Theaflavins mitigate diabetic symptoms in GK rats by modulating the INSR/PI3K-Akt/GSK-3 pathway and intestinal microbiota.

Dietary management and interventions are crucial in the clinical management of diabetes. Numerous active dietary components in black tea have demonstrated positive effects on blood glucose levels and metabolic functions. However, limited research has explored the potential of theaflavins (TF), polyphenols in black tea, for diabetes management. In this study, high-purity TF was administered to Goto-Kakizaki (GK) diabetic model rats for four weeks to investigate its impact on diabetic pathology and analyze the underlying mechanisms through liver transcriptomics, hepatocyte metabolomics, and gut microbiome analysis. The findings indicated that continuous administration of TF (100 mg/kg) significantly suppressed blood glucose levels, reduced insulin resistance, and decreased the expression of oxidative stress indicators and inflammatory factors in GK rats. Further analysis revealed that TF might alleviate insulin resistance by improving hepatic glycogen conversion and reducing hepatic lipid deposition through modulation of key pathways, such as peroxisome proliferator-activated receptors and PI3K/AKT/GSK-3 pathways within the liver, thereby ameliorating diabetic symptoms. Additionally, TF intake facilitated the restoration of the intestinal microbial community structure by reducing the abundance of harmful bacteria and increasing the abundance of beneficial bacteria. It also reduced endotoxin lipopolysaccharide production, thereby lowering the chances of insulin resistance development and enhancing its efficacy in regulating blood glucose levels. These findings offer a novel perspective on the potential of black tea and its active constituents to prevent and treat diabetes and other metabolic disorders, providing valuable references for identifying and applying active dietary components from tea.

Lower levels of vitamin D are associated with an increase in carotid intima-media thickness in children and adolescents with obesity.

BACKGROUND: the relationship between vitamin D deficiency and carotid intima-media thickness (CIMT) in children and adolescents with obesity is unknown. The aim of this study was to investigate the correlation between vitamin D levels and CIMT in children and adolescents with obesity. METHODS: a total of 440 children and adolescents aged 6-16 with obesity were included in the study. Anthropometric measurements, blood pressure measurements, blood lipids, blood glucose, and vitamin D levels were measured. Bilateral carotid ultrasound was performed to assess CIMT. The relationships between vitamin D levels and CIMT were assessed using multivariate linear regression with Generalized Linear Models and restricted cubic splines. Binary logistic regression analyses were conducted to explore the association between vitamin D status and the risk of abnormal CIMT. RESULTS: vitamin D levels were inversely correlated with CIMT in subjects with serum 25-hydroxyvitamin D [25(OH)D] levels less than or equal to 50 nmol/L (ß = -0.147, 95 % CI [-0.263, -0.030], p = 0.013), but this correlation was not significant in subjects with serum 25(OH)D levels above 50 nmol/L. After correcting for various confounders, the risk of abnormal CIMT was significantly higher in the vitamin D deficiency group (OR = 2.080, 95 % CI [1.112, 3.891], p = 0.022). CONCLUSIONS: vitamin D deficiency is an independent risk factor for abnormal CIMT, and vitamin D deficiency may play a promoting role in the atherosclerotic process in children and adolescents with obesity.

Recombinant Human Hepatocyte Growth Factor Plasmids for Treating Patients with Chronic Limb Threatening Ischaemia: A Systematic Review and Meta-analysis.

OBJECTIVE: Recombinant human hepatocyte growth factor (HGF) plasmids are novel alternatives to salvage limbs in patients with chronic limb threatening ischaemia (CLTI). A systematic review and meta-analysis of data were conducted to assess the therapeutic efficacy of HGF plasmids in patients with CLTI. DATA SOURCES: Randomised controlled studies evaluating HGF plasmid efficacy in patients with CLTI were identified using Medline, Embase, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov databases. REVIEW METHODS: Meta-analyses of the reported relative risks (RR) or mean differences (MD) were conducted. Subgroup analyses determined the efficacy of HGF plasmids in cohorts excluding Buerger's disease. Certainty of evidence for each outcome was assessed. RESULTS: Seven studies (n = 655) were included. Based on low certainty evidence, patients treated with HGF had a significantly higher complete ulcer healing rate (RR 1.99, 95% CI 1.30 - 3.04; p = .015) than patients treated with placebo. The HGF treatment was associated with reduced visual analogue scale (VAS) scores of pain severity (MD -1.56, 95% CI -2.12 - -1.00; p < .001) vs. placebo in patients with CLTI assessed at the 3 month follow up (low certainty evidence); no significant differences were observed in major amputation (RR 0.91, 95% CI 0.48 - 1.73; p = .77) (low certainty evidence), or all-cause mortality (RR 0.93, 95% CI 0.38 - 2.27; p = .87) (low certainty evidence) between patients treated with HGF and placebo. Low certainty evidence suggested no significant differences in change in ankle-brachial index at 6 months (MD 0.00, 95% CI -0.09 - 0.09; p = 1.0) between patients treated with HGF and placebo. The complete ulcer healing rate and improved 3 month VAS scores of pain severity benefits persisted in subgroup analyses (low certainty evidence). CONCLUSION: Hepatocyte growth factor treatment is associated with an increased complete ulcer healing rate and reduced ischaemic pain in patients with CLTI.

Insights into the flavor profiles of different grades of Huangpu black tea using sensory histology techniques and metabolomics.

Significant differences exist in aroma and taste of different grades of large-leaf black tea. In this study, sensory histology combined with metabolomics were used to investigate the sensory characteristics and phytochemical profiles of different grades of Huangpu black tea (HPBT). Sensory evaluation showed that high grade HPBT had high intensity of pekoe, fresh aroma and umami, with aroma and taste scores declining with decreasing grades. 173 non-volatiles were identified, of which 23 marker metabolites could be used as discrimination of different grades HPBT taste. In addition, 154 volatile compounds were identified in the different grades of HPBT, with 15 compounds as key odorants for distinguishing the aroma of different grades of HPBT. Furthermore, correlation analysis revealed that linalool, geraniol and nonanal contributed to the aroma quality score of HPBT. This study will provide a more comprehensive understanding for processing, quality evaluation and grade evaluation system of large-leaf black tea.

Multilevel Regulation of NF-κB Signaling by NSD2 Suppresses Kras-Driven Pancreatic Tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase that has been reported to play a crucial role in promoting tumorigenesis. Here, the study demonstrates that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of IκBα, which inhibits the phosphorylation of p65 and NF-κB nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-κB transcriptional activity. Furthermore, inhibition of NF-κB signaling relieves the symptoms of Nsd2-deficient mice and sensitizes Nsd2-null PDAC to gemcitabine. Clinically, NSD2 expression decreased in PDAC patients and negatively correlated to nuclear p65 expression. Together, the study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study opens therapeutic opportunities for PDAC patients with NSD2 low/loss by combined treatment with gemcitabine and NF-κBi.

Asymmetrically Coordinated Calcium Single Atom for High-Performance Oxygen Reduction Reaction.

S-block single atoms represent an ideal catalyst for the oxygen reduction reaction (ORR) as they can suppress the Fenton reaction. However, the symmetry of the s/p orbitals tends to generate either an excessively strong or weak interaction with intermediates. Herein, Ca single atoms coordinated with -S, -OP, and three N atoms (Ca/NPS-HC) were fabricated to modulate the adsorption of intermediates and promote the efficiency of s-block ORR catalysts. The experimental results from ORR demonstrated that the Ca/NPS-HC catalyst exhibited outstanding catalytic capability with a half-wave potential of 0.89 V, a kinetic current density of 56.6 mA cm-2 at 0.85 V, and a Tafel slope of 42 mV dec-1, outperforming commercial Pt/C. The detailed mechanistic studies revealed that the asymmetric coordination of Ca single atoms led to the symmetry-breaking of electron distribution in Ca single atoms, attenuating the s-p hybridization from the intermediate adsorption process, and thereby minimizing the energy barrier of the whole ORR.

An Electrocatalytic Cascade Reaction for the Synthesis of Ketones Using CO2 as a CO Surrogate.

The construction of carbonyl compounds via carbonylation reactions using safe CO sources remains a long-standing challenge to synthetic chemists. Herein, we propose a catalyst cascade Scheme in which CO2 is used as a CO surrogate in the carbonylation of benzyl chlorides. Our approach is based on the cooperation between two coexisting catalytic cycles: the CO2-to-CO electroreduction cycle promoted by [Fe(TPP)Cl] (TPP=meso-tetraphenylporphyrin) and an electrochemical carbonylation cycle catalyzed by [Ni(bpy)Br2] (2,2'-bipyridine). As a proof of concept, this protocol allows for the synthesis of symmetric ketones from good to excellent yields in an undivided cell with non-sacrificial electrodes. The reaction can be directly scaled up to gram-scale and operates effectively at a CO2 concentration of 10 %, demonstrating its robustness. Our mechanistic studies based on cyclic voltammetry, IR spectroelectrochemistry and Density Functional Theory calculations suggest a synergistic effect between the two catalysts. The CO produced from CO2 reduction is key in the formation of the [Ni(bpy)(CO)2], which is proposed as the catalytic intermediate responsible for the C-C bond formation in the carbonylation steps.

Nanoparticles as an antidote for poisoned gold single-atom catalysts in sustainable propylene epoxidation.

The development of sustainable and anti-poisoning single-atom catalysts (SACs) is essential for advancing their research from laboratory to industry. Here, we present a proof-of-concept study on the poisoning of Au SACs, and the antidote of Au nanoparticles (NPs), with trace addition shown to reinforce and sustain propylene epoxidation. Multiple characterizations, kinetics investigations, and multiscale simulations reveal that Au SACs display remarkable epoxidation activity at a low propylene coverage, but become poisoned at higher coverages. Interestingly, Au NPs can synergistically cooperate with Au SACs by providing distinct active sites required for H2/O2 and C3H6 activations, as well as hydroperoxyl radical to restore poisoned SACs. The difference in reaction order between C3H6 and H2 (nC3H6-nH2) is identified as the descriptor for establishing the volcano curves, which can be fine-tuned by the intimacy and composition of SACs and NPs to achieve a rate-matching scenario for the formation, transfer, and consumption of hydroperoxyl. Consequently, only trace addition of Au NPs antidote (0.3% ratio of SACs) stimulates significant improvements in propylene oxide formation rate, selectivity, and H2 efficiency compared to SACs alone, offering a 56-fold, 3-fold, and 22-fold increase, respectively, whose performances can be maintained for 150 h.

(-)-Epicatechin ameliorates type 2 diabetes mellitus by reshaping the gut microbiota and Gut-Liver axis in GK rats.

As one of the most abundant plant polyphenols in the human diet, (-)-epicatechin (EC) can improve insulin sensitivity and regulate glucose homeostasis. However, the primary mechanisms involved in EC anti-T2DM benefits remain unclear. The present study explored the effects of EC on the gut microbiota and liver transcriptome in type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats for the first time. The findings showed that EC protected glucose homeostasis, alleviated systemic oxidative stress, relieved liver damage, and increased serum insulin. Further investigation showed that EC reshaped gut microbiota structure, including inhibiting the proliferation of lipopolysaccharide (LPS)-producing bacteria and reducing serum LPS. In addition, transcriptome analysis revealed that the insulin signaling pathway may be the core pathway of the EC anti-T2DM effect. Therefore, EC may modulate the gut microbiota and liver insulin signaling pathways by the gut-liver axis to alleviate T2DM. As a diet supplement, EC has promising potential in T2DM prevention and treatment.

Gut Microbiota Alterations in Adolescent Idiopathic Scoliosis Are Associated with Aberrant Bone Homeostasis.

OBJECTIVE: Low bone mineral density is the major prognostic factor for adolescent idiopathic scoliosis (AIS), but the underlying mechanisms remain unclear. Accumulating evidence suggests that gut microbiota (GM) have the potential to affect bone development, and the GM signatures are altered in AIS patients. However, the effect of GM alterations on aberrant bone homeostasis in AIS remains unclear. This study aims to investigate the GM profile in AIS patients with different bone mineral density (BMD) and explore the association between GM, osteopenia, and aberrant bone turnover. METHODS: A total of 126 patients with AIS who received surgical treatment were retrospectively included in this study. We analyzed the composition of the GM by 16S rRNA sequencing and BMD by dual X-ray absorptiometry. Based on the BMD of the femur neck, the patients were divided into the osteopenia group (OPN) if the Z score < -1, and the normal (NOR) group if the Z score ≥ -1 SD compared to the healthy control. For the 16S rRNA sequencing, the raw reads were filtered to remove low-quality reads, and operational taxonomic units were identified with the Uparse program. Weighted UniFrac distance matrix for the beta-diversity metrics and principal coordinate analysis (PCoA) was performed, and the statistical comparisons were made with permutational multivariate analysis of variance (PERMANOVA) and analysis of similarity (ANONISM). Linear discriminant analysis effect size (LEfSe) was used to identify the enriched species in two groups. The "Random forest" was applied to determine the optimal biomarker for OPN according to the mean decrease in Gini value. The metabolic function was predicted by the Tax4Fun analysis. The Pearson correlation coefficient was used to evaluate the associations between GM species, bone turnover markers, and BMD. RESULTS: The serum ß-CTX was increased in the OPN group (n = 67) compared to the NOR group (n = 59). Patients in OPN groups showed significantly decreased α diversity indicated by the Shannon index. Principal coordinate analysis (PCoA) analysis showed significant clustering of GM between OPN and NOR groups. At genus level, the Escherichia-Shigella and Faecalibacterium were significantly enriched in the OPN group compared to that in the NOR group (p < 0.05), whereas the abundance of Prevotella was significantly decreased (p = 0.0012). The relative abundance of Megamonas and Prevotella was positively correlated with the femur BMD. The abundance of Escherichia-Shigella was negatively correlated with femur BMD and positively correlated with serum ß-CTX levels. Functional analysis revealed significant differences in starch and sucrose metabolism, pyruvate and cysteine, and methionine metabolism between NOR and OPN groups. CONCLUSION: The alterations of GM in AIS patients are correlated with osteopenia. The association between enriched species, BMD, and bone turnover markers provides novel diagnostic and therapeutic targets for the clinical management of AIS.

Endovascular repair with a physician-modified fenestrated endograft to treat abdominal aortic pseudoaneurysm with Behcet's disease: a case report.

BACKGROUND: Aortic involvement in patients with Behcet's disease (BD) is rare, but it is one of the most severe manifestations. Open surgical repair of aortic aneurysm is challenging considering the high risk of postoperative recurrent anastomotic pseudoaneurysms and is associated with a much higher mortality rate. Recently, endovascular treatment has proven to be a feasible, less invasive alternative to surgery for these patients. CASE PRESENTATION: We report a total endovascular repair of a paravisceral abdominal aortic pseudoaneurysm in a 25-year-old male patient with BD. The pseudoaneurysm was successfully excluded, and the blood supply of visceral arteries was preserved with a physician-modified three-fenestration endograft under 3D image fusion guidance. Immunosuppressive therapy was continued for 1 year postoperatively. At 18 months, the patient was asymptomatic without abdominal pain. Computed tomography angiography demonstrated the absence of pseudoaneurysm recurrence, good patency of visceral vessels. DISCUSSION AND CONCLUSIONS: Endovascular repair using physician-modified fenestrated endografts is a relatively safe and effective approach for treating paravisceral aortic pseudoaneurysm in BD patients. This technique enables the preservation of the visceral arteries and prevents aneurysm recurrence at the proximal and distal landing zones, which are common complications of open surgical repair in these patients. Furthermore, we emphasize the importance of adequate immunosuppressive therapy before and after surgical repair in BD patients, which is a major risk factor for recurrence and poor prognosis.

7.5F Mini Flexible Ureteroscope in Retrograde Intrarenal Surgery: Initial Results from a Multicenter Randomized Clinical Trial.

Objective: To report the initial results of an randomized clinical trail comparing the safety and efficacy between 7.5F and 9.2F flexible ureteroscope (FUS) in the management of renal calculi <2 cm. Materials and Methods: Eighty patients were enrolled and received retrograde intrarenal surgery (RIRS) with a different size FUS. The operation results and complications were compared. Results: Two cases in the 7.5F group and four cases in the 9.2F group failed to insert the 12/14F ureteral access sheath (UAS), respectively, and no significant difference (p = 0.396) was noted. However, 10/12F UAS was inserted in the 7.5F group, but not available in the 9.2F group, and thus, the 10/12F UAS inserting rate in the 7.5F group was higher than in the 9.2F group (100% vs 0%, p = 0.014), and the UAS insertion failure rate in 9.2F group was higher than in the 7.5F group (10% vs 0%, p = 0.040). The operation time in 7.5F group was shorter than the 9.2F group (35.60 ± 7.86 vs 41.05 ± 8.14, p = 0.003). Less irrigation was required in 7.5F group (813.93 ± 279.47 mL vs 1504.18 ± 385.31 mL, p = 0.000). The postoperative fever rate in 9.2F group was higher than 7.5F group (20% vs 5%, p = 0.043). There was no significant difference in sepsis (0% vs 2.5%, p = 0.314) between the two groups. No significant difference was noted in hospital stay (0.93 ± 0.49 days vs 1.14 ± 0.64 days, p = 0.099) between the two groups. The final stone-free rate (SFR) in 7.5F group was higher than 9.2F group (95% vs 80%, p = 0.043). Conclusion: The latest 7.5F mini FUS was a reliable instrument in RIRS to keep a good visualization with low requirement of irrigation, low postoperative infection complication, and also a high SFR when compared with the conventional 9.2F FUS. Clinical Trial Registration: NCT05231577.

An Anatomic Classification Scheme for Surgical Planning of Renal Artery Aneurysms.

PURPOSE: Renal artery aneurysm (RAA) is a rare disease. This study proposed and evaluated a new classification for RAA to assist in surgical decision-making. MATERIALS AND METHODS: Single-center data of 105 patients with RAAs from the vascular department of vascular surgery were collected retrospectively. A new classification scheme was proposed. Type I aneurysms arise from the main trunk, accessory branch, or first-order branches away from any bifurcation. Type II aneurysms arise from the first bifurcation with narrow necks (defined as dome-to-neck ratio >2) or from intralobular branches. Type III aneurysms with a wide neck arise from the first bifurcation and affect 2 or more branches that cannot be sacrificed without significant infarction of the kidney. RESULTS: There was 50 (47.62%) type I, 33 (31.43%) type II, and 22 (20.95%) type III aneurysms. The classification assigned endovascular repair as first-line treatment (for type I or II), while open techniques were conducted if anatomically suitable (for type III). A kappa level of 0.752 was achieved by the classification compared with a level of 0.579 from the classic Rundback classification. Technical primary success was achieved in 100% and 96.05%, and symptoms were completely resolved in 100% and 84.85%, while hypertension was relieved in 84.21% and 72.92% of patients receiving open surgery or endovascular repair, respectively. No significant difference was observed for perioperative or long-term complications among the 3 classification types. CONCLUSION: The new classification proved to be a convenient and effective method for facilitating choice of intervention for RAAs. CLINICAL IMPACT: This study proposed and evaluated a new classification scheme for renal artery aneurysms, which proved to be a convenient and effective method for facilitating surgical decision-making. Coil embolization was the first-line treatment if suitable, while aneurysm resection and reconstruction with vein graft were conducted for some complex lesions. The safety and efficacy of both open and endovascular methods were validated.

Electromagnetic interference shielding of flexible carboxymethyl cellulose/MWCNT@Fe3O4 composite film with ultralow reflection loss.

Nowadays, various high-performance electromagnetic interference (EMI) shielding materials have enormous application potential in electronic field. However, traditional EMI shielding materials often have high conductivity, resulting in the serious mismatch between the impedance of the material surface and the free space, which will cause a large amount of reflection of electromagnetic (EM) waves, leading to secondary reflection pollution. In this paper, we report a novel flexible EMI shielding composite film with extremely low reflection loss and efficient EM wave absorption, which was prepared by assisted self-assembly based on simple vacuum filtration using carboxymethyl cellulose as the matrix and MWCNT@Fe3O4 synthesized by chemical coprecipitation as the composite functional filler. By adjusting the Fe3O4 coating degree of MWCNTs in the filler, the composite film achieved the construction of a conductive network with high Fe3O4 content. Benefit by the good adaptability of conductivity and magnetic permeability, the composite film has good impedance matching ability and microwave absorption performance. The reflection loss of the composite film with the thickness of 28 µm in the X-band was only 0.23 dB, accounting for 1.7 % of the total loss. This work provides new insights for the development of EMI materials and effective mitigation secondary EM wave reflection pollution.

Setd2 deficiency promotes gastric tumorigenesis through inhibiting the SIRT1/FOXO pathway.

Gastric cancer (GC) is the fifth most common cancer and the second leading cause of cancer death globally. SETD2 is a histone methyltransferase catalyzing tri-methylation of H3K36 (H3K36me3) and has been shown to participate in diverse biological processes and human tumors. However, the mechanism of SETD2 in GC remains unclear. Here, we reported that Setd2 deficiency predicts poor prognosis of gastric cancer. SETD2 loss facilitated H. felis/MNU and c-Myc-induced gastric tumorigenesis, respectively. The mouse model of stomach-specific Setd2 depletion together with c-MYC overexpression (AMS) developed high-grade epithelial defects, intestinal metaplasia and dysplasia at only 10-12 weeks of age. Mechanistically, Setd2 depletion resulted in impaired epigenetic regulation of Sirt1, thus inhibiting the SIRT1/FOXO pathway. Moreover, the agonists of FOXO signaling or overexpression of SIRT1 significantly rescued the enhanced cell proliferation and migration caused by Setd2 deficiency in SGC7901 cells. Together, our findings highlight an epigenetic mechanism by which SETD2 regulates gastric tumorigenesis through SIRT1/FOXO pathway. It may also pave the way for the development of targeted, patient-tailored therapies for GC patients with Setd2 deficiency.

SETD2 deficiency promotes renal fibrosis through the TGF-ß/Smad signalling pathway in the absence of VHL.

BACKGROUND: Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. Epigenetic alteration is a significant intrinsic factor contributing to the development of renal fibrosis. SET domain-containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalysing H3K36 trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. METHODS: Kidney tissues from mice as well as HK2 cells were used as research subjects. Clinical databases of patients with renal fibrosis were analysed to investigate whether SETD2 expression is reduced in the occurrence of renal fibrosis. SETD2 and Von Hippel-Lindau (VHL) double-knockout mice were used to further investigate the role of SETD2 in renal fibrosis. Renal tubular epithelial cells isolated from mice were used for RNA sequencing and chromatin immunoprecipitation sequencing to search for molecular signalling pathways and key molecules leading to renal fibrosis in mice. Molecular and cell biology experiments were conducted to analyse and validate the role of SETD2 in the development of renal fibrosis. Finally, rescue experiments were performed to determine the molecular mechanism of SETD2 deficiency in the development of renal fibrosis. RESULTS: SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the transforming growth factor-ß (TGF-ß)/Smad signalling pathway, thereby preventing the activation of the TGF-ß/Smad signalling pathway. Deletion of SETD2 leads to reduced Smad7 expression, which results in activation of the TGF-ß/Smad signalling pathway and ultimately renal fibrosis in the absence of VHL. CONCLUSIONS: Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-ß/Smad signalling pathway in renal fibrogenesis and provide an innovative insight into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.

Loss of SETD2 aggravates colorectal cancer progression caused by SMAD4 deletion through the RAS/ERK signalling pathway.

BACKGOUND: Colorectal cancer (CRC) is a complex, multistep disease that arises from the interplay genetic mutations and epigenetic alterations. The histone H3K36 trimethyltransferase SET domain-containing 2 (SETD2), as an epigenetic signalling molecule, has a 5% mutation rate in CRC. SETD2 expression is decreased in the development of human CRC and mice treated with Azoxymethane /Dextran sodium sulfate (AOM/DSS). Loss of SETD2 promoted CRC development. SMAD Family member 4 (SMAD4) has a 14% mutation rate in CRC, and SMAD4 ablation leads to CRC. The co-mutation of SETD2 and SMAD4 predicted advanced CRC. However, little is known on the potential synergistic effect of SETD2 and SMAD4. METHODS: CRC tissues from mice and SW620 cells were used as research subjects. Clinical databases of CRC patients were analyzed to investigate the association between SETD2 and SMAD4. SETD2 and SMAD4 double-knockout mice were established to further investigate the role of SETD2 in SMAD4-deficient CRC. The intestinal epithelial cells (IECs) were isolated for RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) to explore the mechanism and the key molecules resulting in CRC. Molecular and cellular experiments were conducted to analyze the role of SETD2 in SMAD4-deficient CRC. Finally, rescue experiments were performed to confirm the molecular mechanism of SETD2 in the development of SMAD4-dificient CRC. RESULTS: The deletion of SETD2 promotes the malignant progression of SMAD4-deficient CRC. Smad4Vil-KO ; Setd2Vil-KO mice developed a more severe CRC phenotype after AOM/DSS induction, with a larger tumour size and a more vigorous epithelial proliferation rate. Further mechanistic findings revealed that the loss of SETD2 resulted in the down-regulation of DUSP7, which is involved in the inhibition of the RAS/ERK signalling pathway. Finally, the ERK1/2 inhibitor SCH772984 significantly attenuated the progression of CRC in Smad4Vil-KO ;Setd2Vil-KO mice, and overexpression of DUSP7 significantly inhibited the proliferation rates of SETD2KO ; SMAD4KO SW620 cells. CONCLUSIONS: Our results demonstrated that SETD2 inhibits the RAS/ERK signaling pathway by facilitating the transcription of DUSP7 in SMAD4-deficient CRC, which could provide a potential therapeutic target for the treatment of advanced CRC.

Effects of Mulberry Leaf Fu Tea on the Intestines and Intestinal Flora of Goto-Kakizaki Type 2 Diabetic Rats.

Type 2 diabetes mellitus is a disease caused by hyperglycemia, an imbalance in the intestinal flora and disruption of the endocrine system. At present, it is primarily controlled through drug treatment and an improved diet. Mulberry leaf and fu brick tea were considered to have excellent hypoglycemic effects. This study used mulberry leaves and fu brick tea as raw materials to develop a dietary regulator that can assist in the prevention and alleviation of diabetes. The experiment used the Goto-Kakizaki (GK) rat model to investigate the hypoglycemic effect of mulberry leaf fu tea (MFT) and its influence on the intestinal flora of diabetic rats through methods including ELISA, tissue section observation and 16S RNA microbial sequencing. The results showed that, compared with the GK group, the intervention of mulberry leaf fu tea significantly reduced the activities of α-glucosidase (p < 0.05) and α-amylase (p < 0.05) in the duodenum of GK diabetic rats. The height of the duodenal villi was significantly reduced (p < 0.001), leading to decreased intestinal sugar absorption. At the same time, MFT alleviates the imbalance of intestinal flora caused by high blood sugar, promotes the growth of beneficial bacteria (Lactobacillus, Bifidobacterium, etc.), and inhibits the reproduction of harmful bacteria (Blautia, Klebsiella, Helicobacter, Alistipes, etc.). MFT helps reduce the secretion of toxic substances (lipopolysaccharide, p < 0.001), decreases oxidative stress and inflammation, mitigates organ damage, and improves symptoms of diabetes. Finally, the random blood glucose value of GK rats dropped from 22.79 mmol/L to 14.06 mmol/L. In summary, mulberry leaf fu tea can lower sugar absorption in diabetic rats, reduce the body's oxidative stress and inflammatory response, regulate intestinal flora, and reduce blood sugar levels in GK rats. It is hinted that mulberry leaf fu tea could be used as a functional drink to help prevent the occurrence of diabetes.

Effects of pile-fermentation on the aroma quality of dark tea from a single large-leaf tea variety by GC × GC-QTOFMS and electronic nose.

Aroma is one of the significant quality factors of dark tea (DT). However, for a single large-leaf tea variety, there are few studies analyzing the effect of pile-fermentation on the aroma quality of DT. The GC × GC-QTOFMS, electronic nose (E-nose) and GC-olfactometry (GC-O) techniques were employed to analysis the difference of tea products before and after pile-fermentation. A total of 149 volatile metabolites (VMs) were identified, with 92 VMs exhibiting differential characteristics. Among these, 31 VMs with OAV > 1.0 were found to be correlated with E-nose results (|r| > 0.8). Additionally, GC-O analysis validated seven major differential metabolites. Notably, naphthalene, 2-methylnaphthalene, and dibenzofuran were found to enhance the woody aroma, while (Z)-4-heptenal, 2-nonenal and 1-hexanol were associated with an increase in mushroom, fatty and sweet odors, respectively. Moreover, 1-octen-3-ol was linked to reducing pungent fishy smell. These findings could provide a certain theoretical basis for understanding the influence of pile-fermentation on the aroma quality of dark tea.

SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer.

Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain-containing 2 (SETD2) has been identified as an important tumor suppressor and an immunosuppressor in ccRCC. However, the role of SETD2 in ccRCC generation in PKD remains largely unexplored. Herein, we perform metabolomics, lipidomics, transcriptomics and proteomics within SETD2 loss induced PKD-ccRCC transition mouse model. Our analyses show that SETD2 loss causes extensive metabolic reprogramming events that eventually results in enhanced sphingomyelin biosynthesis and tumorigenesis. Clinical ccRCC patient specimens further confirm the abnormal metabolic reprogramming and sphingomyelin accumulation. Tumor symptom caused by Setd2 knockout is relieved by myriocin, a selective inhibitor of serine-palmitoyl-transferase and sphingomyelin biosynthesis. Our results reveal that SETD2 deficiency promotes large-scale metabolic reprogramming and sphingomyelin biosynthesis during PKD-ccRCC transition. This study introduces high-quality multi-omics resources and uncovers a regulatory mechanism of SETD2 on lipid metabolism during tumorigenesis.