Artificial and natural interventions for chemotherapy- and / or radiotherapy-induced cognitive impairment: A systematic review of animal studies.

BACKGROUND: Cancer survivors frequently experience cognitive impairments. This systematic review assessed animal literature to identify artificial (pharmaceutical) or natural interventions (plant/endogenously-derived) to reduce treatment-related cognitive impairments. METHODS: PubMed, EMBASE, PsycINFO, Web of Science, and Scopus were searched and SYRCLE's tool was used for risk of bias assessment of the 134 included articles. RESULTS: High variability was observed and risk of bias analysis showed overall poor quality of reporting. Results generally showed positive effects in the intervention group versus cancer-therapy only group (67% of 156 cognitive measures), with only 15 (7%) measures reporting cognitive impairment despite intervention. Both artificial (61%) and natural (75%) interventions prevented cognitive impairment. Artificial interventions involving GSK3B inhibitors, PLX5622, and NMDA receptor antagonists, and natural interventions utilizing melatonin, curcumin, and N-acetylcysteine, showed most consistent outcomes. CONCLUSIONS: Both artificial and natural interventions may prevent cognitive impairment in rodents, which merit consideration in future clinical trials. Greater consistency in design is needed to enhance the generalizability across studies, including timing of cognitive tests and description of treatments and interventions.

Changes in glycemia, insulin and gut hormone responses to a slowly ingested solid low-carbohydrate mixed meal after laparoscopic gastric bypass or band surgery.

OBJECTIVE: To evaluate early changes in glycemia, insulin physiology and gut hormone responses to an easily tolerated and slowly ingested solid, low-carbohydrate mixed meal test (MMT) following laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery. SUBJECTS/METHODS: This was a prospective non-randomized study. Plasma glucose, insulin and c-peptide (to estimate hepatic insulin extraction; %HIE), incretins (GIP, aGLP-1) and pancreatic polypeptide (PP) responses to the MMT were measured at 4-8 weeks before and after surgery in obese, metabolically healthy patients (RYGB=10F or LAGB =7F/1M). Supplementary clamp data on basal endogenous glucose production (EGP) and peripheral insulin action (Rd=rate of glucose disposal) and metabolic clearance rates of insulin (MCR-INS) were available in five of the RYGB patients. Repeated measures were appropriately accounted for in the analyses. RESULTS: Following LAGB surgery, C-peptide and insulin MMT profiles (P=0.004 and P=0.0005, respectively) were lower with no change in %HIE (P=0.98). In contrast, in RYGB subjects, both fasting glucose and insulin (Δ=-0.66 mmol l-1, P⩽0.05 and Δ=-44.4 pmol l-1, P⩽0.05, respectively) decreased, and MMT glucose (P<0.0001) and insulin (P=0.001) but not c-peptide (P= 0.69) decreased. Estimated %HIE increased at fasting (Δ=8.4%, P⩽0.05) and during MMT (P=0.0005). Early (0-20 min) prandial glucose (0.27±0.26 versus 0.006±0.21 mmol l-1, P⩽0.05) and insulin (63(48, 66) versus 18(12, 24) pmol l-1, P⩽0.05) responses increased after RYGB. RYGB altered the trajectory of prandial aGLP-1 responses (treatment × trajectory P=0.02), and PP was lower (P<0.0001). Clamp data in a subset of RYGB patients showed early improvement in basal EGP (P=0.001), and MCR-INS (P=0.015). CONCLUSION: RYGB results in distinctly different changes in plasma glucose, insulin and gut hormone response patterns to a solid, slowly ingested low-carbohydrate MMT versus LAGB. Altered nutrient delivery, along with indirect evidence for changes in hepatic and peripheral insulin physiology, are consistent with the greater early improvement in glycemia observed after RYGB versus LAGB surgery.

mRNA concentrations of MIF in subcutaneous abdominal adipose cells are associated with adipocyte size and insulin action.

OBJECTIVE: To determine whether the mRNA concentrations of inflammation response genes in isolated adipocytes and in cultured preadipocytes are related to adipocyte size and in vivo insulin action in obese individuals. DESIGN: Cross-sectional inpatient study. SUBJECTS: Obese Pima Indians with normal glucose tolerance. MEASUREMENTS: Adipocyte diameter (by microscope technique; n=29), expression of candidate genes (by quantitative real-time PCR) in freshly isolated adipocytes (monocyte chemoattractant protein (MCP) 1 and MCP2, macrophage inflammatory protein (MIP) 1alpha, MIP1beta and MIP2, macrophage migration inhibitory factor (MIF), tumor necrosis factor alpha, interleukin (IL) 6 and IL8; n=22) and cultured preadipocytes (MCP1, MIP1alpha, MIF, IL6 and matrix metalloproteinase 2; n=33) from subcutaneous abdominal adipose tissue (by aspiration biopsy, n=34), body fat by dual-energy X-ray absorptiometry, glucose tolerance by 75 g oral glucose tolerance test and insulin action by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) (all n=34). RESULTS: MIF was the only gene whose expression in both freshly isolated adipocytes and cultured preadipocytes was positively associated with adipocytes diameter and negatively associated with peripheral and hepatic insulin action (all P<0.05). In multivariate analysis, the association between adipocyte MIF mRNA concentrations and adipocytes diameter was independent of the percentage of body fat (P=0.03), whereas adipocyte MIF mRNA concentrations, but not adipocyte diameter, independently predicted peripheral insulin action. The mRNA expression concentrations of the MIF gene in adipocytes were not associated with plasma concentrations of MIF, but were negatively associated with plasma adiponectin concentrations (P=0.004). In multivariate analysis, adipocyte MIF RNA concentrations (P=0.03) but not plasma adiponectin concentrations (P=0.4) remained a significant predictor of insulin action. CONCLUSIONS: Increased expression of MIF gene in adipose cells may be an important link between obesity characterized by enlarged adipocytes and insulin resistance in normal glucose tolerant people.

Metabolic actions of estradiol: significance for acute and chronic exercise responses.

Although estradiol (E2) is considered primarily for its role in reproduction, it can exert numerous physiological actions on a variety of tissues. However, there are several difficulties in isolating these actions and determining its impact for in vivo situations. Despite the limitations, it does appear that E2 can alter, under certain conditions, resting and acute exercise metabolism and blood glucose regulation. Specifically, E2 can increase lipid availability and utilization and decrease gluconeogenesis and glycogenolysis. Development of glucose intolerance as a result of insulin insensitivity has also been documented. The mechanisms of E2 may be through direct alterations in key enzyme activity and membrane permeability or indirectly via changes in insulin:glucagon, cortisol, hGH, and catecholamine levels or sensitivity. Future research should focus on understanding the effects of exercise and diet on chronic E2 status and the resulting impact for a variety of conditions that include reproductive and skeletal integrity and predisposing metabolic risk factors for CAD and diabetes. In order to make meaningful correlations between E2 levels and physiological measurements such as bone mineral content, lipid profiles, glucose intolerance, etc., there needs to be a standard guideline for determining and defining one's "estrogen status." Finally, in order to identify underlying mechanisms, an understanding of and appreciation for the interrelationships among the numerous compositional, metabolic, and (neuro)endocrine factors involved is needed. A general model is presented, along with specific applications, to study these interactions.

Comparison of estradiol and testosterone levels during and immediately following prolonged exercise in moderately active and trained males and females.

Estradiol (E2) and testosterone (T) levels were compared among 28 subjects, ages 21-30, classified as male controls (MC), male runners (MR), female controls (FC) or female runners (FR). Serial blood samples were drawn from an indwelling venous catheter during rest (2 hrs), treadmill exercise (1 hr at 60% VO2max), and immediate recovery (15 min). Two-way ANOVA resulted in expected sex differences (p less than .01) in resting levels of E2 (M = 43.2 +/- 26.4; F = 142.4 +/- 72.8 pg/ml) and T (M = 4.8 +/- 1.2; F = 0.6 +/- 0.4 ng/ml). Significant (p less than .01) percent (%) and absolute (ABS) increases in E2 were observed in all subjects. Exercise increases in T were only significant in the MRs. ABS and % changes were compared among groups during exercise and during recovery. Training-related differences were found in the nature of the steroid responses. Runners exhibited greater ABS and % increases in T and E2 during recovery while the controls' greatest increases occurred during exercise. It was concluded that the greater (and more rapid) exercise responses of E2 in the MCs and T in the FCs as compared to the MRs and FRs, respectively were due to increased adrenal stimulation. The greater (and more delayed) recovery responses of the runners were due to gonadal production or differences in gonadal blood flow dynamics immediately post-exercise. The significance of this training difference may be relevant for steroidal induction of anabolic processes that lead to training adaptations.

Sex and training differences in human growth hormone levels during prolonged exercise.

Human growth hormone (hGH) levels were measured during rest, prolonged treadmill exercise at 60% maximum O2 uptake (VO2max), and immediate recovery in four groups of subjects (n = 7/group), ages 21-30 yr, classified as male runners (MR), female runners (FR), male controls (MC), and female controls (FC) to determine whether sex differences in the hGH response are related to resting 17 beta-estradiol (E2) and/or cardiorespiratory endurance (CRE). Glucose (Glc), E2, and hGH levels were determined from serial blood samples taken from an intravenous catheter. Glc did not change significantly during exercise, but different trends for the runners (increases) vs. controls (decreases) resulted in higher (P less than 0.01) postexercise levels in the runners. Resting hGH was higher (P less than 0.05) in the FRs and FCs than the MRs and MCs, respectively, and continued to be higher in the FCs (vs. MCs) during the first 30 min of exercise. The MRs achieved higher peak hGH levels and exhibited higher values than the MCs throughout exercise and recovery. There were no statistically significant training differences in the females. The strongest predictors for peak hGH were absolute work load and group (runners vs. controls), both of which combined accounted for 32-36% of the variability (P less than 0.01) in hGH response. Significant sex-related variables (sex, resting E2) accounted for 11-19% of the variability in peak or percent change in hGH, with E2 having a positive effect at rest but a negative effect during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)