CAF Group Research Articles

Molecular Subtyping in Prognostication of Neoadjuvant Chemotherapy Response in Patients of Locally Advanced Breast Cancer

Aim: The aim of this study is to predict the response of neoadjuvant chemotherapy (NACT) based on preoperative molecular subtyping of locally advanced breast cancer patients. Materials and Methods: The present single-blind, observational study was conducted at the tertiary health-care center of Acharya Vinoba Bhave Rural Hospital from October 2018 to September 2020. This study comprised 46 patients suffering from breast cancer with TNM stage IIIA and IIIB. The patients received either NACT with cyclophosphamide/adriamycin/5-fluorouracil or paclitaxel, respectively, followed by the standard surgical procedure of modified radical mastectomy. Baseline ultrasound was followed by Trucut biopsy of the tumor which was done with 18-G Bard Trucut biopsy needle under local anesthesia in all aseptic conditions. The specimens were collected and preserved in formalin and were sent for the assessment of tumor histological examination, Scarff-Bloom-Richardson grade, and immunohistochemistry (IHC) evaluation. Depending on the luminal status obtained by IHC preoperatively, further response to chemotherapy was assessed. Results: In the CAF group, patients with human epidermal growth factor receptor 2/neu (HER2/neu)-enriched status had (91.40% ± 7.76%) tumor response followed by luminal B status (89.33% ± 5.77%), triple-negative status (87.34% ± 9.55%), and finally luminal A status with (84.87% ± 8.11%) a statistically nonsignificant relation. In the paclitaxel group, patients with triple-negative status had a tumor response of (96.59% ± 4.48%) followed by luminal B status (96.28% ± 3.27%), HER2/neu-enriched status (91.33% ± 6.85%), and finally luminal A status (82.40% ± 11.29%) with a statistically significant relation (P = 0.023). Conclusion: It can be concluded from the results that overall, HER2/neu-enriched and triple-negative status patients showed better tumor response to NACT in both groups.

Early life Western diet-induced memory impairments and gut microbiome changes in female rats are long-lasting despite healthy dietary intervention

ABSTRACT Objective Western diet consumption during adolescence results in hippocampus (HPC)-dependent memory impairments and gut microbiome dysbiosis. Whether these adverse outcomes persist in adulthood following healthy dietary intervention is unknown. Here we assessed the short- and long-term effects of adolescent consumption of a Western diet enriched with either sugar or both sugar and fat on metabolic outcomes, HPC function, and gut microbiota. Methods Adolescent female rats (PN 26) were fed a standard chow diet (CHOW), chow with access to 11% sugar solution (SUG), or a junk food cafeteria-style diet (CAF) containing various foods high in fat and/or sugar. During adulthood (PN 65+), metabolic outcomes, HPC-dependent memory, and gut microbial populations were evaluated. In a subsequent experiment, these outcomes were evaluated following a 5-week dietary intervention where CAF and SUG groups were maintained on standard chow alone. Results Both CAF and SUG groups demonstrated impaired HPC-dependent memory, increased adiposity, and altered gut microbial populations relative to the CHOW group. However, impaired peripheral glucose regulation was only observed in the SUG group. When examined following a healthy dietary intervention in a separate experiment, metabolic dysfunction was not observed in either the CAF or SUG group, whereas HPC-dependent memory impairments were observed in the CAF but not the SUG group. In both groups the composition of the gut microbiota remained distinct from CHOW rats after the dietary intervention. Conclusions While the metabolic impairments associated with adolescent junk food diet consumption are not present in adulthood following dietary intervention, the HPC-dependent memory impairments and the gut microbiome dysbiosis persist.

Single gingival recession associated with non-carious cervical lesion treated by partial restoration and coronally advanced flap with or without xenogenous collagen matrix: A randomized clinical trial evaluating the coverage procedures and restorative protocol.

Evaluate the use of collagen matrix (CM) as adjunctive to coronally advanced flap (CAF versus CAF + CM) to treat gingival recession (GR) associated with non-carious cervical lesion-combined defects (CDs). Sixty-two patients presenting 62 CDs (RT1 GR and non-carious cervical lesion (NCCLs) were randomly allocated to either CAF group (n=31): partial restoration of the NCCL and CAF; or to CAF + CM group (n=31): partial restoration of the NCCL and CAF associated with CM. Clinical, esthetic, patient-centered outcomes, and restorative parameters were assessed. After 12 months, CD coverage were 55.2% for CAF and 54.4% for CAF + CM (P=0.8). Recession reduction were 1.9 ± 0.8mm for CAF and 2.0 ± 0.7mm for CAF + CM (P=0.6). CAF+CM resulted in higher increase in keratinized tissue (KT) width (CAF: 0.3 ± 0.7mm; CAF + CM: 0.9 ± 0.8mm; P=0.004) and KT thickness gain (CAF: 0.1 ± 0.3mm; CAF + CM: 0.7 ± 0.2mm; P=0.001). Both treatments presented low postoperative pain and resulted in esthetics improvements. In addition, no restoration was lost, 27.4% showed a reduction of the superficial polishing, and 8% showed marginal staining, but still clinically acceptable. Partial resin composite restoration (with the apical limit up to 1mm of the estimated CEJ) and CAF alone or combined with CM are suitable for treating CDs. The use of CM provided additional benefits in terms of KT width and thickness gain. (NCT03341598).

Effect of acute caffeine supplementation before intermittent high-intensity exercise on cytokine levels and psychobiological parameters: A randomized, cross-over, placebo-controlled trial

The present study aimed to verify the effects of caffeine supplementation on psychobiological parameters and its relationship with inflammatory cytokines in non-athlete subjects. We hypothesized that IL-10 may be responsible for the reduction in fatigue perception in response to caffeine supplementation. It was a randomized, double-blinded, cross-over, placebo-controlled study. Ten non-athlete subjects (26.9 ± 4.01 years old; 73.44 ± 9.57 kg; 15.94 ± 4.32 body fat kg) were evaluated. Sixty-min after caffeine (6 mg−1.kg−1 body mass) or placebo supplementation, high-intensity interval exercise test (1 min at 90% of Wmax and 2 min at 50% of Wmax) was performed to maximum voluntary exhaustion. Cytokine concentrations and psychobiological parameters were evaluated before (BE), immediately after (post-PE) and 1 h after exercise (1 h post-PE). We verify that IL-6 (0.35; 95% CI: 0.13 to 0.56; z = 3.24; p = 0.001; d = 1.14) and IL-10 (9.06; 95% CI 0.41 to 17.70; z = 2.05; p = 0.04; d = 1.12) increases post-PE in CAF group versus PLA group. Still, IL-10 levels were higher in CAF group 1 h post-PE (25.04; 95% CI: 8.95 to 41.31; z = 3.05; p = 0.002; d = 1.9) than PLA group. Moreover, 1 h post-PE vigor level was higher in the CAF group versus PLA group (4.53; 95% CI: 1.27 to 7.80; z = 2.72; p = 0.006; d = 0.46), and fatigue was lower in CAF group than PLA group (-5.08; 95% CI: −9.93 to −0.227; z = -2.05; p = 0.040; d = 0.67). We conclude that 1 h post-PE caffeine was able to decrease fatigue and increase vigor perception. IL-10 levels were higher 1 h post-PE in CAF group, suggesting, according to our hypothesis, that IL-10 may be associated with decrease fatigue perceptions after exercise.

Periosteal pedicle graft with coronally advanced flap and its comparison with modified coronally advanced flap in the treatment of multiple adjacent gingival recessions-a randomized clinical trial

The present study aimed at evaluating clinical utility of periosteal pedicle graft with coronally advanced flap (PPG ​+ ​CAF) vs modified coronally advanced flap (M-CAF) in cases of multiple adjacent gingival recessions involving maxillary and mandibular anteriors labially. Random allocation of 40 patients with 269 gingival recessions was done into two groups. In Test group (20 patients) periosteal pedicle graft followed by coronally advanced flap (PPG ​+ ​CAF) technique was performed and in control group (20 patients) modified coronally advanced flap (M-CAF) was attempted. Primary outcome measures included percentage root coverage (PRC), gingival thickness (GT), probing depth (PD), clinical attachment level (CAL), recession depth (RD) and width of keratinized gingiva (WKG). Secondary outcomes measures were patient centred outcomes, plaque index (PI) and gingival index (GI). Patients were recalled at baseline, 3,6 and 18 months postoperatively. ResultsThere was a significant decrease in the mean recession depth from 3.58 ​± ​0.53 ​mm (baseline) to 0.22 ​± ​0.01 ​mm (18 months) in PPG ​+ ​CAF test group and 3.7 ​± ​0.56 ​mm (baseline) to 0.21 ​± ​0.01 mm (18 months) in M-CAF control group. With 85% root coverage in test group and 78% root coverage in control group, the difference was statistically significant at 18 months. The test group showed significant higher clinical attachment level gain and increase in width of keratinized gingiva as compared to control group. ConclusionIn both the study groups PPG ​+ ​CAF and M-CAF, significant root coverage was achieved. However, in terms of increase in width of keratinized gingiva, gingival thickness and percentage root coverage, PPG ​+ ​CAF group presented significantly better results than M-CAF group at 18 months follow up. Thus, periosteum can be used as a pedicle graft along with coronally advanced flap as an alternative method in achieving better results with minimal cost.

Caffeine mouth rinse enhances performance, fatigue tolerance and reduces muscle activity during moderate-intensity cycling.

We investigated the effects of caffeine mouth rinse on endurance performance, muscle recruitment (i.e., electromyographic activity of the vastus lateralis and rectus femoris), rating of perceived effort and heart rate. Twelve physically-active healthy men cycled at 80% of their respiratory compensation point until task failure. The participants rinsed their mouths for 10 seconds with placebo (PLA, 25 mL of a solution composed of non-caloric mint essence) or caffeine (CAF, 25 mL of 1.2% of anhydrous caffeine concentration with non-caloric mint essence) every 15 minutes of exercise. Time until exhaustion increased 17% (effect size = 0.70) in CAF compared to PLA (p = 0.04). The wavebands of low-frequency electromyographic activity (EMG) of the vastus lateralis and rectus femoris was lower in CAF group than PLA at 50% of the time until exhaustion (p = 0.04). The global EMG signal was lower in CAF group than PLA at 100% of the time until exhaustion (p = 0.001). The rating of perceived effort pooled was higher in CAF mouth rinse (p = 0.001) than PLA group. No effect was found on the heart rate between the groups (p > 0.05). Caffeine mouth rinse increases endurance performance, rating of perceived effort and decreases muscle activity during a moderate-intensity exercise.

Caffeine Intake Influences The Blood Pressure Response To Strenuous Physical Exertion Among Firefighters

Caffeine may diminish the immediate blood pressure (BP) reductions that occur after an exercise bout, termed post-exercise hypotension (PEH). Neither PEH nor the influence of caffeine on PEH have been studied in firefighters (FF), who have a disproportionate high risk of sudden cardiac death on the job, partially due to its strenuous nature and poor nutrition. PURPOSE: To examine the influence of caffeine intake (CAF) on PEH after a maximal graded exercise stress test (GEST) in FF. METHODS: FF (n=15) completed a non-exercise control (CONTROL) and GEST in random order on separate non-work days. They left the laboratory attached to an ambulatory BP (ABP) monitor for 19hr. CAF was assessed with the National Health and Nutrition Examination Survey food-frequency questionnaire. Repeated measures ANCOVA in SAS tested if the ABP response after GEST vs CONTROL differed by CAF group divided by the median as high (806.8+190.7mg) and low (239.3+202.9mg) with baseline ABP as a covariate. RESULTS: FF were overweight (29.0+3.9kg/m2), middle-aged (40.2+9.5yr) men with elevated resting BP (124.1+10.3/79.6+11.5mmHg). CAF tended to be positively correlated with resting SBP (r=.50, p=.06) and DBP (r=.50, p=.06). Among the total sample, the systolic ABP (ASBP) (18.0+4.8mmHg, p<.01) and diastolic ABP (ADBP) (9.1+1.5mmHg, p<.01) changes from baseline were greater after GEST vs CONTROL over 19hr, independent of CAF (Ps>0.05), but with significant interactions among ASBP, ADBP, and CAF over 19hr (Ps<0.05). These interactions revealed ASBP was consistently greater after GEST vs CONTROL over 19hr in high CAF (p<=0.01 GEST vs CONTROL); whereas in low CAF the difference in ASBP after GEST vs CONTROL was variable over 19hr (p=0.03 GEST vs CONTROL x Time). By contrast, the ADBP response after GEST vs CONTROL over 19hr tended to be greater in low (15.3+4.5mmHg, p=.08) than high CAF (4.4+2.4mmHg, p=.05). DISCUSSION: This small sample of FF exhibited post-exercise hypertension and CAF seemed to modulate this adverse response. Further study is needed in a larger sample of FF to confirm our findings and better establish the relationship of these associations. Supported by the University of Connecticut Institute for Collaboration on Health Intervention and Policy and the United States Department of Agriculture (SAES, HATCH Project No. CONS00954).

Aerobic Exercise Training Prevents Obesity and Insulin Resistance Independent of Changes in the Skeletal Muscle ACE2/Ang 1‐7/Mas Axis.

Aerobic exercise training (AET) has been widely used for the prevention and treatment of obesity and insulin resistance (IR). Improvements in the oxidative capacity of skeletal muscle can mediate the protective effect of AET. Considering the role of angiotensin converting enzyme 2 (ACE2)/angiotensin 1‐7 (Ang 1‐7)/receptor Mas axis activation in reducing cardiometabolic diseases, the present study aimed to evaluate if the prevention of obesity and IR through AET is associated with changes in the ACE2/Ang (1‐7)/Mas axis in the skeletal muscle. Adult male C57BL6/J mice were assigned into groups (n=10/group): chow‐fed controls (C), chow‐fed trained (T), cafeteria diet (CAF), and cafeteria diet and trained (CAFT). AET was performed simultaneously with diet and consisted of 8‐wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committee from School of Arts, Science and Humanities, University of Sao Paulo, Brazil (#001/2016). The CAF group presented higher body weight gain and adiposity, glucose intolerance, IR and increased lipid deposition in the liver while AET prevented such damages in the CAFT group. Food consumption did not change among the groups. During the maximal physical exertion test, the T group increased VO2máx and both T and CAFT groups showed higher maximal speed, higher speed on the VO2máx and lower relative running cost compared to C and CAF groups. The enzymatic activity of citrate synthase and β‐hydroxyacyl‐CoA dehydrogenase (β‐HAD) in the soleus muscle increased in the T (352 ± 21.5 mmol/min/mg and 80.1 ± 6.6 mmol/min/mg) and CAFT (350 ± 22.4 mmol/min/mg and 87.9 ± 7.3 mmol/min/mg) groups compared to C (272.7 ± 9.5 mmol/min/mg and 62.7 ± 3.9 mmol/min/mg) and CAF (254.6 ± 15.7 mmol/min/mg and 46.7 ± 1.6 mmol/min/mg) groups. Protein expression of mitofusin 1, mitofusin 2 and dynamin related protein 1 (Drp1) did not change among groups. Also, no differences were observed in the ACE2 and Ang (1‐7) levels nor in the receptor Mas protein expression. In conclusion, the AET prevented the increase in body weight, adiposity and IR induced by cafeteria diet, improved the aerobic capacity and promoted the increase in oxidative enzymes activity in the soleus muscle. However, the adaptations induced by AET were not associated with changes in the ACE2/Ang (1‐7)/Mas axis in the skeletal muscle.Support or Funding InformationSão Paulo Research Foundation (FAPESP #2015/04948‐4; #2016/23783‐9; #2016/20659‐5).

Prenatal caffeine exposure induces down-regulation of the protein kinase A/ryanodine receptor/large-conductance Ca2+-activated K+ pathway in the cerebral arteries of old offspring rats

The current study investigated the long-term effects of prenatal caffeine (Caf) exposure on cerebral vessels of old offspring rats. Pregnant rats were treated with Caf (20 mg/kg, twice daily) or 0.9% normal saline during gestational days 3.5-19.5, and offspring were tested at 24 months old. Vascular functions of middle cerebral arteries and ion channel activities in smooth muscle cells were examined using myograph system and patch-clamp. Prenatal Caf exposure decreased isoprenaline (β-adrenergic agonist)-induced dilatation of the middle cerebral artery in the offspring. Treatment with protein kinase A (PKA) inhibitor reduced isoprenaline-mediated vasodilatation to a greater extent in the control. Forskolin-mediated vasodilatation and membrane hyperpolarization were reduced in the Caf group. Large-conductance Ca-activated K (BKCa) channel inhibitor iberiotoxin significantly attenuated forskolin-induced vasodilatation and reduced depolarization in the control, not in the Caf group. The PKA agonist-activated cell-attached single BKCa currents to a greater extent in the control. The mRNA and protein expression levels of PKA-Cα were decreased. The sensitivity of ryanodine receptors to the PKA agonist was blunted in the Caf group, whereas the mRNA expression of ryanodine receptor 2 subunit was reduced. Voltage/Ca sensitivity of BKCa was decreased accompanied by reduced mRNA and protein expression of BKCa-β1 subunits in the Caf group. PKA agonist-stimulated inside-out BKCa currents were weaker in the Caf group. Prenatal exposure to Caf-affected isoprenaline/forskolin-mediated vascular functions in aged cerebral arteries, related to dysfunction of the PKA/ryanodine receptors/BKCa signaling pathway.

Cafeteria diet administered from lactation to adulthood promotes a change in risperidone sensitivity on anxiety, locomotion, memory, and social interaction of Wistar rats

PurposeTo evaluate the nutritional status and behavior of animals fed a cafeteria diet from the onset of lactation after the addition of risperidone. MethodsDuring the lactation period, 14 litters of Wistar rats (dam + 8 pups) were fed one of two diets: control (CTRL; n = 7) or cafeteria (CAF; n = 7). After weaning, the males were placed in individual cages, receiving the same diet as offered to their respective dams. Food and caloric intake, body weight, feed and energy efficiency, and adipose tissue weight were evaluated in the male offspring. In adulthood, they were assigned to receive treatment with saline (CTRL-S, CAF-S) or risperidone (CTRL-R, CAF-R) (n = 21 in each group). They then underwent behavioral testing, which included the elevated plus maze, open field, object recognition, and social interaction tests. Variance analysis (ANOVA) was used, followed by Newman–Keuls when p-values were < 0.05. ResultsThe CAF group exhibited higher caloric intake, weight gain, feed efficiency, and adipose tissue than the CTRL group. The animals in the CAF group exhibited oxidative stress characteristics in the hippocampus, which may have compromised the function of this structure and promoted behavioral changes. The CAF-S group exhibited anxiety, as indicated by the greater number of entrances and time spent in the center of the open field. They also showed greater locomotion through a greater number of quadrants traveled. CAF-S animals also demonstrated memory impairments, assessed using the object recognition test, and decreased social interaction. The CAF-R group demonstrated anxiety and decreased locomotion in the open field. There was a decrease in their interaction with both objects in the object recognition test. The CAF-R group obtained greater sociability in the social interaction test. Such effects may be associated with changes in the serotonergic system of these animals. ConclusionRisperidone administered to animals on a cafeteria diet led to a greater reduction in locomotion, had an anxiogenic effect, caused impaired memory, and improved social interaction.

Effects of different diets used in diet-induced obesity models on insulin resistance and vascular dysfunction in C57BL/6 mice

The aim of the present study was to compare different diets used to induce obesity in a head-to-head manner with a focus on insulin resistance and vascular dysfunction. Male C57BL/6J mice were put on standard chow diet (SCD), normal-fat diet (NFD), cafeteria diet (CAF) or high-fat diet (HFD) for 12 weeks starting at the age of 6 weeks. Both CAF and HFD led to obesity (weight gain of 179% and 194%, respectively), glucose intolerance and insulin resistance to a comparable extent. In aortas containing perivascular adipose tissue (PVAT), acetylcholine-induced vasodilation was best in the NFD group and worst in the CAF group. Reduced phosphorylation of endothelial nitric oxide synthase at serine 1177 was observed in both CAF and HFD groups. Plasma coagulation activity was highest in the HFD group and lowest in the SCD group. Even the NFD group had significantly higher coagulation activity than the SCD group. In conclusions, CAF and HFD are both reliable mouse diets in inducing visceral obesity, glucose intolerance and insulin resistance. CAF is more effective than HFD in causing PVAT dysfunction and vascular dysfunction, whereas hypercoagulability was mostly evident in the HFD group. Coagulation activity was higher in NFD than NCD group.

Does caffeine ingestion before a short-term sprint interval training promote body fat loss?

We investigated the effect of caffeine ingestion combined with a 2-wk sprint interval training (SIT) on training-induced reductions in body adiposity. Twenty physically-active men ingested either 5 mg/kg of cellulose as a placebo (PLA, n=10) or 5 mg/kg of caffeine (CAF, n=10) 60 min before each SIT session (13×30 s sprint/15 s of rest). Body mass and skinfold thickness were measured pre- and post-training. Energy expenditure was measured at rest, during exercise, and 45 min after exercise in the first SIT session. Body fat was similar between PLA and CAF groups at pre-training (P>0.05). However, there was a significant decrease in body fat after training in the CAF group (−5.9±4.2%, P<0.05) but not in PLA (1.5±8.0%, P>0.05). There was no difference in energy expenditure at rest and during exercise between PLA and CAF groups (P>0.05), but the post-exercise energy expenditure was 18.3±21.4% greater in the CAF than in the PLA group (P<0.05). In conclusion, caffeine ingestion before SIT sessions induced a body fat loss that may be associated with higher post-exercise energy expenditure.

Oral caffeine administered during late gestation increases gestation length and piglet temperature in naturally farrowing sows

Selection of sows for large litter size has adverse consequences including lesser and more variable birth weights, reduced piglet viability and greater peri- and post-natal piglet mortality. One approach to improve survival might be to feed caffeine to the sow, which improves piglet viability after induced farrowing, but has not been evaluated in sows which farrow naturally. Large White x Landrace sows were fed 0 (CON: n = 30) or 6 g/day caffeine (CAF: n = 34) with their daily feed from 3 days before expected parturition until farrowing. Numbers of piglets born alive and stillborn, as well as piglet vitality and meconium staining score were recorded at birth. Piglet rectal temperature was measured at 3 and 24 h and piglet survival was recorded through lactation. Compared with CON animals, sows of the CAF group had longer gestations (CON: 115.6 ± 0.3 days; CAF: 116.6 ± 0.3 days, P = 0.01) and piglets of CAF sows had greater rectal temperatures 3 h after birth (CON: 37.6 ± 0.2 °C, CAF 38.0 ± 0.2 °C, P<0.05). Although there was no difference in the stillborn numbers per litter fewer CAF sows delivered stillborn piglets when compared to CON sows (CON: 43.3%, CAF: 20.6%, P = 0.05). Piglet survival to day 18 of lactation was not altered by treatment (CON: 90.4 ± 3.2%, CAF: 92.0 ± 2.4%, P>0.05). The current data suggest that maternal supplementation with caffeine is a promising treatment to prevent premature farrowing and increase piglet temperature at birth, and may decrease the incidence of litters with stillborn piglets.

Resveratrol attenuates metabolic, sperm, and testicular changes in adult Wistar rats fed a diet rich in lipids and simple carbohydrates

High-fat diets affect male reproduction and sexual function. Therefore, we evaluated the effects of prolonged resveratrol administration on the metabolic, sperm, and testicular parameters of rats fed a cafeteria diet. Male Wistar rats were divided at weaning into control (C, n = 20) and cafeteria (CAF, n = 16) groups. At 3 months, half of them were given daily supplementations of resveratrol (C-R, n = 10; CAF-R, n = 8) at a dosage of 30 mg kg−1 body mass for 2 months. Animals were killed at 5 months of age, and blood, spermatozoa, and testes were collected for further analysis. Data were analyzed by one-way ANOVA, and P < 0.05 was considered statistically significant. The CAF diet promoted hyperglycemia (P < 0.0001), and treatment with resveratrol reversed this condition (P < 0.0001). The CAF diet reduced sperm viability and motility, while resveratrol improved these parameters (P < 0.05). Regarding testicular morphology, the height of the seminiferous epithelium was reduced in the CAF group compared with that of the C group (P = 0.0007). Spermatogenic cell proliferation was also reduced in the CAF group compared with that of the C group. However, the CAF-R showed an increase in cell proliferation rate compared with that of the untreated CAF group (P = 0.0024). Although it did not modify body mass, the consumption of a CAF diet promoted hyperglycemia, adverse testicular morphology remodeling, and abnormal sperm, which were attenuated by treatment with resveratrol, thus suggesting a protective effect of this antioxidant on spermatogenesis.

The Effects of Acute and Chronic Sprint-Interval Training on Cytokine Responses Are Independent of Prior Caffeine Intake.

We examined the effect of acute and chronic sprint interval training (SIT), with or without prior caffeine intake, on levels of exercise-induced inflammatory plasma cytokines [interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α]. Twenty physically-active men ingested either a placebo (n = 10) or caffeine (n = 10) 1 h before each SIT session(13-s × 30-s sprint/15 s of rest) during six training sessions (2 weeks). The early (before, immediately after, and 45 min after the exercise) and late (24 and 48 h after the exercise) cytokine and creatine kinase (CK) responses were analyzed for the first and last training sessions. Plasma IL-6 and IL-10 peaked 45 min after the exercise, and then returned to basal values within 24 h (p < 0.05) in both groups on both occasions (p > 0.05). On both occasions, and for both groups, plasma TNF-α increased from rest to immediately after the exercise and then decreased at 45 min before reaching values at or below basal levels 48 h after the exercise (p < 0.05). Serum CK increased from rest to 24 and 48 h post-exercise in the first training session (p < 0.05), but did not alter in the last training session for the PLA group (p > 0.05). Serum CK was unchanged in both the first and last training sessions for the CAF group (p > 0.05). Two weeks of SIT induced a late decrease in the IL-6/IL-10 ratio (p < 0.05) regardless of caffeine intake, suggesting an improved overall inflammatory status after training. In conclusion, a single session of SIT induces muscle damage that seems to be mitigated by caffeine intake. Two weeks of SIT improves the late SIT-induced muscle damage and inflammatory status, which seems to be independent of caffeine intake.

The prevention of cardiometabolic risk factors is associated with the improvement in aerobic capacity

Physical inactivity reduces aerobic capacity and is directly associated with an increase in cardiometabolic risk factors. Here we investigated whether there is an association between increased aerobic capacity and the prevention of obesity and insulin resistance through aerobic exercise training (AET). Adult male C57BL6/J mice were assigned into chow‐fed controls (C, n=10), cafeteria diet (CAF, n=8), chow‐fed trained (T, n=9), and cafeteria diet plus trained (CAFT, n=8) groups. AET was performed simultaneously with diet and consisted of 8‐wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committee from School of Arts, Science and Humanities, University of Sao Paulo, Brazil (#001/2016). Both trained groups showed lower body weight at the end of protocol compared to C and CAF groups. However, only CAFT group had reduced body weight gain compared to the CAF group. Cafeteria diet induced glucose intolerance and insulin resistance in the CAF group, which was counteracted by AET in CAFT group. Indirect calorimetry measurement at rest revealed no difference in the variables oxygen uptake (VO2), carbon dioxide expiration (VCO2), respiratory exchange ratio (RER), energy expenditure (EE), carbohydrate and fat oxidation among groups. During maximal exercise tests, T and CAFT groups showed an increase in VO2máx (13% and 9.2%, p=0.07) and VO2peak (11.3% and 8.6%, p=0.07) compared to C and CAF, respectively. However no differences among groups were found for RER and rate of substrate oxidation. AET increased the time to exhaustion and maximal velocity in the T compared to C and CAF groups, and in the CAFT compared to CAF. The exercise intensity corresponding to the VO2máx (iVO2) was higher in the T group (2.30 ± 0.42 km⁄h) compared to C (1.86 ± 0.41 km/h) and CAF (1.73 ± 0.17 km/h) groups, and in the CAFT (2.23 ± 0.11 km/h) compared to CAF. Both trained groups showed late anaerobic threshold, improved the relative cost of running, and higher activity of citrate synthase and β‐HAD enzymes in the soleus muscle compared to C and CAF groups. In conclusion, these results revealed that the prevention of obesity and insulin resistance is associated with the improvement in aerobic capacity induced by AET.Support or Funding InformationFinancial Support: FAPESP # 2015/04948‐4; 2016/20659‐5.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The role of ACE2/Ang 1–7/Mas axis in the white adipose tissue for the prevention of obesity and insulin resistance through aerobic exercise training

The activation of angiotensin converting enzyme 2 (ACE2)/angiotensin 1–7 (Ang 1–7)/receptor Mas axis has been associated with cardiovascular and metabolic improvement, and may represent a new therapeutic target for cardiometabolic diseases. Aerobic exercise training (AET) has been widely used for the prevention and treatment of obesity and insulin resistance (IR). In the present study we evaluated if the prevention of obesity and IR through AET is associated with changes in the ACE2/Ang (1–7)/Mas axis in the white adipose tissue (WAT). Adult male C57BL6/J mice were assigned into chow‐fed controls (C, n=5), chow‐fed trained (T, n=5), cafeteria diet (CAF, n=5), and cafeteria diet plus trained (CAFT, n=5). AET was performed simultaneously with diet and consisted of 8‐wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committee from Faculty of Medicine of University of São Paulo (#002/15). The body weight of the T and CAFT groups were lower from the third week of experimental protocol compared to C. The CAF group had higher retroperitoneal and subcutaneous (SC) fat pads weights compared to C, but the AET was able to prevent these increases in the CAFT group. Periepididimal (PE) fat pad weight was lower in T group compared to other groups. Cafeteria diet induced glucose intolerance and IR in CAF group (AUC: 35200± 1076 mg/dL/120 min; kITT: 2.5 ± 0.17 %/min) compared to the C group (AUC: 28333±1305 mg/dL/120 min; kITT: 3.7 ± 0.21 %/min), which were counteracted by AET in CAFT group (AUC: 28896 ± 1133 mg/dL/120 min; kITT: 3.9 ± 0.33 %/min). In the PE‐WAT, the activity of ACE2 was higher in CAF and CAFT groups compared to C and T groups, but Ang 1–7 concentration and Mas protein expression were not different among groups. In the SC‐WAT, no differences were found in ACE2 activity and Mas protein expression, but the Ang 1–7 concentration was lower in CAF and CAFT compared to C and T groups. In conclusion, the prevention of obesity and IR by AET was independent of the ACE2/Ang 1–7/Mas axis activation in the visceral and subcutaneous WAT.Support or Funding InformationSupport: FAPESP #2015/04948‐4; #2016/23783‐9.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Aerobic exercise training prevents renal lipotoxicity associated with insulin resistance in mice

Insulin resistance is associated with lipid accumulation in the kidney which leads to lipotoxicity, inflammation and renal damage. We investigated the potential of aerobic exercise training (AET) to prevent renal lipotoxicity in mice with diet‐induced insulin resistance. Adult male C57BL6/J mice were assigned into chow‐fed controls (C, n=5), cafeteria diet (CAF, n=5), chow‐fed trained (T, n=5), and cafeteria diet plus trained (CAFT, n=5). The standard chow diet contained 4% of kilocalories from fat, 55% from carbohydrate and 22% from proteins (Nuvilab®, Paraná, Brazil). The cafeteria diet contained 18.7% of kilocalories from fat, 56% from carbohydrate and 14.8% from proteins. AET was performed simultaneously with diet and consisted of 8‐wk running session of 60 min at 60% of maximal speed, 5 days/wk. Experimental procedures were approved by Ethics Committee from Faculty of Medicine of University of São Paulo (#18/2014). Cafeteria diet induced insulin resistance in CAF group compared to C group during insulin tolerance test, which was counteracted by AET in CAFT group. Histological analysis showed that CAF group increased intra‐renal lipid deposition (4.12 ± 0.48 %/area) compared to C group (1.70 ± 0.55 %/area), and that AET was able to prevent this increase in CAFT group (2.11 ± 0.51 %/area). Immunohistochemistry measurement revealed no difference in the expression of TGF‐β, Collagen IV and fibronectin. In the western blot analysis, CAF (2.12 ± 0.7 % vs. C) and CAFT (2.74 ± 0.5 % vs. C) groups showed a tendency (p=0.07) to increase the expression of IL‐6 compared to C group (1 ± 0.07 % vs. C). Furthermore, there was an increase in TNF‐α expression in the CAF (1.72 ± 0.05 % vs. C) and CAFT (1.46 ± 0.02 % vs. C) compared to C group. In conclusion, our results showed that cafeteria diet was able to induce renal lipotoxicity associated with insulin resistance and AET was efficient to prevent this damage independent of inflammatory profile changes.Support or Funding InformationFinancial Support: FAPESP # 2015/04948‐4.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cocaine and Caffeine Effects on the Conditioned Place Preference Test: Concomitant Changes on Early Genes within the Mouse Prefrontal Cortex and Nucleus Accumbens.

Caffeine is the world's most popular psychostimulant and is frequently used as an active adulterant in many illicit drugs including cocaine. Previous studies have shown that caffeine can potentiate the stimulant effects of cocaine and cocaine-induced drug seeking behavior. However, little is known about the effects of this drug combination on reward-related learning, a key process in the maintenance of addiction and vulnerability to relapse. The goal of the present study was thus to determine caffeine and cocaine combined effects on the Conditioned Place Preference (CPP) test and to determine potential differential mRNA expression in the Nucleus Accumbens (NAc) and medial prefrontal cortex (mPFC) of immediate-early genes (IEGs) as well as dopamine and adenosine receptor subunits. Mice were treated with caffeine (5 mg/kg, CAF), cocaine (10 mg/kg, COC), or their combination (caffeine 5 mg/kg + cocaine 10 mg/kg, CAF-COC) and trained in the CPP test or treated with repeated injections inside the home cage. NAc and mPFC tissues were dissected immediately after the CPP test, after a single conditioning session or following psychostimulant injection in the home cage for mRNA expression analysis. CAF-COC induced a marked change of preference to the drug conditioned side of the CPP and a significant increase in locomotion compared to COC. Gene expression analysis after CPP test revealed specific up-regulation in the CAF-COC group of Drd1a, cFos, and FosB in the NAc, and cFos, Egr1, and Npas4 in the mPFC. Importantly, none of these changes were observed when animals received same treatments in their home cage. With a single conditioning session, we found similar effects in both CAF and CAF-COC groups: increased Drd1a and decreased cFos in the NAc, and increased expression of Drd1a and Drd2, in the mPFC. Interestingly, we found that cFos and Npas4 gene expression were increased only in the mPFC of the CAF-COC. Our study provides evidence that caffeine acting as an adulterant could potentiate reward-associated memories elicited by cocaine. This is associated with specific changes in IEGs expression that were observed almost exclusively in mice that received the combination of both psychostimulants in the context of CPP memory encoding and retrieval. Our results highlight the potential relevance of caffeine in the maintenance of cocaine addiction which might be mediated by modifying neural plasticity mechanisms that strengthen learning of the association between drug and environment.

Effects Of Different Types Of Chemotherapy On Cardiopulmonary Fitness In Patients With Breast Cancer

Two most popular adjuvant chemotherapeutic regimens, including cyclophosphamide, doxorubicin, and fluorouracil (CAF) and doxorubicin plus cyclophosphamide followed by taxanes (AC→T), are currently used for treating the early stages breast cancer. However, it has not been clear whether the cardiopulmonary fitness and cardiovascular responses would be perturbed by the administrations of these chemotherapeutic regimens. PURPOSE: To investigate the effects of the administrations of CAF and AC→T on cardiopulmonary fitness and cardiovascular responses in patients with early stage breast cancer. METHODS: Twenty-seven patients with early stages of breast cancer (age: 45.0±1.5 yrs; Stage I-II) voluntarily participated in this study, and they were assigned to either CAF (n=12) or AC→T (n=15) group depending on oncological specialists’ clinical decisions. Their cardiopulmonary fitness (measured by resting heart rate and six-minute walking test) and cardiovascular response (measured by pulse wave velocity - PWV) were accessed at before and after receiving adjuvant chemotherapy. RESULTS: There were no differences in all measurements between CAF and AC→T groups at baseline. In the completion of adjuvant chemotherapy, the participants in AC→T group showed significantly higher resting heart rate by ~14.9% than CAF group. Although the walking speed, distance, and metabolic equivalent of task (MET) during six-minute walking test were not different between groups, the AC→T group exhibited a remarkably higher relative stress in response to exercise test (measured by the % of maximal heart rate – %MHR; AC→T: 68.8%MHR vs. CAF: 59.4%MHR, p<.05) in compared with those with CAF treatment. There was no difference in PWV between CAF and AC→T groups at the end of chemotherapy. CONCLUSION: We demonstrated that doxorubicin plus cyclophosphamide followed by taxanes (AC→T) increased resting heart rate and relative stress to the 6-minute walking test at the end of chemotherapy. However, the PWV was not different between two adjuvant chemotherapeutic groups. Our data suggest that, in compared to CAF, AC→T might cause greater adverse effects on cardiopulmonary fitness but not cardiovascular functions in patients with early stage breast cancer.