Omental fibroma combined with right indirect inguinal hernia masquerades as a scrotal tumor: A case report.

BACKGROUND: The most common causes of scrotal enlargement in patients include primary tumor of the scrotum, inflammation, hydrocele of the tunica vaginalis, and indirect inguinal hernia; scrotal enlargement caused by external tumors of the scrotum is rare. The patient had both a greater omentum tumor and an inguinal hernia, and the tumor protruded into the scrotum through the hernia sac, which is even rarer. Moreover, omental tumors are mostly metastatic, and primary omental fibroma is rare. CASE SUMMARY: Here, we report a rare case of a 25-year-old young man with scrotal enlargement and pain for 3 months. Preoperative examination and multidisciplinary discussions considered intra-abdominal tumor displacement and inguinal hernia, and intraoperative exploration confirmed that the greater omentum tumor protruded into the scrotum. Therefore, tumor resection and tension-free inguinal hernia repair were performed. The final diagnosis was benign fibroma of the greater omentum accompanied by an indirect inguinal hernia. CONCLUSION: This unusual presentation of a common inguinal hernia disease illustrates the necessity of performing detailed history taking, physical examination, and imaging before surgery.

Moxibustion's protective role against atherosclerosis: Inhibition of Ca2+ overload-triggered oxidative stress and inflammatory response via P2Y12/PI3K/AKT pathway.

OBJECTIVE: This study aims to investigate the protective mechanism of moxibustion in combating atherosclerosis (AS). METHODS: Apolipoprotein E (ApoE)-deficient mice, aged 8 weeks, were randomly assigned into four groups: the model group (n = 6), SC79 group (n = 6), moxibustion group (n = 6), and moxibustion+SC79 group (n = 6). All mice were fed with a high-fat diet (HFD). Concurrently, 8-week-old C57BL/6 mice of the same genetic background were utilized as the control group (n = 6) and were given a regular diet. Macrophages were isolated via flow cytometry. The intracellular Ca2+ expression in macrophages was evaluated, and aortic plaques were quantitatively assessed through en face oil red O and Masson staining. The presence of macrophages and smooth muscle cells in AS plaques was determined by MAC-3 and α-smooth muscle actin (α-SMA) immunohistochemistry. The relative fluorescence intensity of nuclear factor-κB (NF-κB) in macrophages was identified by immunofluorescence staining. The expressions of proteins related to the P2Y12/phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT) signaling pathway were examined by Western blotting. RESULTS: Moxibustion reduced free Ca2+ expression in macrophage cytoplasm, inhibiting Ca2+ influx and oxidative stress. Significant reductions in atherosclerotic plaque formation and inflammation markers, including TNF-α and IL-1ß, were noted in the moxibustion group. Moxibustion modulated the P2Y12/PI3K/AKT pathway, impacting various inflammatory and oxidative stress-related proteins. Introduction of the AKT activator SC79 counteracted moxibustion's benefits, highlighting the P2Y12/PI3K/AKT pathway's central role. CONCLUSION: Moxibustion, through the P2Y12/PI3K/AKT signaling pathway, can inhibit Ca2+ overload-induced oxidative stress and inflammatory response, decrease macrophage infiltration, and increase the content of smooth muscle cells and collagen, thereby exerting a protective effect against AS.

Phytic acid improves osteogenesis and inhibits the senescence of human bone marrow mesenchymal stem cells under high-glucose conditions via the ERK pathway.

Hyperglycaemia causes impairment of osteogenic differentiation and accelerates stem cell senescence, resulting in weakened osteogenesis and disordered bone metabolism. Phytic acid (PA) is an antioxidant that is reportedly beneficial to bone homeostasis. The present study aims to clarify how PA affects the osteogenic capacity and cellular senescence of bone marrow mesenchymal stem cells (BMSCs) exposed to high-glucose environments, as well as the potential molecular mechanisms. Our results indicate that osteogenic differentiation in BMSCs cultivated in high-glucose conditions is enhanced by PA, as evidenced by increased alkaline phosphatase activity and staining, Alizarin Red S staining, osteogenic marker in in vitro studies, and increased osteogenesis in animal experiments. PA also prevented high-glucose-induced senescence of BMSCs, as evidenced by the repression of reactive oxygen species production, senescence-associated ß-galactosidase staining, and P21 and P53 expression. Furthermore, it was found that PA rescued the high-glucose-inhibited expression of phosphorylated extracellular regulated protein kinases (p-ERK). The inhibition of ERK pathway by the specific inhibitor PD98059 blocked the PA-enhanced osteogenesis of BMSCs and promoted cell senescence. Our results revealed that PA enhances osteogenic differentiation and inhibits BMSC senescence in a high-glucose environment. In addition, the activation of the ERK pathway seems to mediate the beneficial effects of PA. The findings provide novel insights that could facilitate bone regeneration in patients with diabetes.

Effects of N fertilizer reduction combined with straw biochar application on the yield, Si, and N nutrition of double-cropping rice.

Nitrogen (N) and silicon (Si) are important nutritional elements for rice. However, excessive N fertili-zer application and the ignorance of Si fertilizer are common in practice. Straw biochar is rich in Si, which can be used as a potential Si fertilizer. In this study, we conducted a consecutive 3-year field experiment to explore the effects of N fertilizer reduction combined with straw biochar application on rice yield, Si and N nutrition. There were five treatments: conventional N application (180 kg·hm-2, N100), 20% N reduction (N80), 20% N reduction with 15 t·hm-2 biochar (N80+BC), 40% N reduction (N60), and 40% N reduction with 15 t·hm-2 biochar (N60+BC). The results showed that compared with N100, 20% N reduction did not affect the accumulation of Si and N in rice; 40% N reduction reduced foliar N absorption, but significantly increased foliar Si concentration by 14.0%-18.8%; while combined application of biochar significantly increased foliar Si accumulation, with an increase of Si concentration by 38.0%-63.3% and Si absorption by 32.3%-49.9%, but further reduced foliar N concentration. There was a significant negative correlation between Si and N concentration in mature rice leaves, but no correlation between Si and N absorption. Compared with N100, N reduction or combined application of biochar did not affect soil ammonium N and nitrate N, but increased soil pH. Nitrogen reduction combined application of biochar significantly increased soil organic matter by 28.8%-41.9% and available Si content by 21.1%-26.9%, with a significant positive correlation between them. Compared with N100, 40% N reduction reduced rice yield and grain setting rate, while 20% N reduction and combined application of biochar did not influence rice yield and yield components. In summary, appropriate N reduction and combined with straw biochar can not only reduce N fertilizer input, but also improve soil fertility and Si supply, which is a promising fertilization method in double-cropping rice fields.

Essential Oil Nanoemulsion Hydrogel with Anti-Biofilm Activity for the Treatment of Infected Wounds.

The formation of a bacterial biofilm on an infected wound can impede drug penetration and greatly thwart the healing process. Thus, it is essential to develop a wound dressing that can inhibit the growth of and remove biofilms, facilitating the healing of infected wounds. In this study, optimized eucalyptus essential oil nanoemulsions (EEO NEs) were prepared from eucalyptus essential oil, Tween 80, anhydrous ethanol, and water. Afterward, they were combined with a hydrogel matrix physically cross-linked with Carbomer 940 (CBM) and carboxymethyl chitosan (CMC) to prepare eucalyptus essential oil nanoemulsion hydrogels (CBM/CMC/EEO NE). The physical-chemical properties, in vitro bacterial inhibition, and biocompatibility of EEO NE and CBM/CMC/EEO NE were extensively investigated and the infected wound models were proposed to validate the in vivo therapeutic efficacy of CBM/CMC/EEO NE. The results showed that the average particle size of EEO NE was 15.34 ± 3.77 nm with PDI ˂ 0.2, the minimum inhibitory concentration (MIC) of EEO NE was 15 mg/mL, and the minimum bactericidal concentration (MBC) against S. aureus was 25 mg/mL. The inhibition and clearance of EEO NE against S. aureus biofilm at 2×MIC concentrations were 77.530 ± 7.292% and 60.700 ± 3.341%, respectively, demonstrating high anti-biofilm activity in vitro. CBM/CMC/EEO NE exhibited good rheology, water retention, porosity, water vapor permeability, and biocompatibility, meeting the requirements for trauma dressings. In vivo experiments revealed that CBM/CMC/EEO NE effectively promoted wound healing, reduced the bacterial load of wounds, and accelerated the recovery of epidermal and dermal tissue cells. Moreover, CBM/CMC/EEO NE significantly down-regulated the expression of two inflammatory factors, IL-6 and TNF-α, and up-regulated three growth-promoting factors, TGF-ß1, VEGF, and EGF. Thus, the CBM/CMC/EEO NE hydrogel effectively treated wounds infected with S. aureus, enhancing the healing process. It is expected to be a new clinical alternative for healing infected wounds in the future.

Effects of ginger essential oil on physicochemical and structural properties of agar­sodium alginate bilayer film and its application to beef refrigeration.

To maintain the freshness of meat products, an agar­sodium alginate (AS) bilayer antibacterial film incorporated with ginger essential oil (GEO) was developed. The effect of GEO at different concentrations (1%, 2%, 3% and 4% v/v) on the physical properties, micro-structure and antibacterial activity closely related to AS film's application to beef refrigeration was extensively studied. In addition, the effects of AS bilayer active film on refrigeration quality and shelf life of beef were systematically evaluated. The porous structure and number of oil droplets became more obvious with the increase of GEO amount in AS film. The incorporation and increase of GEO could delay the lipid oxidation and protein decomposition of beef, reduce the total counts of the tested microorganisms (total viable bacteria, psychrotrophic bacteria, Escherichia coli, Staphylococcus aureus, yeast, and mold) in meat samples. Compared with commercial polyethylene (PE) packaging, the accumulation of basic compounds from the degradation of beef protein as well as the microbial contamination was obviously improved, which could extend the comprehensive shelf life of beef by 4-6 days. Consequently, AS bilayer films incorporated with GEO, especially GEO at 4.0% (v/v) GEO concentration can be developed to be an antibacterial active packaging material for beef refrigeration.

RHBDL2 promotes the proliferation, migration, and invasion of pancreatic cancer by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway.

Pancreatic cancer (PC) is one of the most malignant types of cancer, and is characterized by early metastasis, limited response to chemotherapeutics, and poor prognosis. Therefore, there is an urgent need to explore new therapeutic strategies for PC treatment. Human rhomboid-like 2 (RHBDL2) is differentially expressed in cervical and breast cancer. However, the correlation between RHBDL2 and PC remains unclear. We found that RHBDL2 is highly expressed in human PC cells and tissues and is significantly associated with distant metastasis and poor survival of patients with PC. Gain- and loss-of-function assays indicated that RHBDL2 could accelerate PC cell proliferation and mobility in vitro and in vivo. The RNA-Seq results suggest that RHBDL2 may be involved in the activation of Notch signaling pathway. IMR-1 could restore the proliferation and metastatic capacity of PC cells mediated by RHBDL2. RHBDL2 interacted with and cleaved Notch1, resulting in the release of N1ICD. RHBDL2 decreased the ubiquitination level of N1ICD and collaborated with Ovarian tumor domain-containing 7B (OTUD7B) to stabilize N1ICD via the ubiquitin-proteasome pathway. RHBDL2 facilitated PC cell proliferation and mobility by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway. Thus, targeting this novel pathway may be a potential therapeutic strategy for PC.

MICAL1 facilitates pancreatic cancer proliferation, migration, and invasion by activating WNT/ß-catenin pathway.

BACKGROUND: MICAL1 is involved in the malignant processes of several types of cancer; however, the role of MICAL1 in pancreatic cancer (PC) has not been well-characterized. This study aimed to investigate the expression and function of MICAL1 in PC. METHODS: RT-qPCR and immunohistochemistry were used to detect MICAL1 expression in PC and adjacent nontumor tissues. Cell Counting Kit-8, EdU, clone formation, wound healing, and Transwell assays as well as animal models were used to investigate the effects of overexpression or inhibition of MICAL1 expression on the proliferation, invasion, and metastasis of PC cells. RNA-seq was used to explore the main pathway underlying the functions of MICAL1. Proteomics, mass spectrometry, and co-immunoprecipitation assays were used to investigate the interaction of proteins with MICAL1. Rescue experiments were conducted to validate these findings. RESULTS: Both MICAL1 mRNA and protein levels were upregulated in PC tissues compared with matched adjacent nontumor tissues. The expression level of MICAL1 was associated with the proliferative and metastatic status of PC. Repression of MICAL1 significantly inhibited PC cell growth, migration, and invasion in vitro and in vivo. RNA sequencing analysis indicated that MICAL1 was closely correlated with the WNT pathway. Overexpression of MICAL1 (1) promoted the phosphorylation of TBC1D1 at the Ser660 site, (2) facilitated the distribution of FZD7 on the cytomembrane, (3) inhibited the degradation of FZD7 in the lysosome, and (4) activated the WNT pathway. CONCLUSIONS: MICAL1 was upregulated in PC and involved in stimulating the progression of PC cells by activating the WNT/ß-catenin signaling pathway. Therefore, MICAL1 is a potential therapeutic target for PC.

High expression of syndecan-4 is related to clinicopathological features and poor prognosis of pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic adenocarcinoma (PAAD) is a leading cause of cancer-related mortality in adults. Syndecan-4 (SDC4) is involved in cancer pathogenesis. Therefore, this study aimed to explore the expression and clinical significance of SDC4 in PAAD. METHODS: Differentially expressed genes (DEGs) between PAAD and normal pancreas were screened from the GTEx and TCGA databases, and the correlationship between the DEGs and prognosis were analyzed. The prognostic value of the screened SDC4, SERPINE1, and SLC2A1 was evaluated using the Kaplan-Meier curve and SDC4 was subsequently selected as the better candidate. Also, SDC4 expression was analyzed in PAAD tissues, the other risk factors affecting postoperative survival were analyzed using Cox regression analysis, and SDC4-mediated pathways enrichment was identified by GSVA and GSEA. SDC4 expression in PAAD tissues and adjacent normal tissues of selected PAAD patients was detected by RT-qPCR and immunohistochemistry. The correlation between SDC4 and clinical features was evaluated by the χ2 test. RESULTS: SDC4 was highly expressed in PAAD tissues. Elevated SDC4 was correlated with reduced overall survival. SDC4 enrichment pathways included spliceosome function, proteasome activity, pentose phosphate pathway, base excision repair, mismatch repair, DNA replication, oxidative phosphorylation, mitotic spindle formation, epithelial-mesenchymal transition, and G2M checkpoints. SDC4 was elevated in PAAD tissues of PAAD patients compared with adjacent normal tissues. High SDC4 expression was related to metastatic differentiation, TNM stage, lymphatic metastasis, and lower 3-year survival rate. SDC4 was an independent risk factor affecting postoperative survival. CONCLUSION: SDC4 was highly expressed in PAAD and was related to clinicopathological features and poor prognosis, which might be an important index for PAAD early diagnosis and prognosis.

Heparin purification by expanded bed anion exchange in a countercurrent chromatography column.

In this study, an expanded bed anion exchange in a countercurrent chromatography column (EB-CCC) technique for separation and purification of heparin, an anticoagulant and antithrombotic glycosaminoglycan, is reported for the first time. A comparative evaluation of the EB-CCC technique with the conventional fixed bed column chromatography (FBCC) revealed its effectiveness in improving adsorption at high flow rates and reducing separation time. A significantly higher maximum adsorption (91.66%) was exhibited by EB-CCC in comparison with FBCC (45.16%) at the eluent flow rate of 1 mL·min-1. Similarly, the experimental adsorption capacity of heparin was enhanced by 1.69, 2.06 and 2.58 times in the case of EB-CCC at the flow rates of 1, 2 and 5 mL·min-1, respectively. Moreover, the directly proportional amplification of double loaded resin and double column volume was demonstrated at an EB-CCC rotational speed of 300 rpm and a flow rate of 2 mL·min-1, and the experimental adsorption capacity was observed to increase from 66.42 to 136.48 mg·g-1 after amplification. Heparin purified by EB-CCC displayed higher potency (216.09 ± 11.89 IU·mg-1) as compared to FBCC (205.51 ± 7.90 IU·mg-1) and the initial crude heparin 134.17 ± 4.12 IU·mg-1. Furthermore, comparing to the purified heparin by FBCC, heparin purified by EB-CCC had low molecular weight, high FXa/FIIa, superior anticoagulation effect and enhanced suitability as an exogenous anticoagulant.

FOXD1 facilitates pancreatic cancer cell proliferation, invasion, and metastasis by regulating GLUT1-mediated aerobic glycolysis.

Although FOXD1 has been found to be involved in the malignant processes of several types of cancers, its role in pancreatic cancer (PC) is not well understood. This study aimed to investigate the expression and function of FOXD1 in PC. We found that FOXD1 mRNA and protein expression were upregulated in PC tissues compared with non-tumor tissues, and high expression level of FOXD1 was associated with an adverse prognostic index of PC. The results of in vitro and in vivo assays indicate that overexpression of FOXD1 promotes aerobic glycolysis and the capacity of PC cells to proliferate, invade, and metastasize, whereas FOXD1 knockdown inhibits these functions. The results of mechanistic experiments suggest that FOXD1 can not only directly promote SLC2A1 transcription but also inhibit the degradation of SLC2A1 through the RNA-induced silencing complex. As a result, FOXD1 enhances GLUT1 expression and ultimately facilitates PC cell proliferation, invasion, and metastasis by regulating aerobic glycolysis. Taken together, FOXD1 is suggested to be a potential therapeutic target for PC.

B-Cell-Epitope-Based Fluorescent Quantum Dot Biosensors for SARS-CoV-2 Enable Highly Sensitive COVID-19 Antibody Detection.

A new antibody diagnostic assay with more rapid and robust properties is demanded to quantitatively evaluate anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity in a large population. Here, we developed a nanometer-scale fluorescent biosensor system consisting of CdSe-ZnS quantum dots (QDs) coupled with the highly sensitive B-cell epitopes of SARS-CoV-2 that could remarkably identify the corresponding antibody with a detection limit of 100 pM. Intriguingly, we found that fluorescence quenching of QDs was stimulated more obviously when coupled with peptides than the corresponding proteins, indicating that the energy transfer between QDs and peptides was more effective. Compared to the traditional enzyme-linked immunosorbent assay (ELISA), the B-cell-epitope-based QD-biosensor could robustly distinguish coronavirus disease 2019 (COVID-19) antibody-positive patients from uninfected individuals with a higher sensitivity (92.3-98.1% positive rates by QD-biosensor vs. 78.3-83.1% positive rates by ELISAs in 207 COVID-19 patients' sera) in a more rapid (5 min) and labor-saving manner. Taken together, the 'QD-peptides' biosensor provided a novel real-time, quantitative, and high-throughput method for clinical diagnosis and home-use tests.

Isoflavones from Semen Sojae Preparatum Improve Atherosclerosis and Oxidative Stress by Modulating Nrf2 Signaling Pathway through Estrogen-Like Effects.

Atherosclerosis (AS) often occurs in cardiovascular disease, which is a chronic vascular disease and is harmful to human health. Oxidative stress is involved in its etiology. This study aimed to determine the effectiveness of Isoflavones from semen sojae preparatum (ISSP) in inhibiting oxidative stress and its important molecular mechanisms through in vivo and in vitro experiments. ApoE-/- mice were used to establish atherosclerosis models through a high-fat diet, and endothelial cells were used to establish oxidative stress injury models through ox-LDL induction. The degree of oxidative stress damage was assessed by detecting changes in ET-1, LDH, SOD, and MDA indicators. It was observed that after ISSP treatment, the oxidative stress damage of mice and endothelial cells was improved. The Nrf2/AER signaling pathway is an important antioxidant pathway that has attracted our attention. Western blotting and qRT-PCR were used to detect the expression of Nrf2, HO-1, and NQO1 in mice aortae and endothelial cells. The results showed that the Nrf2 signaling pathway was activated after ISSP intervention. In addition, in this study, after preantagonizing the estrogen receptors GPR30 and ERß, it was observed that the effects of ISSP in treating endothelial cell oxidative damage and activating the Nrf2 signaling pathway were weakened. After silencing Nrf2 by Nrf2-siRNA transfection, the effect of ISSP in treating endothelial cell oxidative damage was inhibited. This study shows that ISSP may reduce oxidative stress damage and atherosclerosis through the Nrf2 signaling pathway, and this effect may involve the GPR30 and ERß estrogen receptors.

Autophagy-associated circRNA circATG7 facilitates autophagy and promotes pancreatic cancer progression.

Dysregulation of autophagy and circular RNAs (circRNAs) are involved in the pancreatic cancer (PC) progression. However, the regulatory network between circRNAs, autophagy, and PC progression remains unknown. Herein, we demonstrated that autophagy-associated circRNA circ-autophagy related 7 (circATG7) was elevated in PC tissues compared to adjacent tissues, and in PC cells treated with EBSS and hypoxia. circATG7 expression was positively associated with tumor diameter and lymph node invasion in patients with PC. circATG7 overexpression promoted PC cell proliferation, mobility, and autophagy in vitro, while circATG7 knockdown induced the opposite effects. ATG7 inhibition attenuated the effects of circATG7 on the biological functions of PC cells. CircATG7 is located in the cell cytoplasm and nucleus. Cytoplasmic circATG7 sponged miR-766-5p and decreased its expression, and increased the expression of ATG7, a target gene of miR-766-5p. Nuclear circATG7 acted as a scaffold to increase the interaction between the human antigen R protein and ATG7 mRNA and enhanced ATG mRNA stability. Furthermore, we demonstrated that circATG7 regulates PC cell proliferation and metastasis in vivo via ATG7-dependent autophagy. In conclusion, our results demonstrated that circATG7 accelerates PC progression via miR-766-5p/ATG7 and that HUR/ATG7 depends on autophagic flux. Thus, circATG7 may be a potential therapeutic target for PC.

Hypoxia-induced long noncoding RNA NR2F1-AS1 maintains pancreatic cancer proliferation, migration, and invasion by activating the NR2F1/AKT/mTOR axis.

Accumulating evidence has demonstrated the essential role of long noncoding RNAs (lncRNAs) in various types of human cancer, including pancreatic cancer (PC). However, the functions and regulatory mechanisms of nuclear receptor subfamily 2 group F member 1 antisense RNA 1 (NR2F1-AS1) that are responsible for its role in the malignant progression of PC cells remains to be investigated. In this study, the biological effects of NR2F1-AS1 and NR2F1 in PC were investigated by in vitro and in vivo experiments. The mechanisms of NR2F1-AS1 were monitored by bioinformatic predictive analysis and confirmatory experiments. Our results indicated that NR2F1-AS1 was overexpressed and positively correlated with poor survival in PC. Depletion of NR2F1-AS1 restrained PC cell proliferation, migration, invasion, and suppressed xenograft tumor growth and metastasis in vitro and in vivo. Mechanistic experiments suggested that NR2F1-AS1 positively regulated the neighboring NR2F1 gene, which subsequently activated AKT/mTOR signaling, resulting in the upregulation of hypoxia-inducible factor-1α (HIF-1α). Further investigations elucidated that NR2F1-AS1 expression was transcriptionally regulated by HIF-1α under hypoxia. These findings demonstrated that hypoxia-induced NR2F1-AS1 expression directly increased NR2F1 levels to promote PC cell proliferation, migration, and invasion by activating AKT/mTOR signaling. Together, these findings suggest that NR2F1-AS1 could be a prospective therapeutic target for PC.

Imparting reusable and SARS-CoV-2 inhibition properties to standard masks through metal-organic nanocoatings.

Face masks are effective response to address this havoc pandemic caused by respiratory infection virus, but they are lack of reusable, antibacterial, and antiviral abilities due to their simple filtration mechanism, bringing to a supply shortage and severe plastic pollution globally. Herein, we designed reusable, antiviral, and antibacterial masks (referred to as R2A masks) that transformed from commonly-used standard masks and household fabrics based on the polyphenol-based surface functionalization. R2A nanocoatings are mainly composed of supramolecular complexation of natural polyphenols and metal ions, possessing a high performance of antibacterial property and comprehensive recyclability. Interfacial interaction of R2A nanocoating can effectively capture the spreading of particulate matters and aerosols containing virus-mimic nanoparticles even after 10 recycles. Moreover, R2A masks exist antibacteria and antivirus for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Collectively, this simple functional enhancement of masks provides a sustainable and strategic preparation for combating the infectious respiratory diseases.

Anti-Lung Cancer Activities of 1,2,3-Triazole Curcumin Derivatives via Regulation of the MAPK/NF-κB/STAT3 Signaling Pathways.

In this study, a series of curcumin derivatives containing 1,2,3-triazole were designed and synthesized, and their inhibitory activities against the proliferation of lung cancer cells were studied. Compound 5 k (3,4-dichlorobenzyltriazole methyl curcumin) had the best activity against A549 cells, with a half-maximal inhibitory concentration (IC50 ) of 2.27 µM, which was approximately 10 times higher than that of the lead curcumin and higher than that of gefitinib (IC50 =8.64 µM). Western blotting revealed that 5 k increased the phosphorylation levels of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Compound 5 k also promoted the expression of the inhibitor of nuclear factor-κB (IκBα) and decreased that of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), and ß-catenin. Therefore, 5 k suppresses A549 cell proliferation by activating the mitogen-activated protein kinases and suppressing NF-κB/STAT3 signaling pathways. So, 5 k can potentially be used for treating non-small cell lung cancer.

Prodigiosin inhibits cholangiocarcinoma cell proliferation and induces apoptosis via suppressing SNAREs-dependent autophagy.

BACKGROUND: Prodigiosin (PG), a natural red pigment produced by numerous bacterial species, has been a eye-catching research point in recent years for its anticancer activity. However, the role of PG in the cancer biology of cholangiocarcinoma (CCA) remains vague. METHODS: The proliferation of CCA cells was detected by Cell Counting Kit-8(CCK-8), Colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay. Cell apoptosis was evaluated by flow cytometry assay and western blot assay. The effects of PG or SNAREs on cell autophagy were measured by autophagy flux assay and western blot assay. Xenograft mouse models were used to assess the role of PG in CCA cells in vivo. RESULTS: PG could inhibit the proliferation and viability of CCA cells in a concentration- and time-dependent manner via suppressing the late stage of autophagy. Mechanistically, PG inhibits the fusion of autophagosomes and lysosomes by blocking STX17 and SNAP29, components of soluble N-ethyl-maleimide-sensitive factor attachment protein receptors (SNAREs)complex. When STX17 and SNAP29 were overexpressed, the inhibitory effect of PG on CCA cells autophagy was relieved. In addition, PG showed obvious inhibitory effects on cancer cell viability but no toxic effects on organs in xenotransplantation models. CONCLUSION: Taken together, our results demonstrated that PG inhibits CCA cell proliferation via suppressing SNAREs-dependent autophagy, implying that PG could be a potential chemotherapy drug for advanced CCA.

CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis.

Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined. The core set of genes relating to histone methylation (KMT2D, KMT2C, EZH2), histone acetylation (CREBBP, EP300), DNA methylation (TET2), and chromatin remodeling (ARID1A) were detected in the training cohort of 316 patients by whole-genome/exome sequencing (WGS/WES) and in the validation cohort of 303 patients with newly diagnosed DLBCL by targeted sequencing. Their correlation with peripheral blood immune cells and clinical outcomes were assessed. Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo. Among all 619 DLBCL patients, somatic mutations in KMT2D (19.5%) were most frequently observed, followed by mutations in ARID1A (8.7%), CREBBP (8.4%), KMT2C (8.2%), TET2 (7.8%), EP300 (6.8%), and EZH2 (2.9%). Among them, CREBBP/EP300 mutations were significantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios, as well as inferior progression-free and overall survival. In B-lymphoma cells, the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation, downregulated FBXW7 expression, activated the NOTCH pathway, and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.