Weight and metabolic changes in early psychosis-association with daily quantification of medication exposure during the first hospitalization.

BACKGROUND: The most common causes of death in schizophrenia are cardiovascular disorders, which are closely related to metabolic syndrome/obesity. To better understand the development of metabolic alterations early in the course of illness, we quantified daily medication exposure in the first days of the first hospitalization for psychosis and related it to changes in weight and metabolic markers. STUDY DESIGN: We recruited participants with first episode psychosis (FEP, N = 173) during their first psychiatric hospitalization and compared them to controls (N = 204). We prospectively collected weight, body mass index, metabolic markers, and exact daily medication exposure at admission and during hospitalization. STUDY RESULTS: Individuals with FEP gained on average 0.97 ± 2.26 BMI points or 3.46 ± 7.81 kg of weight after an average of 44.6 days of their first inpatient treatment. Greater antipsychotic exposure was associated with greater BMI increase, but only in people with normal/low baseline BMI. Additional predictors of weight gain included type of medication and duration of treatment. Medication exposure was not directly related to metabolic markers, but higher BMI was associated with higher TGC, TSH, and lower HDL. Following inpatient treatment, participants with FEP had significantly higher BMI, TGC, prolactin, and lower fT4, HDL than controls. CONCLUSION: During their first admission, people with FEP, especially those with normal/low baseline BMI, showed a rapid and clinically significant weight increase, which was associated with exposure to antipsychotics, and with metabolic changes consistent with metabolic syndrome. These findings emphasize weight monitoring in FEP and suggest a greater need for caution when prescribing metabolically problematic antipsychotics to people with lower BMI.

Effects of Increased Central Cholinergic Activity on the Metabolic Challenge Induced by Submaximal Exercise in Rats: Adrenomedullary Secretion Influences.

AIM: The aim of this study was to assess the influence of adrenomedullary secretion on the plasma glucose, lactate, and free fatty acids (FFAs) during running exercise in rats submitted to intracerebroventricular (i.c.v.) injection of physostigmine (PHY). PHY i.c.v. was used to activate the central cholinergic system. METHODS: Wistar rats were divided into sham-saline (sham-SAL), sham-PHY, adrenal medullectomy-SAL, and ADM-PHY groups. The plasma concentrations of glucose, lactate, and FFAs were determined immediately before and after i.c.v. injection of 20 µL of SAL or PHY at rest and during running exercise on a treadmill. RESULTS: The i.c.v. injection of PHY at rest increased plasma glucose in the sham group, but not in the ADM group. An increase in plasma glucose, lactate, and FFAs mobilization from adipose tissue was observed during physical exercise in the sham-SAL group; however, the increase in plasma glucose was greater with i.c.v. PHY. Moreover, the hyperglycemia induced by exercise and PHY in the ADM group were blunted by ADM, whereas FFA mobilization was unaffected. CONCLUSION: These results indicate that there is a dual metabolic control by which activation of the central cholinergic pathway increases plasma glucose but not FFA during rest and exercise, and that this hyperglycemic response is dependent on adrenomedullary secretion.

Metformin treatment of juvenile mice alters aging-related developmental and metabolic phenotypes.

Accumulating evidence suggests that the influence on developmental traits might have long-term effects on aging and health later in life. Metformin is a widely used drug for treating type 2 diabetes and is also used for delaying sexual maturation in girls with precocious puberty. The current report focuses on investigating the effects of metformin on development and metabolic traits. Heterogeneous mice (UM-HET3) were treated with i.p. metformin between the ages of 15 and 56 days. Our results show that body weight and food consumption were increased in both sexes, and sexual maturation was delayed in females. Tail length and circulating insulin-like growth factor 1 (IGF1) levels were significantly increased in both sexes. No significant difference was found in insulin tolerance test, but glucose tolerance was significantly reduced in the males. Circulating adiponectin and insulin levels were altered by metformin treatment in a sex-specific manner. Analysis of quantitative insulin sensitivity check index (QUICKI) suggests that metformin treatment increased insulin sensitivity in female pups, but had opposite effect in male pups. This study revealed that early life metformin treatment alters development and metabolism of mice in both sex-specific and non-specific manners. These effects of metformin may have long-term impacts on aging-related traits.

Metabolomics approach: Interpretation of changes in rat plasma metabolites after solifenacin treatment

Abstract Changes in metabolite levels of patients using the long-term drug can be comprehensively demonstrated by pharmacometabolomic studies. In this study, biological alterations induced by the administration of solifenacin succinate were investigated with a pharmacometabolomics approach on rat metabolism. Plasma samples obtained from rats were analyzed by LC-Q- TOF/MS/MS. METLIN and HMDB databases were used to identify metabolites. Data were processed and classified with MATLAB 2017b. 53 m/z values were found to be significantly different between the drug and control groups (p ≤ 0.01 and fold analysis > 1.5) and identified by comparing METLIN and HMDB databases. According to multivariate data analysis, changes in arachidonic acid, thromboxane A2, palmitic acid, choline, calcitriol, histamine phosphate, retinyl ester, l-cysteine, l-leucine, beta-alanine, l-histidine levels were found to be statistically significant compare to the control group. Differences in the biosynthesis of phenylalanine, aminoacyl-tRNA, tyrosine, tryptophan, metabolism of glycerophospholipid, cysteine, methionine, histidine, arachidonic metabolism have been successfully demonstrated by the metabolomics approach. Our study provides important information to explain the efficacy and toxicity of chronic administration of solifenacin succinate

The Determination of Efficacy of CircuCare on Blood Circulation and Metabolism: An Animal Model Study.

OBJECTIVES: To determine whether feeding CircuCare to rats improves blood circulation, metabolism, immune regulation, endocrine activity, and oxidative stress. METHODS: 28 eight-week-old male Sprague-Dawley rats were evenly randomized into control and experimental groups. The control group was fed with ordinary drinking water, while the experimental group was fed with CircuCare at a daily dose of 93.75 mg per 300 g of body weight over eight weeks. Both groups were subjected to a swimming test, and blood samples were taken to observe any variations in various biochemical parameters before and after the test. Key Findings. The experimental group's mean swimming exhaustion duration was 53.2% longer and had a significantly higher lactic acid removal ratio. Their mean prostaglandin E2 level and mean glucose, cortisol, and glutathione level (30 minutes after swimming test) were also significantly higher. No undesirable impacts from CircuCare relating to general blood biochemistry values and bone mineral density were reported. CONCLUSIONS: The present results show that CircuCare can be safely used to increase stamina and exercise capability, expedite the metabolism of lactic acid, accelerate muscle repair, and promote the antioxidant activity of cells in rats.

High-dose dexamethasone injection disordered metabolism and multiple protein kinases expression in the mouse kidney.

Glucocorticoids (GCs) have been widely used in clinical treatment as anti-inflammatory, anti-shock and immunosuppressive medicines. However, the effect of excessive GCs on immune response and metabolism of kidney remains unclear. Here, we profiled the gene expression of kidney from mice with high-dose dexamethasone (DEX) treatment. A total of 1193 differentially expressed genes (DEGs) were screened in DEX treatment group compared with the saline group, including 715 down- regulated and 478 up-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of these DEGs showed extracellular matrix (ECM)-receptor interaction, cell adhesion molecules signaling pathway were significantly enriched, and that the vast majority of DEGs were involved in monocarboxylic acid metabolism, leukocyte cell-cell adhesion and fatty acid metabolism. Gene set enrichment analysis (GSEA) revealed that DEGs were strongly associated with immune-response and cell adhesion gene sets, such as Fc γ R-mediated phagocytosis, leukocyte transendothelial migration, T-cell receptor signaling pathway, cell adhesion, ECM-receptor interaction and focal adhesion-associated pathways. KEGG pathway analysis of differentially expressed kinases (DEKs) showed T-cell receptor and forkhead box class O signaling pathway were enriched. Furthermore, we found multiple protein kinases expression were dysregulated greatly after dexamethasone treatment, including classical effector of GCs stimulation-serum and GC-regulated kinase. These protein kinases are involved in multiple signaling pathways in mice kidney, such as mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. We profiled the gene expression of the kidney from high-dose dexamethasone-treated mice and provided important information for further study the mechanism of side effects of GCs in clinical therapy.

A Novel Method for the Production of an Autologous Anti-Inflammatory and Anti-Catabolic Product (Cytorich) from Human Blood: A Prospective Treatment for the COVID-19-Induced Cytokine Storm.

BACKGROUND Autologous blood-derived products can target specific inflammatory molecular pathways and have potentially beneficial therapeutic effects on inflammatory pathologies. The purpose of this study was to assess in vitro the anti-inflammatory and anti-catabolic potential of an autologous blood product as a possible treatment for COVID-19-induced cytokine storm. MATERIAL AND METHODS Blood samples from healthy donors and donors who had recovered from COVID-19 were incubated using different techniques and analyzed for the presence of anti-inflammatory, anti-catabolic, regenerative, pro-inflammatory, and procatabolic molecules. RESULTS The highest concentrations of therapeutic molecules for targeting inflammatory pathways were found in the blood that had been incubated for 24 h at 37°C, whereas a significant increase was observed after 6 h of incubation in blood from COVID-19-recovered donors. Beneficially, the 6-h incubation process did not downregulate anti-COVID-19 immunoglobulin G concentrations. Unfortunately, increases in matrix metalloproteinase 9, tumor necrosis factor alpha, and interleukin-1 were detected in the product after incubation; however, these increases could be blocked by adding citric acid, with no effect on the concentration of the target therapeutic molecules. Our data allow for safer and more effective future treatments. CONCLUSIONS An autologous blood-derived product containing anti-inflammatory and anti-catabolic molecules, which we term Cytorich, has a promising therapeutic role in the treatment of a virus-induced cytokine storm, including that associated with COVID-19.

Thiamine, Ascorbic Acid, and Hydrocortisone As a Metabolic Resuscitation Cocktail in Sepsis: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis.

OBJECTIVES: Sepsis is a common condition in the ICU. Despite much research, its prognosis remains poor. In 2017, a retrospective before/after study reported promising results using a combination of thiamine, ascorbic acid, and hydrocortisone called "metabolic resuscitation cocktail" and several randomized controlled trials assessing its effectiveness were performed. DESIGN: We conducted a systematic review and meta-analysis of randomized controlled trials in septic ICU patients to assess the effects of this combination therapy. SETTING: PubMed, Embase, and the Cochrane library databases were searched from inception to March of 2021. Data were extracted independently by two authors. The main outcome was the change in Sequential Organ Failure Assessment score within 72 hours. Secondary outcomes included renal composite endpoints (acute kidney injury) Kidney Disease - Improving Global Outcome organization stage 3 or need for renal replacement therapy, vasopressor duration, and 28-day mortality. SUBJECTS: We included randomized controlled trials with patients admitted to the ICU with sepsis or septic shock. INTERVENTION: The trials compared a combination of thiamine, ascorbic acid, and hydrocortisone to standard care or placebo in patients admitted to ICU with sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: We included eight randomized controlled trials (n = 1,335 patients). Within 72 hours, the median of mean improvement was -1.8 and -3.2 in the control and intervention groups, respectively (eight randomized controlled trials, n = 1,253 patients); weighted mean difference -0.82 (95% CI, -1.15 to -0.48). Data were homogeneous and the funnel plot did not suggest any publication bias. Duration of vasopressor requirement was significantly reduced in the intervention group (six randomized controlled trials). There was no evidence of a difference regarding the ICU mortality and the renal composite outcome (acute kidney injury KDIGO 3 or need for renal replacement therapy, seven randomized controlled trials). CONCLUSIONS: Metabolic resuscitation cocktail administrated in ICU septic patients improves change in Sequential Organ Failure Assessment score within 72 hours. However, this improvement is modest and its clinical relevance is questionable. The impact on renal failure and mortality remains unclear.

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models.

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is, therefore, critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11ß-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive HSD11B1 activity and amplification of local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and ageing-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated mechanisms by which glucocorticoids exert their metabolic effects and have guided us towards more targeted future treatments for metabolic diseases.

Growth and Metabolic Changes After Antiretroviral Initiation in South African Children.

BACKGROUND: Poor growth and metabolic disturbances remain concerns for children living with HIV (CLHIV). We describe the impact of viral load (VL) on growth and lipid outcomes in South African CLHIV <12 years initiating World Health Organization recommended first-line antiretroviral therapy (ART) from 2012 to 2015. METHODS: Z scores for length-for-age (LAZ), weight-for-age (WAZ) and body mass index-for-age were calculated. Lipids (total cholesterol, low-density lipoprotein and high-density lipoprotein) were measured. Hemoglobin A1C ≥5.8 was defined as at risk for type 2 diabetes. Mixed effects models were used to assess the association of VL at ART initiation with Z scores and lipids over time. RESULTS: Of 241 CLHIV, 151 (63%) were <3 years initiating LPV/r-based ART and 90 (37%) were ≥3 years initiating EFV-based ART. Among CLHIV <3 years, higher VL at ART initiation was associated with lower mean LAZ (ß: -0.30, P=0.03), WAZ (ß: -0.32, P=0.01) and low-density lipoprotein (ß: -6.45, P=0.03) over time. Among CLHIV ≥3, a log 10 increase in pretreatment VL was associated with lower mean LAZ (ß: -0.29, P=0.07) trending towards significance and lower WAZ (ß: -0.32, P=0.05) as well as with more rapid increases in LAZ (ß: 0.14 per year, P=0.01) and WAZ (ß: 0.19 per year, P=0.04). Thirty percent of CLHIV were at risk for type 2 diabetes at ART initiation. CONCLUSIONS: CLHIV initiating ART <3 years exhibited positive gains in growth and lipids, though high viremia at ART initiation was associated with persistently low growth and lipids, underscoring the need for early diagnosis and rapid treatment initiation. Future studies assessing the long-term cardiometabolic impact of these findings are warranted.

Influence of betahistine repeated administration on a weight gain and selected metabolic parameters in the model of excessive eating in rats.

It is important to search for a promising therapeutic target or small molecules that can control excessive eating since limiting the intake of foods, especially tasty ones, could be effective in the treatment or prevention of obesity. Some studies indicate betahistine as an unique drug having the ability to ameliorate, for example, antipsychotic-induced weight gain. This study aimed to determine whether repeated administration of betahistine (histamine H1R agonist and H3R antagonist) could be beneficial in reducing the intake of tasty foods or the body's response to overeating via mechanisms such as by influencing the levels of hormones involved in the regulation of food intake or the levels of selected metabolic parameters. Studies were performed in the excessive eating model in rats, which perfectly illustrates the harmful high-caloric intake from freely available tasty products rich in sugar and fat. Our results indicated that repeated administration of betahistine to rats caused lower gain of body mass compared to the control rats fed palatable feed. Interestingly, betahistine treatment increased the consumption of cheese, which is a source of histamine. Although betahistine did not prevent the development of metabolic disorders, such as reduced glucose tolerance, in test animals, it significantly increased the level of high-density lipoprotein cholesterol, which could certainly be considered beneficial. Further studies should be conducted to investigate the effect of repeated administration of betahistine on satiety, gastrointestinal disorders, and the preference for histamine-containing foods.

Orexin-2 receptor antagonism in the cornu ammonis 1 region of hippocampus prevented the antinociceptive responses induced by chemical stimulation of the lateral hypothalamus in the animal model of persistent pain.

Orexins are excitatory neuropeptides, mainly produced by neurons located in the lateral hypothalamus, which project to many brain areas. The orexinergic system plays a fundamental role in arousal, sleep/wakefulness, feeding, energy homeostasis, motivation, reward, stress and pain modulation. As a prominent part of the limbic system, the hippocampus has been involved in formalin-induced nociception modulation. Moreover, hippocampus regions express both orexin-1 (OX1) and orexin-2 (OX2) receptors. The present study investigated the role of OX2 receptors (OX2R) within the cornu ammonis 1 (CA1) region of the hippocampus in the mediation of lateral hypothalamus-induced antinociception. Fifty-three male Wistar rats were unilaterally implanted with two separate cannulae into the lateral hypothalamus and CA1. Animals were pretreated with intra-CA1 TCS OX2 29 as an OX2R antagonist before intra-lateral hypothalamus administration of carbachol (250 nM) as a muscarinic agonist for chemical stimulation of orexinergic neurons. Formalin test was used as an animal model of persistent pain, following intra-lateral hypothalamus carbachol microinjection. Results showed that the chemical stimulation of the lateral hypothalamus significantly attenuated formalin-evoked nociceptive behaviors during both phases of the formalin test, and administration of TCS OX2 29 into the CA1 blocked these antinociceptive responses in both phases, especially in the late phase. These findings suggest that OX2 receptors in the CA1 partially mediate the lateral hypothalamus-induced antinociceptive responses in persistent inflammatory pain.

Temporal effect of fructose supplementation at different concentrations on hepatic metabolism of Wistar rats.

INTRODUCTION: Introduction: in the last few years important changes have occurred in nutritional patterns. There has been an increase in the consumption of simple carbohydrates such as fructose, which has been associated with numerous metabolic disorders, including hepatic steatosis. Materials and methods: we sought to evaluate the impact of fructose consumption, as diluted in water at different concentrations, for two time periods, on the metabolic parameters of Wistar rats using ANOVA. Results: our data indicate that both time and fructose concentration promote variations in animal body mass, and in food, water, and caloric intake. The time variable influenced the modulation of biochemical parameters such as serum concentrations of glucose and total cholesterol. Both fructose concentration and time of exposure influenced the concentrations of serum triglycerides, creatinine, AST, TNF, and IL-6. When evaluating redox status and oxidative damage markers, we observed that fructose concentration and exposure time had an effect on total glutathione levels, which decreased with an increase in concentration and time. For superoxide dismutase, we evaluated the effects of time and interaction. A significant interaction was observed for TBARS. For carbonylated proteins, exposure time was a fundamental factor in generating an effect. Conclusions: we demonstrated that fructose modulates the parameters of triglycerides and total liver cholesterol, and that time influences the number of hepatocytes. Our data suggest that fructose concentration, exposure time, and an interaction between these two parameters have a significant effect on the metabolic parameters responsible for the development of non-alcoholic fatty liver disease.

INTRODUCCIÓN: Introducción: en los últimos años se han producido cambios importantes en los patrones nutricionales. Ha habido un aumento del consumo de carbohidratos simples como la fructosa, que se ha asociado con numerosos trastornos metabólicos, incluida la esteatosis hepática. Materiales y métodos: buscamos evaluar el impacto del consumo de fructosa, diluida en agua a diferentes concentraciones, durante dos períodos de tiempo sobre los parámetros metabólicos de ratas Wistar, utilizando para ello el ANOVA. Resultados: nuestros datos indican que tanto el tiempo como la concentración de fructosa promueven variaciones en la masa corporal animal y la ingesta de alimentos, agua y calorías. La variable tiempo influyó en la modulación de parámetros bioquímicos tales como las concentraciones séricas de glucosa y colesterol total. Tanto la concentración de fructosa como el tiempo de exposición influyeron en las concentraciones séricas de triglicéridos, creatinina, AST, TNF e IL-6. Al evaluar el estado redox y los marcadores de daño oxidativo, observamos que la concentración de fructosa y el tiempo de exposición tuvieron un efecto sobre los niveles de glutatión total, que disminuyeron al aumentar la concentración y el tiempo. Para la superóxido dismutasa evaluamos los efectos del tiempo y la interacción. Se observó una interacción significativa para TBARS. Para las proteínas carboniladas, el tiempo de exposición fue un factor fundamental para generar algún efecto. Conclusiones: demostramos que la fructosa modula los parámetros de los triglicéridos y el colesterol total del hígado, y que el tiempo influye en el número de hepatocitos. Nuestros datos sugieren que la concentración de fructosa, el tiempo de exposición y cierta interacción entre estos dos parámetros tienen un efecto significativo sobre los parámetros metabólicos responsables del desarrollo de la enfermedad del hígado graso no alcohólico.

Pseudomonas syringae pv. phaseolicola Uses Distinct Modes of Stationary-Phase Persistence To Survive Bacteriocin and Streptomycin Treatments.

Antimicrobial treatment of bacteria often results in a small population of surviving tolerant cells, or persisters, that may contribute to recurrent infection. Antibiotic persisters are metabolically dormant, but the basis of their persistence in the presence of membrane-disrupting biological compounds is less well understood. We previously found that the model plant pathogen Pseudomonas syringae pv. phaseolicola 1448A (Pph) exhibits persistence to tailocin, a membrane-disrupting biocontrol compound with potential for sustainable disease control. Here, we compared physiological traits associated with persistence to tailocin and to the antibiotic streptomycin and established that both treatments leave similar frequencies of persisters. Microscopic profiling of treated populations revealed that while tailocin rapidly permeabilizes most cells, streptomycin treatment results in a heterogeneous population in the redox and membrane permeability state. Intact cells were sorted into three fractions according to metabolic activity, as indicated by a redox-sensing reporter dye. Streptomycin persisters were cultured from the fraction associated with the lowest metabolic activity, but tailocin persisters were cultured from a fraction associated with an active metabolic signal. Cells from culturable fractions were able to infect host plants, while the nonculturable fractions were not. Tailocin and streptomycin were effective in eliminating all persisters when applied sequentially, in addition to eliminating cells in other viable states. This study identifies distinct metabolic states associated with antibiotic persistence, tailocin persistence, and loss of virulence and demonstrates that tailocin is highly effective in eliminating dormant cells.IMPORTANCE Populations of genetically identical bacteria encompass heterogeneous physiological states. The small fraction of bacteria that are dormant can help the population survive exposure to antibiotics and other stresses, potentially contributing to recurring infection cycles in animal or plant hosts. Membrane-disrupting biological control treatments are effective in killing dormant bacteria, but these treatments also leave persister-like survivors. The current work demonstrates that in Pph, persisters surviving treatment with membrane-disrupting tailocin proteins have an elevated redox state compared to that of dormant streptomycin persisters. Combination treatment was effective in killing both persister types. Culturable persisters corresponded closely with infectious cells in each treated population, whereas the high-redox and unculturable fractions were not infectious. In linking redox states to heterogeneous phenotypes of tailocin persistence, streptomycin persistence, and infection capability, this work will inform the search for mechanisms and markers for each phenotype.

Zwitterion-Based Hydrogen Sulfide Nanomotors Induce Multiple Acidosis in Tumor Cells by Destroying Tumor Metabolic Symbiosis.

Destruction of tumor metabolism symbiosis is an attractive cancer treatment method which targets tumor cells with little harm to normal cells. Yet, a single intervention strategy and poor penetration of the drug in tumor tissue result in limited effect. Herein, we propose a zero-waste zwitterion-based hydrogen sulfide (H2 S)-driven nanomotor based on the basic principle of reaction in human body. When loaded with monocarboxylic acid transporter inhibitor α-cyano-4-hydroxycinnamic acid (α-CHCA), the nanomotor can move in tumor microenvironment and induce multiple acidosis of tumor cells and inhibit tumor growth through the synergistic effect of motion effect, driving force H2 S and α-CHCA. Given the good biosafety of the substrate and driving gas of this kind of nanomotor, as well as the limited variety of nanomotors currently available to move in the tumor microenvironment, this kind of nanomotor may provide a competitive candidate for the active drug delivery system of cancer treatment.

Inhibition of Autophagy at Different Stages by ATG5 Knockdown and Chloroquine Supplementation Enhances Consistent Human Disc Cellular Apoptosis and Senescence Induction rather than Extracellular Matrix Catabolism.

The intervertebral disc is the largest avascular organ. Autophagy is an important cell survival mechanism by self-digestion and recycling damaged components under stress, primarily nutrient deprivation. Resident cells would utilize autophagy to cope with the harsh disc environment. Our objective was to elucidate the roles of human disc cellular autophagy. In human disc cells, serum deprivation and pro-inflammatory interleukin-1ß (IL-1ß) stimulation increased autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and decreased autophagy substrate p62/sequestosome 1 (p62/SQSTM1), indicating enhanced autophagy. Then, RNA interference (RNAi) of autophagy-related gene 5 (ATG5), essential for autophagy, showed decreases in ATG5 protein (26.8%-27.4%, p < 0.0001), which suppressed early-stage autophagy with decreased LC3-II and increased p62/SQSTM1. Cell viability was maintained by ATG5 RNAi in serum-supplemented media (95.5%, p = 0.28) but reduced in serum-free media (80.4%, p = 0.0013) with IL-1ß (69.9%, p = 0.0008). Moreover, ATG5 RNAi accelerated IL-1ß-induced changes in apoptosis and senescence. Meanwhile, ATG5 RNAi unaffected IL-1ß-induced catabolic matrix metalloproteinase release, down-regulated anabolic gene expression, and mitogen-activated protein kinase pathway activation. Lysosomotropic chloroquine supplementation presented late-stage autophagy inhibition with apoptosis and senescence induction, while catabolic enzyme production was modest. Disc-tissue analysis detected age-related changes in ATG5, LC3-II, and p62/SQSTM1. In summary, autophagy protects against human disc cellular apoptosis and senescence rather than extracellular matrix catabolism.

Glycerol Monocaprylate Modulates Gut Microbiota and Increases Short-Chain Fatty Acids Production without Adverse Effects on Metabolism and Inflammation.

Glycerol monocaprylate (GMC) is a glycerol derivative of medium-chain fatty acids (MCFAs) and is widely used as a preservative in food processing. However, GMC and its hydrolytic acid (octylic acid) have antibacterial properties that may affect the physiology and intestinal microecology of the human body. Therefore, in this study, the effects of two different dosages of GMC (150 and 1600 mg kg-1) on glucose, lipid metabolism, inflammation, and intestinal microecology of normal diet-fed C57BL/6 mice were comprehensively investigated. The obtained results showed that the level of triglycerides (TGs) in the low-dose group down-regulated significantly, and the anti-inflammatory cytokine interleukin 10 (IL-10) significantly increased, while the pro-inflammatory cytokines monocyte chemotactic protein 1 (MCP-1) and interleukin 1beta (IL-1ß) in the high-dose group were significantly decreased. Importantly, GMC promoted the α-diversity of gut microbiota in normal-diet-fed mice, regardless of dosages. Additionally, it was found that the low-dose treatment of GMC significantly increased the abundance of Lactobacillus, while the high-dose treatment of GMC significantly increased the abundance of SCFA-producers such as Clostridiales, Lachnospiraceae, and Ruminococcus. Moreover, the content of short-chain fatty acids (SCFAs) was significantly increased by GMC supplementation. Thus, our research provides a novel insight into the effects of GMC on gut microbiota and physiological characteristics.

SIRT1 provides new pharmacological targets for polydatin through its role as a metabolic sensor.

The SIRT family of proteins constitutes highly conserved deacetylases with diverse and extensive functions. These proteins have specific biological functions, including regulation of transcription, cell cycle, cell differentiation, apoptosis, stress, metabolism, and genomic stability. Polydatin is a monocrystalline compound isolated from a Chinese herb, Polygonum cuspidatum. The pharmacological mechanisms of polydatin are mostly unclear but involve members of the SIRT protein family, among which SIRT1 plays a vital role. Polydatin is usually considered a potential SIRT1 activator. This review summarizes the signaling mechanism of polydatin involving SIRT1 and discusses the roles of related signal molecules such as PGC-1α, Nrf2, p38-MAPK, NLPR3 inflammasome, and p53. Further, we describe the metabolic regulation of related biological macromolecules and demonstrate that SIRT1, as a metabolic sensor, may act as a new pharmacological target for polydatin.

Ninjin'yoeito modulates feeding and activity under negative energy balance conditions via the NPY system.

The central and peripheral neuropeptide Y (NPY) system is critically involved in feeding and energy homeostasis control. Disease conditions as well as aging can lead to reduced functionality of the NPY system and boosting it represents a promising option to improve health outcomes in these situations. Here we show that Ninjin-yoeito (NYT), a Japanese kampo medicine comprising twelve herbs, and known to be effective to treat anorexia and frailty, mediates part of its action via NPY/peptide YY (PYY) related pathways. Especially under negative energy homeostasis conditions NYT is able to promote feeding and reduces activity to conserve energy. These effects are in part mediated via signalling through the NPY system since lack of Y4 receptors or PYY leading to modification in these responses highlighting the possibility for combination treatment to improve aging related conditions on energy homeostasis control.

Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy.

The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.