Benzothiazole-Phthalimide Hybrids as Anti-Breast Cancer and Antimicrobial Agents.

The benzothiazole nucleus is a major heterocyclic scaffold whose therapeutic potential has been thoroughly explored due to its structural simplicity and ease of synthesis. In fact, several benzothiazole derivatives have been synthesized over time, demonstrating numerous pharmacological properties such as anticancer, antimicrobial, anti-inflammatory, and antioxidant activities. Herein, we propose a new series of benzothiazole-phthalimide hybrids obtained by linking the phthalimide moiety to differently substituted benzothiazole nuclei through the N atom. These compounds have been screened for their anticancer properties against two human breast cancer cell lines. Furthermore, we delved into the mechanism of action of the most active hybrid, compound 3h, by assessing its capability to damage the nuclear DNA, trigger the apoptotic process in the high metastatic MDA-MB-231 cells, and prevent cellular migration. Moreover, in view of the documented antimicrobial activities of the two scaffolds involved, we explored the antibacterial and antifungal effects of the studied compounds by means of the broth microdilution method. Among the studied compounds, 3h showed the highest antimicrobial activity, both against gram-positive and gram-negative bacterial strains belonging to the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and against fungal strains of the Candida species with MICs values ranging from 16 to 32 µg/mL.

Overview of the Polyphenols in Salicornia: From Recovery to Health-Promoting Effect.

Nowadays, there has been considerable attention paid toward the recovery of waste plant matrices as possible sources of functional compounds with healthy properties. In this regard, we focus our attention on Salicornia, a halophyte plant that grows abundantly on the coasts of the Mediterranean area. Salicornia is used not only as a seasoned vegetable but also in traditional medicine for its beneficial effects in protecting against diseases such as obesity, diabetes, and cancer. In numerous research studies, Salicornia consumption has been highly suggested due to its high level of bioactive molecules, among which, polyphenols are prevalent. The antioxidant and antiradical activity of polyphenols makes Salicornia a functional food candidate with potential beneficial activities for human health. Therefore, this review provides specific and compiled information for optimizing and developing new extraction processes for the recovery of bioactive compounds from Salicornia; focusing particular attention on polyphenols and their health benefits.

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex multi-factorial neurodegenerative disorder for which only few drugs (including donepezil, DPZ) are available as symptomatic treatments; thus, researchers are focusing on the development of innovative multi-target directed ligands (MTDLs), which could also alter the course of the disease. Among other pathological factors, oxidative stress has emerged as an important factor in AD that could affect several pathways involved in the onset and progression of the pathology. Herein, we propose a new series of hybrid molecules obtained by linking a phenothiazine moiety, known for its antioxidant properties, with N-benzylpiperidine or N-benzylpiperazine fragments, mimicking the core substructure of DPZ. The investigation of the resulting hybrids showed, in addition to their antioxidant properties, their activity against some AD-related targets, such as the inhibition of cholinesterases (both AChE and BChE) and in vitro Aß1-40 aggregation, as well as the inhibition of the innovative target fatty acid amide hydrolase (FAAH). Furthermore, the drug-likeness properties of these compounds were assessed using cheminformatic tools. Compounds 11d and 12d showed the most interesting multi-target profiles, with all the assayed activities in the low micromolar range. In silico docking calculations supported the obtained results. Compound 13, on the other hand, while inactive in the DPPH assay, showed the best results in the in vitro antioxidant cell assays conducted on both HepG2 and SHSY-5Y cell lines. These results, paired with the low or absent cytotoxicity of these compounds at tested concentrations, allow us to aim our future research at the study of novel and effective drugs and pro-drugs with similar structural characteristics.

Supplementation of Acqua Lete® (Bicarbonate Calcic Mineral Water) improves hydration status in athletes after short term anaerobic exercise.

BACKGROUND: Experimental studies suggest that mineral waters with high concentrations of calcium and bicarbonate can impact acid-base balance. The purpose of this study was to test the effect on acid-base balance and specific urine gravity, of a bicarbonate calcic mineral water (Acqua Lete®) compared to a minimally mineralized water. METHODS: 88 amateur male athletes underwent two experimental trials with a modified Wingate test: the first was carried out without hydration (Control Test, Test C, n = 88); the second was carried out after one week of controlled hydration (Test with hydration, Test H, n = 88), with 1.5 L/day of a very low mineral content water (Group A, n = 44) or 1.5 L/day of Acqua Lete® (Group B, n = 44). Measure of body temperature, bioimpedance analysis, muscular ultrasound, and urinalysis were taken before (t0), immediately after (t1), 5' (t2), and 30' (t3) after exercise. RESULTS: Hydration results in a decreased core temperature; muscular ultrasound showed increased muscle thickness after exercise related to content of body water. Regarding urinalysis, in test H, we found in both groups after exercise a significant decrease of specific urine gravity with significantly lower levels in Group B. We also found a significant increase of pH in the same Group B. CONCLUSIONS: In conclusion all the athletes hydrated with Acqua Lete® showed a positive impact on hydration status after anaerobic exercise with significant decrease of specific urine gravity and a positive effect on pH.

T2-T3 sympathectomy versus sympathicotomy for essential palmar hyperhidrosis: comparison of effects on cardio-respiratory function.

OBJECTIVES: The aim of this study was to determine cardio-respiratory changes after endothoracic sympathetic denervation and their correlation with the extent of denervation. METHODS: A total of 45 patients with essential palmar hyperhidrosis were randomized into two groups: the conventional group (CG; 23 patients) and the simplified group (SG; 22 patients). In the CG, excision of T2 and T3 ganglia was performed, whereas in the SG only separation of the sympathetic chain was performed at the same level. Patients underwent respiratory and cardiovascular exercise tests before, at 2 weeks and again at 6 months after the procedure. The postoperative values were then compared with the preoperative values to assess the statistical difference. RESULTS: Twenty-one patients in each group completed the study. In the SG, forced expiratory volume in 1 s (FEV 1; P < 0.01) and forced vital capacity (FVC; P < 0.01) were significantly reduced at 2 weeks, but returned to similar baseline values 6 months after the procedure. No significant cardiac changes were observed. In the CG, both FEV 1 and FVC were significantly reduced at 2 weeks (P < 0.01) and at 6 months after operation (P < 0.05). A significant reduction in forced expiratory flow between 25 and 75% of vital capacity (P < 0.01) and a relevant increase in airway resistance (P < 0.05) during the entire postoperative course were also observed. Heart rates at rest and at peak exercise were significantly reduced at 2 weeks (P < 0.01) and significantly decreased 6 months after the procedure (P < 0.05). No other changes were registered. The cardio-respiratory alterations remained at a sub-clinical level; all patients completed the exercise test without symptoms. CONCLUSION: Sympathectomy may result in a disturbance of bronchomotor tone and cardiac function. Such changes remained at a sub-clinical level and seemed directly correlated with the extension of denervation.

Oxidative stress effects on endothelial cells treated with different athletes' sera.

PURPOSE: Exercise training is a nonpharmacological intervention that improves cardiovascular function and enhances endothelial homeostasis in patients with cardiovascular diseases. However, the amount of benefit achieved varies widely depending on the type and duration of exercise. Moreover, data about the long-term effects of physical activity are scarce. METHODS: In this study, endothelial cells, exposed or not to oxidative stress, were conditioned with sera from athletes regularly participating in sports classified as "aerobic" (triathlon), "mixed aerobic-anaerobic" (soccer), and "anaerobic" (sprint running). RESULTS: Functional and hemodynamic variables did not differ between groups of athletes, whereas there were dramatic changes in serum markers for oxidative stress. Lipid peroxidation assessed by the thiobarbituric acid reactive substances assay and catalase activity were the lowest and nitric oxide availability was the highest in sera of triathletes. Endothelial cells cultured in serum from triathletes (T-endothelial cells) had the highest survival, evaluated by viability assay, BrdU incorporation, and senescence-associated ß galactosidase assays, and preserved the endothelial appearance before and after stress in contrast to the cells grown in sera from the other athletes. T-endothelial cells also had the highest catalase messenger RNA expression and, after stress, the highest catalase activity of all the endothelial cells. Moreover, poststress activity of Sirt1, a NAD(+)-dependent deacetylase involved in cellular stress resistance and a key regulator of longevity, was significantly increased in T-endothelial cells. CONCLUSIONS: Different types of exercise training induced different molecular effects in terms of survival, morphology, and antioxidant system efficiency. The in vitro technique used herein may help to shed light on the molecular basis of effects of long-term physical activity in humans.

Persistent HyperCKemia in Athletes.

UNLABELLED: We compared the effects of exercise on serum levels of creatin kinase (CK) in athletes with persistent hyperCKemia at rest (CK group) and in healthy athletes (control group). Prospective controlled study. Eighteen male Caucasian athletes with high serum CK levels at rest (CK between 80 and 150 U/L) and 25 male Caucasian athletes with normal serum CK levels at rest (CK between 10 and 80 U/L). MAIN OUTCOME MEASURES: Blood samples were collected at rest, 30 minutes, 6 hours, 24 hours, 48 hours and 72 hours after a progressive cycloergometer test to exhaustion. The levels of serum CK and its isoenzymes were measured. In the control group, serum CK values at rest were normal (48.18 ± 14.14 U/L). After exercise, they increased slightly, though they always remained <80 U/L, decreasing to the rest level after 48 hours. The CK group had serum CK levels at rest higher than normal (116.56 ± 33.30 U/L). Serum CK levels were still outwith the normal range after 48 hours (130.11 ± 46.95 U/L) and 72 hours (116.55 ± 24.84 U/L). Serum CK levels were significantly different in both groups both before and after progressive cycloergometer test to exhaustion. In athletes with high serum CK levels at rest, serum CK levels remained elevated and had a different kinetics after exercise when compared with healthy athletes.

Cardiotrophin-1 and TNF-alpha circulating levels at rest and during cardiopulmonary exercise test in athletes and healthy individuals.

BACKGROUND: There is a growing body of evidence that physical training exerts its potential benefits on the individual health status by modulating the immune system and the whole body metabolism. A better knowledge of the physiologic immune response to exercise may help to understand the benefits of physical exercise in healthy individuals and elite athletes. AIMS: This study aims to analyse cardiotrophin-1 (CT-1) and Tumor Necrosis Factor-alpha (TNF-alpha) plasma levels at rest and during exercise in elite athletes and healthy controls. METHODS: We studied 20 triathletes (TA) and 20 matched controls (CG). Chambers dimensions, left ventricular mass and left ventricular mass index were analysed by echocardiography. VO2 peak and VE/VCO2 were calculated by metabolic stress test. Blood samples were collected before the exercise session, at the exercise peak, and after the end of exercise. ELISA assays were used to measure CT-1 and TNF-alpha plasma levels. RESULTS: Among TA and CG, no significant differences were found for CT-1 (0.25+/-0.14 vs 0.20+/-0.14 fm/l; p=0.29) and TNF-alpha (10.8+/-2.7 vs 9.7+/-4.0 pm/l; p=0.29) basal levels. In the TA, plasma levels of CT-1 were significantly different at rest and during exercise (basal 0.25+/-0.13 pm/l; peak 1.07+/-1.5 pm/l; post-exercise 0.67+/-0.77 pm/l; p=0.04). Conversely, no significant differences were found between basal, peak and post-exercise plasma values of TNF-alpha (basal 10.8+/-2.7 pm/l; peak 11.7+/-2.1 pm/l; post-exercise 11.4+/-2.5 pm/l; p=0.78) in TA. CONCLUSIONS: This study gives novel insights on the behavior of inflammatory cytokines during physical exercise in athletes and healthy individuals.

Serum enzyme monitoring in sports medicine.

Total creatin kinase (CK) and lactate dehydrogenase (LDH) serum levels depend on age, gender, race, muscle mass, physical activity, and climatic conditions. High CK serum levels in athletes following rest and without any further predisposing factors should prompt a full diagnostic workup, with special regards to signs of muscle weakness or other signs not always evident. In subjects who have silent myopathy, repeated intense prolonged exercise may produce negative effects, because given the continuous loss of muscle proteins, it does not induce the physiological muscle adaptations to physical training. Serum total LDH and specific isozyme activities change with the training status of the athlete. Variation in LDH isozymes profile might have a role in studying muscle response to training.

Changes in skeletal muscle architecture following a cycloergometer test to exhaustion in athletes.

We determined whether a short-term exhaustive dynamic exercise (cycling) for about 18min induces changes in the intramuscular architecture of the quadriceps in trained athletes. Thirty-five male athletes (age 28.8+/-9.8 years; height: 175.4.+/-5.5cm; weight: 74+/-11.5kg; average years spent training: 11.1+/-8.4 years; mean weekly duration of training: 10.4+/-3.20h) underwent an incremental cycloergometer test to exhaustion. Muscle thickness of the right quadriceps femoris (rectus femoris + vastus intermedius), and the angle of pennation of the right vastus lateralis on the quadriceps tendon were determined by high-resolution real time ultrasonography. Quadriceps thickness increased from 32.1+/-3.3mm at rest to 34.9+/-3.0mm after the test (p=0.001). The pennation angles were significantly greater after exercise (12.8+/-2.1 degrees at rest; 14.4+/-2.5 degrees after the test (p=0.001)). There are marked changes in intramuscular architecture of the quadriceps following a bout of cycloergometer exercise to exhaustion, with significant increase of quadriceps thickness and pennation angle. Ultrasonography allows to evaluate the changes of muscle architecture following exercise.

Creatine kinase monitoring in sport medicine.

AREAS OF GENERAL AGREEMENT: Total creatine kinase (CK) levels depend on age, gender, race, muscle mass, physical activity and climatic condition. High levels of serum CK in apparently healthy subjects may be correlated with physical training status, as they depend on sarcomeric damage: strenuous exercise that damages skeletal muscle cells results in increased total serum CK. The highest post-exercise serum enzyme activities are found after prolonged exercise such as ultradistance marathon running or weight-bearing exercises and downhill running, which include eccentric muscular contractions. Total serum CK activity is markedly elevated for 24 h after the exercise bout and, when patients rest, it gradually returns to basal levels. Persistently increased serum CK levels are occasionally encountered in healthy individuals and are also markedly increased in the pre-clinical stages of muscle diseases. AREAS THAT ARE CONTROVERSIAL: Some authors, studying subjects with high levels of CK at rest, observed that, years later, subjects developed muscle weakness and suggested that early myopathy may be asymptomatic. Others demonstrated that, in most of these patients, hyperCKemia probably does not imply disease. In many instances, the diagnosis is not formulated following routine examination with the patients at rest, as symptoms become manifest only after exercise. Some authors think that strength training seems to be safe for patients with myopathy, even though the evidence for routine exercise prescription is still insufficient. Others believe that, in these conditions, intense prolonged exercise may produce negative effects, as it does not induce the physiological muscle adaptations to physical training given the continuous loss of muscle proteins. GROWING POINTS: High CK serum levels in athletes following absolute rest and without any further predisposing factors should prompt a full diagnostic workup with special regards to signs of muscle weakness or other simple signs that, in both athletes and sedentary subjects, are not always promptly evident. These signs may indicate subclinical muscle disease, which training loads may evidence through the onset of profound fatigue. It is probably safe to counsel athletes with suspected myopathy to continue to undertake physical activity at a lower intensity, so as to prevent muscle damage from high intensity exercise and allow ample recovery to favour adequate recovery. AREAS TIMELY FOR DEVELOPING RESEARCH: CK values show great variability among individuals. Some athletes are low responders to physical training, with chronically low CK serum levels. Some athletes are high responders, with higher values of enzyme: the relationship among level of training, muscle size, fibre type and CK release after exercise should be investigated further. In addition, more details about hyperCKemia could come from the evaluation of the kinetics of CK after stress in healthy athletes with high levels of CK due to exercise, comparing the results with the ones obtained from athletes with persistent hyperCKemia at rest. Finally, it would be important to quantify the type of exercise more suited to athletes with myopathy and the intensity of exercise not dangerous for the progression of the pathology.

Left ventricular hypertrophy in Caucasian master athletes: Differences with hypertension and hypertrophic cardiomyopathy.

AIM: To study, by conventional echocardiography, left ventricular remodelling and function in master athletes, hypertension and hypertrophic cardiomyopathy. METHODS: We studied 30 master athletes (MA; soccer players; mean age 43.9+/-5.9), 24 subjects with essential hypertension (HYP; 46.6+/-6), 20 patients with hypertrophic cardiomyopathy (HCM; 42.2+/-9) and 30 normal individuals (CG; 43.4+/-5). An integrated M-mode/two-dimensional echocardiographic analysis was performed to determine chambers dimensions, relative wall thickness (RWT) and left ventricular mass (LVM), indexed to height in meters raised to the power of 2.7 (LVM/h(2.7)). Cut-off levels for LVM/h(2.7) and RWT were defined to assess 4 different patterns of LV geometric remodelling. In addition, we measured indexes of global systolic performance and indexes of global diastolic function. RESULTS: LV wall thickness and LV end-diastolic dimensions were higher in MA than controls, but significantly lower than other groups. LVH/h(2.7) was increased in 79% of HYP and in 95% of HCM, but was within the normal limits in MA. LV geometry was normal in 22 out of 30 MA (73%), while the remaining (8 athletes, 27%) showed a concentric remodelling. Systolic function (FS and EF) was normal in MA, but was slightly reduced in HYP and increased in HCM. Analysis of diastolic function showed an abnormal relaxation pattern in all HYP and 95% of HCM, but was normal in all MA. The ratio between peak filling rate and stroke volume (PFR/SV), a relatively independent index of diastolic function, was significantly greater in hypertensive patients with normal LV remodelling compared to those without it (4+/-0.39 vs. 4.91+/-0.19; P = 0.0002). CONCLUSION: MA showed lower values of wall thickness, LV dimensions and LV mass compared with HYP and HCM. Despite an abnormal remodelling, all the athletes showed a normal systolic and diastolic function. The differential diagnosis between MA, HYP and HCM is feasible by accurate, comprehensive standard Doppler echocardiography.

Vigorous exercise acutely changes platelet and B-lymphocyte CD39 expression.

CD39/ATP diphosphohydrolase is expressed on B lymphocytes, cytotoxic T lymphocytes, monocytes, platelets, and endothelial cells, and it has a critical role in the inhibition of platelet responsiveness. To determine whether strenuous exercise could acutely change expression of CD39 in platelets and lymphocytes, eight healthy sedentary men, 34 yr old (SD 7), and eight physically active men, 34 yr old (SD 6), performed graded upright cycle ergometry to volitional exhaustion. Blood samples collected both at baseline and after exercise test were employed to measure CD39 expression in platelets and lymphocytes. The percentage of circulating platelet-platelet aggregates, the "in vitro" ADP and collagen-induced platelet aggregation, and the expression of both platelet glycoprotein IIb-IIIa (PAC-1) and P-selectin (CD62) were also considered markers of platelet activation. After strenuous exercise, all subjects demonstrated significant platelet activation as judged by the increased percentage of platelet-platelet aggregates. The in vitro ADP-induced platelet aggregation and the expression of CD62P on ADP-stimulated platelets significantly increased in sedentary but not in active subjects. After exercise, all of the subjects showed a significant reduction of CD39 expression in platelet [sedentary: from 2.2 (SD 0.8) to 1.1% (SD 0.8), P = 0.008; active: from 0.6 (SD 0.2) to 0.35% (SD 0.1), P = 0.009] and an increase of CD39 expression in B lymphocytes [sedentary: from 47 (SD 13) to 60% (SD 11), P = 0.0039; active: from 46 (SD 11) to 59% (SD 11), P = 0.0038]. Taken together, these findings confirm the critical role of this ADPase in inhibition of platelet responsiveness, also suggesting a possible role of B lymphocytes in thromboregulation mechanism.

Association between left ventricular structure and cardiac performance during effort in two morphological forms of athlete's heart.

AIM: The aim of the study was to evaluate in 263 competitive athletes possible correlations between changes induced by different sport activities in left ventricular (LV) structure and cardiac response during maximal physical effort. METHODS: A total of 160 top-level endurance athletes (ATE; swimmers, runners; 28+/-4 years; 98 male) and 103 strength-trained athletes (ATS; weight-lifters, body-builders; 27+/-5 years; male), selected on the basis of training protocol (dynamic vs. static exercise), underwent standard Doppler echocardiography, heart rate variability analysis and maximal exercise stress test by bicycle ergometry. M- and B-mode echocardiographic LV measurements were determined at rest, while the following functional indexes were assessed during effort: maximal heart rate (HR), maximal systolic blood pressure (SBP) and maximal workload (Watts reached by bicycle test). RESULTS: The two groups were comparable for age and sex, but ATS at rest showed higher HR, SBP, and body surface area (BSA). By echo analysis, LV mass index and ejection fraction did not significantly differ between the two groups. However, ATS showed increased sum of wall thickness (septum+posterior wall), relative wall thickness and LV end-systolic stress, while LV stroke volume and LV end-diastolic diameter (P<0.01) were greater in ATE. HR variability analysis underlined in ATE increased indexes of vagal tone (P<0.01). During maximal physical effort, ATE showed a better functional capacity, with greater maximal workload (P<0.001) reached with lower maximal HR and SBP. After adjusting for HR, age, sex, BSA and SBP, distinct multiple linear regression models evidenced in ATE independent associations of maximal effort workload with LV end-diastolic diameter (P<0.001), HR (P<0.001) at rest and LV end-systolic stress (P<0.01) were found in ATE. On the other hand, independent direct correlation of SBP max during effort with sum of wall thickness (P<0.001), BSA (P<0.05) and LV end-systolic stress (P<0.001) was evidenced in ATS. CONCLUSIONS: LV structural changes in competitive athletes represent adaptation to hemodynamic overload induced by training and are consistent with different kinds of sport activity. Work capacity during exercise is positively influenced by preload increase in ATE, while increased afterload due to isometric training in ATS determines higher systemic resistance during physical effort.