Gut commensal Parabacteroides distasonis alleviates inflammatory arthritis.

OBJECTIVE: Gut microbiota dysbiosis is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify potential probiotic gut microbes that can ameliorate the development of RA. DESIGN: Microbiota profiling in patients with RA and healthy individuals was investigated via 16S rDNA bacterial gene sequencing and shotgun metagenomics. Collagen-induced arthritic mice and TNF-α transgenic mice were used to evaluate the roles of the gut commensal Parabacteroides distasonis in RA. The effects of P. distasonis-derived microbial metabolites on the differentiation of CD4+ T cells and macrophage polarisation were also investigated. RESULTS: The relative abundance of P. distasonis in new-onset patients with RA and patients with RA with history of the disease was downregulated and this decrease was negatively correlated with Disease Activity Score-28 (DAS28). Oral treatment of arthritic mice with live P. distasonis (LPD) considerably ameliorated RA pathogenesis. LPD-derived lithocholic acid (LCA), deoxycholic acid (DCA), isolithocholic acid (isoLCA) and 3-oxolithocholic acid (3-oxoLCA) had similar and synergistic effects on the treatment of RA. In addition to directly inhibiting the differentiation of Th17 cells, 3-oxoLCA and isoLCA were identified as TGR5 agonists that promoted the M2 polarisation of macrophages. A specific synthetic inhibitor of bile salt hydrolase attenuated the antiarthritic effects of LPD by reducing the production of these four bile acids. The natural product ginsenoside Rg2 exhibited its anti-RA effects by promoting the growth of P. distasonis. CONCLUSIONS: P. distasonis and ginsenoside Rg2 might represent probiotic and prebiotic agents in the treatment of RA.

A phase I dose-escalation study of SYHA1813, a VEGFR and CSF1R inhibitor, in patients with recurrent High-Grade Gliomas or Advanced Solid Tumors.

SYHA1813 is a potent multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs)/colony-stimulating factor 1 receptor (CSF1R). This study aimed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of escalating doses of SYHA1813 in patients with recurrent high-grade gliomas (HGGs) or advanced solid tumors. This study adopted a combination of accelerated titration and a 3 + 3 design for dose escalation, with a starting dose of 5 mg once daily. The dose escalation continued at successive dose levels until the maximum tolerated dose (MTD) was determined. A total of 14 patients were enrolled and treated, including 13 with WHO grade III or IV gliomas and 1 with colorectal cancer. Two patients experienced dose-limiting toxicities (grade 4 hypertension and grade 3 mucositis oral) at 30 mg SYHA1813. The MTD was defined as 15 mg once daily. Hypertension (n = 6, 42.9%) was the most frequent treatment-related adverse event. Among evaluable patients (n = 10), 2 (20%) patients achieved partial response, and 7 (70%) had stable disease. The exposure increased with increasing doses within the studied dose range of 5 to 30 mg. Biomarker assessments demonstrated significant reductions in the levels of soluble VEGFR2 (P = .0023) and increases in the levels of VEGFA (P = .0092) and placental growth factor (P = .0484). The toxicities of SYHA1813 were manageable, and encouraging antitumor efficacy was observed in patients with recurrent malignant glioma. This study is registered with the Chinese Clinical Trial Registry ( www.chictr.org.cn/index.aspx ; identifier ChiCTR2100045380).

Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn's disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration.

1. Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn's disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug. 2. Although the systemic TSA exposures were low (AUC0-t approximately 330 ng*h/ml) in both the normal and colitis models after oral administration TSA 20 mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies. 3. Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher plasma concentration of TSA glucuronides in the model mice at 0.5, 1 and 2 h after TSA administration. 4. Together, these results reveal high accumulation at the site of inflammation and minimal systemic concentration of TSA, which are favorable pharmacokinetic behaviors to meet the requirements for CD treatment.

[HPLC specific chromatogram spectrum-effect relationship for Shuanghuanglian on MDCK cell injury induced by influenza A virus (H1N1)].

To establish HPLC specific chromatogram and its correlation with the protection effect of Shuanghuanglian on MDCK (Madin-Darby canine kidney) cell injury induced by influenza A virus( H1N1). Nine recipes of Shuanghuanglian based on the official prescription were prepared according to orthogonal test for HPLC analysis and MDCK cells protection experiment separately (cytopathic effect (CPE) method was used for observing the virus infectivity and MTT staining results were used as the determining indexes for drug concentration selection and analyzing cell viability). The results suggested that all the other Shuang-Huang-Lian recipes except recipe1 demonstrate protecting effect on MDCK cell injury induced by influenza A virus (P < 0.01, P < 0.001). Stepwise regression analysis was used for analyzing the relationships between HPLC fingerprint and the protecting effect of Shuanghuanglian on influenza A virus induced MDCK cell injury. Peak 2, 3, 6, 8 and 12 were found to be strongly related with anti-influenza A virus efficacy. Stepwise regression analysis of recipes data and efficacy data showed that Lonicerae Japonicae Flos and Forsythiae Fructus were positively associated with the protecting effect of cells injury. From HPLC fingerprints, we found that peak 2, 3, 12 were from Lonicerae Japonicae Flos and peak 6, 8 were from Forsythiae Fructus. Four peaks were identified through comparing the retention time between the standard and Shuanghuanglian recipes, and they were chlorogenicacid, cryptochlorogenic acid, forsythoside B and 3,4-dicaffeoylquinic acid respectively. Caffeic acid derivatives in Lonicerae Japonicae Flos and Forsythiae Fructus were found to be greatly correlated with anti-influenza A virus efficacy and maybe the substance basis of Shuanghuanglian.

A network pharmacology-based approach to explore the active ingredients and molecular mechanism of Shen-Kui-Tong-Mai granules on a rat model with chronic heart failure.

OBJECTIVES: This study aimed to comprehensively investigate the potential active components and therapeutic mechanisms of Shen-Kui-Tong-Mai granule (SKTMG) in the treatment of heart failure. METHODS: Network pharmacology combined with ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS), molecular docking, and in vivo validation was performed to identify the active components and the potential targets for SKTMG to improve chronic heart failure (CHF). KEY FINDINGS: The network pharmacology identified 192 active compounds and 307 potential consensus targets for SKTMG. On the other hand, network analysis discovered 10 core target genes related to the MAPK signal pathway. These genes include AKT1, STAT3, MAPK1, P53, SRC, JUN, TNF, APP, MAPK8 and IL6. The molecular docking results revealed that the SKTMG components were luteolin, quercetin, astragaloside IV and kaempferol, which could bind AKT1, MAPK1, P53, JUN, TNF and MAPK8. Additionally, SKTMG inhibited phosphorylation of AKT, P38, P53 and c-JUN, and reduced TNF-α expression in CHF rats. CONCLUSIONS: The present results demonstrated that network pharmacology combined with UHPLC-MS/MS, molecular docking and in vivo validation can facilitate the identification of active components and the potential targets for SKTMG to improve CHF.

Extraction and characterisation of pigment from Yanzhiguo [Prunus napaulensis (Ser.) Steud.].

Yanzhiguo [Prunus napaulensis (Ser.) Steud] belongs to Rosaceae family and is consumed as wild fruit, pulp and juice. However, its potential for extracting natural pigment has not yet been explored. Herein, the components in the fresh Yanzhiguo pulp were preliminarily analyzed by liquid chromatography coupled to mass spectrometry. And, the optimal pre-treatment conditions were established for further extraction of Yanzhiguo pigment based on the a* value. Then, by combining the data from single-factor experiments and response surface methodology, the optimal extraction process was established as: 35% EtOH, a liquid-solid ratio of 200:1 mL g-1, an extraction time of 65 min, and an extraction temperature of 100 °C. Moreover, it was found that the a* value and yield had high fitness except when extracted into ethanol (EtOH) with different concentrations. Meanwhile, our result demonstrated Yanzhiguo pigment had high stability in general environments with carmine (a synthetic pigment) as control, except for extreme environments such as direct (hot) sunlight, high temperature (75 °C) and strong alkaline (pH ≥ 11). Also, Yanzhiguo pigment exhibited good antioxidant activity. Our results contribute to more information on Yanzhiguo pigment and promote its application by providing efficient extraction technology.

Jianpi Yangzheng Xiaozheng decoction alleviates gastric cancer progression via suppressing exosomal PD-L1.

Jianpi Yangzheng Xiaozheng decoction (JPYZXZ) is an empirical traditional Chinese medicine formula that has been reported to significantly prolong the survival of patients with advanced gastric cancer (GC). However, its underlying mechanism have not been fully elucidated. The present work aims to explore the possible mechanism of JPYZXZ on regulating GC progression. We firstly confirmed the inhibitory effect of JPYZXZ in GC MKN74 cells and 615-strain mice, which was possibly mediated with IL-6/JAK2/STAT3 pathway dependent PD-L1 expression. Moreover, we showed that JPYZXZ diminished the expression levels of GC-derived exosomal PD-L1 in MFC murine cells and xenograft GC model, as well as stage IIA-IIIB GC patients. We further found that in different types of tumor-infiltrating immune cells, PD-L1 expression was most positively correlated with myeloid-derived suppressor cells (MDSCs) in GC in the TISIDB database. We isolated exosomes derived from supernatants of MFC cells and co-cultured with bone marrow cells derived from C57BL/6 mice, and further revealed that the expansion of MDSCs was mediated by GC-derived exosomal PD-L1. Meanwhile, our results indicated that JPYZXZ inhibited the delivery of exosomal PD-L1 from GC cells to bone marrow cells, thereby alleviating exosomal PD-L1-induced differentiation and expansion of MDSCs in the tumor microenvironment. This led to a decrease in the levels of several immunosuppressive factors, including iNOS, Arg-1, TGF-ß, IL-10, and IL-6, in 615-strain mice. Moreover, clinical data also revealed a significant positive relationship between exosomal PD-L1 and polymorphonuclear MDSCs under the JPYZXZ treatment in stage IIA-IIIB GC patients. In conclusion, our study confirmed that exosomal PD-L1 could be a key factor in controlling MDSCs differentiation in GC. JPYZXZ alleviated GC progression via suppressing exosomal PD-L1 mediated expansion of MDSCs, thereby remodeling the immunosuppressive tumor microenvironment, which provided the experimental evidence for the clinical application of JPYZXZ in the treatment of GC via PD-L1.

[Effects of guanxinping tablet containing serum on H2O2-induced apoptosis and NF-kappaB expressions in vascular endothelial cells].

OBJECTIVE: To study the effects of Guanxinping Tablet (GT) containing serum on H2O2-induced apoptosis and the nuclear factor kappa B (NF-kappaB) expression in vascular endothelial cells (VECs). METHODS: Rabbits were randomly divided into the normal control group (treated with normal saline, 10 mL/kg), the verapamil group (0. 02 g/kg, 10 mL/kg), the small dose GT group (2; 8 g/kg, 10 mL/kg), the middle dose GT group (5.6 g/kg, 10 mL/kg), and the large dose GT group (11.2 g/kg, 10 mL/kg), 3 in each group. The medication was given to rabbits by gastrogavage for 3 successive days. The gastrogavage was performed twice on the last day with an interval of 2 h. One h after the last medication the peripheral blood was sampled from the vein of the ear edge. The blood was put for 1 h and centrifuged at 2 500 r/min for 30 min. The serum was extracted and deactivated at 56 degrees C for 30 min to prepare the drug containing serum. The apoptosis injury model was established using 100 micromol/L H2O2 induced VECs in the log phase growth. After modeling they were divided into 6 groups, 5 samples in each group, i. e., the normal group (10% vehicle serum culture solution), the model group (10% vehicle serum culture solution +100 micromol/L H2O2), the verapamil group (10% verapamil serum culture solution +100 micromol/L H2O2), the low dose GT group (10% low dose GT culture solution +100 micromol/L H2O2), the middle dose GT group (10% middle dose GT culture solution + 100 micromol/L H2O2), and the high dose GT group (10% high dose GT culture solution + 100 micromol/L H2O2). THE VEC apoptotic rate was detected using flow cytometry. The protein expression of NF-kappaB was detected using Western blot. RESULTS: The VEC apoptosis rate (9.00% +/- 1.18%) and the protein expression of NF-kappaB (0.39% +/- 0.06%) increased more in the model group than in the normal control group (P<0.01). Compared with the model group, the VEC apoptosis rate of the verapamil group (6.00% +/- 0.18%), the large dose GT group (5.30% +/- 0.08%), and the middle dose GT group (6.83% +/- 0.51%) were obviously lower. The expression of NF-kappaB of each treatment group significantly decreased (the verapamil group: 0.28% +/- 0.03%; the small dose GT group: 0.33% +/- 0.03%; the middle dose GT group: 0.30% +/- 0.03%; the large dose GT group: 0.28% +/- 0.04%, P<0.01, P<0.05). CONCLUSIONS: GT could fight against H2O2-induced VEC cell apoptosis. Its mechanism might be correlated with regulating the expression of NF-kappaB protein.

Hyperbaric oxygen treatment improves pancreatic ß­cell function and hepatic gluconeogenesis in STZ­induced type­2 diabetes mellitus model mice.

Type­2 diabetes mellitus (T2DM) causes several complications that affect the quality of life and life span of patients. Hyperbaric oxygen therapy (HBOT) has been used to successfully treat several diseases, including carbon monoxide poisoning, ischemia, infections and diabetic foot ulcer, and increases insulin sensitivity in T2DM. The present study aimed to determine the effect of HBOT on ß­cell function and hepatic gluconeogenesis in streptozotocin (STZ)­induced type­2 diabetic mice. To establish a T2DM model, 7­week­old male C57BL/6J mice were fed a high­fat diet (HFD) and injected once daily with low­dose STZ for 3 days after 1­week HFD feeding. At the 14th week, HFD+HBOT and T2DM+HBOT groups received 1­h HBOT (2 ATA; 100% pure O2) daily from 5:00 to 6:00 p.m. for 7 days. The HFD and T2DM groups were maintained under normobaric oxygen conditions and used as controls. During HBOT, the 12­h nocturnal food intake and body weight were measured daily. Moreover, blood glucose was measured by using a tail vein prick and a glucometer. After the final HBO treatment, all mice were sacrificed to conduct molecular biology experiments. Fasting insulin levels of blood samples of sacrificed mice were measured by an ultrasensitive ELISA kit. Pancreas and liver tissues were stained with hematoxylin and eosin, while immunohistochemistry was performed to determine the effects of HBOT on insulin resistance. TUNEL was used to determine the effects of HBOT on ß­cell apoptosis, and immunoblotting was conducted to determine the ß­cell apoptosis pathway. HBOT notably reduced fasting blood glucose and improved insulin sensitivity in T2DM mice. After HBOT, ß­cell area and ß­cell mass in T2DM mice were significantly increased. HBOT significantly decreased the ß­cell apoptotic rate in T2DM mice via the pancreatic Bcl­2/caspase­3/poly(ADP­ribose) polymerase (PARP) apoptosis pathway. Moreover, HBOT improved the morphology of the liver tissue and increased hepatic glycogen storage in T2DM mice. These findings suggested that HBOT ameliorated the insulin sensitivity of T2DM mice by decreasing the ß­cell apoptotic rate via the pancreatic Bcl­2/caspase­3/PARP apoptosis pathway.

Intermittent Fasting versus Continuous Calorie Restriction: Which Is Better for Weight Loss?

We conducted a systematic review and meta-analysis of randomized clinical trials and pilot trial studies to compare the effectiveness of intermittent fasting (IF) and continuous calorie restriction (CCR) in overweight and obese people. The parameters included body mass index (BMI), body weight, and other metabolism-related indicators. A systematic search in PubMed, Embase, Cochrane Library, and Web of Science was conducted up to January 2022. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to measure the effectiveness. Publication bias was assessed using Egger's test. The stability of the results was evaluated using sensitivity analyses. The significance of body weight change (SMD = -0.21, 95% CI (-0.40, -0.02) p = 0.028) was more significant after IF than CCR. There was no significant difference in BMI (SMD = 0.02, 95% CI (-0.16, 0.20) p = 0.848) between IF and CCR. These findings suggest that IF may be superior to CCR for weight loss in some respects.

Effect of modified Jianpi Yangzheng on regulating content of PKM2 in gastric cancer cells-derived exosomes.

BACKGROUND: Modified Jianpi Yangzheng decoction (mJPYZ), as an empirical decoction of Traditional Chinese medicine has been shown significantly to prolong the survival of patients with advanced stage gastric cancer. Pyruvate kinase M2 (PKM2), has attracted attention for its important role on cellular aerobic glycolysis, however, few studies focus on PKM2 non-metabolic roles in tumor progression. PURPOSE: Our study aimed to investigate the potential role of gastric cancer exosomes containing PKM2 in regulating tumor-associated macrophages (TAM) and the mechanism of mJPYZ against gastric cancer. METHODS: Colony Formation Assay, flow cytometry and TUNEL staining were employed to estimate the effect of mJPYZ on gastric cancer in tumor-bearing mice and cells. Western blot analyzed apoptosis-related protein expression changes. Network pharmacology and bioinformatics predicted potential exosomes modulation of mJPYZ in gastric cancer. Exosomes were isolated and co-cultured with TAM. Diff-Quik Staining observed the TAM morphological changes when incubating with gastric cancer cells exosomes. Flow cytometry and immunofluorescence were performed to demonstrate whether exosomes PKM2 involved in TAM polarization. RESULTS: mJPYZ induced apoptosis of gastric cancer cells by targeting PKM2 and downregulating PI3K/Akt/mTOR axis in vivo and in vitro. Network pharmacology showed potential exosomes modulation of mJPYZ in gastric cancer. We extracted exosomes and found mJPYZ decreased the abundance of serum exosomes PKM2 in patients with advanced gastric cancer and xenograft tumor model. Additionally, we firstly detected and confirmed that PKM2 is a package protein of exosomes extracted from gastric cancer cells, and mJPYZ could diminish the content of exosomal PKM2 in gastric cancer cells. Importantly, mJPYZ reduced the delivery of exosomal PKM2 from tumor cells to macrophages, and alleviated exosomal PKM2-induced differentiation of M2-TAM in tumor microenvironment, eventually inhibited gastric cancer progression. CONCLUSION: Gastric cancer exosomes containing PKM2 could lead to M2 macrophages differentiation, thereby promoting gastric cancer progression. Our findings provide a rationale for potential application of mJPYZ in the treatment of gastric cancer via PKM2.

The effects of bariatric surgery on cognition in patients with obesity: a systematic review and meta-analysis.

Obesity impairs cognition. Bariatric surgery can result in substantial weight loss in patients with severe obesity; however, the impact of bariatric surgery on cognitive function remains controversial. To quantify the effect of bariatric surgery on cognition in patients with severe obesity, we performed a meta-analysis of 20 studies retrieved from PubMed, Cochrane, and Embase. Of these, 6 cohort studies found that Roux-en-Y gastric bypass leads to better performance for immediate verbal memory function (standardized mean difference [SMD] = .56; 95% confidence interval [CI]: .30-.82, P < .0001; I2 = 0%) and delayed memory function (SMD = .64; 95% CI: .38-.90, P < .00001; I2 = 0%) during in the short term. Similarly, positive impacts on immediate verbal memory function (SMD = .46; 95% CI: .09-.83, P < .00001) and delayed memory function (SMD = .84; 95% CI: .46-1.22, P < .0001) were identified during a long-term follow-up. The Roux-en-Y gastric bypass group showed no improvements in attention, cognitive speed, and executive function compared with the control obese group. In 14 longitudinal studies (12 single-arm pre-post comparison studies and 2 cohort studies whose control group had no follow-up cognitive data), patients performed better postoperatively than preoperatively in all cognitive domains during repeated assessments. The analysis for the 20 operative groups showed that individuals treated with bariatric surgery had higher scores after repeated assessment of most neuropsychological tests except for animal fluency and letter fluency than baseline scores. These findings suggest that patients with severe obesity may obtain immediate verbal and delayed memory function benefits from Roux-en-Y gastric bypass.

Identification of the antibacterial mechanism of cryptotanshinone on methicillin-resistant Staphylococcus aureus using bioinformatics analysis.

Cryptotanshinone (CT) is an extract from the traditional Chinese medicine Salvia miltiorrhiza, which inhibits the growth of methicillin-resistant Staphylococcus aureus (MRSA) in vitro. This study aims to determine the antibacterial mechanisms of CT by integrating bioinformatics analysis and microbiology assay. The microarray data of GSE13203 was retrieved from the Gene Expression Omnibus (GEO) database to screen the differentially expressed genes (DEGs) of S. aureus strains that were treated with CT treatment. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to identify the potential target of CT. Data mining on the microarray dataset indicated that pyruvate kinase (PK) might be involved in the antimicrobial activities of CT. The minimum inhibition concentrations (MICs) of CT or vancomycin against the MRSA strain ATCC43300 and seven other clinical strains were determined using the broth dilution method. The effects of CT on the activity of PK were further measured. In vitro tests verified that CT inhibited the growth of an MRSA reference strain and seven other clinical strains. CT hampered the activity of the PK of ATCC43300 and five clinical MRSA strains. CT might hinder bacterial energy metabolism by inhibiting the activity of PK.

PKM2 Is the Target of a Multi-Herb-Combined Decoction During the Inhibition of Gastric Cancer Progression.

Gastric cancer is the third leading cause of cancer death worldwide. Traditional Chinese medicine (TCM) is increasingly extensively applied as a complementary therapy for gastric cancer (GC) in China, which shows unique advantages in preventing gastric cancer metastasis. Previous study indicates modified Jian-pi-yang-zheng (mJPYZ) decoction inhibit the progression of gastric cancer by regulating tumor-associated macrophages (TAM). However, it is unclear whether mJPYZ can affect metabolic reprogramming of gastric cancer cells. Here, we showed that mJPYZ effectively attenuated GC cells proliferation, migration and invasion. Meantime, mJPYZ reduced the aerobic glycolysis level of GC cells in vivo and in vitro by regulating the expression and nuclear translocation of PKM2. Overexpression of PKM2 that could reverse the inhibitory effect of mJPYZ, migration and epithelial to mesenchymal transition (EMT). Our results showed PKM2/HIF-1α signaling was the key metabolic regulator of mJPYZ in GC cells. In summary, our present study suggested that abnormal PKM2 is required for maintaining the malignant phenotype of GC cells. The TCM decoction mJPYZ inhibited GC cells growth and EMT by reducing of glycolysis in PKM2 dependent manner. This evidence expanded our understanding of the anti-tumor mechanism of mJPYZ and further indicated mJPYZ a potential anti-tumor agent for GC patients. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: Rutin (PubChem CID: 5280805); Lobetyolin (PubChem CID: 53486204); Calycosin-7-glucoside (PubChem CID: 71571502); Formononetin (PubChem CID: 5280378); Calycosin (PubChem CID: 5280448); Ononin (PubChem CID: 442813); P-Coumaric Acid (PubChem CID: 637542).

GC-MS Based Metabolomics Reveals the Synergistic Mechanism of Gardeniae Fructus-Forsythiae Fructus Herb Pair in Lipopolysaccharide-Induced Acute Lung Injury Mouse Model.

Compatibility remains among the crucial and significant characteristics of traditional Chinese medicines. The Gardeniae Fructus (FG)-Forsythiae Fructus (FF) herb pair, an epitome of formulations for heat-clearing and detoxification, is extensively used to treat bacterial pneumonia in clinical settings. However, there are few reports on their synergistic effects. This study thus investigated their compatibility by GC-MS based metabolomics using a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. Differential metabolites were identified by both variable importance in the projection (VIP) > 1 in orthogonal partial least-squares discriminant analysis (OPLS-DA) mode and P < 0.05. Results of biochemistry and histopathology indicated that FG-FF herb pair exerted more promising lung protective effect than its individual decoction against the LPS-induced ALI model. From the metabolomics study, 32 differential metabolites in vehicle vs. model groups, 21 differential metabolites in FF vs. model groups, 21 differential metabolites in FG vs. model groups, and 20 differential metabolites in FG-FF herb pair vs. model groups were found. Among them, the levels of 3-hydroxybutyric acid, alanine, isophthalic acid, and terephthalic acid were restored significantly in the FF group, while silanol and cholesterol were restored significantly in the FG group. For FG-FF treatment, the amount of behenic acid, a metabolite with anti-inflammatory properties, was increased, while palmitic acid, a proinflammatory metabolite, was decreased. Meanwhile, the two biomarkers were restored more significantly than that by FG or FF treatment, which indicated that the synergistic effects by FF coupled with FG might be attributed to restoring fatty acids metabolic pathway.

The Association of Trp64Arg Polymorphism in the Beta-Adrenergic Receptor With Insulin Resistance: Meta-Analysis.

Background: Insulin resistance is a metabolic disorder that occurs in type 2 diabetes mellitus and obesity. Genetic factors such as ß3-adrenoceptor polymorphism (Trp64Arg) may be involved in IR and insulin secretion. However, their association is controversial. Therefore, the current meta-analysis was conducted to clarify the relationship between the Trp64Arg and IR. Methods: The literature search was performed in PubMed, Embase, and Web of Science using the keywords "Receptors, Adrenergic, beta-3, Receptors, Adrenergic, Insulin Resistance, Protein-Coupled Receptor Kinase 3" from 2005 to February 7, 2021. We used a random-effects model to calculate the pooled effect size. We conducted subgroup analysis and regression analysis to identify sources of heterogeneity; and Egger's test and funnel plot were used to test publication bias. Finally, we conducted a sensitivity analysis. Results: We included eight papers with 1,586 subjects. There was a positive correlation between Trp64Arg mutation and insulin level (standardized mean difference = 0.20, 95% confidence intervals: 0.00 to 0.39, I2 = 57.6%, p = 0.016). However, there was no association between Trp64Arg and the homeostasis model (HOMA-IR) assessment. Egger's tests showed no publication bias; the sensitivity analysis showed that our results were stable. Regression analysis revealed no source of heterogeneity. Conclusion: Trp64Arg may be associated with IR. European ancestry, obesity, plasma insulin level, and test status may be potential factors affecting the relationship between Trp64Arg and IR.

The effects of bariatric surgery on dyslipidemia and insulin resistance in overweight patients with or without type 2 diabetes: a systematic review and network meta-analysis.

Obesity has become an epidemic in several regions globally; it may lead to cardiovascular diseases, diabetes, and dyslipidemia. Despite many therapies, all bariatric procedures fail in some patients. There is a lack of literature comparing treatment effects on specific metabolic indexes. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant articles. GeMTC and R software were used to perform a network meta-analysis, draw forest plots, investigate the possibility of statistical heterogeneity, generate I2 statistics, rank probabilities, and evaluate relative effects of surgical procedures. All analyses were based on a Bayesian consistency model. We included 35 randomized controlled trials, comprising 2198 individuals and 13 interventions. For patients with high insulin resistance, single-anastomosis (mini-) gastric bypass (SAGB) and sleeve gastrectomy (SG) may be effective options, with mean differences (95% confidence intervals [CIs]) of -4.45 (-9.04 to -.34) and -4.23 (-6.74 to -2.22), respectively, compared with control groups. For patients with severe dyslipidemia, in addition to SAGB and SG, duodenal switch (DS) may be an effective surgery, with mean differences (95% CIs) of -.97 (-1.39 to -.55), -1.98 (-3.76 to -.19), .53 (.04 to 1.04), and -.94 (-1.66 to -.16) compared with control groups in terms of triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) concentrations, respectively. In adult overweight patients with or without diabetes, SAGB and SG are most effective at ameliorating insulin resistance. SAGB, Roux-en-Y gastric bypass + omentectomy, and DS are useful for reducing triglycerides, total cholesterol, and LDL-C. SG + omentectomy elevates HDL-C concentrations best. Adjustable gastric band and biliopancreatic diversion may not control insulin resistance or dyslipidemia well.

Modified Jian-pi-yang-zheng decoction inhibits gastric cancer progression via the macrophage immune checkpoint PI3Kγ.

Jian-pi-yang-zheng Decoction (JPYZ) is a traditional Chinese medicine that is used for the treatment of advanced gastric cancer, and it shows good efficacy in patients. A previous study indicated that JPYZ inhibited the progression of gastric cancer via the regulation of tumor-associated macrophages (TAMs), but the underlying molecular target of JPYZ regulation of TAMs has not been determined. The present study used modified-JPYZ (mJPYZ) to extend our investigation of gastric cancer. Our results showed that mJPYZ inhibited gastric cancer progression in vivo and in vitro. We found that mJPYZ decreased the activity of PI3-kinase γ (PI3Kγ) in TAMs, reduced the anti-inflammatory factor IL-10 and increased the expression of pro-inflammatory cytokines, such as TNF-α and IL-1ß, which ultimately promoted the conversion of TAMs from M2 to M1. Our findings also indicated that mJPYZ inhibited the growth and metastasis of gastric cancer by alleviating the unfavorable differentiation of TAMs via the PI3Kγ signaling cascades. In conclusion, the present findings indicated that mJPYZ inhibited gastric cancer cell EMT via PI3Kγ-dependent TAM reprogramming, which eventually suppressed gastric cancer growth and metastasis. Our study provides an underlying mechanism of a Chinese medicine in the treatment of gastric cancer via PI3Kγ in macrophages.

Association Between Serum Insulin and C-Peptide Levels and Breast Cancer: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Several studies have reported that hyperinsulinemia plays a part in the etiology of breast cancer. However, no consensus has been reached. Therefore, we conducted a meta-analysis to explore the role of insulin and C-peptide in breast cancer. METHODS: A systematic search in PubMed, Embase, and The Cochrane Library was conducted up to September, 2020. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to measure effect sizes. Publication bias was assessed using the Egger test. Stability of these results was evaluated using sensitivity analyses. RESULTS: Fourteen articles including 27,084 cases and five articles including 2,513 cases were extracted for serum insulin levels and C-peptide levels. We found that C-peptide levels were positively associated with breast cancer with overall SMD = 0.37 (95% CI = 0.09-0.65, I2 = 89.1%). Subgroup analysis by control source illustrated a positive relationship between breast cancer and C-peptide levels in population-based control. Subgroup analysis by C-peptide level indicated a positive correlation between breast cancer and C-peptide levels no matter C-peptide levels in case group is ≤3 ng/ml or >3 ng/ml. Subgroup analysis by age showed that C-peptide level positively correlated to breast cancer in women between the ages of 50 and 60. However, we did not identify any relationship between breast cancer and insulin levels (SMD = 0.22, 95% CI = -0.06-0.50, I2 = 97.3%). CONCLUSION: This meta-analysis demonstrated that C-peptide levels were positively related to breast cancer in women, and no relationship between insulin levels and breast cancer was found.

Wu Mei Wan attenuates CAC by regulating gut microbiota and the NF-kB/IL6-STAT3 signaling pathway.

BACKGROUND: Colorectal cancer (CRC) has a high incidence and mortality rate worldwide. Colitis-associated CRC (CAC) is used for describing the relationship between inflammation and CRC. No chemopreventive agents have been found to be both effective and safe in CRC. Therefore, the prevention and treatment of CAC are extremely urgent. Wu Mei Wan (WMW) has been used for the clinical treatment of enteritis with a remarkable efficacy. Here, we aim to investigate the underlying mechanism of WMW in the prevention of CAC. METHODS: The AOM/DSS-induced CAC mouse model was used, and the mice were divided into normal control (NC), AOM/DSS model control (MC), and AOM/DSS plus WMW (WMW). The weight of mice, the score of DAI, survival rate, number of tumors and sample collection were performed at the end of the 14th week. Histopathological examination was performed using Hematoxylin-Eosin (HE) staining. Tumor cell proliferation was indicated by the expression of PCNA, and p65 and p-STAT3 were detected by immunohistochemistry. Serum IL-6 levels were detected by enzyme-linked immunosorbent assay (ELISA). The expression of p65, IL-6 and p-STAT3 in the colon was detected by Western Blot. Intestinal flora was analyzed by 16S rDNA sequencing. RESULTS: WMW improved the survival rate of mice in the MC group and also attenuated CAC symptoms such as abnormal clinical colitis and pathological changes to intestinal tissue by reducing DAI score, tumor formation, tumor volume, and grade of tumorigenesis. WMW also reduced the proliferation of tumor cells in colon tissues. WMW decreased the expression of p65, IL-6, and p-STAT3 in colon tumors of CAC mice. WMW decreased Bacteroidetes and increased Firmicutes at the phylum level, while decreasing bacteroidales_s24-7_group and increasing the number of Lachnospiraceae at the family level. CONCLUSION: WMW attenuates CAC by regulating the balance between "tumor-promoting bacteria" and "tumor-suppressing bacteria" and the NF-kB/IL-6/STAT3 pathway. WMW has the potential to be a safe and effective chemopreventive drug but further clinical evidence is necessary.