Ursolic acid alleviates cancer cachexia by inhibiting STAT3 signaling pathways in C2C12 myotube and CT26 tumor-bearing mouse model.

Cancer cachexia, a multi-organ disorder resulting from tumor and immune system interactions, prominently features muscle wasting and affects the survival of patients with cancer. Ursolic acid (UA) is known for its antioxidant, anti-inflammatory, and anticancer properties. However, its impact on cancer cachexia remains unexplored. This study aimed to assess the efficacy of UA in addressing muscle atrophy and organ dysfunction in cancer cachexia and reveal the mechanisms involved. UA dose-dependently ameliorated C2C12 myotube atrophy. Mechanistically, it inhibited the expression of muscle-specific RING finger containing protein 1 (MURF1) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and upregulated the mRNA or protein levels of myogenic differentiation antigen and myogenin in cultured C2C12 myotubes treated with conditioned medium. In vivo, UA protected CT26 tumor-bearing mice against loss of body weight, as well as increased skeletal muscle and epididymal fat without affecting tumor growth. Additionally, UA increased food intake in CT26 tumor-bearing mice. The mRNA expression of tumor necrosis-α and interleukin 6 was significantly downregulated in the intestine, gastrocnemius, and heart tissues following 38 d UA administration. UA treatment reversed the levels of myocardial function indicators, including creatine kinase, creatine kinase-MB, lactate dehydrogenase, car-dial troponin T, and glutathione. Finally, UA treatment significantly inhibited the expression of MURF1, the phosphorylation of nuclear factor kappa-B p65, and STAT3 in the gastrocnemius muscle and heart tissues of cachexic mice. Our findings suggest that UA is a promising natural compound for developing dietary supplements for cancer cachexia therapy owing to its anti-catabolic effects.

Neuroprotective effects of icariin in neonatal hypoxia-ischemic brain damage via its anti-apoptotic property.

INTRODUCTION: Neonatal hypoxic-ischemic brain damage (HIBD) is a brain disease that is caused by perinatal asphyxia. Icariin (ICA), which is an active component of Epimedii (a Chinese medicinal herb), has been verified to demonstrate a wide range of therapeutic effects, such as alleviating various kinds of brain injury. OBJECTIVE: The current study aims to examine the neuroprotective effects of ICA on neonatal HIBD in mice. MATERIALS AND METHODS: A modified version of the Rice-Vannucci method was performed to establish neonatal HIBD in 7-day-old mouse pups that were pretreated with ICA or vehicle. The infarct volume was measured, and behavioral tests were conducted to assess the protective effects of ICA on the neonatal brain and to evaluate functional recovery after injury. TUNEL staining was used to detect cell apoptosis, and the levels of cleaved caspase-3 and phosphorylated protein kinase B (Akt) were determined by using Western blot. RESULTS: We showed that pretreatment with ICA could significantly reduce brain damage, improve neurobehavioral outcomes, and suppress apoptotic cell death following HI injury. ICA reversed the HI-induced reduction in phosphorylated Akt and activation of cleaved caspase-3. CONCLUSION: The results demonstrate that ICA exerts potential neuroprotective effects on neonatal HIBD, which may be mediated by its anti-apoptotic activity.

LC-MS-based metabolomics analysis of Berberine treatment in ulcerative colitis rats.

Inflammatory bowel disease (IBD) is often accompanied by metabolic imbalance and Berberine can relieve the symptoms of IBD, but the mechanism is still unclear. To explore the relationship between IBD, metabolism and Berberine, dextran sulfate sodium-induced ulcerative colitis (UC) model was built and urine and feces samples were analyzed with ultra-performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry, followed by multivariate statistical analyses. Targeted metabolomics was applied to verify and supplement the result of amino acids tested by non-targeted metabolomics. The study found that Berberine could ameliorate UC and improve metabolic disorders. The level of 4 metabolites increased and 35 decreased in urine and these metabolites mainly belong to amino acid, glucide, organic acid and purine. Besides, Berberine could reduce the level of 5 metabolites and raise the level of 7 metabolites in feces, which mainly belong to amino acid and lipid. Additionally, these altered metabolites were mainly related to amino acids metabolism, purine metabolism, vitamin metabolism, lipid metabolism and citrate cycle pathways. Furthermore, microbiome metabolism may be regulated by Berberine in UC. In general, this study provides a useful approach for exploring the mechanism of Berberine in the treatment of UC from the perspective of metabolomics.

Pretreatment of Grape Seed Proanthocyanidin Extract Exerts Neuroprotective Effect in Murine Model of Neonatal Hypoxic-ischemic Brain Injury by Its Antiapoptotic Property.

Grape seed proanthocyanidin extract (GSPE), an active component extracted from the grape, has been reported to demonstrate antioxidant, anti-inflammatory, anticancer, and antiapoptosis effects. However, little is known about the role of GSPE on neonatal hypoxic-ischemic (HI) brain injury. The aim of this study was to evaluate the neuroprotective effect of GSPE pretreatment on neonatal HI brain injury in mice. A modified Rice-Vannucci method was performed to induce neonatal HI brain injury in the 7-day-old mouse pups pretreated with GSPE or vehicle. The infarct volumes were determined by TTC staining. TUNEL staining was used to detect cells apoptosis, and the expressions of apoptosis-related proteins: bax, bcl2, and cleaved caspase-3 were assayed by Western blot. Behavioral tests were also conducted to assess the functional recovery after injury. We showed that the brain damage and neurobehavioral outcomes improvement was observed in GSPE pretreated group. GSPE was proved to suppress apoptosis through inhibition of bax and cleaved caspase-3 expression. It demonstrates that GSPE could alleviate brain damage maybe through its antiapoptotic activity in a neonatal HI brain injury model, and GSPE has the potential to be a new drug for effective prevention of this disorder.

Supplementation with compound polysaccharides contributes to the development and metabolic activity of young rat intestinal microbiota.

Dietary intervention during early life has a significant impact on colonization of the gut microbiota. In addition, some polysaccharides have the potential to selectively stimulate the growth and metabolic activity of intestinal bacteria associated with health and well-being. However, less is known about the effect of polysaccharides on the development of gut microbiota in younger individuals. This study was conducted to investigate the health effects of supplementation with dietary compound polysaccharides (Lycium barbarum polysaccharides (LBP), Poria cocos polysaccharides (PCPs) and Lentinan, 1 : 1 : 1) on the intestinal microecosystem and metabolism of young rats. Male 21-day-old Sprague-Dawley rats received daily intragastric administration of either compound polysaccharides (three dosages, 6 g kg-1, 12 g kg-1 or 24 g kg-1) or saline for 28 consecutive days. 1H-NMR spectroscopy integrated with multi-variate pattern recognition analysis was applied to reveal the metabolism of the host and microflora, while 16S rRNA gene sequencing was used to monitor the dynamic changes in the gut microbiota. The relative concentrations of 35 urinary metabolites and 24 faecal metabolites were significantly changed compared with the control group. 16S rRNA analysis showed that the relative abundances of 4 bacterial genera (Bifidobacterium, Lactobacillus, Allobaculum and Oligella) significantly increased, whereas the relative abundance of 1 bacterial genus (Enterococcus) significantly declined in the compound polysaccharide-treated groups compared with the control group. Meanwhile, dietary compound polysaccharide treatment promoted the functional maturation of the gut bacterial community, characterised by increased basic metabolism (amino acid metabolism and energy metabolism), short chain fatty acid (SCFA)-related metabolism and nucleotide metabolism. These findings suggest that compound polysaccharides may help to promote the colonisation and functional maturation of infant intestinal microbiota and maintain the health of the intestinal microecosystem.

Huang-Lian-Jie-Du-Decoction Ameliorates Hyperglycemia and Insulin Resistant in Association With Gut Microbiota Modulation.

Background: Huang-Lian-Jie-Du-Decoction (HLJDD), a prescription of traditional Chinese medicine, has been clinically used to treat diabetes for thousands of years and its mechanism was reported to be related to gut microbiota. However, no study has explored the effect of HLJDD on the gut microbiota in type 2 diabetes mellitus (T2DM) yet. Therefore, in this study, we investigated the modulation of gut microbiota induced by HLJDD treatment in T2DM in order to unveil the underlying mechanism. Methods: A combination of high-fat diet (HFD) and streptozotocin (STZ) was used to induce T2DM in rats. Bacterial communities in the fecal samples from the control group, the T2DM model group, and the HLJDD-treated T2DM group were analyzed by 16S gene sequencing, followed with a subset sample analyzed by shotgun sequencing. Results: The HLJDD treatment significantly ameliorated hyperglycemia and inflammation in T2DM rats. Additionally, our results indicated that HLJDD treatment could not only restore the gut dysbiosis in T2DM rats, which was proved by an increasing amount of short chain fatty acids (SCFAs)-producing and anti-inflammatory bacteria such as Parabacteroides, Blautia, and Akkermansia as well as a decreasing amount of conditioned pathogenic bacteria (e.g., Aerococcus, Staphylococcus, and Corynebacterium), but also modulate the dysregulated function of gut microbiome in T2DM rats, including an up-regulation in bile acid biosynthesis as well as a reduction in glycolysis/gluconeogenesis and nucleotide metabolism. Conclusion: HLJDD treatment could ameliorate hyperglycemia and restore the dysregulated microbiota structure and function to a normal condition mainly by increasing SCFAs-producing bacteria and reducing conditioned pathogenic bacteria in T2DM rats, which provides insights into the mechanism of HLJDD treatment for T2DM from the view of gut microbiota.

Metabolomics insights into the modulatory effects of long-term compound polysaccharide intake in high-fat diet-induced obese rats.

BACKGROUND: Polysaccharides can alleviate obesity in mammals; however, studies on mechanism of this alleviation are limited. A few studies have indicated that polysaccharides improve obesity by regulating the metabolism of the body. Therefore, a metabolomics approach, consisting of high resolution nuclear magnetic resonance (NMR) spectroscopy and a multivariate statistical technique, was applied to explore the mechanism of the protective effects of lentinan and Flos Lonicera polysaccharides (LF) on high-fat diet (HFD) induced obesity. METHODS: In this study, rats were randomly divided into three groups: control diet (CD), HFD, and HFD supplemented with a mixture of lentinan and Flos Lonicera polysaccharide. Histopathological and clinical biochemical assessments were also conducted. A combination of a NMR metabolomics study and a multivariable statistical analysis method to distinguish urinary and fecal metabolites was applied. RESULTS: Significant obesity symptoms appeared in HFD rats (for example, significant weight gain, epididymal adipose accumulation and lipid deposition in hepatocytes), which was attenuated in the LF group. Additionally, the HFD induced a reduction of choline, citrate, pyruvate and glycerol and increased the levels of trimethylamine oxide (TMAO) and taurine. Of note, these metabolic disorders were reversed by LF intervention mainly through pathways of energy metabolism, choline metabolism and gut microbiota metabolism. CONCLUSIONS: LF supplementation had a re-balancing effect on the disturbed metabolic pathways in the obese body. The results of this study validate the therapeutic effect of the compound polysaccharide--LF in obesity and described the biochemical and metabolic mechanisms involved.

Metabonomic strategy for the detection of metabolic effects of probiotics combined with prebiotic supplementation in weaned rats.

The purpose of this study is to investigate the effects of probiotics combined with prebiotics (PP) supplementation on weaned rat metabolism. A metabonomic strategy employing 1H-NMR spectroscopy and multivariate data analysis was used to examine weaned rat biological responses to PP supplementation. Male Sprague-Dawley rats (post-natal day 21, PD 21) received probiotics (Lactobacillus acidophilus NCFM (L-NCFM) and Bifidobacterium lactis Bi-07 (B-LBi07), 1 : 1, 1.0 × 1011 cfu kg-1) and prebiotics (Lycium barbarum polysaccharides (LBP), Poria cocos polysaccharides (PCPs) and Lentinan, 1 : 1 : 1, 24 g kg-1) via intragastric administration for 28 consecutive days. Urine and feces were collected for analysis. Significant topographical metabolic variations were present in urine and feces. Urinary metabolites upregulated by PP treatment included alanine, N-acetylglycine, glutamine, dimethylamine, phosphorylcholine, ethylene glycol, mannitol, phenylacetylglycine and glycoate, which were related to alanine, aspartate and glutamate metabolism, and choline metabolism. Feces-derived metabolites, including caproate, valerate, butyrate, propionate, lactate, acetate, succinate, methanol, threonine and methionine, were significantly increased, which were related to short-chain fatty acid (SCFA) metabolism and TCA cycle metabolism. These results indicate that dietary PP supplementation can regulate common systemic metabolic processes, including energy metabolism, amino acid metabolism, lipid metabolism, nucleic acid metabolism, and gut microbiota-related metabolism. This study also illuminates the vital role of PP supplementation in regulating the metabolism of weaned rats.

Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-ß through TFEB Activation.

A strategy for activating transcription factor EB (TFEB) to restore autophagy flux may provide neuroprotection against Alzheimer's disease. Our previous study reported that gypenoside XVII (GP-17), which is a major saponin abundant in ginseng and Panax notoginseng, ameliorated amyloid-ß (Aß)25-35-induced apoptosis in PC12 cells by regulating autophagy. In the present study, we aimed to determine whether GP-17 has neuroprotective effects on PC12 cells expressing the Swedish mutant of APP695 (APP695swe) and APP/PS1 mice. We also investigated the underlying mechanism. We found that GP-17 could significantly increase Atg5 expression and the conversion of LC3-I to LC3-II in APP695 cells, which was associated with a reduction in p62 expression. GP-17 also elevated the number of LC3 puncta in APP695 cells transduced with pCMV-GFP-LC3. GP-17 promoted the autophagy-based elimination of AßPP, Aß40, and Aß42 in APP695swe cells and prevented the formation of Aß plaques in the hippocampus and cortex of APP/PS1 mice. Furthermore, spatial learning and memory deficits were cured. Atg5 knockdown could abrogate the GP-17-mediated removal of AßPP, Aß40, and Aß42 in APP695swe cells. GP-17 upregulated LAMP-1, increased LysoTracker staining, and augmented LAMP-1/LC3-II co-localization. GP-17 could release TFEB from TFEB/14-3-3 complexes, which led to TFEB nuclear translocation and the induction of autophagy and lysosome biogenesis and resulted in the amelioration of autophagy flux. The knockdown of TFEB could abolish these effects of GP-17. In summary, these results demonstrated that GP-17 conferred protective effects to the cellular and rodent models of Alzheimer's disease by activating TFEB.

[The anesthesiologic value of transcutaneous acupoint electrical stimulation combined with general intravenous anesthesia in endoscopic thyroidectomy patients: a clinical study].

OBJECTIVE: To explore the clinical anesthesia value of transcutaneous acupoint electrical stimulation (TAES) combined with general intravenous anesthesia in endoscopic bilateral thyroidectomy patients. METHODS: Totally 60 patients who underwent endoscopic bilateral thyroidectomy were equally randomly assigned to 2 groups, the treatment group and the control group, 30 in each group. Patients in the treatment group received TAES combined general intravenous anesthesia, while those in the control group received total intravenous anesthesia. Anesthesia was maintained by target controlled infusion of propofolum combined constant speed infusion of remifentanil in the two groups. TAES was maintained from 30 min before anesthesia induction to the end of endoscopic thyroidectomy at bilateral Hegu (L14) and Neiguan (PC6). The mean artery pressure (MAP) and heart rate (HR) were recorded at different time points of anesthesia, i.e., immediately after entry into the operating room (TO), immediately after intubation (T1), 5 min after intubation (T2), 5 min before incision (T3), 5 min after incision (T4), 30 min after inflation (T5), at the end of surgery (T6), 5 min before extubation (T7), immediately after extubation 0 (T8), and 5 min after extubation (T9). The concentration of IL-6 and TNF-alpha were measured at TO, T3, T5, and T6. The target concentration of propofol was also recorded at T3, T4, and T5. RESULTS: There was no statistical difference in the operation time between the two groups (P >0.05). Compared with TO in the same group, HR at T3-T4 decreased and increased at T8-T9, and MAP increased at T7-T9 in the treatment group; HR decreased at T3 and increased at T7-T9, MAP increased at T1, T5, T7-T9, and MAP decreased at T2-T3 in the control group. IL-6 increased at T5-T6, while TNF-alpha decreased at T6 in the two groups (P <0.01,P <0.05). Compared with the control group at the same time point, HR decreased at T6-T9, MAP decreased at T1, T4, T5, T7-T9, MAP increased at T3, and IL-6 decreased at T5-T6 in the treatment group (P <0. 05). The concentration and the total amount of propofol were significantly lower in the treatment group than in the control group (P <0.01,P <0.05). CONCLUSIONS: TAES could maintain the hemodynamics more stably and inhibit the stress response in endoscopic thyroidectomy. It also reduce the dosage of anesthetics and improve the safety of anesthesia.