PGAM5 knockout causes depressive-like behaviors in mice via ATP deficiency in the prefrontal cortex.

INTRODUCTION: Major depressive disorder (MDD) affects about 17% population in the world. Although abnormal energy metabolism plays an important role in the pathophysiology of MDD, however, how deficiency of adenosine triphosphate (ATP) products affects emotional circuit and what regulates ATP synthesis are still need to be elaborated. AIMS: Our study aimed to investigate how deficiency of PGAM5-mediated depressive behavior. RESULTS: We firstly discovered that PGAM5 knockout (PGAM5-/- ) mice generated depressive-like behaviors. The phenotype was reinforced by the observation that chronic unexpected mild stress (CUMS)-induced depressive mice exhibited lowered expression of PGAM5 in prefrontal cortex (PFC), hippocampus (HIP), and striatum. Next, we found, with the using of functional magnetic resonance imaging (fMRI), that the functional connectivity between PFC reward system and the PFC volume were reduced in PGAM5-/- mice. PGAM5 ablation resulted in the loss of dendritic spines and lowered density of PSD95 in PFC, but not in HIP. Finally, we found that PGAM5 ablation led to lowered ATP concentration in PFC, but not in HIP. Coimmunoprecipitation study showed that PGAM5 directly interacted with the ATP F1 F0 synthase without influencing the interaction between ATP F1 F0 synthase and Bcl-xl. We then conducted ATP administration to PGAM5-/- mice and found that ATP could rescue the behavioral and neuronal phenotypes of PGAM5-/- mice. CONCLUSIONS: Our findings provide convincing evidence that PGAM5 ablation generates depressive-like behaviors via restricting neuronal ATP production so as to impair the number of neuronal spines in PFC.

Enteral nutrition management in stroke patients: a narrative review.

OBJECTIVE: We aimed to summarize the enteral nutrition (EN) management of stroke patients according to recent evidence. BACKGROUND: Stroke patients have a high incidence of dysphagia, which is the main cause of malnutrition, and stroke with malnutrition leads to high recurrence and mortality. Insufficient food intake caused by dysphagia is the main cause of malnutrition in stroke patients, which is associated with poor prognosis, increased mortality, and deteriorated outcomes in patients with stroke. Dehydration is also worthy of attention. METHODS: Non-systematic searches of the PubMed database were conducted to retrieve relevant English-language articles, and the CNKI and Wanfang database were searched for relevant Chinese-language articles. Fifteen recent guidelines or expert consensuses on the clinical nutritional management of stroke patients were published between 2013 and 2021, of which eight are from China. CONCLUSIONS: Before providing nutritional support, swallowing, hydration, and risk of malnutrition need to be screened by a dietitian or professional. Although the initiation time of nutritional support is different in each guideline, tube feeding is preferable for patients with dysphagia. The appropriate dosage, formula, and treatment of complications need to be further studied. Also, nutritional support for stroke patients at different stages needs to be further improved. The continuous improvement and details of stroke nutrition guidelines contribute to standardized clinical nutrition practices and benefit patients.

Gamma linolenic acid suppresses hypoxia-induced proliferation and invasion of non-small cell lung cancer cells by inhibition of HIF1α.

BACKGROUND: The main therapies for cancer often results in many side effects and drug resistance. Gamma linolenic acid (GLA) is a kind of natural reagent with negligible cytotoxicity. OBJECTIVE: This work aims at detecting whether GLA possesses anti-cancer activity in NSCLC cells and elucidating the potential molecular mechanism. METHODS: Cytotoxicity of GLA was evaluated by MTT assay and soft agar colony formation method. Immunoblotting analysis examined the effect of GLA on protein expressions of cell proliferation markers (e.g., PCNA, Ki-67 and MCM2), pro-survival protein bcl-2, apoptosis-associated proteins (e.g., bax and cleaved caspase 3), HIF1α and VEGF. Wound healing assay and transwell invasion assay were performed to test the effect of GLA on hypoxia-induced cell migration and invasion. Cell transfection was used to overexpress HIF1α followed by the treatment of GLA to test the effect of HIF1α overexpression on the tumoricidal activity of GLA in NSCLC cell lines. RESULTS: MTT and soft agar colony formation tests showed that GLA dose-dependently suppressed cell proliferation in both Calu-1 and SK-MES-1 cell lines. Immunoblotting analysis demonstrated that GLA suppressed protein expressions of PCNA, Ki-67, MCM2 and bcl-2, while GLA induced bax and cleaved caspase 3 expressions. Wound healing assay and transwell invasion assay revealed that GLA was very effective on the inhibition of NSCLC cell migration and invasion. Immunoblotting analysis and cell transfection method indicated that GLA inhibited hypoxia-induced cell proliferation and invasion by suppressing HIF1α-VEGF pathway. CONCLUSION: GLA suppresses hypoxia-induced proliferation and invasion of NSCLC cells by inhibition of HIF1α pathway in vitro.

Gamma linolenic acid suppresses hypoxia-induced gastric cancer cell growth and epithelial-mesenchymal transition by inhibiting the Wnt/b-catenin signaling pathway.

INTRODUCTION: Gastric cancer is one of the most common malignancies in China and the fifth most common cancer in the world. Gamma linolenic acid (GLA) was reported to have anti-inflammatory and anti-cancer effects. The purpose of this research was to investigate the effect and mechanism of GLA on gastric cancer cell growth under hypoxic conditions. MATERIAL AND METHODS: The hypoxia models of SGC-7901 and MGC-803 cells were established, and then were exposed to different concentrations of 50, 100 or 200 µM GLA. MTT assay, colony formation assay, wound healing assay and transwell assay were used to investigate the effects of GLA treatment on gastric cancer cell growth under hypoxia (1% O2). The expression of apoptosis- and epithelial-mesenchymal transition (EMT)-related proteins was detected by qPCR and western blot. RESULTS: GLA treatment significantly decreased viability and inhibited colony formation (p < 0.05, p < 0.01) of SGC-7901 and MGC-803 cells under hypoxia. Western blotting analysis showed that GLA treatment decreased the expression of proliferating cell nuclear antigen (PCNA), microchromosome maintenance complex component 2 (MCM-2) and anti-apoptotic protein Bcl-2, while increased the expression of pro-apoptotic proteins (Bax and Cleaved Caspase-3) (p < 0.05 and p < 0.01). In addition, Wound healing analysis and Transwell assays showed that GLA treatment inhibited the migration and invasion of SGC-7901 and MGC-803 cells in a dose-dependent manner (p < 0.01). Western blotting analysis showed that GLA treatment increased the expression of epithelial marker proteins (g-catenin and E-cadherin), while decreased the expression of stromal and extracellular matrix marker proteins (fibronectin, Snail and b-catenin) (p < 0.01). Further analyses showed that GLA treatment decreased the expression of b-catenin in Wnt/b-catenin pathway (p < 0.01). Moreover, exogenous Wnt3a reversed the inhibitory effect of GLA on b-catenin expression, and further reversed the inhibitory effect of GLA on gastric cancer cell growth and EMT markers (p < 0.05, p < 0.01). CONCLUSION: These findings suggest that GLA should be tested in animal models and in clinical studies as a potentially effective bioactive phytochemical substance for the treatment of gastric cancer.

[Correlation Study between Syndrome Types of Chinese Medicine and Molecular Subtyping of Breast Cancer in Consolidate Period].

Objective To observe the correlation between syndrome types of Chinese medicine (CM) and molecular subtyping of breast cancer in consolidation period. Methods Multivariate statistical analysis was applied in this research. Totally 612 breast cancer patients in consolidation period were as- signed to 4 syndrome types of CM [qi deficiency syndrome (22. 22% , 136/612) , Gan-qi stagnation syn- drome (21.73%, 133/612), Gan-Shen yin deficiency syndrome (20.10%, 123/612), Shen deficiency blood stasis syndrome (35. 95%, 220/612) ]. The correlation between each syndrome type and each molecular subtyping was respectively analyzed using Χ² (R x C table) test. Results Through statistical a- nalysis and expert consultation, results showed that cluster four types in consolidate period of breast cancer were compatible. Each syndrome type was correlated with each molecular subtyping in 612 breast cancer patients in consolidation period. Luminal type A was correlated with Gan-qi stagnation syndrome (P <0. 05). Luminal type B and triple negative type were correlated with qi deficiency syndrome and Gan- Shen yin deficiency syndrome (P <0. 05). But each syndrome type was not obviously correlated with dis- ease course. There was no obvious correlation between molecular subtyping and age/disease course (P >0. 05). Conclusion Luminal type A occupied the highest ratio in Gan-qi stagnation syndrome, with relatively better prognosis.

A high-throughput metabolomic approach to explore the regulatory effect of mangiferin on metabolic network disturbances of hyperlipidemia rats.

This paper was designed to study metabolomic characters of the high-fat diet (HFD)-induced hyperlipidemia and the intervention effects of Mangiferin (MG). In this study, we aimed to investigate the intervention of MG on rats with hyperlipidemia induced by HFD and explore the possible mechanisms of hyperlipidemia. Urine metabolic profiles were analyzed using ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) coupled with the principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) models, Heatmap and metabolism pathway analysis. PCA was applied to study the trajectory of the urinary metabolic phenotype of hyperlipidemia rat after administration of MG. The VIP-plot of orthogonal PLS-DA was used for discovering potential biomarkers to clarify the mechanism of MG. Biochemical analyses indicate that MG can alleviate the hyperlipidemia damage. Twenty significantly changed metabolites (potential biomarkers) were found to be reasonable in explaining the action mechanism of MG. The effectiveness of MG on hyperlipidemia is proved using the established metabolomic method and the regulated metabolic pathways involve the TCA cycle, taurine and hypotaurine metabolism, glyoxylate and dicarboxylate metabolism, glycine and serine and threonine metabolism, glycerophospholipid metabolism, primary bile acid biosynthesis etc. The results indicated that MG has a favourable protective effect on HFD-induced hyperlipidemia by adjusting the metabolic disorders. It also suggests that the metabolomic technology is a powerful approach for elucidation of the action mechanisms of MG.

Weight loss, inflammatory markers, and improvements of iron status in overweight and obese children.

OBJECTIVE: To assess the effect of a weight-loss program on improving iron status in overweight and obese school-aged children. STUDY DESIGN: The data were analyzed in overweight and obese children (7-11 years of age; 114 girls and 212 boys) with body mass index-for-age z-scores (BAZ) >1 from a weight-loss program. Schools were randomly divided into 2 groups: intervention and control. Children in the intervention group underwent a 1-year, nutrition-based comprehensive intervention weight-loss program. Anthropometric, dietary intake, and physical activity data were collected at baseline and follow-up (1 year). Iron status and inflammatory markers were assessed within a month. RESULTS: In the intervention group, BAZ decreased more than that in the control group (-0.4 ± 0.7 vs -0.1 ± 0.6, P < .0001); and iron profiles and inflammation status were improved at follow-up. In multivariable linear regression models, a greater decrease of BAZ and inflammation factors predicted a better improvement of iron status. After adjustment of ΔBAZ, ΔC-reactive protein was significantly associated with Δserum ferritin (ß: 1.89; 95% CI, 0.70-3.09; P = .002) and Δsoluble transferrin receptor (ß: 0.88; 95% CI, 0.16-0.59; P = .017); Δinterleukin-6 was significantly associated with Δserum ferritin (ß: 1.22; 95% CI, 0.64-1.79; P < .0001). CONCLUSIONS: Iron status and inflammation were improved by weight reduction. The improvement in inflammatory markers during weight reduction was independently associated with improvements of iron status.

Long-term calcium supplementation may have adverse effects on serum cholesterol and carotid intima-media thickness in postmenopausal women: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Several studies have focused on the effects of calcium intake on serum lipid concentrations in postmenopausal women. However, many premenopausal women are taking calcium supplements in China. To our knowledge, no studies have assessed whether the effects of calcium supplementation on blood lipids are similar between premenopausal and postmenopausal women. OBJECTIVE: We assessed the effects of calcium supplementation on blood lipid concentrations in premenopausal and postmenopausal women with dyslipidemia. DESIGN: A total of 190 premenopausal women (30-40 y old) and 182 postmenopausal women (50-60 y old) with dyslipidemia were given 800 mg Ca/d or a placebo for 2 y in a double-blind, randomized, placebo-controlled trial. Blood pressure, fasting glucose and serum lipid concentrations, carotid intima-media thickness (CIMT), dietary nutrient intakes, and physical activity levels were determined at baseline and after 2 y. RESULTS: There was a significant interaction between calcium supplementation and menopausal status on serum cholesterol concentrations (P < 0.001) and CIMT (P = 0.017). Serum cholesterol concentrations and CIMT were significantly increased in postmenopausal women (P < 0.01) after 2 y. Serum triglyceride, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol concentrations were not affected after 2 y. CONCLUSIONS: Calcium supplementation in postmenopausal women with dyslipidemia increases serum total cholesterol concentrations and CIMT. In postmenopausal women with dyslipidemia, calcium supplements should be prescribed with caution. This trial was registered at http://www.chictr.org/cn/ as ChiCTR-TRC-12002806.

The phytochemical, EGCG, extends lifespan by reducing liver and kidney function damage and improving age-associated inflammation and oxidative stress in healthy rats.

It is known that phytochemicals have many potential health benefits in humans. The aim of this study was to investigate the effects of long-term consumption of the phytochemical, epigallocatechin gallate (EGCG), on body growth, disease protection, and lifespan in healthy rats. 68 male weaning Wistar rats were randomly divided into the control and EGCG groups. Variables influencing lifespan such as blood pressure, serum glucose and lipids, inflammation, and oxidative stress were dynamically determined from weaning to death. The median lifespan of controls was 92.5 weeks. EGCG increased median lifespan to 105.0 weeks and delayed death by approximately 8-12 weeks. Blood pressure and serum glucose and lipids significantly increased with age in both groups compared with the levels at 0 week. However, there were no differences in these variables between the two groups during the whole lifespan. Inflammation and oxidative stress significantly increased with age in both groups compared with 0 week and were significantly lower in serum and liver and kidney tissues in the EGCG group. Damage to liver and kidney function was significantly alleviated in the EGCG group. In addition, EGCG decreased the mRNA and protein expressions of transcription factor NF-κB and increased the upstream protein expressions of silent mating type information regulation two homolog one (SIRT1) and forkhead box class O 3a (FOXO3a). In conclusion, EGCG extends lifespan in healthy rats by reducing liver and kidney damage and improving age-associated inflammation and oxidative stress through the inhibition of NF-κB signaling by activating the longevity factors FoxO3a and SIRT1.

Effects of transforming growth factor-beta1 and signal protein Smad3 on rat cardiomyocyte hypertrophy.

BACKGROUND: SMAD proteins have recently been identified as the first family of putative transforming growth factor-beta1 (TGF-beta1) signal transducers. This study was to investigate the effects of TGF-beta1 and signal protein Smad3 on rat cardiac hypertrophy. METHODS: The incorporation of [(3)H]-leucine was measured to determine the hypertrophy of cardiomyocyte incubated with different doses of TGF-beta1 in cultured neonatal cardiomyocytes. The model of rat cardiac hypertrophy was produced with constriction of the abdominal aorta. At different times after the operation, rats were killed, and their left ventricular mass index (LVMI) determined. The mRNA expression of TGF-beta1 and Smad3 of cultured cells and hypertrophic left ventricles were assessed by RT-PCR. The protein expression of Smad3 was assessed by Western blot. RESULTS: In cultured neonatal cardiomyocytes, TGF-beta1 significantly promoted incorporation of [(3)H]-leucine. With the concentration of 3 pg/L, it increased the expression of Smad3 in mRNA and protein levels after 15 minutes, and continued for up to 8 hours of cultured cardiomyocytes. The LVMI and the expression of TGF-beta1 (mRNA) and Smad3 (mRNA and protein) of hypertrophic left ventricle were increased by day 3 after the operation and continued to the 4th week. The peak expression of these was in the second week after operation. CONCLUSION: TGF-beta1 has positive effects on rat cardiomyocyte hypertrophy. Signal protein Smad3 could be related to the pathologic progression of rat cardiac hypertrophy.