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The effect of different extraction processes on the physicochemical characterization, digestibility, antioxidant activity and prebiotic activity of Isaria cicadae Miquel fruiting body polysaccharides (ICM) was studied.

Purpose. Atrial fibrillation (AF) is the most frequent arrhythmia in clinical practice. The pathogenesis of AF is not yet clear. Therefore, exploring the molecular information of AF displays much importance for AF therapy. Methods. The GSE2240 data were acquired from the Gene Expression Omnibus (GEO) database. The R limma software package was used to screen DEGs. Based on the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) databases, we conducted the functions and pathway enrichment analyses. Then, the STRING and Cytoscape software were employed to build Protein-Protein Interaction (PPI) network and screen for hub genes. Finally, we used the Cell Counting Kit-8 (CCK-8) experiment to explore the effect of hub gene knockdown on the proliferation of AF cells. Result. 906 differentially expressed genes (DEGs), including 542 significantly upregulated genes and 364 significantly downregulated genes, were screened in AF. The genes of AF were mainly enriched in vascular endothelial growth factor-activated receptor activity, alanine, regulation of histone deacetylase activity, and HCM. The PPI network constructed of significantly upregulated DEGs contained 404 nodes and 514 edges. Five hub genes, ASPM, DTL, STAT3, ANLN, and CDCA5, were identified through the PPI network. The PPI network constructed by significantly downregulated genes contained 327 nodes and 301 edges. Four hub genes, CDC42, CREB1, AR, and SP1, were identified through this PPI network. The results of CCK-8 experiments proved that knocking down the expression of CDCA5 gene could inhibit the proliferation of H9C2 cells. Conclusion. Bioinformatics analyses revealed the hub genes and key pathways of AF. These genes and pathways provide information for studying the pathogenesis, treatment, and prognosis of AF and have the potential to become biomarkers in AF treatment.

Mismatch repair (MMR) is a replication-coupled DNA repair mechanism and plays multiple roles at the replication fork. The well-established MMR functions include correcting misincorporated nucleotides that have escaped the proofreading activity of DNA polymerases, recognizing nonmismatched DNA adducts, and triggering a DNA damage response. In an attempt to determine whether MMR regulates replication progression in cells expressing an ultramutable DNA polymerase ɛ (Polɛ), carrying a proline-to-arginine substitution at amino acid 286 (Polɛ-P286R), we identified an unusual MMR function in response to hydroxyurea (HU)-induced replication stress. Polɛ-P286R cells treated with hydroxyurea exhibit increased MRE11-catalyzed nascent strand degradation. This degradation by MRE11 depends on the mismatch recognition protein MutSα and its binding to stalled replication forks. Increased MutSα binding at replication forks is also associated with decreased loading of replication fork protection factors FANCD2 and BRCA1, suggesting blockage of these fork protection factors from loading to replication forks by MutSα. We find that the MutSα-dependent MRE11-catalyzed fork degradation induces DNA breaks and various chromosome abnormalities. Therefore, unlike the well-known MMR functions of ensuring replication fidelity, the newly identified MMR activity of promoting genome instability may also play a role in cancer avoidance by eliminating rogue cells.

Lactic acid bacteria (LAB) are a representative probiotic. As the dominant flora in the human intestinal tract, LAB can regulate the balance of human intestinal flora and improve host health. The purpose of this study was to isolate and screen LAB that are well suited to the intestinal characteristics of the Chinese population, with excellent probiotics and high antibacterial activity. After 16S ribosomal RNA (rRNA) homology and phylogenetic tree analysis, potential probiotics were tested for their antibacterial activity, resistance to artificial gastrointestinal fluid and drugs, surface hydrophobicity, and safety. Three strains of LAB with acid resistance, bile salt resistance, epithelial cell adhesion, and no multidrug resistance were selected: Lactobacillus salivarius, Leuconostoc lactis, and Lactobacillus paracasei. Analysis of the antibacterial active substances in the three strains and their fermentation broths revealed that the main antibacterial substances of L. lactis were organic acids, whereas those of L. salivarius and L. paracasei were organic acids and bacteriocins with broad-spectrum antibacterial activity. These three strains of probiotic LAB with high antibacterial activity were identified as bacterial resources that could potentially be used to develop probiotic preparations for the prevention and treatment of intestinal diseases caused by intestinal pathogens.

Probiotics and prebiotics for preventing and alleviating the degenerative changes associated with aging have received extensive attention. In the present work, Lactobacillus plantarum (L. plantarum) 69-2 with the highest antioxidant capacity combined with galacto-oligosaccharide (GOS) was used in aging model mice to evaluate the effect on aging and the regulation of gut microbiota. The combination of L. plantarum 69-2 and GOS supplementation could significantly (P < 0.05) improve liver function, antioxidant capacity, and inflammation accompanied by regulating the gut microbiota, increasing the short chain fatty acid (SCFA) levels, and activating the hepatic AMPK/SIRT1 regulatory pathway. The results showed that L. plantarum 69-2 and GOS could activate the hepatic AMPK/SIRT1 signaling pathway by regulating the gut microbiota and metabolites through the liver-gut axis to restore hepatic antioxidant activity to alleviate aging. The study provided a new insight for targeting the gut microbiota to relieve aging through the gut-liver axis.

DNA mismatch repair (MMR) relies on MutS and MutL ATPases for mismatch recognition and strand-specific nuclease recruitment to remove mispaired bases in daughter strands. However, whether the MutS–MutL complex coordinates MMR by ATP-dependent sliding on DNA or protein–protein interactions between the mismatch and strand discrimination signal is ambiguous. Using functional MMR assays and systems preventing proteins from sliding, we show that sliding of human MutSα is required not for MMR initiation, but for final mismatch removal. MutSα recruits MutLα to form a mismatch-bound complex, which initiates MMR by nicking the daughter strand 5′ to the mismatch. Exonuclease 1 (Exo1) is then recruited to the nick and conducts 5′ → 3′ excision. ATP-dependent MutSα dissociation from the mismatch is necessary for Exo1 to remove the mispaired base when the excision reaches the mismatch. Therefore, our study has resolved a long-standing puzzle, and provided new insights into the mechanism of MMR initiation and mispair removal.

Non-amphiphilic WIQPKTKVIPYVRYL (WI-6) derived from bovine αs2-casein f (193-207) was modified by a defined mutation method to obtain five engineered peptides with mirror symmetry structures. The five engineered peptide sequences were WF-1 (WFQVKTRVRTKVQFW), FW-2 (FWRRYKKVKKYRRWF), FW-3 (FWQVIKKVKKIVQWF), FK-4 (FKQFYRRVRRYFQKF), and FR-5 (FRQWYRRVRRYWQRF). However, FW-2, FW-3, FK-4, and FR-5 had obvious XXYXX sequences. Among these, FW-3 was demonstrated to have the highest antibacterial activity, which indicates that the non-perfectly amphipathic α-helical structure containing the XXYXX sequence has a better bactericidal effect. Therefore, peptide FW-3 could be widely used as a substitute for antibiotics in food, medicine, and other fields. These findings provide a potential method for designing novel antimicrobial peptides.

Changes in the physiological state and adhesion of probiotics under stresses affect their interaction with the host. The effects of osmotic (3% NaCl, 6% NaCl, and 3% NaCl + 3% KCl), acid (pH 5.0), and alkali (pH 8.0) stress on the physiological characteristics, adhesion ability and pathogen adhesion inhibition of Lactobacillus plantarum KLDS 1.0328 were investigated. The results showed that 6% NaCl resulted in lower acid production, growth and antimicrobial activity of cells compared to control and 3% NaCl treatment. Reduced surface hydrophobicity, aggregation ability, adhesion ability and pathogen adhesion inhibition were observed when L. plantarum KLDS 1.0328 was exposed to 6% NaCl. These changes were weakened when NaCl was partially replaced by KCl. Exposure to stresses other than alkali stress significantly increased the ratio of unsaturated fatty acid to saturated fatty acid in the cell membrane. The autoaggregation and adhesion ability of cells were increased under pH 5.0 treatment. The results demonstrated that the abilities of cells to adhere and inhibit pathogen adhesion were significantly positively correlated with the ability to coaggregate with pathogens. This study provides a basis for our understanding of the response of L. plantarum to stresses and the related molecular mechanisms.

Oxidative DNA damage contributes to aging and the pathogenesis of numerous human diseases including cancer. 8-hydroxyguanine (8-oxoG) is the major product of oxidative DNA lesions. Although OGG1-mediated base excision repair is the primary mechanism for 8-oxoG removal, DNA mismatch repair has also been implicated in processing oxidative DNA damage. However, the mechanism of the latter is not fully understood. Here, we treated human cells defective in various 8-oxoG repair factors with H

In this study, shell-core fibers were successfully prepared by using Eudragit S100 (ES100) and poly(vinyl alcohol) (PVA)/pectin (PEC) through coaxial electrospinning technology. The electrospun fiber was characterized by attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and X-ray diffraction (XRD). Thermo-gravimetric analysis (TGA) showed that the coaxial electrospun fiber encapsulated with Lactobacillus rhamnosus 1.0320 (L. rhamnosus) had higher thermal stability than the electrospun fiber prepared by uniaxial electrospinning. L. rhamnosus encapsulated by coaxial electrospun fiber maintained 90.07% and 91.96% survivability in simulated gastric and intestinal fluids. After continuous simulated gastrointestinal fluid treatment, the survival rate of L. rhamnosus encapsulated by coaxial electrospun fiber was 81.40%. The results indicate that shell-core fiber-encapsulated probiotics can improve the tolerance of probiotics to the harsh environment of gastrointestinal tract. The fiber prepared in this study can be applied to the preparation of functional fermented food such as probiotic yogurt fermentation in the future.

Soybean oil bodies (SOB) are naturally pre-emulsified lipid droplets recovered directly from soybean seeds. Almost all food emulsions contain salts. However, it was not clear how the incorporation of salts affected the physicochemical stability of SOB.This study investigated the effect of NaCl (0-1.2%) on the physical and oxidative stability of SOB emulsions under neutral (pH 7) and acidic (pH 3) conditions. In the presence of NaCl, the SOB emulsion (pH 7) showed strong flocculation during storage due to electrostatic screening. The NaCl-induced flocculation of SOB was attenuated at pH 3, which may be due to the difference in conformation or interaction of the protein interfaces covering SOB at different pH values. The increase in ionic strength or acid conditioning treatment resulted in a remarkable increase in the stability of SOB emulsions against coalescence. The confocal laser scanning microscopy images also confirmed the NaCl-induced changes in the flocculation/coalescence properties of SOB. The oxidative behavior tests indicated that SOB emulsions containing NaCl were more susceptible to lipid oxidation but protein oxidation was inhibited due to electrostatic screening, which reduced pro-oxidant accessibility of unadsorbed proteins in the emulsion. This oxidative behavior was attenuated at pH 3.The incorporation of NaCl significantly reduced the physical and oxidative stability of the SOB emulsion, and acidic pH mitigated NaCl-induced flocculation and lipid oxidation of SOB. © 2021 Society of Chemical Industry.

Huntington's disease (HD), a neurodegenerative disease characterized by progressive dementia, psychiatric problems, and chorea, is known to be caused by CAG repeat expansions in the HD gene HTT. However, the mechanism of this pathology is not fully understood. The translesion DNA polymerase θ (Polθ) carries a large insertion sequence in its catalytic domain, which has been shown to allow DNA loop-outs in the primer strand. As a result of high levels of oxidative DNA damage in neural cells and Polθ's subsequent involvement in base excision repair of oxidative DNA damage, we hypothesized that Polθ contributes to CAG repeat expansion while repairing oxidative damage within HTT. Here, we performed Polθ-catalyzed in vitro DNA synthesis using various CAG•CTG repeat DNA substrates that are similar to base excision repair intermediates. We show that Polθ efficiently extends (CAG)n•(CTG)n hairpin primers, resulting in hairpin retention and repeat expansion. Polθ also triggers repeat expansions to pass the threshold for HD when the DNA template contains 35 repeats upward. Strikingly, Polθ depleted of the catalytic insertion fails to induce repeat expansions regardless of primers and templates used, indicating that the insertion sequence is responsible for Polθ's error-causing activity. In addition, the level of chromatin-bound Polθ in HD cells is significantly higher than in non-HD cells and exactly correlates with the degree of CAG repeat expansion, implying Polθ's involvement in triplet repeat instability. Therefore, we have identified Polθ as a potent factor that promotes CAG•CTG repeat expansions in HD and other neurodegenerative disorders.

DNA mismatch repair (MMR) maintains genome stability primarily by correcting replication errors. MMR deficiency can lead to cancer development and bolsters cancer cell resistance to chemotherapy. However, recent studies have shown that checkpoint blockade therapy is effective in MMR-deficient cancers, thus the ability to identify cancer etiology would greatly benefit cancer treatment. MutS homolog 2 (MSH2) is an obligate subunit of mismatch recognition proteins MutSα (MSH2-MSH6) and MutSβ (MSH2-MSH3). Precise regulation of MSH2 is critical, as either over- or underexpression of MSH2 results in an increased mutation frequency. The mechanism by which cells maintain MSH2 proteostasis is unknown. Using functional ubiquitination and deubiquitination assays, we show that the ovarian tumor (OTU) family deubiquitinase ubiquitin aldehyde binding 1 (OTUB1) inhibits MSH2 ubiquitination by blocking the E2 ligase ubiquitin transfer activity. Depleting OTUB1 in cells promotes the ubiquitination and subsequent degradation of MSH2, leading to greater mutation frequency and cellular resistance to genotoxic agents, including the common chemotherapy agents N-methyl-N'-nitro-N-nitrosoguanidine and cisplatin. Taken together, our data identify OTUB1 as an important regulator of MSH2 stability and provide evidence that OTUB1 is a potential biomarker for cancer etiology and therapy.

This paper presents an in-depth study and analysis of the 3D arterial centerline in spiral CT coronary angiography, and constructs its detection and extraction technique. The first time, the distance transform is used to complete the boundary search of the original figure; the second time, the distance transform is used to calculate the value of the distance transform of all voxels, and according to the value of the distance transform, unnecessary voxels are deleted, to complete the initial contraction of the vascular region and reduce the computational consumption in the next process; then, the nonwitnessed voxels are used to construct the maximum inner joint sphere model and find the skeletal voxels that can reflect the shape of the original figure. Finally, the skeletal lines were optimized on these initially extracted skeletal voxels using a dichotomous-like principle to obtain the final coronary artery centerline. Through the evaluation of the experimental results, the algorithm can extract the coronary centerline more accurately. In this paper, the segmentation method is evaluated on the test set data by two kinds of indexes: one is the index of segmentation result evaluation, including dice coefficient, accuracy, specificity, and sensitivity; the other is the index of clinical diagnosis result evaluation, which is to refine the segmentation result for vessel diameter detection. The results obtained in this paper were compared with the physicians’ labeling results. In terms of network performance, the Dice coefficient obtained in this paper was 0.89, the accuracy was 98.36%, the sensitivity was 93.36%, and the specificity was 98.76%, which reflected certain advantages in comparison with the advanced methods proposed by previous authors. In terms of clinical evaluation indexes, by performing skeleton line extraction and diameter calculation on the results obtained by the segmentation method proposed in this paper, the absolute error obtained after comparing with the diameter of the labeled image was 0.382 and the relative error was 0.112, which indicates that the segmentation method in this paper can recover the vessel contour more accurately. Then, the results of coronary artery centerline extraction with and without fine branch elimination were evaluated, which proved that the coronary artery centerline has higher accuracy after fine branch elimination. The algorithm is also used to extract the centerline of the complete coronary artery tree, and the results prove that the algorithm has better results for the centerline extraction of the complete coronary vascular tree.

In this study, pectin-based nanofibers were prepared by electrospinning for the first time to encapsulate probiotics. Different proportions of electrospun nanofibers were prepared by blending poly(vinyl alcohol) (PVA) with pectin (PEC). With increasing PEC proportion, the viscosity and conductivity of the solution increased, which decreased the nanofiber diameter. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) analysis showed that PVA and PEC were combined by hydrogen bonding. Thermal analysis showed that PVA/PEC nanofibers had good thermal stability. When the PVA:PEC proportion was 9:1, the viable count of Lactobacillus rhamnosus 1.0320 encapsulated by electrospinning technology was the largest, and the survival rate was 89.26%. The survival rate of PVA/PEC nanofiber-encapsulated Lactobacillus rhamnosus 1.0320 was 84.63% after storage at 4 °C for 21 days. PVA/PEC nanofibers have potential applications in probiotic preservation.

Oral squamous cell carcinoma (OSCC) is a common subtype of head and neck squamous cell carcinoma (HNSCC), but the pathogenesis underlying familial OSCCs is unknown. Here, we analyzed whole-genome sequences of a family with autosomal dominant expression of oral tongue cancer and identified proto-oncogenes VAV2 and IQGAP1 as the primary factors responsible for oral cancer in the family. These two genes are also frequently mutated in sporadic OSCCs and HNSCCs. Functional analysis revealed that the detrimental variants target tumorigenesis-associated pathways, thus confirming that these novel genetic variants help to establish a predisposition to familial OSCC.

Non-amphiphilic WIQPKTKVIPYVRYL (WI-6) derived from bovine α

The aim of the present study was to estimate the prevalence of Salmonella and investigate the dominant serovars distribution in raw beef and to screen the isolated serovars for the prescense of beta-lactamases and virulence genes. A total of 150 samples of raw beef sold at butcher shops (n = 75) and supermarkets (n = 75) in Karachi city were collected (50 samples each from muscles, lymph nodes, and minced beef). The samples were cultured according to the ISO-6579-1guidlines. The overall prevalence of Salmonella strains was found to be 21.34%. A total of 56 isolates of Salmonella belonging to four serogroups (Salmonella Pullorum, Salmonella Enteritidis, Salmonella Typhimurium and Salmonella Choleraesuis) were isolated from beef muscles (12%), lymph nodes (24%) and minced beef (28%) samples collected from butcher shops (av. 21.34%). No Salmonella was detected in beef samples collected from supermarkets. S. Enteritidis contamination was highest (37.5%), followed by S. Choleraesuis (30.4%), S. Pullorum (19.6%) and S. Typhimurium (12.5 %). Antibiotic susceptibility testing revealed that Salmonella isolates were highly resistant to Oxytetracycline (90%), Ampicillin (90.5%), Amoxicillin (81.1%), Tetracycline (76%), Neomycin, (79.8%) and Ciprofloxacin (61.4%). The Salmonella isolates examined were more susceptible to the Cephalosporin antibiotics such as Cefixime (43.2%), Cefepime (48.2) and Cefoxitin (49.8%). PCR based screening of blaTEM, blaCTX-M and blaSHV revealed that blaCTX-M and blaTEM were the dominant resistant genes in S. Enteritidis and S. Typhimurium followed by S. Pullorum and S. Choleraesuis whereas blaSHV was the least detected beta-lactamase in Salmonella isolates. Virulence genes screening revealed that at least five genes were present in all the serovars, highest being present in S. Enteritidis (12/17) and S. Typhimurium (12/17). S. Cholerasuis (5/17) carried the least number of virulence genes followed by S. Pullorum (6/17). The present data suggest that beef samples from butcher shops of Karachi city are heavily contaminated with MDR Salmonella. The presence of resistance and virulence genes in MDR strains of Salmonella may play a significant role in transmission and development of Salmonella infection in humans.

Somatic mutations on glycine 34 of histone H3 (H3G34) cause pediatric cancers, but the underlying oncogenic mechanism remains unknown. We demonstrate that substituting H3G34 with arginine, valine, or aspartate (H3G34R/V/D), which converts the non-side chain glycine to a large side chain-containing residue, blocks H3 lysine 36 (H3K36) dimethylation and trimethylation by histone methyltransferases, including SETD2, an H3K36-specific trimethyltransferase. Our structural analysis reveals that the H3 “G33-G34” motif is recognized by a narrow substrate channel, and that H3G34/R/V/D mutations impair the catalytic activity of SETD2 due to steric clashes that impede optimal SETD2–H3K36 interaction. H3G34R/V/D mutations also block H3K36me3 from interacting with mismatch repair (MMR) protein MutSα, preventing the recruitment of the MMR machinery to chromatin. Cells harboring H3G34R/V/D mutations display a mutator phenotype similar to that observed in MMR-defective cells. Therefore, H3G34R/V/D mutations promote genome instability and tumorigenesis by inhibiting MMR activity.

The aim of the present study was to estimate the prevalence of Salmonella and investigate the dominant serovars distribution in raw beef and to screen the isolated serovars for the prescense of beta-lactamases and virulence genes. A total of 150 samples of raw beef sold at butcher shops (n = 75) and supermarkets (n = 75) in Karachi city were collected (50 samples each from muscles, lymph nodes, and minced beef). The samples were cultured according to the ISO-6579-1guidlines. The overall prevalence of Salmonella strains was found to be 21.34%. A total of 56 isolates of Salmonella belonging to four serogroups (Salmonella Pullorum, Salmonella Enteritidis, Salmonella Typhimurium and Salmonella Choleraesuis) were isolated from beef muscles (12%), lymph nodes (24%) and minced beef (28%) samples collected from butcher shops (av. 21.34%). No Salmonella was detected in beef samples collected from supermarkets. S. Enteritidis contamination was highest (37.5%), followed by S. Choleraesuis (30.4%), S. Pullorum (19.6%) and S. Typhimurium (12.5 %). Antibiotic susceptibility testing revealed that Salmonella isolates were highly resistant to Oxytetracycline (90%), Ampicillin (90.5%), Amoxicillin (81.1%), Tetracycline (76%), Neomycin, (79.8%) and Ciprofloxacin (61.4%). The Salmonella isolates examined were more susceptible to the Cephalosporin antibiotics such as Cefixime (43.2%), Cefepime (48.2) and Cefoxitin (49.8%). PCR based screening of blaTEM, blaCTX-M and blaSHV revealed that blaCTX-M and blaTEM were the dominant resistant genes in S. Enteritidis and S. Typhimurium followed by S. Pullorum and S. Choleraesuis whereas blaSHV was the least detected beta-lactamase in Salmonella isolates. Virulence genes screening revealed that at least five genes were present in all the serovars, highest being present in S. Enteritidis (12/17) and S. Typhimurium (12/17). S. Cholerasuis (5/17) carried the least number of virulence genes followed by S. Pullorum (6/17). The present data suggest that beef samples from butcher shops of Karachi city are heavily contaminated with MDR Salmonella. The presence of resistance and virulence genes in MDR strains of Salmonella may play a significant role in transmission and development of Salmonella infection in humans.

Histone H3 trimethylation at lysine 36 (H3K36me3) is an important histone mark involved in both transcription elongation and DNA mismatch repair (MMR). It is known that H3K36me3 recruits the mismatch-recognition protein MutSα to replicating chromatin via its physical interaction with MutSα's PWWP domain, but the exact role of H3K36me3 in transcription is undefined. Using ChIP combined with whole-genome DNA sequencing analysis, we demonstrate here that H3K36me3, together with MutSα, is involved in protecting against mutation, preferentially in actively transcribed genomic regions. We found that H3K36me3 and MutSα are much more co-enriched in exons and actively transcribed regions than in introns and nontranscribed regions. The H3K36me3–MutSα co-enrichment correlated with a much lower mutation frequency in exons and actively transcribed regions than in introns and nontranscribed regions. Correspondingly, depleting H3K36me3 or disrupting the H3K36me3–MutSα interaction elevated the spontaneous mutation frequency in actively transcribed genes, but it had little influence on the mutation frequency in nontranscribed or transcriptionally inactive regions. Similarly, H(2)O(2)-induced mutations, which mainly cause base oxidations, preferentially occurred in actively transcribed genes in MMR-deficient cells. The data presented here suggest that H3K36me3-mediated MMR preferentially safeguards actively transcribed genes not only during replication by efficiently correcting mispairs in early replicating chromatin but also during transcription by directly or indirectly removing DNA lesions associated with a persistently open chromatin structure.

Oral squamous cell carcinoma (OSCC) is a common subtype of head and neck squamous cell carcinoma (HNSCC), but the pathogenesis underlying familial OSCCs is unknown. Here, we analyzed whole-genome sequences of a family with autosomal dominant expression of oral tongue cancer and identified proto-oncogenes VAV2 and IQGAP1 as the primary factors responsible for oral cancer in the family. These two genes are also frequently mutated in sporadic OSCCs and HNSCCs. Functional analysis revealed that the detrimental variants target tumorigenesis-associated pathways, thus confirming that these novel genetic variants help to establish a predisposition to familial OSCC.

Proliferating cell nuclear antigen (PCNA) and its posttranslational modifications regulate DNA metabolic reactions, including DNA replication and repair, at replication forks. PCNA phosphorylation at Tyr-211 (PCNA-Y211p) inhibits DNA mismatch repair and induces misincorporation during DNA synthesis. Here, we describe an unexpected role of PCNA-Y211p in cancer promotion and development. Cells expressing phosphorylation-mimicking PCNA, PCNA-Y211D, show elevated hallmarks specific to the epithelial-mesenchymal transition (EMT), including the up-regulation of the EMT-promoting factor Snail and the down-regulation of EMT-inhibitory factors E-cadherin and GSK3β. The PCNA-Y211D–expressing cells also exhibited active cell migration and underwent G(2)/M arrest. Interestingly, all of these EMT-associated activities required the activation of ATM and Akt kinases, as inactivating these protein kinases by gene knockdown or inhibitors blocked EMT-associated signaling and cell migration. We concluded that PCNA phosphorylation promotes cancer progression via the ATM/Akt/GSK3β/Snail signaling pathway. In conclusion, this study identifies a novel PCNA function and reveals the molecular basis of phosphorylated PCNA-mediated cancer development and progression.

In this study, gum arabic (GA)-based nanofibres were prepared and characterized in combination with pullulan (PUL) by electrospinning for the first time, and they served as the wall material for Lactobacillus encapsulation. The presence of GA in hybrid solutions resulted in increased conductivity, reduced surface tension and lower viscosity (P

Tumors with defective mismatch repair (dMMR) are responsive to immunotherapy because of dMMR-induced neoantigens and activation of the cGAS-STING pathway. While neoantigens result from the hypermutable nature of dMMR, it is unknown how dMMR activates the cGAS-STING pathway. We show here that loss of the MutLα subunit MLH1, whose defect is responsible for ~50% of dMMR cancers, results in loss of MutLα-specific regulation of exonuclease 1 (Exo1) during DNA repair. This leads to unrestrained DNA excision by Exo1, which causes increased single-strand DNA formation, RPA exhaustion, DNA breaks, and aberrant DNA repair intermediates. Ultimately, this generates chromosomal abnormalities and the release of nuclear DNA into the cytoplasm, activating the cGAS-STING pathway. In this study, we discovered a hitherto unknown MMR mechanism that modulates genome stability and has implications for cancer therapy.

Rhizome of Curcuma wenyujin, which is called EZhu in China, is a traditional Chinese medicine used to treat blood stasis for many years. However, the underlying mechanism of EZhu is not clear at present. In this study, plasma metabolomics combined with network pharmacology were used to elucidate the therapeutic mechanism of EZhu in blood stasis from a metabolic perspective. The results showed that 26 potential metabolite markers of acute blood stasis were screened, and the levels were all reversed to different degrees by EZhu preadministration. Metabolic pathway analysis showed that the improvement of blood stasis by Curcuma wenyujin rhizome was mainly related to lipid metabolism (linoleic acid metabolism, ether lipid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism) and amino acid metabolisms (tryptophan metabolism, lysine degradation). The component-target-pathway network showed that 68 target proteins were associated with 21 chemical components in EZhu. Five metabolic pathways of the network, including linoleic acid metabolism, sphingolipid metabolism, glycerolipid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis, were consistent with plasma metabolomics results. In conclusion, plasma metabolomics combined with network pharmacology can be helpful to clarify the mechanism of EZhu in improving blood stasis and to provide a literature basis for further research on the therapeutic mechanism of EZhu in clinical practice.