Background This study was designed to clarify the function and potential mechanism of gentiopicroside (GPS) in regulating the malignant progression of gastric cancer (GC) through in vitro cellular experiments and in vivo animal models. Methods AGS and HGC27 cells were divided into control group and GPS treatment groups (50 µM and 100 µM). Then, the cellular proliferation, colony formation, migration, invasion, and apoptosis were detected, respectively. Transmission electron microscope (TEM) was used to observe the mitochondrial changes, and the mitochondrial membrane potential (MMP) was determined using the JC-1 commercial kit. Network pharmacology analysis was utilized to screen the potential molecule that may be related to the GPS activity on GC cells, followed by validation tests using Western blot in the presence of specific activator. In addition, xenografted tumor model was established using BALB/c nude mice via subcutaneous injection of HGC27 cells, along with pulmonary metastasis model. Then, the potential effects of GPS on the tumor growth and metastasis were detected by immunohistochemistry (IHC) and HE staining. Results GPS inhibited the proliferation, invasion and migration of GC cell lines in a dose-dependent manner. Besides, it could induce mitochondrial apoptosis. Epidermal growth factor receptor (EGFR) may be a potential target for GPS action in GC by network pharmacological analysis. GPS inhibits activation of the EGFR/PI3K/AKT axis by reducing EGFR expression. In vivo experiments indicated that GPS induced significant decrease in tumor volume, and it also inhibited the pulmonary metastasis. For the safety concerns, GPS caused no obvious toxicities to the heart, liver, spleen, lung and kidney tissues. IHC staining confirmed GPS downregulated the activity of EGFR/PI3K/AKT. Conclusions Our investigation demonstrated for the first time that GPS could inhibit GC malignant progression by targeting the EGFR/PI3K/AKT signaling pathway. This study indicated that GPS may be serve as a safe anti-tumor drug for further treatment of GC.

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.

Tripartite motif-containing protein 7 (TRIM7), as an E3 ligase, plays an important regulatory role in various physiological and pathological processes. However, the role of TRIM7 in gastric cancer (GC) is still undefined. Our study detected the expression of TRIM7 in clinical specimens and investigated the regulatory effect and molecular mechanism of TRIM7 on GC progression through in vitro and in vivo experiments. Our finding showed that TRIM7 was significantly downregulated in GC, and patients with high expression of TRIM7 showed long overall survival. Both in vitro and in vivo experiments showed that TRIM7 dramatically suppressed the malignant progression of GC. Further investigation showed that ferroptosis was the major death type mediated by TRIM7. Mechanistically, TRIM7 interacted with SLC7A11 through its B30.2/SPRY domain and promoted Lys48-linked polyubiquitination of SLC7A11, which effectively suppressing SLC7A11/GPX4 axis and inducing ferroptosis in GC cells. In vivo experiments and correlation analysis based on clinical specimens further confirmed that TRIM7 inhibited tumor growth through suppressing SLC7A11/GPX4 axis. In conclusion, our investigation demonstrated for the first time that TRIM7, as a tumor suppressor, induced ferroptosis via targeting SLC7A11 in GC, which provided a new strategy for the molecular therapy of GC by upregulating TRIM7.

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.

This study was designed to investigate the roles of autophagy in the attenuation of hepatic lipid accumulation after sleeve gastrectomy (SG). Thirty-two rats were divided into normal control, obesity group, sham group, and SG group. Then serum glucagon-like polypeptide-1 (GLP-1) and lipid accumulation were determined, followed by measuring the activity of autophagy based on immunohistochemistry (IHC) and Western blot analysis. Our data showed significant decrease in the lipid accumulation after SG compared with sham group. GLP-1 and autophagy showed significant increase in rats underwent SG compared with the sham group (P < 0.05). In vitro experiments were conducted to analyze the roles of GLP-1 in autophagy. We knock-downed the expression of Beclin-1 in HepG2, and then analyzed the expression of autophagy-related protein (i.e. LC3BII and LC3BI) and lipid droplet accumulation. In HepG2 cells, GLP-1 analog reduced lipid accumulation by activating autophagy through modulating the AMPK/mTOR signaling pathway. All these concluded that SG decreased hepatic lipid accumulation by inducing autophagy through modulating AMPK/mTOR pathway.

Anti-PD1/PDL1 monotherapy has failed to acquire sufficiently ideal results in most solid tumors. Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on some tumors, but the functions of MSCs in colorectal cancer (CRC) need further research. In this study, we aimed to investigate the therapeutic effect and the improvement of sensitivity of MSCs to anti-PD1 antibodies (αPD1) in CRC and to evaluate the possible mechanism. The relative distribution of immune cells in tumor microenvironment was examined after the mice were treated with MSC and/or αPD1. Our study revealed that MSC recruits CX3CR1high macrophages and promotes M1 polarization to inhibit tumor growth via highly secretion of CX3CL1.The combination of MSC and αPD1 was superior to monotherapy against CRC. MSC inhibits PD1 expression on CD8+ T cells by facilitating M1 macrophage polarization, which promotes the proliferation of CD8+ T cells, thus improving the sensitivity to αPD1 therapy in CRC. Additionally, the above therapeutic effect disappeared after inhibiting the secretion of CX3CL1 in MSC. Our MSC-based immunotherapeutic strategy simultaneously recruited and activated immune effector cells at the tumor site, suggesting that the combination of MSC and αPD1 could be a potential therapy for CRC.

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 GSK3β compared with the SHAM group. Conclusion SG attenuated the DCD in DM rats, which may be related to the activation of PI3K signaling pathway.

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.