EGR3 Inhibits Tumor Progression by Inducing Schwann Cell-Like Differentiation.

The mechanism and function of the expression of Schwann characteristics by nevus cells in the mature zone of the dermis are unknown. Early growth response 3 (EGR3) induces Schwann cell-like differentiation of melanoma cells by simulating the process of nevus maturation, which leads to a strong phenotypic transformation of the cells, including the formation of long protrusions and a decrease in cell motility, proliferation, and melanin production. Meanwhile, EGR3 regulates the levels of myelin protein zero (MPZ) and collagen type I alpha 1 chain (COL1A1) through SRY-box transcription factor 10 (SOX10)-dependent and independent mechanisms, by binding to non-strictly conserved motifs, respectively. Schwann cell-like differentiation demonstrates significant benefits in both in vivo and clinical studies. Finally, a CD86-P2A-EGR3 recombinant mRNA vaccine is developed which leads to tumor control through forced cell differentiation and enhanced immune infiltration. Together, these data support further development of the recombinant mRNA as a treatment for cancer.

Brain connectome-based imaging markers for identifiable signature of migraine with and without aura.

Background: Cortical spreading depression (CSD) has been considered the prominent theory for migraine with aura (MwA). However, it is also argued that CSD can exist in patients in a silent state, and not manifest as aura. Thus, the MwA classification based on aura may be questionable. This study aimed to capture whole-brain connectome-based imaging markers with identifiable signatures for MwA and migraine without aura (MwoA). Methods: A total of 88 migraine patients (32 MwA) and 49 healthy controls (HC) underwent a diffusion tensor imaging and resting-state functional magnetic resonance imaging scan. The whole-brain structural connectivity (SC) and functional connectivity (FC) analysis was employed to extract imaging features. The extracted features were subjected to an all-relevant feature selection process within cross-validation loops to pinpoint attributes demonstrating substantial efficacy for patient categorization. Based on the identified features, the predictive ability of the random forest classifiers constructed with the 88 migraine patients' sample was tested using an independent sample of 32 migraine patients (eight MwA). Results: Compared to MwoA and HC, MwA showed two reduced SC and six FC (five increased and one reduced) features [all P<0.01, after false discovery rate (FDR) correction], involving frontal areas, temporal areas, visual areas, amygdala, and thalamus. A total of four imaging features were significantly correlated with clinical rating scales in all patients (r=-0.38 to 0.47, P<0.01, after FDR correction). The predictive ability of the random forest classifiers achieved an accuracy of 78.1% in the external sample to identify MwA. Conclusions: The whole-brain connectivity features in our results may serve as connectome-based imaging markers for MwA identification. The alterations of SC and FC strength provide possible evidence in further understanding the heterogeneity and mechanism of MwA which may help for patient-specific decision-making.

Aberrant brain functional hubs and causal effective connectivity in menstrually-related and non-menstrually-related migraine without aura.

Background: Menstrual migraine without aura (MRM) is common in female migraineurs and is closely related to cerebral functional abnormalities. However, whether the whole brain networks and directional functional connectivity of MRM patients are altered remains unclear. The purpose of this study was to detect the alterations of resting-state functional networks and directional functional connectivity between MRM and non-menstrual migraine without aura (NMM) patients using functional magnetic resonance imaging (fMRI) with degree centrality (DC) and Granger causality analysis (GCA) methods. Methods: In this retrospective and cross-sectional study, 45 MRM and 40 NMM patients (matched in age, gender, and years of education) were recruited in the study between May 2018 and June 2022. All participants had undergone resting-state fMRI scanning at the Neurology and Pain Outpatient Department of Nanjing First Hospital. Their brain functions were analyzed in terms of DC and GCA, with the significant threshold at voxel level P<0.01 and cluster level P<0.05, Gaussian random field corrected. Correlation analysis was adopted to assess the relationships between the fMRI results and clinical features (P<0.05, Bonferroni corrected). Results: Compared with those in the NMM group, MRM patients showed decreased DC in the right insula (T=-4.253). Using the right insula as the seed region, patients with MRM demonstrated enhanced effective connectivity from the right insula to the ipsilateral middle temporal gyrus (T=4.138) and contralateral superior temporal gyrus (T=3.523). Furthermore, the MRM group also showed decreased effective connectivity from several brain regions to the right insula, which included the right inferior occipital gyrus (T=-4.498), left middle frontal gyrus (T=-4.879), right precuneus (T=-4.644), and left inferior parietal gyrus (T=-4.113). The average Self-rating Anxiety Scale score of the MRM group was significantly higher than that of the NMM group [P=0.032, 95% confidence interval (CI): 0.363-7.761]. In the MRM group, disease duration was negatively correlated with the mean value of DC in right insula (r=-0.428, P=0.01). Conclusions: The present research demonstrated that patients with MRM have disruption in insula resting-state functional networks. Disrupted networks contained regions associated with cognitive processes, emotional perception, and migraine attack in MRM patients. These results may improve our comprehension of the neuromechanism of menstrually-related migraine.

HSF4/COIL complex-dependent R-loop mediates ultraviolet-induced inflammatory skin injury.

Intense ultraviolet (UV) exposure can cause phototoxic reactions, such as skin inflammation, resulting in injury. UV is a direct cause of DNA damage, but the mechanisms underlying transcriptional regulation within cells after DNA damage are unclear. The bioinformatics analysis of transcriptome sequencing data from UV-irradiated and non-UV-irradiated skin showed that transcription-related proteins, such as HSF4 and COIL, mediate cellular response to UV irradiation. HSF4 and COIL can form a complex under UV irradiation, and the preference for binding target genes changed because of the presence of a large number of R-loops in cells under UV irradiation and the ability of COIL to recognize R-loops. The regulation of target genes was altered by the HSF4-COIL complex, and the expression of inflammation and ageing-related genes, such as Atg7, Tfpi, and Lims1, was enhanced. A drug screen was performed for the recognition sites of COIL and R-loop. N6-(2-hydroxyethyl)-adenosine can competitively bind COIL and inhibit the binding of COIL to the R-loop. Thus, the activation of downstream inflammation-related genes and inflammatory skin injury was inhibited.

Alternative Z-genome biosynthesis pathway shows evolutionary progression from Archaea to phage.

Many bacteriophages evade bacterial immune recognition by substituting adenine with 2,6-diaminopurine (Z) in their genomes. The Z-genome biosynthetic pathway involves PurZ that belongs to the PurA (adenylosuccinate synthetase) family and bears particular similarity to archaeal PurA. However, how the transition of PurA to PurZ occurred during evolution is not clear; recapturing this process may shed light on the origin of Z-containing phages. Here we describe the computer-guided identification and biochemical characterization of a naturally existing PurZ variant, PurZ0, which uses guanosine triphosphate as the phosphate donor rather than the ATP used by PurZ. The atomic resolution structure of PurZ0 reveals a guanine nucleotide binding pocket highly analogous to that of archaeal PurA. Phylogenetic analyses suggest PurZ0 as an intermediate during the evolution of archaeal PurA to phage PurZ. Maintaining the balance of different purines necessitates further evolvement of guanosine triphosphate-using PurZ0 to ATP-using PurZ in adaptation to Z-genome life.

The adenosinergic machinery in cancer: In-tandem insights from basic mechanisms to therapy.

Extracellular adenosine (eADO) signaling has emerged as an increasingly important regulator of immune responses, including tumor immunity. eADO is mainly produced from extracellular ATP (eATP) hydrolysis. eATP is rapidly accumulated in the extracellular space following cell death or cellular stress triggered by hypoxia, nutrient starvation, or inflammation. eATP plays a pro-inflammatory role by binding and activating the P2 purinergic receptors (P2X and P2Y), while eADO has been reported in many studies to mediate immunosuppression by activating the P1 purinergic receptors (A1, A2A, A2B, and A3) in diverse immune cells. Consequently, the hydrolysis of eATP to eADO alters the immunosurveillance in the tumor microenvironment (TME) not only by reducing eATP levels but also by enhancing adenosine receptor signaling. The effects of both P1 and P2 purinergic receptors are not restricted to immune cells. Here we review the most up-to-date understanding of the tumor adenosinergic system in all cell types, including immune cells, tumor cells, and stromal cells in TME. The potential novel directions of future adenosinergic therapies in immuno-oncology will be discussed.

The Functions and Mechanisms of Translatable Circular RNAs.

Circular RNAs (circRNAs) are covalently closed RNA produced by back-splicing. CircRNAs have been considered as a type of noncoding RNAs for a long time. However, recent studies have shown that circRNAs can be translated into functional proteins. Proteins specifically encoded by circRNAs have been proved to play important roles in cancer pathology. In this review, we introduce the methods commonly used to identify and validate circRNA translation in detail. We also describe the major mechanisms driving the translation of these circRNAs. In addition, we summarize the main functions of the circRNA-encoded proteins in both physiologic and pathologic conditions. Finally, we discuss the therapeutic potential and challenges in the usage of synthetic translatable circRNAs. This brief review highlights recent discoveries made in this field and the progress of therapy based on translatable circRNAs. SIGNIFICANCE STATEMENT: Understanding the translation of circRNA could facilitate the identification of novel drug targets in various diseases. Moreover, some circRNA encoded proteins were demonstrated to have therapeutic functions in cancer. The application of synthetic circRNAs as carriers to achieve stable protein expression in vitro and in vivo has tremendous therapeutic potential.

GmYSL7 controls iron uptake, allocation, and cellular response of nodules in soybean.

Iron (Fe) is essential for DNA synthesis, photosynthesis and respiration of plants. The demand for Fe substantially increases during legumes-rhizobia symbiotic nitrogen fixation because of the synthesis of leghemoglobin in the host and Fe-containing proteins in bacteroids. However, the mechanism by which plant controls iron transport to nodules remains largely unknown. Here we demonstrate that GmYSL7 serves as a key regulator controlling Fe uptake from root to nodule and distribution in soybean nodules. GmYSL7 is Fe responsive and GmYSL7 transports iron across the membrane and into the infected cells of nodules. Alterations of GmYSL7 substantially affect iron distribution between root and nodule, resulting in defective growth of nodules and reduced nitrogenase activity. GmYSL7 knockout increases the expression of GmbHLH300, a transcription factor required for Fe response of nodules. Overexpression of GmbHLH300 decreases nodule number, nitrogenase activity and Fe content in nodules. Remarkably, GmbHLH300 directly binds to the promoters of ENOD93 and GmLbs, which regulate nodule number and nitrogenase activity, and represses their transcription. Our data reveal a new role of GmYSL7 in controlling Fe transport from host root to nodule and Fe distribution in nodule cells, and uncover a molecular mechanism by which Fe affects nodule number and nitrogenase activity.

Neuropeptide Y regulates cholesterol uptake and efflux in macrophages and promotes foam cell formation.

The dysregulation of lipid metabolic pathways (cholesterol uptake and efflux) in macrophages results in the formation of lipid-dense macrophages, named foam cells, that participate in plaque formation. NPY binding to NPY receptors in macrophages can modulate cell functions and affect the process of atherosclerotic plaques. The present study aimed to determine whether NPY affects the formation of macrophage-derived foam cells and its underlying mechanisms in macrophages. THP-1-derived macrophages were incubated with oxidized low-density lipoprotein (ox-LDL) and treated with different concentrations of NPY. We analysed the relative levels of proteins related to cholesterol uptake and efflux. We found that NPY effectively increased cholesterol uptake and intracellular cholesterol content via the Y1 and Y5 receptors, and this effect was blocked by Y1 and Y5 antagonists. Mechanistically, NPY enhanced the expression of SRA and CD36 via the PKC/PPARγ pathways, promoting macrophage cholesterol uptake. Moreover, NPY significantly decreased cholesterol efflux to the extracellular cholesterol acceptors ApoA1 and HDL in macrophages. NPY mediated decreases in ABCA1, ABCG1 and SR-BI expression through the inhibition of the JAK/STAT3 pathways. Our results suggest that NPY binding to the Y1 and Y5 receptors enhances foam cell formation by regulating cholesterol uptake and efflux in macrophages.

Profiling the role of microorganisms in quality improvement of the aged flue-cured tobacco.

BACKGROUND: The aging process in the tobacco production, as in other food industries, is an important process for improving the quality of raw materials. In the spontaneous aging, the complex components in flue-cured tobacco (FT) improve flavor or reduce harmful compounds through chemical reactions, microbial metabolism, and enzymatic catalysis. Some believed that tobacco-microbe played a significant part in this process. However, little information is available on how microbes mediate chemical composition to improve the quality of FT, which will lay the foundation for the time-consuming spontaneous aging to seek ways to shorten the aging cycle. RESULTS: Comparing aged and unaged FT, volatile and non-volatile differential compounds (DCs) were multi-dimensionally analyzed with the non-targeted metabolomes based on UPLC-QTOP-MS (the ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry), GC-MS (gas chromatography-mass spectrometer) assisted derivatization and HP-SPME-GC/MS (headspace solid-phase micro-extraction assisted GC-MS). Products associated with the degradation pathways of terpenoids or higher fatty acids were one of the most important factors in improving FT quality. With the microbiome, the diversity and functions of microbial flora were analyzed. The high relative abundance function categories were in coincidence with DCs-related metabolic pathways. According to the correlation analysis, Acinetobacter, Sphingomonas and Aspergillus were presumed to be the important contributor, in which Aspergillus was associated with the highest number of degradation products of terpenoids and higher fatty acids. At last, the screened Aspergillus nidulans strain F4 could promote the degradation of terpenoids and higher fatty acids to enhance tobacco flavor by secreting highly active lipoxygenase and peroxidase, which verified the effect of tobacco-microbes on FT quality. CONCLUSIONS: By integrating the microbiome and metabolome, tobacco-microbe can mediate flavor-related substances to improve the quality of FT after aging, which provided a basis for identifying functional microorganisms for reforming the traditional spontaneous aging.

Effects of Inoculation With Acinetobacter on Fermentation of Cigar Tobacco Leaves.

Metabolic activity of the microbial community greatly affects the quality of cigar tobacco leaves (CTLs). To improve the quality of CTLs, two extrinsic microbes (Acinetobacter sp. 1H8 and Acinetobacter indicus 3B2) were inoculated into CTLs. The quality of CTLs were significantly improved after fermentation. The content of solanone, 6-methyl-5-hepten-2-one, benzeneacetic acid, ethyl ester, cyclohexanone, octanal, acetophenone, and 3,5,5-trimethyl-2-cyclohexen-1-one were significantly increased after inoculated Acinetobacter sp. 1H8. The inoculation of Acinetobacter sp. 1H8 enhanced the normal evolutionary trend of bacterial community. The content of trimethyl-pyrazine, 2,6-dimethyl-pyrazine, and megastigmatrienone were significantly increased after inoculated Acinetobacter indicus 3B2. The inoculation of Acinetobacter indicus 3B2 completely changed the original bacterial community. Network analysis revealed that Acinetobacter was negatively correlated with Aquabacterium, positively correlated with Bacillus, and had significant correlations with many volatile flavor compounds. This work may be helpful for improving fermentation product quality by regulating microbial community, and gain insight into the microbial ecosystem.

Semiconducting Polymer Nanoparticles with Surface-Mimicking Protein Secondary Structure as Lysosome-Targeting Chimaeras for Self-Synergistic Cancer Immunotherapy.

Immunotherapy has received tremendous attention for tumor treatment, but the efficacy is greatly hindered by insufficient tumor-infiltration of immune cells and immunosuppressive tumor microenvironment. The strategy that can efficiently activate cytotoxic T lymphocytes and inhibit negative immune regulators will greatly amplify immunotherapy outcome, which is however very rare. Herein, a new kind of semiconducting polymer (SP) nanoparticles is developed, featured with surface-mimicking protein secondary structure (SPSS NPs) for self-synergistic cancer immunotherapy by combining immunogenic cell death (ICD) and immune checkpoint blockade therapy. The SPs with excellent photodynamic property are synthesized by rational fluorination, which can massively induce ICD. Additionally, the peptide antagonists are introduced and self-assembled into ß-sheet protein secondary structures on the photodynamic NP surface via preparation process optimization, which function as efficient lysosome-targeting chimaeras (LYTACs) to mediate the degradation of programmed cell death ligand-1 (PD-L1) in lysosome. In vivo experiments demonstrate that SPSS NPs can not only elicit strong antitumor immunity to suppress both primary tumor and distant tumor, but also evoke long-term immunological memory against tumor rechallenge. This work introduces a new kind of robust immunotherapy agents by combining well-designed photosensitizer-based ICD induction and protein secondary structures-mediated LYTAC-like multivalence PD-L1 blockade, rendering great promise for synergistic immunotherapy.

Analysis of Microbial Community, Volatile Flavor Compounds, and Flavor of Cigar Tobacco Leaves From Different Regions.

Despite the booming international trade in cigar tobacco leaves (CTLs), the main characteristics of tobacco leaves from different producing areas are rarely reported. This study aimed to characterize the microbial community, volatile flavor compounds (VFCs), and flavor of CTLs from four famous cigar-producing areas, including Dominica, Brazil, Indonesia, and China. High-throughput sequencing results showed that the dominant genera in CTLs were Staphylococcus, Pseudomonas, Aspergillus, Sampaiozyma, and Alternaria. Sensory analysis revealed that Indonesian and Chinese CTLs were characterized by leathery, peppery, and baked aroma. Brazilian CTLs were dominated by caramel and herb aroma. Dominican CTLs had aromas of milk, fruity, sour, cream, flower, nutty, and honey. Supplemented with the determination of volatile flavor compounds (VFCs), the flavor of CTLs could be scientifically quantified. Most of these VFCs were aldehydes and ketones, and 20 VFCs showed significant differences in CTLs from different regions. The microbial community, VFCs, and flavor of CTLs vary widely due to geographic differences. Network analysis revealed the microbial community was closely related to most VFCs, but the relationships between the fungal community and VFCs were less than the bacterial community, and most of them were negative. Furthermore, it also found that the bacterial community had a greater contribution to the flavor of CTLs than the fungal community. This study obtained essential information on CTLs, which laid a foundation for deeply excavating the relationship between microbes and VFCs and flavor, and establishing a tobacco information database.

Metabolite-based cell sorting workflow for identifying microbes producing carbonyls in tobacco leaves.

Carbonyl compounds represented by aldehydes and ketones make an important contribution to the flavor of tobacco. Since most carbonyl compounds are produced by microbes during tobacco fermentation, identifying their producers is important to improve the quality of tobacco. Here, we created an efficient workflow that combines metabolite labeling with fluorescence-activated cell sorting (ML-FACS), 16S rRNA gene sequencing, and microbial culture to identify the microbes that produce aldehydes or ketones in fermented cigar tobacco leaves (FCTL). Microbes were labeled with a specific fluorescent dye (cyanine5 hydrazide) and separated by flow cytometry. Subsequently, the sorted microbes were identified and cultured under laboratory conditions. Four genera, Acinetobacter, Sphingomonas, Solibacillus, and Lysinibacillus, were identified as the main carbonyl compound-producing microbes in FCTL. In addition, these microorganisms could produce flavor-related aldehydes and ketones in a simple synthetic medium, such as benzaldehyde, phenylacetaldehyde, 4-hydroxy-3-ethoxy-benzaldehyde, and 3,5,5-trimethyl-2-cyclohexene-1-one. On the whole, this research has developed a new method to quickly isolate and identify microorganisms that produce aldehydes or ketones from complex microbial communities. ML-FACS would also be used to identify other compound-producing microorganisms in other systems. KEY POINTS: • An approach was developed to identify target microbes in complex communities. • Microbes that produce aldehyde/ketone flavor compounds in fermented cigar tobacco leaves were identified. • Functional microbes that produce aldehyde/ketone flavor compounds from the native environment were captured in pure cultures.

Semiconducting Polymer Nanoparticles with Intramolecular Motion-Induced Photothermy for Tumor Phototheranostics and Tooth Root Canal Therapy.

Much effort is devoted to develop agents with superior photoacoustic/photothermal properties for improved disease diagnosis and treatment. Herein, a new fused two isoindigo (DIID)-based semiconducting conjugated polymer (named PBDT-DIID) is rationally designed and synthesized with a strong near-infrared absorption band ranging from 700 to 1000 nm. Water-dispersing nanoparticles (NPs) of PBDT-DIID are prepared with good biocompatibility and a rather high photothermal conversion efficiency (70.6%), as the active excited-state intramolecular twist around the central double bonds in DIID permits most of the absorbed excitation energy flow to heat deactivation pathway through internal conversion. The photoacoustic signal can be further magnified by incorporation of polylactide (PLA) in the NP core to confine the generated heat of PBDT-DIID within NPs. The resultant doped NPs show excellent performance in photoacoustic imaging-guided photothermal therapy in an orthotopic 4T1 breast tumor-bearing mouse model. It is also found that the photothermal effect of the PBDT-DIID NPs is safe and quite efficacious to highly improve the root canal treatment outcome by heating the 1% NaClO solution inside the root canal upon 808 nm laser irradiation in a human extracted tooth root canal infection model.

Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.

BACKGROUND: A comprehensive understanding of atherosclerotic plaques aids physicians in evaluation and treatment of stroke. This study set out to evaluate the characteristics and diagnostic value of atherosclerotic plaques in patients with acute stroke and stenotic middle cerebral artery (MCA) using high-resolution magnetic resonance imaging. METHODS: Sixty-five consecutive patients with transient ischemic attack or recent ischemic stroke were prospectively recruited. All enrolled patients underwent routine magnetic resonance scans and cross-sectional scans of the stenotic MCA vascular wall. Differences in vascular wall parameters and location, the enhancement degree, and remodelling patterns of plaques in the stenotic MCA were compared between symptomatic (n=30) and asymptomatic (n=35) groups of patients. The statistically significant indicators were then subjected to logistic regression analysis to identify which factors could better predict acute stroke. RESULTS: Compared with the asymptomatic group, the symptomatic group had a smaller lumen area (LA) (P=0.027), larger plaque area (P<0.001), larger remodelling index (P<0.001), more superior/posterior plaques (P=0.001), more obviously enhanced plaques (P<0.001), and a greater number of PR patterns (P<0.001) in the stenotic MCA. Logistic regression analysis showed that the plaque area, remodelling patterns, LA in the stenotic MCA, enhancement degree, and plaque location were predictors of acute stroke. The combination of the plaque area and LA in the stenotic MCA, and the plaque enhancement degree had optimal predictive value (area under the curve =0.927). CONCLUSIONS: A larger plaque area and smaller LA in the stenotic MCA, and obvious plaque enhancement might indicate that a patient is prone to acute stroke.

Function-driven design of Bacillus kochii and Filobasidium magnum co-culture to improve quality of flue-cured tobacco.

Flue-cured tobacco (FCT) is an economical raw material whose quality affects the quality and cost of the derived product. However, the time-consuming and inefficient spontaneous aging is the primary process for improving the FCT quality in the industry. In this study, a function-driven co-culture with functional microorganisms was built in response to the quality-driven need for less irritation and more aroma in FCT. The previous study has found that Bacillus kochii SC could degrade starch and protein to reduce tobacco irritation and off-flavors. The Filobasidium magnum F7 with high lipoxygenase activity was screened out for degrading higher fatty acid esters and terpenoids to promote the aroma and flavor of FCT. Co-cultivation with strain SC and F7 obtained better quality improvement than mono-culture at an initial inoculation ratio of 1:3 for 2 days, representing a significant breakthrough in efficiency and a reduction in production costs compared to the more than 2 years required for the spontaneous aging process. Through the analysis of microbial diversity, predicted flora functions, enzyme activities and volatile compositions within the mono- and co-cultivation, our study showed the formation of a function-driven co-culture between two strains through functional division of labor and nutritional feeding. Herein, the function-driven co-culture via bioaugmentation will become an increasingly implemented approach for the tobacco industry.

Bioaugmentation of Bacillus amyloliquefaciens-Bacillus kochii co-cultivation to improve sensory quality of flue-cured tobacco.

Flue-cured tobacco (FCT) with irritating and undesirable flavor must be aged. However, the spontaneous aging usually takes a very long time for the low efficiency. Bioaugmentation with functional strains is a promising method to reduce aging time and improve sensory quality. To eliminate the adverse effect of excessive starch or protein content on the FCT quality, we used the flow cytometry to sort Bacillus amyloliquefaciens LB with high alpha-amylase and Bacillus kochii SC with high neutral protease from the FCT microflora. The mono, co-culture of strains was performed the solid-state fermentation with FCT. Bacillus amyloliquefaciens monoculture for 2 days and Bacillus kochii monoculture for 2.5 days achieved the optimum quality. B. amyloliquefaciens-B. kochii co-culture at a ratio of 3:1 for 2 days of fermentation showed a more comprehensive quality enhancement and higher functional enzyme activity than mono-cultivation. Through OPLS-DA model (orthogonal partial least-squares-discriminant analyzes), there were 38 differential compounds between bioaugmentation samples. In co-cultivation, most of Maillard reaction products and terpenoid metabolites were at a higher level than other samples, which promoted an increase in aroma, softness and a decrease in irritation. This result validated the hypothesis of quality improvement via the co-culture. In our study, we presented a promising bioaugmentation technique for changing the sensory attributes of FCT in a short aging time.

Antiplatelet drug ticagrelor delays gastric ulcer healing in rats.

Adenosine diphosphate P2Y12 receptor antagonist clopidogrel is not sufficiently safe for the gastric mucosa in patients with high risk of peptic ulcer, since it may impair healing of gastric erosions. However, the safety of the novel P2Y12 receptor antagonist ticagrelor in the gastric mucosa has not been elucidated to date. The present study aimed to examine whether ticagrelor delays gastric ulcer healing and to elucidate the involved mechanisms. Gastric kissing ulcers were produced in rats by luminal application of acetic acid solution, and ticagrelor was administered at dose of 10 or 20 mg/kg/day orally for 7 days. On day 8 after ulcer induction, the ulcer size, mucosal epithelial cell proliferation of the ulcer margin, expression levels of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), and signal transduction pathways for cell proliferation and angiogenesis were measured and compared between the ticagrelor-treated and untreated model groups. The results revealed that the ulcer size was significantly greater in the ticagrelor-treated group compared with the model group, while the mucosal epithelial cell proliferation of the ulcer margin was significantly decreased in the ticagrelor-treated group. In addition, ticagrelor significantly decreased the ulcer-stimulated expression levels of EGF, VEGF, phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated P38 mitogen-activated protein kinase and nuclear factor-κB P65 at the ulcer margin (P<0.05). These findings suggested that ticagrelor delayed gastric ulcer healing. Furthermore, the possible mechanisms underlying the effect of ticagrelor were associated with its functions of attenuating the expression levels of VEGF and EGF, as well as suppressing the phosphorylation activation of ERK1/2, P38 and nuclear factor-κB P65. Finally, the gastric epithelial cell proliferation and angiogenesis were also inhibited.