRA), and healthy donors (HD), providing some clues on the relative contribution of each JAK protein to the downstream of the IL-6-induced STAT3 pathway. Clinical data and blood samples from 80 subjects (41 RA, 14 nRA, and 25 HD) were collected. The activity of the JAKSTAT3 pathway was assessed by Western Blot and Real Time-PCR analysis for the quantification of STAT3 in peripheral blood mononuclear cells (PBMC). Furthermore, the impact of JAK-1, -2, and TYK2 inhibitors on pSTAT3 was assessed in vitro by FACS, with and without IL-6 stimulation in RA patients na & iuml;ve to treatment with DMARD and steroids. The pSTAT3 (%) was significantly higher in PBMC from RA compared to nRA patients and HD. Furthermore, pSTAT3 (%) was significantly associated with inflammation and disease activity (ESR, CRP, and DAS28). The JAK-1 inhibitor was more effective in reducing pSTAT3 expression in CD14pos cells of RA patients, while the JAK-2 selective compound was more effective in CD4pos cells of RA patients. On the contrary, the TYK2 selective agent showed no significant effects. This study highlights the importance of the JAK/STAT3 pathway in RA. Some differences among various JAK proteins have been pointed out, with JAK1 and JAK2 standing as the most relevant mediators of the STAT3 pathway in this in-vitro model after IL-6R activation.

关键词： Obstructive sleep apnea   Lung transplantation   Serum markers   ELISA  

摘要： PurposeTo analyze the correlation between obstructive sleep apnea (OSA) and hypoxia-inducible factor (HIF)-1, interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) in patients complicated with OSA after lung transplantation. To identify serum markers of OSA after lung transplantation. MethodsWe retrospectively selected patients who planned to undergo lung transplantation between 2018 and 2020, including 25 without OSA before lung transplantation (group A), 20 with OSA after lung transplantation (group B), and 15 patients without OSA after lung transplantation (group C). Sleep monitoring was performed, general information collection and hematological samples were collected. HIF-1, IL-6 and iNOS were detected by ELISA. ResultsGroup B were older [59.2 +/- 10.1 (B) vs. 49.8 +/- 15.1 (A), 58.2 +/- 3.3 (C), yrs.], had a bigger neck circumference [38.1 +/- 4.7 (B) vs. 34.6 +/- 4.2 (A),35.7 +/- 4.2 (C), cm], and a greater abdominal circumference [88.2 +/- 12.5 (B) vs. 76.2 +/- 7.9 (A), 82.5 +/- 6.5 (C), cm] compared with Groups A and C (P < 0.05). iNOS in group B (4784.8 +/- 1365.2 (B) vs. 1925.2 +/- 1868.5 (A), 2838.7 +/- 3015.5 (C), pg/mL) was significantly increased compared to groups A and C (P < 0.05). iNOS was positively correlated with AHI. ConclusionsiNOS is significantly increased in OSA after lung transplantation, and maybe an important indicator of OSA.

关键词： Lysophosphatidic acid   Porcine skin-derived stem cells   Tumor necrosis factor alpha   Cryopreservation   Apoptosis  

摘要： Preserving the viability and functionality of stem cells during cryopreservation is crucial for their successful application in regenerative medicine. The aim of this study is to investigate the effect of lysophosphatidic acid (LPA) on reducing the apoptosis of cryopreserved porcine skin-derived stem cells (pSDSCs). Our findings revealed that LPA, at a concentration of 5 mu M, significantly improved viability and reduced apoptosis in cryopreserved pSDSCs. Furthermore, our data indicated that LPA enters pSDSCs through receptor type 1 (LPAR1). In cryopreserved pSDSCs, after LPA treatment, the expression level of tumor necrosis factor alpha (TNF-alpha) protein decreased, suggesting TNF-alpha involvement in the regulation of the anti-apoptotic process. Additionally, we found that resiquimod (R848), a TNF-alpha activator, increased the level of apoptosis in cryopreserved pSDSCs. When cryopreserved pSDSCs were treated with both LPA and R848, the protective effect of LPA against apoptosis was decreased. In conclusion, our study demonstrates that LPA could effectively counteract the effect of TNF alpha-induced apoptosis, thereby enhancing the survival rates of cryopreserved pSDSCs. Importantly, this study explored a novel mechanism of reducing apoptosis in cryopreserved stem cells.

关键词： cloning   HLA-A*02:07:08   long-range PCR   novel allele   Sanger sequencing  

摘要： The full genomic sequence shows HLA-A*02:07:08 differs from HLA-A*02:07:01:01 only at position 131 in exon 3.

关键词： Oropouche   Immunoinformatics   Vaccinology reverse   Multi-epitope  

摘要： In recent years, Brazil has recorded approximately 500,000 Oropouche virus (OROV) cases in the Amazon region, underscoring the growing global threat posed by emerging and reemerging viruses. Symptoms of OROV closely resemble those of Dengue virus and Zika virus, contributing to underreporting and underestimation of its true impact. In the absence of specific treatments, the development of vaccines becomes essential. This study aimed to identify immunogenic epitopes in three structural proteins of OROV and develop a multi-epitope vaccine candidate. RefSeq sequences of the nucleocapsid protein and the Gn and Gc glycoproteins were obtained from the National Center for Biotechnology Information Virus and submitted to epitope search in Immune Epitope Database. Antigenicity, allergenicity, stability, and toxicity analyses were conducted, and the approved epitopes were aligned to the global protein to remove transmembrane regions and N-glycosylation sites. Thirteen epitopes were selected and used to construct a multi-epitope vaccine candidate, with beta-defensin and PADRE adjuvants. The protein demonstrated optimal antigenicity, low allergenicity, and satisfactory stability and solubility. Predictions of humoral and cellular immune responses were performed, indicating satisfactory results for three doses of the vaccine candidate. 3D modeling of the protein was performed, evaluating the molecular docking of the multi-epitope protein with TLR-2, TLR-3, TLR-6, and TLR-8 receptors. Our findings present a promising vaccine candidate against OROV, potentially protecting immunocompromised individuals and high-risk populations, and establishing a foundation for both in vitro and in vivo testing. The identified epitopes could also aid in immunodiagnostic test development, advancing surveillance and control strategies.

关键词： AVL9   Chemoresistance   NF-κB   KPC   PDAC   AG   gemcitabine combined with albumin-paclitaxel (Abraxane)   AUC   area under the curve   ChIP   chromatin immunoprecipitation   dCDA   dCyd deaminase   dCK   dCyd kinase   DEGs   differentially expressed genes   FNA   fine-needle aspiration   GEM   gemcitabine   HRE   hypoxia response element   IC50   half maximal inhibitory concentration   IFN   interferon   IHC   immunohistochemistry   IKK   inhibitor of kappa B kinase   IκB   inhibitory-κB   KPC   Kras G12D Trp53 R172H Pdx1-Cre   KPCA   Kras G12D Trp53 R172H Pdx1-Cre AVL9 fl/fl   mRNA   messenger RNA   NF-κB   nuclear factor–κB   p-   phosphorylated   PCA   principal components analysis   PDAC   pancreatic ductal adenocarcinoma   PDO   patient-derived organoid   PDX   patient-derived xenograft   scRNA-seq   single cell transcriptomic sequencing   SKP1   S-Phase Kinase Associated Protein 1   TCGA   The Cancer Genome Atlas   tSNE   t-distributed stochastic neighbor embedding  

摘要： BACKGROUND & AIMS: Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen. METHODS: We used organoid models, patient-derived xenografts, and genetically engineered mouse models in our study. Chromatin immunoprecipitat ion, double luciferase assay, coimmunoprecipitation, and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in patient-derived xenografts, patient-derived organoids-based xenograft, and KPC models. RESULTS: Through multistrategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1a, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IkBa to SKP1, leading to enhanced ubiquitination and degradation of IkBa, which further activates the nuclear factor-kB pathway. The potential AVL9targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC. CONCLUSION: AVL9 expression is driven by HIF-1a in PDAC. The physical interaction of AVL9, IkBa, and SKP1 provides a novel molecular mechanism for the abnormal activation of the nuclear factor-kB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.