Interplay of Food-Derived Bioactive Peptides with Gut Microbiota: Implications for Health and Disease Management.

Bioactive peptides (BPs) are protein fragments with beneficial effects on metabolism, physiology, and diseases. This review focuses on proteolytic BPs, which are produced by the action of gut microbiota on proteins in food and have demonstrated to influence the composition of gut microbes. And gut microbiota are candidate targets of BPs to alleviate oxidative stress, enhance immunity, and control diseases, including diabetes, hypertension, obesity, cancer, and immune and neurodegenerative diseases. Despite promising results, further research is needed to understand the mechanisms underlying the interactions between BPs and gut microbes, and to identify and screen more BPs for industrial applications. Overall, BPs offer potential as therapeutic agents for various diseases through their interactions with gut microbes, highlighting the importance of continued research in this area.

Characteristics and Cytological Analysis of Several Novel Allopolyploids and Aneuploids between Brassica oleracea and Raphanus sativus.

Polyploids are essential in plant evolution and species formation, providing a rich genetic reservoir and increasing species diversity. Complex polyploids with higher ploidy levels often have a dosage effect on the phenotype, which can be highly detrimental to gametes, making them rare. In this study, offspring plants resulting from an autoallotetraploid (RRRC) derived from the interspecific hybridization between allotetraploid Raphanobrassica (RRCC, 2n = 36) and diploid radish (RR, 2n = 18) were obtained. Fluorescence in situ hybridization (FISH) using C-genome-specific repeats as probes revealed two main genome configurations in these offspring plants: RRRCC (2n = 43, 44, 45) and RRRRCC (2n = 54, 55), showing more complex genome configurations and higher ploidy levels compared to the parental plants. These offspring plants exhibited extensive variation in phenotypic characteristics, including leaf type and flower type and color, as well as seed and pollen fertility. Analysis of chromosome behavior showed that homoeologous chromosome pairing events are widely observed at the diakinesis stage in the pollen mother cells (PMCs) of these allopolyploids, with a range of 58.73% to 78.33%. Moreover, the unreduced C subgenome at meiosis anaphase II in PMCs was observed, which provides compelling evidence for the formation of complex allopolyploid offspring. These complex allopolyploids serve as valuable genetic resources for further analysis and contribute to our understanding of the mechanisms underlying the formation of complex allopolyploids.

c-Cbl induced podocin ubiquitination contributes to the podocytes injury in diabetic nephropathy.

The ubiquitination function in diabetic nephropathy (DN) has attracted much attention, but there is a lack of information on its ubiquitylome profile. To examine the differences in protein content and ubiquitination in the kidney between db/db mice and db/m mice, we deployed liquid chromatography-mass spectrometry (LC-MS/MS) to conduct analysis. We determined 145 sites in 86 upregulated modified proteins and 66 sites in 49 downregulated modified proteins at the ubiquitinated level. Moreover, 347 sites among the 319 modified proteins were present only in the db/db mouse kidneys, while 213 sites among the 199 modified proteins were present only in the db/m mouse kidneys. The subcellular localization study indicated that the cytoplasm had the highest proportion of ubiquitinated proteins (31.87%), followed by the nucleus (30.24%) and the plasma membrane (20.33%). The enrichment analysis revealed that the ubiquitinated proteins are mostly linked to tight junctions, oxidative phosphorylation, and thermogenesis. Podocin, as a typical protein of slit diaphragm, whose loss is a crucial cause of proteinuria in DN. Consistent with the results of ubiquitination omics, the K261R mutant of podocin induced the weakest ubiquitination compared with the K301R and K370R mutants. As an E3 ligase, c-Cbl binds to podocin, and the regulation of c-Cbl can impact the ubiquitination of podocin. In conclusion, in DN, podocin ubiquitination contributes to podocyte injury, and K261R is the most significant site. c-Cbl participates in podocin ubiquitination and may be a direct target for preserving the integrity of the slit diaphragm structure, hence reducing proteinuria in DN.

Oleanolic acid attenuates hydrogen peroxide-induced apoptosis of IPEC-J2 cells through suppressing c-Jun and MAPK pathway.

Oleanolic acid (OA) is a natural triterpenoid with therapeutic potential for a multitude of diseases. However, the precise mechanism by which OA influences stress-induced apoptosis of intestinal epithelial cells remains elusive. Therefore, the effect of OA on intestinal diseases under stressful conditions and its possible mechanisms have been investigated. In a hydrogen peroxide (H2 O2 )-induced oxidative stress model, OA attenuated H2 O2 -induced apoptosis in a concentration-dependent manner. To investigate the underlying mechanisms, the gene expression profile of OA on IPEC-J2 cells was analyzed using an RNA sequencing system. Results from gene ontology and Kyoto encyclopedia of genes and genomes analysis confirmed that OA may mitigate the cytotoxic effects of H2 O2 by downregulating gene expression through the MAPK signaling pathway. Furthermore, Quantitative real-time polymerase chain reaction results validated the differentially expressed genes data. Western blot analysis further demonstrated that OA effectively suppressed the expression level of c-Jun protein induced by H2 O2 in IPEC-J2 cells. Collectively, our results indicate that OA pretreatment significantly attenuated H2 O2 -induced apoptosis in intestinal epithelial cells through suppressing c-Jun and MAPK pathway.

EcAGL enhances cadmium tolerance in transgenic Arabidopsis thaliana through inhibits cadmium transport and ethylene synthesis pathway.

Cadmium (Cd) is a highly toxic heavy metal with severe impacts on plant growth and development. Although a multitude of plants have acquired strong tolerance to Cd stress, the underlying molecular mechanism has not been fully elucidated. Here, we identified a Agamous-like MADS-box gene (EcAGL) from Erigeron canadensis. The expression of EcAGL was obviously raised under Cd stress and subcellular localization indicated EcAGL was localized in the nucleus. Overexpression of EcAGL in Arabidopsis thaliana showed marked alleviation of the Cd-induced reduction; Compared to wild-type lines, the antioxidant enzymes activities were increased in EcAGL overexpressing lines under Cd stress. The roots Cd content of transgenic lines was not different with the control plants, whereas significant reduction in shoots Cd content was detected in the transgenic lines, indicating that this gene can enhance Cd tolerance by reducing Cd accumulation in Arabidopsis. Moreover, the expression levels of heavy metal ATPase (AtHMA2 and AtHMA3) and natural resistance-associated macrophage protein (AtNRAMP5) genes in the root of transgenic lines decreased under Cd stress, indicating that EcAGL likely hampered the Cd transport pathway. Gene expression profiles in shoot showed that EcAGL likely modulates the expression of 1-aminocyclopropane-1-carboxylic acid synthase gene (AtACS2), which is involved in the ethylene synthesis pathway, to strengthen the tolerance to Cd. Collectively, these results indicate that EcAGL plays a significant role in regulating Cd tolerance in E. canadensis by alleviating oxidative stress, Cd transport and affecting the ethylene biosynthesis pathway, providing new insight into the molecular mechanism underlying plant tolerance to Cd stress.

Application of transabdominal ultrasonography in the diagnosis of absent contractility - a case report.

INTRODUCTION: Absent contractility is a kind of esophageal motility disorder. Patients are often diagnosed by endoscopic ultrasonography or high-resolution manometry (HRM). In this paper, we report two cases of absent esophageal contractility first discovered by transabdominal ultrasonography. CASE PRESENTATION: The main symptom of both cases was acid reflux, and the main diagnosis was absent esophageal contractility. They were all discovered by transabdominal ultrasonography. After the treatment of surgery or drugs, the symptoms relieved during follow-up, without any other discomforts. CONCLUSION: Transabdominal ultrasound as a primary screening method for absent contractility is proposed in this paper, which is non-invasive, real-time, and fast. Ultrasound is expected to improve the diagnostic efficiency of peristalsis and patient experience in combination with the above invasive examinations. The use of sonography in the diagnosis of absent contractility has seldom been studied. Further investigation is required to determine whether this technique may better assess absent contractility.

HIF-1α and Caspase-3 expression in aggressive papillary thyroid carcinoma.

BACKGROUND: Tumor cells adapt to hypoxia by regulating transcription factors that involved in regulation of metabolism, angiogenesis, cell proliferation, and apoptosis. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1), consisting of HIF-1α and HIF-1ß subunits, acts as a key transcription factor mediating the adaptive cellular responses. Caspase-3 is a key apoptosis-related protease that plays a role in tumor growth and development. Studies have shown that caspase-3 could be regulated by HIF-1α under pathological conditions. Therefore, HIF-1α and caspase-3 expression may be related to the poor prognosis of tumors. In this study, we analyzed the possible relationships between these two signaling factors in correlation with the clinical behavior of PTC. METHODS: We detected the expression levels of HIF-1α and caspase-3 in 70 samples of PTC and para-cancerous tissues (control group) by immunohistochemistry (IHC). Furthermore, various clinicopathological parameters were assessed to determine their correlations with HIF-1α and caspase-3 expressions. RESULTS: First, HIF-1α and caspase-3 expressions (60% and 37.1%, respectively) increased significantly in the PTC samples as compared to normal tissues (2.9% for both HIF-1α and caspase-3) (p < 0.05) as determined by IHC. Second, although there was no significant difference between the expression of HIF-1α and caspase-3 in regard to gender, age distribution, tumor size, lymph node metastasis, and BRAFV600E mutation (all p > 0.05), HIF-1α and caspase-3 expressions were associated with capsule invasion and cell subtypes of PTC (p < 0.05). The percent positivity of caspase-3 expression in tall-cell variant (TCV) was the highest (63.6%). Third, HIF-1α expression was positively correlated with that of caspase-3 (rs = 0.326; p < 0.05). CONCLUSIONS: Overexpression of HIF-1α and caspase-3 is associated with carcinogenesis. These factors might serve as promising predictors of aggressive PTC. These findings also suggest their potential as therapeutic targets.

Evaluation of the Efficacy of the Hospital Glycemic Management System for Patients with Malignant Tumors and Hyperglycemia.

OBJECTIVE: To explore the efficacy of the hospital glycemic management system with information integration in patients with malignant tumors and hyperglycemia. METHODS: Three hundred ninety-three patients diagnosed with malignant tumors with hyperglycemia and hospitalized in the non-endocrinology department of a specialized cancer hospital from March 2019 to November 2020 were recruited. All the patients were diagnosed and treated according to the clinical department and disease course. In total, 196 patients were divided into the control group, who received the conventional blood glucose management mode, and 197 patients were divided into the intervention group, who received the hospital glycemic management system with information integration. The average daily glucose levels were recorded before and after breakfast, lunch, and dinner, at bedtime and at night. The average glucose level, glucose compliance rate, hypoglycemia rate, hyperglycemia rate, glucose measurements per day, average number of hospitalization days and patient satisfaction were compared between the groups. RESULTS: In the intervention group, the average glucose level was significantly lower than that in the control group (P<0.05). The hyperglycemia and hypoglycemia rates in the intervention group were lower than those in the control group (P<0.05). The glucose compliance rate in the intervention group was higher than that in the control group (P<0.05). The highest blood glucose level in the intervention group was lower than that in the control group (P<0.05), and the lowest blood glucose level was higher than that in the control group (P<0.05). The glucose measurements per day in the intervention group were higher than those in the control group, and the average number of hospitalization days in the intervention group was lower than that in the control group (P<0.05). Patient satisfaction in the intervention group was higher than that in the control group (P<0.05). CONCLUSION: The hospital glycemic management system with information integration significantly improved the glycemic management of patients with malignant non-endocrine tumors and hyperglycemia, including their glucose level and glucose compliance rate, as well as patient satisfaction, and reduced the average number of hospitalization days and risk of hyperglycemia/hypoglycemia.

Dietary Bioactive Peptide Alanyl-Glutamine Attenuates Dextran Sodium Sulfate-Induced Colitis by Modulating Gut Microbiota.

Inflammatory bowel disease (IBD) is a chronic intestinal disorder threatening human health. Di-peptide alanyl-glutamine (Ala-Gln) has various beneficial effects on gut health. However, its role and functional mechanism in treating IBD are still not clear. Therefore, the protective effects of Ala-Gln and glutamine (Gln) on dextran sulfate sodium- (DSS-) induced colitic mice were investigated in this study. The results showed that oral supplementation of Ala-Gln or Gln significantly attenuated the colitis symptoms in mice, including body weight loss, colon length, disease activity index, histological scores, and tissue apoptosis. The concentrations of interleukin- (IL-) 1ß, IL-6, tumor necrosis factor-α, and myeloperoxidase were significantly decreased, while the concentrations of immunoglobulins (IgA, IgG, and IgM) and superoxide dismutase were significantly increased by Ala-Gln or Gln supplementation. The expression of occludin and peptide transporter 1 (PepT1) was significantly increased by Ala-Gln or Gln. Interestingly, Ala-Gln had better beneficial effects than Gln in alleviating colitis. In addition, 16S rDNA sequencing showed that the DSS-induced shifts of the microbiome (community diversity, evenness, richness, and composition) in the mouse colon were restored by Gln and Ala-Gln, including Lactobacillus, Bacteroides_acidifaciens, Bacteroidales, Firmicutes, Clostridia, Helicobacter, and Bacteroides. Correspondingly, the functions of the microflora metabolism pathways were also rescued by Ala-Gln, including fatty acid metabolism, membrane transporters, infectious diseases, and immune system. In conclusion, the results revealed that Ala-Gln can prevent colitis through PepT1, enhancing the intestinal barrier and modulating gut microbiota and microflora metabolites.

Determining the influence of high glucose on exosomal lncRNAs, mRNAs, circRNAs and miRNAs derived from human renal tubular epithelial cells.

Diabetic nephropathy is a lethal disease that can lead to chronic kidney disease and end-stage kidney disease. Exosomes, which are nanosized extracellular vesicles, are closely involved in intercellular communication. Most importantly, exosomes play critical roles in disease occurrence and development. However, the function of exosomes in diabetic nephropathy progression has not been fully elucidated. In the present study, we determined the expression profiles and differences of lncRNAs, mRNAs, circRNAs and miRNAs in exosomes derived from human renal tubular epithelial cells with or without high glucose (HG) treatment. A total of 169 lncRNAs, 885 mRNAs, 3 circRNAs and 152 miRNAs were differentially expressed in exosomes secreted by HG-challenged HK-2 cells (HG group) compared with controls (NC group). The functions of differentially expressed mRNAs, mRNAs colocalized or coexpressed with differentially expressed lncRNAs (DElncRNAs), potential target genes of miRNAs and source genes of circRNAs were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. According to these differentially expressed RNAs, we established an integrated circRNA-lncRNA-miRNA-mRNA regulatory network. In conclusion, our study suggested that exosomal lncRNAs, mRNAs, circRNAs and miRNAs participate in the progression of diabetic nephropathy and may be possible biomarkers and therapeutic targets in diabetic nephropathy.

Expression Profile Analysis of m6A RNA Methylation Regulators Indicates They Are Immune Signature Associated and Can Predict Survival in Kidney Renal Cell Carcinoma.

N6-Methyladenosine (m6A) refers to the methylation modification occurring at the nitrogen-6 position of adenosine. Many human physiological processes such as modulation of spermatogenesis are caused by m6A RNA modifications. However, the relationship between m6A RNA methylation regulators and kidney renal clear cell carcinoma (KIRC) remains rarely investigated. This work aimed to explore the influence of m6A RNA methylation regulators in KIRC. We examined abnormally expressed m6A RNA methylation regulators among different clinicopathological features of KIRC. We recognized three subgroups (KIRC1, KIRC2, and KIRC3) with significant differences in overall survival through consensus clustering of m6A RNA methylation regulators. Surprisingly, KIRC2 displayed elevated immune activity, but high proportions of immune-inhibitory cells (Tregs and myeloid-derived suppressor cell) based on single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT analysis. Moreover, the KIRC2 subgroup had the lowest tumor mutation burden levels and the highest expression levels of 80% (12/15) of co-inhibitory molecules. Next, correlation analysis indicated that RBM15B expression was negatively correlated with multiple immune signatures, which was verified by ssGSEA and CIBERSORT analyses. Multiple immune-related and cancer-related pathways were enriched in the group with high RBM15B expression. Furthermore, a four-m6A RNA methylation regulator-based risk signature was constructed based on an ArrayExpress (E-MTAB-3267) dataset and confirmed in the The Cancer Genome Atlas (TCGA) testing cohort. In conclusion, our study successfully classified TCGA samples into three subgroups with different immune signatures, and suggested that the worse prognosis of KIRC2 is probably mediated by immune evasion. These findings will facilitate personalized immunotherapy in patients with KIRC. In addition, the risk score system was revealed as an independent prognostic marker that can predict survival in KIRC patients.

Dietary Taxifolin Protects Against Dextran Sulfate Sodium-Induced Colitis via NF-κB Signaling, Enhancing Intestinal Barrier and Modulating Gut Microbiota.

Taxifolin is a natural antioxidant polyphenol with various bioactivities and has many beneficial effects on human gut health. However, little is known of its function on colitis. In this study, the protective effects of taxifolin on colitis symptoms, inflammation, signaling pathways, and colon microbiota were investigated using dextran sulfate sodium (DSS)-induced colitis mice. Intriguingly, pre-administration of taxifolin alleviated the colitis symptoms and histological changes of the DSS-challenged mice. Supplementation of taxifolin significantly inhibited the secretions of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 and significantly increased the secretions of IL-10, secretory immunoglobulin A, superoxide dismutase, and immunoglobulins (IgA, IgG, and IgM) in DSS-induced colitis mice. In addition, the activation of nuclear factor kappa B (NF-κB; p65 and IκBα) signaling was significantly suppressed by taxifolin supplementation. The expression of tight junction proteins (claudin-1 and occludin) was significantly increased by taxifolin. Moreover, 16S rDNA sequencing revealed that the DSS-induced changes of colon microbiota composition and microbial functions (amino acid metabolism and MAPK signaling) were restored by taxifolin, including the decreases of the abundances of Bacteroides, Clostridium ramosum, Clostridium saccharogumia, Sphingobacterium multivorum, and the ratio of Bacteroidetes/Firmicutes, and the increases of the abundances of Desulfovibrio C21 c20 and Gemmiger formicilis at species level. In conclusion, these results revealed that dietary taxifolin has a great potential to prevent colitis by inhibiting the NF-κB signaling pathway, enhancing intestinal barrier, and modulating gut microbiota.

Transcriptome Analysis of Adipose Tissue Indicates That the cAMP Signaling Pathway Affects the Feed Efficiency of Pigs.

Feed efficiency (FE) is one of the main factors that determine the production costs in the pig industry. In this study, RNA Sequencing (RNA-seq) was applied to identify genes and long intergenic non-coding RNAs (lincRNAs) that are differentially expressed (DE) in the adipose tissues of Yorkshire pigs with extremely high and low FE. In total, 147 annotated genes and 18 lincRNAs were identified as DE between high- and low-FE pigs. Seventeen DE lincRNAs were significantly correlated with 112 DE annotated genes at the transcriptional level. Gene ontology (GO) analysis revealed that DE genes were significantly associated with cyclic adenosine monophosphate (cAMP) metabolic process and Ca2+ binding. cAMP, a second messenger has an important role in lipolysis, and its expression is influenced by Ca2+ levels. In high-FE pigs, nine DE genes with Ca2+ binding function, were down-regulated, whereas S100G, which encodes calbindin D9K that serve as a Ca2+ bumper, was up-regulated. Furthermore, ATP2B2, ATP1A4, and VIPR2, which participate in the cAMP signaling pathway, were down-regulated in the upstream of lipolysis pathways. In high-FE pigs, the key genes involved in the lipid biosynthetic process (ELOVL7 and B4GALT6), fatty acid oxidation (ABCD2 and NR4A3), and lipid homeostasis (C1QTNF3 and ABCB4) were down-regulated. These results suggested that cAMP was involved in the regulation on FE of pigs by affecting lipid metabolism in adipose tissues.

Novel Natural Product-like Caged Xanthones Bearing a Carbamate Moiety Exhibit Antitumor Potency and Anti-Angiogenesis Activity In vivo.

DDO-6101, a simplified structure obtained from the Garcinia natural product (NP) gambogic acid (GA), has been previously shown to possess high cytotoxicity to a variety of human tumour cell lines. To improve its physicochemical properties and in vivo cytotoxic potency, a series of novel carbamate-bearing derivatives based on DDO-6101 was synthesized and characterized. The structural modifications revealed that the presence of a carbamate moiety was useful for obtaining comparable cytotoxicity and improved aqueous solubility and permeability. 8n, which contains a bipiperidine carbamate moiety, displayed better drug properties and potential in in vivo antitumor activity. In addition, an antitumor mechanistic study suggested that 8n (DDO-6337) inhibited the ATPase activity of Hsp90 (Heat shock protein 90), leading to the inhibition of HIF-1a and ultimately contributing to its anti-angiogenesis and antitumor properties.

Structure-activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity.

Hsp90 has long been recognized as an attractive and crucial molecular target for cancer therapy. Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported as a natural inhibitor of Hsp90. Here, we present the structure-activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68±0.18µM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression, compound 25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound 25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound 25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy.

Novel natural-product-like caged xanthones with improved druglike properties and in vivo antitumor potency.

DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo cytotoxic potency, a novel series of 19 prenyl group-modified derivatives of DDO-6101 was synthesized and evaluated for their in vitro antitumor activity and druglike properties. The SAR and SPR information of these compounds was also obtained. In the light of the in vitro antitumor activity and druglike properties such as aqueous solubility and permeability, compound 6f (named as DDO-6306) was advanced into in vivo efficacy experiment. The results showed that DDO-6306 is more potent than DDO-6101 in vivo and is a promising antitumor candidate for further evaluation.