Anti-Inflammatory Properties of the Citrus Flavonoid Diosmetin: An Updated Review of Experimental Models.

Inflammation is an essential contributor to various human diseases. Diosmetin (3',5,7-trihydroxy-4'-methoxyflavone), a citrus flavonoid, can be used as an anti-inflammatory agent. All the information in this article was collected from various research papers from online scientific databases such as PubMed and Web of Science. These studies have demonstrated that diosmetin can slow down the progression of inflammation by inhibiting the production of inflammatory mediators through modulating related pathways, predominantly the nuclear factor-κB (NF-κB) signaling pathway. In this review, we discuss the anti-inflammatory properties of diosmetin in cellular and animal models of various inflammatory diseases for the first time. We have identified some deficiencies in current research and offer suggestions for further advancement. In conclusion, accumulating evidence so far suggests a very important role for diosmetin in the treatment of various inflammatory disorders and suggests it is a candidate worthy of in-depth investigation.

The Glycine soja cytochrome P450 gene GsCYP82C4 confers alkaline tolerance by promoting reactive oxygen species scavenging.

Recent studies have demonstrated the crucial role of Cytochrome P450 enzymes (CYPs) in the production of secondary metabolites, phytohormones and antioxidants in plants. However, their functional characterization specifically under alkaline stress remains elusive. CYP82C4 was the key gene screened from a family of wild soybean CYPs in our previous studies. The aim of this present study was to clone the Glycine soja GsCYP82C4 gene and characterize its functions in Arabidopsis and Glycine max. The results showed that the GsCYP82C4 gene displayed a high expression in different plant tissues at mature stages compared to young stages. Further, higher temporal expression of the GsCYP82C4 gene was noted at 6, 12 and 24 h time points after alkali treatment in leaves compared to roots. In addition, overexpression of GsCYP82C4 improved alkaline stress tolerance in Arabidopsis via increased root lengths and fresh biomass and strengthened the antioxidant defense system via a reduction in superoxide radicals in transgenic lines compared to wild type (WT) and atcyp82c4 mutants. Further, the expression levels of stress-related marker genes were up-regulated in GsCYP82C4 OX lines under alkali stress. The functional analysis of GsCYP82C4 overexpression in soybean displayed better hairy root growth, increased fresh weight, higher antioxidant enzyme activities and reduced lipid peroxidation rates in OX lines compared to the soybean WT (K599) line. In total, our study displayed positive roles of GsCYP82C4 overexpression in both Arabidopsis and Glycine max to alleviate alkaline stress via altering expression abundance of stress responsive genes, stronger roots, higher antioxidant enzyme activities as well as reduced rates of lipid peroxidation and superoxide radicals.

Prognostic value of CYFRA 21 - 1 and Ki67 in advanced NSCLC patients with wild-type EGFR.

BACKGROUND: The prognostic value of cytokeratin 19 fragment (CYFRA 21 - 1) and Ki67 in advanced non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) remains to be explored. METHODS: In this study, 983 primary NSCLC patients from January 2016 to December 2019 were retrospectively reviewed. Finally, 117 advanced NSCLC patients with wild-type EGFR and 37 patients with EGFR mutation were included and prognostic value of CYFRA 21 - 1 and Ki67 were also identified. RESULTS: The patients age, smoking history and the Eastern Corporative Oncology Group (ECOG) performance scores were significantly different between CYFRA21-1 positive and negative groups (p < 0.05), while no significant differences were found in Ki67 high and low groups. The results of over survival (OS) demonstrated that patients with CYFRA21-1 positive had markedly shorter survival time than CYFRA21-1 negative (p < 0.001, For whole cohorts; p = 0.002, For wild-type EGFR). Besides, patients with wild-type EGFR also had shorter survival times than Ki67 high group. Moreover, In CYFRA 21 - 1 positive group, patients with Ki67 high had obviously shorter survival time compared to patients with Ki67 low (median: 24vs23.5 months; p = 0.048). However, Ki67 could not be used as an adverse risk factor for patients with EGFR mutation. Multivariate cox analysis showed that age (HR, 1.031; 95%CI, 1.003 ~ 1.006; p = 0.028), Histopathology (HR, 1.760; 95%CI,1.152 ~ 2.690; p = 0.009), CYFRA 21 - 1 (HR, 2.304; 95%CI,1.224 ~ 4.335; p = 0.01) and Ki67 (HR, 2.130; 95%CI,1.242 ~ 3.652; p = 0.006) served as independent prognostic risk factor for advanced NSCLC patients. CONCLUSIONS: Our finding indicated that CYFRA 21 - 1 was an independent prognostic factor for advanced NSCLC patients and Ki67 status could be a risk stratification marker for CYFRA 21 - 1 positive NSCLC patients with wild-type EGFR.

Mitofusin 1-Mediated Redistribution of Mitochondrial Antiviral Signaling Protein Promotes Type 1 Interferon Response in Human Cytomegalovirus Infection.

One of the most potent anti-human cytomegalovirus (HCMV) immune mechanisms possessed by host cells is type I interferon (IFN1), which induces the expression of IFN-stimulated genes (ISGs). During this process, mitochondria play an important role in the IFN1 response, and mitofusin 1 (MFN1) is a key regulator of mitochondrial fusion located on the outer mitochondrial membrane. However, the underlying mechanism of MFN1's promotion of IFN1 during HCMV infection still remains unknown. In this study, HCMV infection promoted IFN1 production and enhanced ISG expression. Meanwhile, it promoted the increase of mitochondrial fusion in THP-1 cells and peripheral blood mononuclear cells (PBMCs), especially the expression of MFN1. Phosphorylation of tank binding kinase 1 (p-TBK1), interferon regulatory factor 3 (p-IRF3), and ISGs was significantly decreased in MFN1 or mitochondrial antiviral signaling protein (MAVS)-knockdown THP-1 cells, and MFN1 was constitutively associated with MAVS, positively regulated mitochondrial fusion, and IFN1 production. Knockdown of MFN1 inhibited the MAVS redistribution without affecting the MAVS expression, whereas the HCMV-induced IFN1 production decreased. Conversely, leflunomide could induce the expression of MFN1, thereby producing IFN1 and stimulating the expression of ISG in leflunomide-treated THP-1 cells. These observations reveal that HCMV infection leads to MFN1-mediated redistribution of MAVS and then induces an antiviral response of IFN1 and that the MFN-agonist leflunomide promotes IFN1 responses and may serve as a potential anti-HCMV therapy. IMPORTANCE Human cytomegalovirus (HCMV) infection is ubiquitous and is often asymptomatic in healthy individuals, but it can cause great damage to newborns, AIDS patients, and other immune deficiency patients. In this study, we found that HCMV infection caused mitochondrial fusion, and expression of mitofusin 1 (MFN1), which is a protein associated with mitochondrial antiviral signaling protein (MAVS), positively regulates mitochondrial fusion and HCMV-induced IFN1 response. Knockdown of MFN1 or MAVS can inhibit the HCMV-induced IFN1 production. What is more, confocal laser-scanning microscope showed that knockdown of MFN1 inhibits the HCMV-induced redistribution of MAVS. Conversely, MFN1 agonist leflunomide could induce IFN1 production. In conclusion, we provide new insight into the relationship between MFN1 and IFN1 during HCMV infection and show that MFN1 may serve as a potential strategy against HCMV infection.

Development and evaluation of machine learning models and nomogram for the prediction of severe acute pancreatitis.

BACKGROUND AND AIM: Severe acute pancreatitis (SAP) in patients progresses rapidly and can cause multiple organ failures associated with high mortality. We aimed to train a machine learning (ML) model and establish a nomogram that could identify SAP, early in the course of acute pancreatitis (AP). METHODS: In this retrospective study, 631 patients with AP were enrolled in the training cohort. For predicting SAP early, five supervised ML models were employed, such as random forest (RF), K-nearest neighbors (KNN), and naive Bayes (NB), which were evaluated by accuracy (ACC) and the areas under the receiver operating characteristic curve (AUC). The nomogram was established, and the predictive ability was assessed by the calibration curve and AUC. They were externally validated by an independent cohort of 109 patients with AP. RESULTS: In the training cohort, the AUC of RF, KNN, and NB models were 0.969, 0.954, and 0.951, respectively, while the AUC of the Bedside Index for Severity in Acute Pancreatitis (BISAP), Ranson and Glasgow scores were only 0.796, 0.847, and 0.837, respectively. In the validation cohort, the RF model also showed the highest AUC, which was 0.961. The AUC for the nomogram was 0.888 and 0.955 in the training and validation cohort, respectively. CONCLUSIONS: Our findings suggested that the RF model exhibited the best predictive performance, and the nomogram provided a visual scoring model for clinical practice. Our models may serve as practical tools for facilitating personalized treatment options and improving clinical outcomes through pre-treatment stratification of patients with AP.

Human cytomegalovirus-induced immune regulation is correlated with poor prognosis in patients with colorectal cancer.

Evidence suggests that human cytomegalovirus (HCMV) infection may be implicated in the progression of colorectal cancer (CRC). However, the correlation between HCMV infection and survival outcomes in patients with CRC remains unclear. Here, we constructed a flow algorithm to identify HCMV sequences based on the RNA-seq data of patients with CRC derived from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The patients' clinical information matrix was used to calculate the Euclidean distance to filter out suitable patients not infected with HCMV, combined with patients' survival outcomes, to reveal how HCMV infection is involved in CRC progression. HCMV infection is widespread in patients with CRC, and the prevalence of HCMV infection ranges from 10 to 36% in four independent CRC datasets, with infection being concentrated in carcinoma tissue rather than in normal tissue. In addition, HCMV-positive patients had a poor survival prognosis, with three HCMV genes, UL82, UL42, and UL117, associated with poor patient survival outcomes. Most importantly, we suppose that the regulation of immune function by HCMV may be key to the poor prognosis of patients with CRC. We found that HCMV infection was associated with poor prognosis in CRC patients and identified three prognosis-associated HCMV genes. The regulation of immune function caused by HCMV infection was the key factor, while HCMV-positive patients with CRC mostly presented with a state of immunosuppression. This may provide new ideas for the personalized treatment of patients with CRC, especially with respect to immunotherapy.

Plasma Phage Load is Positively Related to the Immune Checkpoints in Patients Living with Human Immunodeficiency Virus.

BACKGROUND: Microbial Translocation (MT) and altered gut microbiota are involved in immune activation and inflammation, whereas immune checkpoint proteins play an important role in maintaining immune self-tolerance and preventing excessive immune activation. OBJECTIVE: This study aims to investigate the relationship between plasma phage load and immune homeostasis in people living with HIV(PLWH). METHODS: We recruited 15 antiretroviral therapy (ART)-naive patients, 23 ART-treated (AT) patients, and 34 Healthy Participants (HP) to explore the relationship between the plasma phage load and immune checkpoint proteins. The Deoxyribonucleic Acid (DNA) load of the lambda (λ) phage was detected using fluorescence quantitative Polymerase Chain Reaction (PCR). The Immune Checkpoints (ICPs) were detected using multiplex immunoassay. RESULTS: Our study demonstrated that the plasma phage load was increased in people living with HIV (PLWH) (P<0.05), but not in the ART-naive and AT groups (P>0.05). Plasma ICPs, including cluster of differentiation 27 (CD27), soluble glucocorticoid-induced Tumor Necrosis Factor (TNF) receptor (sGITR), soluble cluster of differentiation 80 (sCD80), sCD86, soluble glucocorticoidinduced TNF receptor-related ligand (sGITRL), soluble induced T-cell Costimulatory (sICOS), sCD40, soluble toll-like receptor 2 (sTLR2), and sCD28, were markedly decreased among the ARTnaive group (P<0.05) but not in the AT and HP groups (P>0.05). The plasma phage load was positively correlated with ICP and C-reactive protein (CRP) levels in PLWH (P<0.05). CONCLUSION: Our study indicated that the plasma phage load in PLWH was positively related to the expression of ICPs and inflammation, which may be used as a promising marker for the immune level of PLWH.

Copper-catalyzed C-N Bond Cleavage: Synthesis of N-sulfonylformamidines from N-(2-pyridinylmethyl)benzenesulfonamides.

A broad range of N-sulfonyformamidines, widely used intermediates for drugs, were synthesized in moderate to excellent yields from 2-Pyridinemethanamine as N-source via Coppercatalyzed C-N cleavage. Firstly, N-(2-pyridinylmethyl)benzenesulfonamides were smoothly synthesized via 2-pyridinemethanamine and sulfonyl chlorides, then reacted with N,Ndimethylformamide dimethyl acetal to obtain the corresponding N-Sulfonylformamidines analogs, during which pyridin-2-ylmethyl and sulfonyl groups were essential for the C-N bond cleavage. The current work presents a valuable complementarity to the synthesis of N-sulfonyformamidines as 2- pyridinemethanamine can provide the N source and sulfonyl chloride,s which could be original materials. BACKGROUND: N-sulfonylamidines have gained considerable attention from schools and industries because of their unique bioactivity. Since Pinner's strategy, expanding the synthesis methods of Nsulfonylamidines has been the goal of many organic chemists over the past decades. Besides the crash reaction conditions and the participation of undesirable reagents, the production of Nsulfonylamidines commonly required unstable ammonia and azides as the source of nitrogen that hindered the further development and application of N-sulfonylamidine derivatives. OBJECTIVE: The study aims to find a stable N source to replace NaN3 or NH3 to synthesize N-sulfonylamidines from sulfonyl chlorides. METHODS: Firstly, N-(2-pyridinylmethyl)benzenesulfonamides were smoothly synthesized via 2- pyridinemethanamine and sulfonyl chlorides. Then the reaction conditions of N-(2-pyridinylmethyl) benzenesulfonamides and N,N-dimethylformamide dimethyl acetal (DMF-DMA) were screened and optimized. The reaction was processed in glycol at 80 degree centigrade for 8 hours with the addition of 5 mol% Cu(OAc)2·H2O as a catalyst. RESULTS: Taking advantage of pyridin-2-ylmethyl, a scope of N-Sulfonylformamidines were synthesized from those N-(2-pyridinylmethyl)benzenesulfonamides under copper-catalyzed C-N bond cleavage. CONCLUSION: This ready synthetic method will be more of a promising inspiration for bioactive compound synthesis and drug development than for an innovative approach to synthesizing N-sulfonylformamidines.

Biodistribution of 89Zr-oxine-labeled human bone marrow-derived mesenchymal stem cells by micro-PET/computed tomography imaging in Sprague-Dawley rats.

PURPOSE: To develop a method for labeling human bone marrow mesenchymal stem cells (hMSCs) with 89Zr-oxine to characterize the biodistribution characteristics of hMSCs in normal Sprague-Dawley (SD) rats in real-time by micro-PET-computed tomography (micro-PET/CT) imaging. METHODS: 89Zr-oxine complex was synthesized from 89Zr-oxalate and 8-hydroxyquinoline (oxine). After hMSCs were labeled with the 89Zr-oxine complex, the radioactivity retention, viability, proliferation, apoptosis, differentiation, morphology, and phenotype of labeled cells were assessed. The biodistribution of 89Zr-oxine-labeled hMSCs in SD rats was tracked in real-time by micro-PET/CT imaging. RESULTS: The cell labeling efficiency was 52.6 ± 0.01%, and 89Zr-oxine was stably retained in cells (66.7 ± 0.9% retention on 7 days after labeling). Compared with the unlabeled hMSCs, 89Zr-oxine labeling did not affect the biological characteristics of cells. Following intravenous administration in SD rats, labeled hMSCs mainly accumulated in the liver (7.35 ± 1.41% ID/g 10 days after labeling, n = 6) and spleen (8.48 ± 1.20% ID/g 10 days after labeling, n = 6), whereas intravenously injected 89Zr-oxalate mainly accumulated in the bone (4.47 ± 0.35% ID/g 10 days after labeling, n = 3). CONCLUSION: 89Zr-oxine labeling and micro-PET/CT imaging provide a useful and non-invasive method of assessing the biodistribution of cell therapy products in SD rats. The platform provides a foundation for us to further understand the mechanism of action and migration dynamics of cell therapy products.

Single-Cell Transcriptome Reveals the Metabolic and Clinical Features of a Highly Malignant Cell Subpopulation in Pancreatic Ductal Adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a high mortality rate. PDAC exhibits significant heterogeneity as well as alterations in metabolic pathways that are associated with its malignant progression. In this study, we explored the metabolic and clinical features of a highly malignant subgroup of PDAC based on single-cell transcriptome technology. Methods: A highly malignant cell subpopulation was identified at single-cell resolution based on the expression of malignant genes. The metabolic landscape of different cell types was analyzed based on metabolic pathway gene sets. In vitro experiments to verify the biological functions of the marker genes were performed. PDAC patient subgroups with highly malignant cell subpopulations were distinguished according to five glycolytic marker genes. Five glycolytic highly malignant-related gene signatures were used to construct the glycolytic highly malignant-related genes signature (GHS) scores. Results: This study identified a highly malignant tumor cell subpopulation from the single-cell RNA sequencing (scRNA-seq) data. The analysis of the metabolic pathway revealed that highly malignant cells had an abnormally active metabolism, and enhanced glycolysis was a major metabolic feature. Five glycolytic marker genes that accounted for the highly malignant cell subpopulations were identified, namely, EN O 1, LDHA, PKM, PGK1, and PGM1. An in vitro cell experiment showed that proliferation rates of PANC-1 and CFPAC-1 cell lines decreased after knockdown of these five genes. Patients with metabolic profiles of highly malignant cell subpopulations exhibit clinical features of higher mortality, higher mutational burden, and immune deserts. The GHS score evaluated using the five marker genes was an independent prognostic factor for patients with PDAC. Conclusion: We revealed a subpopulation of highly malignant cells in PDAC with enhanced glycolysis as the main metabolic feature. We obtained five glycolytic marker gene signatures, which could be used to identify PDAC patient subgroups with highly malignant cell subpopulations, and proposed a GHS prognostic score.

Robust Mg(Ca)Zr-Doped Acid-Base Bifunctional Mesoporous Silica and Their Applications in the Deacetalization-Knoevenagel Reaction.

A series of Mg(Ca)Zr-doped acid-base bifunctional mesoporous silica were synthesized to study the impact of the one-step or two-step impregnation method on material structure. The two-step method seems to be a better way to synthesize metal-based functionalized catalyst and their catalytic performance is investigated using deacetalization-Knoevenagel reaction as the probe reaction. The coexisting dual active sites and suitable designing routes endowed highly efficient (Conv. >99.6%, Sel. >99.8%) and robust stability (10 consecutive cycles) of these materials. The present process succeeded in preparing catalysts decorated with acid-base sites by doping acidic and alkali metal species rather than grafting organic groups.

Synthesis and structure of a ferric complex of 2,6-di(1H-pyrazol-3-yl)pyridine and its excellent performance in the redox-controlled living ring-opening polymerization of ε-caprolactone.

The reaction of FeCl3 with a pincer ligand, 2,6-di(1H-pyrazol-3-yl)pyridine (bppyH2), produced a mononuclear Fe(III) complex [Fe(bppyH2)Cl3] (1), which could be reduced to the corresponding Fe(II) dichloride complex [Fe(bppyH2)Cl2] (2) by suitable reducing agents such as Cp2Co or Fe powder. 1 and 2 exhibited a reversible transformation from each other with appropriate redox reagents. 1 could be utilized as a pre-catalyst to initiate the ring-opening polymerization of ε-caprolactone in the presence of alcohol but did not work. The 1/alcohol system displayed characteristics of a well-controlled polymerization with the resulting poly(ε-caprolactone) having low molecular weight distributions, a linear tendency of molecular weight evolution with conversion, and polymer growth observed for the sequential additions of ε-caprolactone monomer to the polymerization reaction. The polymerization was completely turned off by the in situ reduction of the catalytic Fe center via Cp2Co and then turned back upon the addition of [Cp2Fe]PF6. The rate of polymerization was modified by switching in situ between the Fe(III) and Fe(II) species.