Amelioration of NAFLD by sleeve gastrectomy-triggered hepatocyte regeneration in mice - experimental research.

BACKGROUND: Sleeve gastrectomy (SG) is known to alleviate non-alcoholic fatty liver disease (NAFLD) and restore liver function; however, its underlying mechanism remains unclear. METHODS: We investigated the effect of SG on the metabolic phenotype of diet-induced obese (DIO) mice. Postoperative stained liver images were analyzed to determine the hepatocyte proliferation phenotype. Single-cell RNA sequencing was used to characterize the regeneration signals of the liver after SG in DIO mice, and qRT PCR was performed to verify the above results. We employed Olink proteomics to capture serum element changes and investigated the role of Yes1 protein in liver regeneration and carcinogenesis through the Hippo-YAP pathway. DIO mice were treatment with YAP inhibitor verteporfin after SG mice to clarify whether SG-induced liver regeneration is related to the YAP signaling pathway. RESULTS: SG significantly reduced NAFLD-associated dysfunction in hepatocytes and replaced them with fully functional hepatocytes, which have a high regenerative capacity across the entire liver. SG also enhanced the hepatic regenerative capacity, as demonstrated by SG combined with hepatic lobectomy in healthy mice. Yes1 protein was identified as the signaling molecule most closely related to classical regeneration signals. Our study showed that SG-enhanced proliferation and improved metabolism did not depend on YAP signaling. CONCLUSION: SG can enhance hepatic regenerative capacity and improve liver metabolism. This study provides a better understanding of the mechanisms underlying SG-induced metabolic improvements.

New mechanistic insights of anti-obesity by sleeve gastrectomy-altered gut microbiota and lipid metabolism.

Background: The obesity epidemic has been on the rise due to changes in living standards and lifestyles. To combat this issue, sleeve gastrectomy (SG) has emerged as a prominent bariatric surgery technique, offering substantial weight reduction. Nevertheless, the mechanisms that underlie SG-related bodyweight loss are not fully understood. Methods: In this study, we conducted a collection of preoperative and 3-month postoperative serum and fecal samples from patients who underwent laparoscopic SG at the First Affiliated Hospital of Shandong First Medical University (Jinan, China). Here, we took an unbiased approach of multi-omics to investigate the role of SG-altered gut microbiota in anti-obesity of these patients. Non-target metabolome sequencing was performed using the fecal and serum samples. Results: Our data show that SG markedly increased microbiota diversity and Rikenellaceae, Alistipes, Parabacteroides, Bactreoidales, and Enterobacteraies robustly increased. These compositional changes were positively correlated with lipid metabolites, including sphingolipids, glycerophospholipids, and unsaturated fatty acids. Increases of Rikenellaceae, Alistipes, and Parabacteroide were reversely correlated with body mass index (BMI). Conclusion: In conclusion, our findings provide evidence that SG induces significant alterations in the abundances of Rikenellaceae, Alistipes, Parabacteroides, and Bacteroidales, as well as changes in lipid metabolism-related metabolites. Importantly, these changes were found to be closely linked to the alleviation of obesity. On the basis of these findings, we have identified a number of microbiotas that could be potential targets for treatment of obesity.

Bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is associated with high mortality rates. Bile acids (BAs) reflux is a well-known risk factor for GC, but the specific mechanism remains unclear. During GC development in both humans and animals, BAs serve as signaling molecules that induce metabolic reprogramming. This confers additional cancer phenotypes, including ferroptosis sensitivity. Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression. However, it is not fully defined if BAs can influence GC progression by modulating ferroptosis. AIM: To reveal the mechanism of BAs regulation in ferroptosis of GC cells. METHODS: In this study, we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis. We used gain and loss of function assays to examine the impacts of farnesoid X receptor (FXR) and BTB and CNC homology 1 (BACH1) overexpression and knockdown to obtain further insights into the molecular mechanism involved. RESULTS: Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells. This effect correlated with increased glutathione (GSH) concentrations, a reduced GSH to oxidized GSH ratio, and higher GSH peroxidase 4 (GPX4) expression levels. Subsequently, we confirmed that BAs exerted these effects by activating FXR, which markedly increased the expression of GSH synthetase and GPX4. Notably, BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR. Finally, our results suggested that FXR could significantly promote GC cell proliferation, which may be closely related to its anti-ferroptosis effect. CONCLUSION: This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSH-GPX4 axis in GC cells. This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

Nomogram for predicting overall survival after curative gastrectomy using inflammatory, nutritional and pathological factors.

PURPOSE: To establish a nomogram for predicting the overall survival (OS) in patients with gastric cancer (GC) based on inflammatory, nutritional and pathological factors. METHODS: GC patients underwent curative gastrectomy from January 2012 to June 2017 in our hospital were included, and were classified into training set and validation set with a ratio of 7:3. Then variables associated with OS were analyzed using univariate and multivariate Cox regression analysis. Nomograms predicting OS were built using variables from multivariable Cox models. Finally, Kaplan-Meier curve and Log-rank test were also conducted to analyze the 1-yr, 3-yr and 5-yr OS to validate the efficiency of risk stratification of the nomogram. RESULTS: A total of 366 GC patients were included. After univariate and multivariate Cox regression analysis, age (HR = 1.52, 95% CI = 1.01-2.30, P = 0.044), CA50 (HR = 1.90, 95% CI = 1.12-3.21, P = 0.017), PNI (HR = 1.65, 95% CI = 1.13-2.39, P = 0.009), SII (HR = 1.46, 95% CI = 1.03-2.08, P = 0.036), T stage (HR = 2.26, 95% CI = 1.01-5.05, P = 0.048; HR = 7.24, 95% CI = 3.64-14.40, P < 0.001) were independent influencing factors on the survival time of GC patients. Five factors including CEA, prognostic nutritional index (PNI), systemic immune-inflammation index (SII), ln (tumor size), T stage, and N stage were identified and entered the nomogram, which showed good discrimination and calibration in both sets. On internal validation, 1-yr, 3-yr and 5-yr nomogram demonstrated a good discrimination with an area under the ROC curve (AUC) of 0.77, 0.84 and 0.86, respectively. The AUC for 1-yr, 3-yr and 5-yr nomogram in validation set was 0.77, 0.79 and 0.81, respectively. The OS in low risk group of training cohort and validation cohort was significantly higher than that of intermediate risk group and high risk group, respectively. CONCLUSIONS: We established a nomogram based on PNI, SII and pathological factors for predicting OS in GC patients. In addition, its efficiency was validated by validation set and stratified analysis.

Bariatric surgery for diabetic comorbidities: A focus on hepatic, cardiac and renal fibrosis.

Continuously rising trends in diabetes render this disease spectrum an epidemic proportion worldwide. As the disease progresses, the pathological effects of diabetes may impair the normal function of several vital organs, eventually leading to increase the risk of other diabetic comorbidities with advanced fibrosis such as non-alcoholic fatty liver disease, diabetic cardiomyopathy, and diabetic kidney disease. Currently, lifestyle changes and drug therapies of hypoglycemic and lipid-lowering are effective in improving multi-organ function, but therapeutic efficacy is difficult to maintain due to poor compliance and drug reactions. Bariatric surgery, including sleeve gastrectomy and Roux-en-Y gastric bypass surgery, has shown better results in terms of prognosis for diabetes through long-term follow-up. Moreover, bariatric surgery has significant long-term benefits on the function of the heart, liver, kidneys, and other organs through mechanisms associated with reversal of tissue fibrosis. The aim of this review is to describe the impact of type 2 diabetes mellitus on hepatic, cardiac and renal fibrosis and to summarize the potential mechanisms by which bariatric surgery improves multiple organ function, particularly reversal of fibrosis.

Sleeve gastrectomy attenuated diabetes-related cognitive decline in diabetic rats.

Objective: To investigate the effects of sleeve gastrectomy (SG) on diabetes-related cognitive decline (DCD) in rats with diabetic mellitus (DM). Methods and methods: Forty Wistar rats were randomly divided into control (CON) group (n=10), diabetes mellitus (DM) group (n=10), sham operation (SHAM) group (n=10) and SG group (n=10). DM model was established by high-fat diet (HFD) combined with intraperitoneal injection of streptozocin (STZ). Behavioral evaluation was given using Morris water maze test and Y-maze. In addition, PET-CT, TUNEL assay, histological analysis, transmission electron microscopy (TEM), immunohistochemistry (IHC) and Western blot analysis were used to evaluate the alleviating effects and potential mechanisms of SG on DCD in DM rats. Results: Compared with the sham group, SG induced significant improvement in the metabolic indices such as blood glucose and body weight. Besides, it could attenuate the insulin resistance compared with SHAM group. In addition, SG could improve the cognitive function of DM rats, which were featured by significant decrease in the escape latency (P<0.05), and significant increase in the time in target quadrant and platform crossings (P<0.05) compared with the SHAM group. SG induced significant elevation in the spontaneous alternation compared with SHAM group (P<0.05). Moreover, SG could improve the arrangement and biosynthesis of hippocampus neuron. Moreover, SG triggered the inhibition of apoptosis of hippocampus neurons, and Western blot analysis showed SG induced significant increase in the ratios of Bcl-2/Bax and Caspase3/cleaved Caspase 3. TEM demonstrated SG could significantly improve the microstructure of hippocampus neurons compared with the SHAM group. Western blot and IHC confirmed the significant decrease in the phosphorylation of tau at Ser404 and Ser396 sites in the SG group. Furthermore, SG activated the PI3K signaling pathway by elevating the phosphorylation of PI3K and Akt and GSK3ß compared with the SHAM group. Conclusion: SG attenuated the DCD in DM rats, which may be related to the activation of PI3K signaling pathway.

Sleeve Gastrectomy Ameliorates Diabetes-Induced Cardiac Hypertrophy Correlates With the MAPK Signaling Pathway.

Background: Cardiac hypertrophy as a main pathological manifestation of diabetic cardiomyopathy (DCM), is a significant complication of diabetes. Bariatric surgery has been proven to relieve DCM; however, whether it can alleviate diabetes-induced cardiac hypertrophy is undefined. Methods: Diabetic and obese rats were performed sleeve gastrectomy (SG) after having diabetes for 16weeks. The rats were euthanized 8weeks after SG. Metabolic parameters, heart function parameters, myocardial glucose uptake, morphometric and histological changes, and the expression level of mitogen-activated protein kinases (MAPKs) were determined and compared among the control group (CON group), diabetes mellitus group (DM group), sham operation group (SHAM group), and SG group. Results: Compared with the SHAM group, the blood glucose, body weight, insulin resistance, and other metabolic parameters were significantly improved in the SG group. There was also a marked improvement in myocardial morphometric and histological parameters after SG. Furthermore, the myocardial glucose uptake and heart function were reversed after SG. Additionally, the phosphorylation of MAPKs was inhibited after SG, including p38 MAPKs, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases 1/2 (ERK1/2). The expression of DUSP6, which dephosphorylates ERK1/2, was upregulated after SG. These findings suggest that SG ameliorated diabetes-induced cardiac hypertrophy correlates with the MAPK signaling pathway. Conclusion: These results showed that diabetes-induced cardiac hypertrophy was ameliorated after SG was closely related to the inhibition of the MAPK signaling pathway and upregulation of DUSP6. Therefore, this study provides a novel strategy for treating diabetes-induced cardiac hypertrophy.

The fungal community outperforms the bacterial community in predicting plant health status.

Characterizing the relationship between soil biotic and abiotic properties and plant health status is crucial to understanding the pathogenesis of soil-borne diseases. Here, we compared these properties in the soils of lisianthus with different disease incidence plots and report the cause-effect relationship between soil properties and plant health status using heat treatment coupled with microbiota self/across re-inoculations. The relative importance of soil bacterial and fungal communities in predicting plant health was also analyzed. Results showed that the soils with low and high disease incidences (LDS and HDS) harbored differential microbial communities and physicochemical properties. The LDS soil had relatively low Fusarium oxysporum abundance, electrical conductivity (EC), and NO3--N content. Soil microbial community was the direct determinant of plant health. The disease-suppressive activity of the microbiome in the LDS soil could be transferred to the HDS soil. Also, the relative importance of the fungal community in predicting plant health status was greater than that of the bacterial community, as reflected by (1) the fungal community could drive more complex networks related to healthy plants and (2) the diversity and core taxa of the fungal community had higher mean predictor importance values for plant health. The relative abundances of core genera Acremonium, Mycothermus, and Chryseolinea were significantly and negatively correlated with the disease incidence and the abundances of pathogens, identifying these genera as potential disease-suppressive agents. Taken together, our results reveal a direct relationship between soil properties and plant health status, in which the fungal community composition is most important for predicting plant health status. KEY POINTS: • Soil with differing pathological groups harbors distinct microbial communities. • Soil microbial communities directly determine the plant's health status. • Fungal community is a better predictor of plant health than the bacterial community.

Comparative Microbial Nitrogen Functional Gene Abundances in the Topsoil vs. Subsoil of Three Grassland Habitats in Northern China.

The microbial groups of nitrogen fixers, ammonia oxidizers, and denitrifiers play vital roles in driving the nitrogen cycle in grassland ecosystems. However, the understanding of the abundance and distribution of these functional microorganisms as well as their driving factors were limited mainly to topsoil. In this study, the abundances of nitrogen functional genes (NFGs) involved in nitrogen fixation (nifH), ammonia oxidation (amoA), and denitrification (nirK, nirS, and nosZ) were investigated in both topsoil (0-10 cm, soil layer with concentrated root) and subsoil (30-40 cm, soil layer with spare root) of three grassland habitats in northern China. The abundance of NFGs decreased with soil depth except for the archaeal amoA gene and the distribution of nifH, archaeal amoA, nirK, and nirS gene was significantly impacted by grassland habitats. Moreover, the distribution of NFGs was more responsive to the vertical difference than horizontal spatial heterogeneity. Redundancy analysis revealed that the distribution pattern of overall NFGs was regulated by grassland habitats, and these regulations were more obvious in the subsoil than in the topsoil. Variance partitioning analysis further indicated that soil resource supply (e.g., organic matter) may control the vertical distribution of NFGs. Taken together, the findings in this study could fundamentally improve our understanding of the distribution of N cycling-associated microorganisms across a vertical scale, which would be useful for predicting the soil N availability and guiding the soil N management in grassland ecosystems.