Recent advances in potential therapeutic targets of ferroptosis­associated pathways for the treatment of stroke (Review).

Stroke is a severe neurological disease that is associated with high rates of morbidity and mortality, and the underlying pathological processes are complex. Ferroptosis fulfills a significant role in the progression and treatment of stroke. It is well established that ferroptosis is a type of programmed cell death that is distinct from other forms or types of cell death. The process of ferroptosis involves multiple signaling pathways and regulatory mechanisms that interact with mechanisms inherent to stroke development. Inducers and inhibitors of ferroptosis have been shown to exert a role in the onset of this cell death process. Furthermore, it has been shown that interfering with ferroptosis affects the occurrence of stroke, indicating that targeting ferroptosis may offer a promising therapeutic approach for treating patients of stroke. Hence, the present review aimed to summarize the latest progress that has been made in terms of using therapeutic interventions for ferroptosis as treatment targets in cases of stroke. It provides an overview of the relevant pathways and molecular mechanisms that have been investigated in recent years, highlighting the roles of inducers and inhibitors of ferroptosis in stroke. Additionally, the intervention potential of various types of Traditional Chinese Medicine is also summarized. In conclusion, the present review provides a comprehensive overview of the potential therapeutic targets afforded by ferroptosis­associated pathways in stroke, offering new insights into how ferroptosis may be exploited in the treatment of stroke.

Naringin attenuates Actinobacillus pleuropneumoniae-induced acute lung injury via MAPK/NF-κB and Keap1/Nrf2/HO-1 pathway.

Actinobacillus pleuropneumoniae (APP) causes porcine pleuropneumonia (PCP), which is clinically characterized by acute hemorrhagic, necrotizing pneumonia, and chronic fibrinous pneumonia. Although many measures have been taken to prevent the disease, prevention and control of the disease are becoming increasingly difficult due to the abundance of APP sera, weak vaccine cross-protection, and increasing antibiotic resistance in APP. Therefore, there is an urgent need to develop novel drugs against APP infection to prevent the spread of APP. Naringin (NAR) has been reported to have an excellent therapeutic effect on pulmonary diseases, but its therapeutic effect on lung injury caused by APP is not apparent. Our research has shown that NAR was able to alleviate APP-induced weight loss and quantity of food taken and reduce the number of WBCs and NEs in peripheral blood in mice; pathological tissue sections showed that NAR was able to prevent and control APP-induced pathological lung injury effectively; based on the establishment of an in vivo/in vitro model of APP inflammation, it was found that NAR was able to play an anti-inflammatory role through inhibiting the MAPK/NF-κB signaling pathway and exerting anti-inflammatory effects; additionally, NAR activating the Nrf2 signalling pathway, increasing the secretion of antioxidant enzymes Nqo1, CAT, and SOD1, inhibiting the secretion of oxidative damage factors NOS2 and COX2, and enhancing the antioxidant stress ability, thus playing an antioxidant role. In summary, NAR can relieve severe lung injury caused by APP by reducing excessive inflammatory response and improving antioxidant capacity.

Insights into the history and tendency of glycosylation and digestive system tumor: A bibliometric-based visual analysis.

BACKGROUND: Glycosylation, a commonly occurring post-translational modification, is highly expressed in several tumors, specifically in those of the digestive system, and plays a role in various cellular pathophysiological mechanisms. Although the importance and detection methods of glycosylation in digestive system tumors have garnered increasing attention in recent years, bibliometric analysis of this field remains scarce. The present study aims to identify the developmental trends and research hotspots of glycosylation in digestive system tumors. AIM: To find and identify the developmental trends and research hotspots of glycosylation in digestive system tumors. METHODS: We obtained relevant literature from the Web of Science Core Collection and employed VOSviewer 1.6.19 and CiteSpace (version 6.1.R6) to perform bibliometric analysis. RESULTS: A total of 2042 documents spanning from 1978 to the present were analyzed, with the research process divided into three phases: the period of obscurity (1978-1990), continuous development period (1991-2006), and the rapid outbreak period (2007-2023). These documents were authored by researchers from 66 countries or regions, with the United States and China leading in terms of publication output. Reis Celso A had the highest number of publications, while Pinho SS was the most cited author. Co-occurrence analysis revealed the most popular keywords in this field are glycosylation, expression, cancer, colorectal cancer, and pancreatic cancer. Furthermore, the Journal of Proteome Research was the most prolific journal in terms of publications, while the Journal of Biological Chemistry had the most citations. CONCLUSION: The bibliometric analysis shows current research focus is primarily on basic research in this field. However, future research should aim to utilize glycosylation as a target for treating tumor patients.

[Circular RNA-Encoded Proteins in Gastrointestinal Cancer:A Review].

Circular RNAs(CircRNAs)are a class of non-coding RNAs with a covalently closed-loop structure,high stability,and tissue specificity,with the production mechanisms different from linear RNAs.Recent studies have discovered that some CircRNAs can encode proteins via cap-independent translation mechanisms such as internal ribosome entry site,N6-methyladenosine,and rolling loop translation.The encoded proteins regulate homologous linear proteins or downstream signaling pathways via protein bait or other mechanisms,thereby exerting biological functions.Studies have shown that CircRNAs play a role in various diseases,especially in tumor progression,proliferation,invasion,and metastasis and immune regulation.Therefore,by elucidating the expression and roles of proteins encoded by CircRNAs in tumorigenesis and development,this paper is expected to provide new tumor markers and potential targets for tumor diagnosis and treatment.

Naringin alleviates pneumonia caused by Klebsiella pneumoniae infection by suppressing NLRP3 inflammasome.

Klebsiella pneumoniae (Kpn) is an important pathogen of hospital-acquired pneumonia, which can lead to sepsis and death in severe cases. In this study, we simulated pneumonia induced by Kpn infection in mice to investigate the therapeutic effect of naringin (NAR) on bacterial-induced lung inflammation. Mice infected with Kpn exhibited increases in white blood cells (WBC) and neutrophils in the peripheral blood and pathological severe injury of the lungs. This injury was manifested by increased expression of the inflammatory cytokines interleukin (IL)- 18, IL-1ß, tumor necrosis factor-α (TNF-α) and IL-6, and elevated the expression of NLRP3 protein. NAR treatment could decrease the protein expression of NLRP3, alleviate lung inflammation, and reduce lung injury in mice caused by Kpn. Meanwhile, molecular docking results suggest NAR could bind to NLRP3 and Surface Plasmon Resonance (SPR) analyses also confirm this result. In vitro trials, we found that pretreated with NAR not only inhibited nuclear translocation of nuclear factor (NF)-κB protein P65 but also attenuated the protein interaction of NLRP3, caspase-1 and ASC and inhibited the assembly of NLRP3 inflammasome in mice AMs. Additionally, NAR could reduce intracellular potassium (K+) efflux, inhibiting NLRP3 inflammasome activation. These results indicated that NAR could protect against Kpn-induced pneumonia by inhibiting the overactivation of the NLRP3 inflammasome signaling pathway. The results of this study confirm the efficacy of NAR in treating bacterial pneumonia, refine the mechanism of action of NAR, and provide a theoretical basis for the research and development of NAR as an anti-inflammatory adjuvant.

[Application of a low copper diet guidance based on food exchange portions in children with hepatolenticular degeneration]. / åŸºäºŽé£Ÿç‰©äº¤æ¢ä»½æ³•çš„ä½Žé“œé¥®é£ŸæŒ‡å¯¼åœ¨è‚è±†çŠ¶æ ¸å˜æ€§æ‚£å„¿ä¸­çš„åº”ç”¨æ•ˆæžœ.

OBJECTIVES: To study the efficacy of a low-copper diet guidance based on food exchange portions in children with hepatolenticular degeneration. METHODS: A self-controlled study was conducted from July 2021 to June 2022, including 30 children under the age of 18 who were diagnosed with hepatolenticular degeneration and poorly controlled with a low-copper diet. During the medical visit, personalized low-copper diet guidance was provided to the children and their parents using a copper-containing food exchange table and a copper food exchange chart. During home care, compliance with the low-copper diet of the children was improved by recording dietary diaries and conducting regular follow-ups. The changes in 24-hour urine copper level, liver function indicators, and the low-copper diet knowledge of the children's parents were observed before and after the intervention, with no change in the original drug treatment. RESULTS: After 8, 16, and 24 weeks of intervention, the 24-hour urine copper level decreased significantly compared to before intervention (P<0.05). When compared to 8-week intervention, the urine copper level decreased significantly after 16 and 24 weeks of intervention. The 24-hour urine copper level after 24 weeks of intervention decreased significantly compared to 16 weeks of intervention (P<0.05).After 24 weeks of intervention, the alanine aminotransferase and aspartate aminotransferase levels decreased significantly compared to before intervention (P<0.05). Additionally, in 16 of the cases (53%), alanine aminotransferase and aspartate aminotransferase returned to normal levels. Following 8 weeks of intervention, the low-copper diet knowledge of the children's parents increased significantly (P<0.05). CONCLUSIONS: A low-copper diet guidance based on food exchange portions can effectively decrease the urine copper level and improve liver function in children with hepatolenticular degeneration. Furthermore, it can increase the low-copper diet knowledge of the children's parents.

Differentiated Embryo-Chondrocyte Expressed Gene1 and Parkinson's Disease: New Insights and Therapeutic Perspectives.

Differentiated embryo-chondrocyte expressed gene1 (DEC1), an important transcription factor with a basic helix-loop-helix domain, is ubiquitously expressed in both human embryonic and adult tissues. DEC1 is involved in neural differentiation and neural maturation in the central nervous system (CNS). Recent studies suggest that DEC1 protects against Parkinson's disease (PD) by regulating apoptosis, oxidative stress, lipid metabolism, immune system, and glucose metabolism disorders. In this review, we summarize the recent progress on the role of DEC1 in the pathogenesis of PD and provide new insights into the prevention and treatment of PD and neurodegenerative diseases.

Unique mutation spectrum of progressive pseudorheumatoid dysplasia in the Chinese population: a retrospective genotype-phenotype analysis of 105 patients.

BACKGROUND: Progressive pseudorheumatoid dysplasia (PPRD) is a rare genetic disease with autosomal recessive inheritance. There was a lack of genotype-phenotype correlation data from the Chinese population. This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype-phenotype analysis of Chinese PPRD patients. METHODS: Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital. Medical records were collected from the electronic medical record system and patient-held portable health records. Published Chinese PPRD cases were gathered from both international and Chinese local databases. We collected demographic information, genetic variants, clinical manifestations, and imaging characteristics for further analysis. RESULTS: We included 105 Chinese PPRD patients in the current study. Thirty-three variants, including nine novels and five hotspot variants, were identified, with 26/33 (79%) variants exclusively seen in the Chinese population. Chinese PPRD patients share a phenotype similar to that in international reports. Joint involvement may progress with age (R2 = 0.2541). Long bone shortening and severe deformities occur in three patients with biallelic null variants, of which at least one variant is located in exon 2. Among hotspot variants, c.624dupA (p.C209Mfs*21) were associated with later onset and more involved joints. Elbow joints were more likely to be affected in patients carrying c.624dupA (p.C209Mfs*21) and c.866dupA (p.S209Efs*13). Shoulder joints are more likely to be involved in patients with biallelic null variants (P = 0.027). CONCLUSIONS: Chinese PPRD patients share a unique mutation spectrum. Among the five hotspot variants, c.624dupA is associated with later onset of disease, more extensive joint involvement, and a tendency to affect elbow joints. Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities.

Early recombinant human growth hormone treatment improves mental development and alleviates deterioration of motor function in infants and young children with Prader-Willi syndrome.

BACKGROUND: Recombinant human growth hormone (rhGH) therapy has shown to improve height and body composition in children with Prader-Willi syndrome (PWS), the evidence of early rhGH treatment on motor and mental development is still accumulating. This study explored the time effect on psychomotor development, anthropometric indexes, and safety for infants and young children with PWS. METHODS: A phase 3, single-arm, multicenter, self-controlled study was conducted in six sites. Patients received rhGH at 0.5 mg/m2/day for first four weeks, and 1 mg/m2/day thereafter for up to 52 weeks. Motor development was measured using Peabody Developmental Motor Scales-second edition, mental development using Griffiths Development Scales-Chinese (GDS-C). Height standard deviation score (SDS), body weight SDS, and body mass index (BMI) SDS were also assessed. RESULTS: Thirty-five patients were enrolled totally. Significant improvements were observed in height, body weight, and BMI SDS at week 52; GDS-C score showed significant improvement in general quotient (GQ) and sub-quotients. In a linear regression analysis, total motor quotient (TMQ), gross motor quotient (GMQ), and fine motor quotient were negatively correlated with age; however, treatment may attenuate deterioration of TMQ and GMQ. Changes in GQ and locomotor sub-quotient in < 9-month group were significantly higher than ≥ 9-month group. Mild to moderate severity adverse drug reactions were reported in six patients. CONCLUSION: Fifty-two-week treatment with rhGH improved growth, BMI, mental development, and lessened the deterioration of motor function in infants and young children with PWS. Improved mental development was more pronounced when instituted in patients < 9 months old.

Correction to "Genome-wide CRISPR-Cas9 screening identifies that hypoxia-inducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis".

[This corrects the article on p. 1709 in vol. 13, PMID: 34853645.].

Long noncoding RNA negative regulator of antiviral response contributes to pancreatic ductal adenocarcinoma progression via targeting miR-299-3p.

BACKGROUND: Pancreatic ductal cancer (PDAC) has high malignancy and poor prognosis. Long noncoding RNAs (lncRNAs) are associated with high levels of malignancy, including PDAC. However, the biological and clinical significance of negative regulator of antiviral response (NRAV) in PDAC is unclear. AIM: To study the regulatory role of lncRNA NRAV in PDAC. METHODS: GEPIA analyzed lncRNA NRAV and miRNA (miR-299-3p) expression levels in PDAC tissues and measured them in PDAC cells by quantitative measurements in real time. The specific role of NRAV and miR-299-3p in cell proliferation and transfer potential was evaluated by cell formation analysis, Cell Counting Kit-8 and Transwell analysis. The relationship between NRAV and miR-299-3p was studied by predictive bioinformatics, RNA immunoassay, and fluorescence enzyme analysis. In vivo experiments included transplantation of simulated tumor cells under naked mice. RESULTS: The expression level of lncRNA NRAV was higher in both tumor tissues and cell lines of PDAC and was negatively associated with the clinical survival of PDAC patients. Functionally, overexpression of NRAV promoted cell proliferation and metastasis of PDAC cells, while knockdown of NRAV reversed these effects. Finally, NRAV was performed as a molecular sponge of miR-299-3p. Moreover, overexpression of miR-299-3p could reverse the promoting effects of NRAV on cell proliferation and metastasis of PDAC cells. CONCLUSION: NRAV facilitates progression of PDAC as a molecular sponge of miR-299-3p and may be a potential molecular marker for diagnosis and treatment of PDAC.

Genome-wide CRISPR-Cas9 screening identifies that hypoxia-inducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis.

BACKGROUND: Pancreatic cancer (PC) is one of the most lethal malignancies worldwide. It is known that the proliferation of PC cells is a critical process in the disease. Previous studies have failed to identify the key genes associated with PC cell proliferation, using bioinformatic analysis, genome-wide association studies, and candidate gene testing. AIM: To investigate the function of the chromobox 8 (CBX8)/receptor substrate 1 (IRS1)/AKT axis in PC. METHODS: A genome-wide CRISPR-Cas9 screening was performed to select genes that could facilitate PC cell proliferation. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of CBX8 in PC tissues and cells. The regulatory roles of CBX8 in cell proliferation, migration, and invasion were verified by in vivo and in vitro functional assays. RESULTS: CBX8 was upregulated in PC tissues and shown to drive PC cell proliferation. Higher expression of CBX8 was correlated with worse outcomes of PC patients from two independent cohorts comprising a total of 116 cases. CBX8 was also proved to serve as a promising therapeutic target for a PC xenograft model. We demonstrated that hypoxia-inducible factor (HIF)-1a induced CBX8 transcription by binding to the promoter of CBX8. CBX8 efficiently activated the PI3K/AKT signaling by upregulating insulin IRS1. CONCLUSION: CBX8 is a key gene regulated by HIF-1α, and activates the IRS1/AKT pathway, which suggests that targeting CBX8 may be a promising therapeutic strategy for PC.

Metabolomics and Transcriptomics Analysis on Metabolic Characteristics of Oral Lichen Planus.

OBJECTIVE: To explore metabolic biomarkers related to erosive and reticulated oral lichen planus (OLP) by non-targeted metabolomics methods and correlate metabolites with gene expression, and to investigate the pathological network pathways of OLP from the perspective of metabolism. METHODS: A total of 153 individuals were enrolled in this study, including 50 patients with erosive oral lichen planus (EOLP), 51 patients with reticulated oral lichen planus (ROLP), and 52 healthy controls (HC). The ultra-high-performance liquid chromatography quadrupole-Orbitrap high-resolution accurate mass spectrometry (UHPLC/Q-Orbitrap HRMS) was used to analyze the metabolites of 40 EOLP, 40 ROLP, and 40 HC samples, and the differential metabolic biomarkers were screened and identified. The regulatory genes were further screened through the shared metabolites between EOLP and ROLP, and cross-correlated with the OLP-related differential genes in the network database. A "gene-metabolite" network was constructed after finding the key differential genes. Finally, the diagnostic efficiency of the biomarkers was verified in the validation set and a diagnostic model was constructed. RESULT: Compared with HC group, a total of 19 and 25 differential metabolites were identified in the EOLP group and the ROLP group, respectively. A total of 14 different metabolites were identified between EOLP and ROLP. Two diagnostic models were constructed based on these differential metabolites. There are 14 differential metabolites shared by EOLP and ROLP. The transcriptomics data showed 756 differentially expressed genes, and the final crossover network showed that 19 differential genes were associated with 12 metabolites. Enrichment analysis showed that alanine, aspartate and glutamate metabolism were closely associated with the pathogenesis of OLP. CONCLUSION: The metabolic change of different types of OLP were clarified. The potential gene perturbation of OLP was provided. This study provided a strong support for further exploration of the pathogenic mechanism of OLP.

Long non-coding RNA TP73-AS1 promotes pancreatic cancer growth and metastasis through miRNA-128-3p/GOLM1 axis.

BACKGROUND: Previous studies have suggested that long non-coding RNAs (lncRNA) TP73-AS1 is significantly upregulated in several cancers. However, the biological role and clinical significance of TP73-AS1 in pancreatic cancer (PC) remain unclear. AIM: To investigate the role of TP73-AS1 in the growth and metastasis of PC. METHODS: The expression of lncRNA TP73-AS1, miR-128-3p, and GOLM1 in PC tissues and cells was detected by quantitative real-time polymerase chain reaction. The bioinformatics prediction software ENCORI was used to predict the putative binding sites of miR-128-3p. The regulatory roles of TP73-AS1 and miR-128-3p in cell proliferation, migration, and invasion abilities were verified by Cell Counting Kit-8, wound-healing, and transwell assays, as well as flow cytometry and Western blot analysis. The interactions among TP73-AS1, miR-128-3p, and GOLM1 were explored by bioinformatics prediction, luciferase assay, and Western blot. RESULTS: The expression of TP73-AS1 and miRNA-128-3p was dysregulated in PC tissues and cells. High TP73-AS1 expression was correlated with a poor prognosis. TP73-AS1 silencing inhibited PC cell proliferation, migration, and invasion in vitro as well as suppressed tumor growth in vivo. Mechanistically, TP73-AS1 was validated to promote PC progression through GOLM1 upregulation by competitively binding to miR-128-3p. CONCLUSION: Our results demonstrated that TP73-AS1 promotes PC progression by regulating the miR-128-3p/GOLM1 axis, which might provide a potential treatment strategy for patients with PC.

Comparative study of oncologic efficacy of cephalomedial to lateral dissection versus medial to lateral dissection in laparoscopic total mesorectal excision for rectal cancer: An RCT study.

BACKGROUND AND OBJECTIVES: We compared the 3-year overall survival between cephalomedial-to-lateral approach proctectomy (CEMP) and medial-to-lateral approach proctectomy (MAP) in patients undergoing laparoscopic total mesorectal excision for rectal cancer. The advantages of CEMP and the clinical value of No. 253 lymph nodes resection have not been objectively analyzed in literature. METHODS: This was a prospective, two-arm, multicenter, single-blinded, randomized trial. The primary endpoint was 3-year overall survival, and secondary endpoints included safety, feasibility, oncological radicality (including number of No. 253 lymph nodes harvested), short-term outcome, 3-year disease-free survival, rate of postoperative complications, mortality, and rate of recurrence. RESULTS: From May 2016 to July 2020, 506 patients were enrolled-256 in the CEMP group and 250 in the MAP group. Comparison of overall survival and disease-free survival showed that there was treatment benefit in the CEMP group (28.22 ± 12.12 vs. 27.44 ± 13.06, p = 0.485; 27.24 ± 12.01 vs. 26.42 ± 12.81; p = 0.457). More No. 253 lymph nodes were harvested in the CEMP group, and cases with positive No. 253 lymph nodes had worse prognosis in stage III. Surgical safety was equal for both approaches. CONCLUSIONS: Dissection of No. 253 lymph nodes may be important to improve clinical prognosis, but further studies with larger samples are needed to confirm this finding.

Comparison of Myriophyllum Spicatum and artificial plants on nutrients removal and microbial community in constructed wetlands receiving WWTPs effluents.

The impacts of WWTPs effluents on nutrients removal and epiphytic microbial community in constructed wetlands dominated by submersed macrophytes remain to be fully illustrated. In this study, compared to M. Spicatum, artificial submersed macrophytes (control) generally had higher NH4+-N (78.35% vs 80.52%) and TN (73.35% vs 90.25%) removal rates and similar COD (70.64% vs 70.80%) and TP (59.86% vs 60.82%) removal rates in wetlands receiving simulated effluents of WWTPs (GB18918-2002). Microbial population richness was higher in epiphytic biofilms on M. Spicatum than artificial ones, and substrates played the most decisive role in determining the microbial diversities. Network analysis revealed that there were more complex interactions among environmental parameters, bacteria and eukaryotes in M. Spicatum systems than in artificial ones. Nutrients in effluents could cause damage to M. Spicatum. The results highlight that artificial plants have better performance on effluents deep treatments than submerged plants.

Potential Metabolic Biomarkers for Early Detection of Oral Lichen Planus, a Precancerous Lesion.

Background: Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory disorder and precancerous oral lesion with high incidence. The current diagnostic method of OLP is very limited and metabolomics may provide a new approach for quantitative evaluation. Methods: The Ultra-Performance Liquid Chromatography-Quadrupole/Orbitrap High Resolution Mass Spectrometry (UHPLC-Q-Orbitrap HRMS) was applied to analyze the change of metabolites in serum of patients with OLP. A total of 115 OLP patients and 124 healthy controls were assigned to either a training set (n = 160) or a test set (n = 79). The potential biomarkers and the change of serum metabolites were profiled and evaluated by multivariate analysis. Results: Totally, 23 differential metabolites were identified in the training set between OLP group and healthy group. Three prominent metabolites in receiver operating characteristic (ROC) were selected as a panel to distinguish OLP or healthy individuals in the test set, and the diagnostic accuracy was 86.1%. Conclusions: This study established a new method for the early detection of OLP by analyzing serum metabolomics using UHPLC-Q-Orbitrap HRMS, which will help in understanding the pathological processes of OLP and identifying precancerous lesions in oral cavity.

A PD-1 peptide antagonist exhibits potent anti-tumor and immune regulatory activity.

Antibodies blocking the PD-1/PD-L1 pathway have achieved great success. However, some disadvantages of antibodies have been found, which limit their clinical applications. Peptide antagonists are alternatives to antibodies in PD-1/PD-L1 blockage, but successful studies in this area are limited. A PD-1 targeting peptide, P-F4, was identified using phage display. P-F4 bound PD-1 with an affinity of 0.119 µM, inhibited PD-1/PD-L1 interaction at the cellular level and modulated T cell activity in vitro. We have overcome the poor solubility and rapid degradation problems of this peptide by packaging P-F4 in nanoparticles. In vivo experiments demonstrated that P-F4 nanoparticles could strongly inhibit tumor growth in a CT26 mouse model. Further research revealed that treatment of P-F4 nanoparticles increased CD8+T cells and reduced Tregs in the tumor microenvironment and tumor-draining lymph nodes. It was shown that treatment of P-F4 nanoparticles also increased lymphocytic activities, including proliferation, cytokine secretion and cytolytic activity. Moreover, computer modeling suggested that the P-F4 binding site to PD-1 overlaps with the PD-L1 binding surface. In this study, a peptide candidate for cancer immunotherapy was provided, and its working mechanisms were studied.

Genome-Wide Identification and Analysis of Enhancer-Regulated microRNAs Across 31 Human Cancers.

Enhancers are cis-regulatory DNA elements that positively regulate the transcription of target genes in a tissue-specific manner, and dysregulation of target genes could lead to various diseases, such as cancer. Recent studies have shown that enhancers can regulate microRNAs (miRNAs) and participate in their biological synthesis. However, the network of enhancer-regulated miRNAs across multiple cancers is still unclear. Here, a total of 2,418 proximal enhancer-miRNA interactions and 1,280 distal enhancer-miRNA interactions were identified through the integration of genomic distance, co-expression, and 3D genome data in 31 cancers. The results showed that both proximal and distal interactions exhibited a significant cancer type-specific feature trend at the tissue level rather than at the single-cell level, and there was a noteworthy positive correlation between the expression of the miRNA and the number of enhancers regulating the same miRNA in most cancers. Furthermore, we found that there was a high correlation between the formation of enhancer-miRNA pairs and the expression of enhancer RNAs (eRNAs) whether in distal or proximal regulation. The characteristics analysis showed that miRes (enhancers that regulated miRNAs) and non-miRes presented significant differences in sequence conservation, guanine-cytosine (GC) content, and histone modification signatures. Notably, GC content, H3K4me1, and H3K36me3 were present differently between distal and proximal regulation, suggesting that they might participate in chromosome looping of enhancer-miRNA interactions. Finally, we introduced a case study, enhancer: chr1:1186391-1186507 ∼ miR-200a was highly relevant to the survival of thyroid cancer patients and a cis-eQTL SNP on the enhancer affected the expression of the TNFRSF18 gene as a tumor suppressor.

MiR-301a transcriptionally activated by HIF-2α promotes hypoxia-induced epithelial-mesenchymal transition by targeting TP63 in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is one of the deadliest cancers worldwide. PC metastasis involves a complex set of events, including epithelial-mesenchymal transition (EMT), that increase tumor cell invasiveness. Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis; however, the mechanisms remain elusive. AIM: To investigate the role of miR-301a in hypoxia-induced EMT in PC cells. METHODS: Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions. Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression. Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout. Luciferase assay was used to detect the miR-301a promoter and the 3' untranslated region activity of TP63. Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo. In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples (adjacent paratumor and paired tumor tissues). . RESULTS: Hypoxic environment could directly promote the EMT of PC cells. The expression level of miR-301a was increased in a HIF2α dependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells. Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells, while knocking out miR-301a result in the suppression of hypoxia-induced EMT. TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells. Furthermore, miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo. Additionally, miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis. CONCLUSION: The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.