Myokines as mediators of exercise-induced cognitive changes in older adults: protocol for a comprehensive living systematic review and meta-analysis.

Background: The world's population is aging, but life expectancy has risen more than healthy life expectancy (HALE). With respect to brain and cognition, the prevalence of neurodegenerative disorders increases with age, affecting health and quality of life, and imposing significant healthcare costs. Although the effects of physical exercise on cognition in advanced age have been widely explored, in-depth fundamental knowledge of the underlying mechanisms of the exercise-induced cognitive improvements is lacking. Recent research suggests that myokines, factors released into the blood circulation by contracting skeletal muscle, may play a role in mediating the beneficial effect of exercise on cognition. Our goal in this ongoing (living) review is to continuously map the rapidly accumulating knowledge on pathways between acute or chronic exercise-induced myokines and cognitive domains enhanced by exercise. Method: Randomized controlled studies will be systematically collected at baseline and every 6 months for at least 5 years. Literature search will be performed online in PubMed, EMBASE, PsycINFO, Web of Science, SportDiscus, LILACS, IBECS, CINAHL, SCOPUS, ICTRP, and ClinicalTrials.gov. Risk of bias will be assessed using the Revised Cochrane Risk of Bias tool (ROB 2). A random effects meta-analysis with mediation analysis using meta-analytic structural equation modeling (MASEM) will be performed. The primary research question is to what extent exercise-induced myokines serve as mediators of cognitive function. Secondarily, the pooled effect size of specific exercise characteristics (e.g., mode of exercise) or specific older adults' populations (e.g., cognitively impaired) on the relationship between exercise, myokines, and cognition will be assessed. The review protocol was registered in PROSPERO (CRD42023416996). Discussion: Understanding the triad relationship between exercise, myokines and cognition will expand the knowledge on multiple integrated network systems communicating between skeletal muscles and other organs such as the brain, thus mediating the beneficial effects of exercise on health and performance. It may also have practical implications, e.g., if a certain myokine is found to be a mediator between exercise and cognition, the optimal exercise characteristics for inducing this myokine can be prescribed. The living review is expected to improve our state of knowledge and refine exercise regimes for enhancing cognitive functioning in diverse older adults' populations. Registration: Systematic review and meta-analysis protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on the 24th of April 2023 (registration number CRD42023416996).

Maternal separation increased memory function and anxiety without effects of environmental enrichment in male rats.

Maternal separation is a detrimental postnatal influence, whereas environmental enrichment is a therapeutic and protective agent. It is unclear if long-term environmental enrichment can compensate for the effects of maternal separation stress on memory-related alterations. This study examined how environmental enrichment affected memory functions, anxiety level, Grin2a, Grin2b, BDNF, and cFos expressions in the maternally separated rats. There are seven groups in this study: control (C), maternal separation+standard cage (MS), maternal separation + enriched cage (MSE), enriched cage (E), the maternal separation that decapitated at postnatal 21 (MS21) and standard cage that decapitated at PN21 (C21) for hormone and gene expression analysis. The maternal separation procedure consisted of postnatal 21 days. Learning and memory performance were determined with the Morris water tank test; anxiety and locomotor activity were examined with the open field and elevated plus-maze test. The expression levels of genes were measured by the RT-PCR method. Blood corticosterone level was evaluated by the ELISA method. Results showed that MS increased memory performance, locomotor activity, and anxiety, but it did not change gene expression levels. An enriched environment did not change the memory performance, locomotor activity, and related gene expression levels. MSE group increased their memory performance, but the anxiety, locomotor activity, and gene expression level did not change. Grin2a, Grin2b, and BDNF gene expression and corticosterone levels increased in the MS21 group. Maternal separation increased memory performance, but it also increased anxiety. Environmental enrichment alone was insufficient to cause alterations in the memory performance.

Chronic caffeine consumption improves the acute sleep deprivation-induced spatial memory impairment while altering N-methyl-D-aspartate receptor subunit expression in male rats.

Caffeine is a psychostimulant substance that is mostly used to prevent fatigue, increase alertness, and ameliorate sleep loss situations. In this study, we aimed to investigate the effect of chronic caffeine consumption on learning and memory functions and related genes in rapid eye movement (REM) sleep-deprived rats. During the neonatal period (postnatal day [PND] 28) Wistar albino male rats (n = 32) were randomly assigned into four groups: Control (C), caffeine application (Cf), acute REM sleep-deprivation (RD), and caffeine application + acute RD (Cf + RD). The 48 h of RD was executed when caffeine administration was completed. The learning and memory performance was evaluated by the Morris water maze test (MWMT). Following this, the rats were decapitated to isolate hippocampus tissues. In MWMT, time spent in the targeted quadrant decreased significantly in the RD group compared with the C and Cf + RD group. NR2A expression level increased in the RD group compared with C, Cf, and Cf + RD groups (p < 0.05). NR2B expression level increased in RD and Cf + RD groups compared with C and Cf groups (p < 0.05). BDNF and c-Fos expression levels did not differ significantly between the groups. RD impaired hippocampal spatial memory performance in the MWMT test. Our results indicated that chronic caffeine consumption has a therapeutic effect on spatial memory deterioration impairment caused by RD. Furthermore, it seems that the effect of caffeine RD on the hippocampus may be mediated by NR2A.

Environmental enrichment as a strategy: Attenuates the anxiety and memory impairment in social isolation stress.

BACKGROUND: Social isolation (SI) early in life produces behavioral and cognitive abnormalities. On the contrary, environmental enrichment (EE) offers beneficial effects on brain plasticity and development. This study was designed to examine how EE affects memory functions, anxiety level, and the expression levels of memory/anxiety-related genes such as NR2A, NR2B, BDNF, and cFos in the hippocampus of socially isolated rats. MATERIALS AND METHODS: Wistar albino male rats (n = 40) were separated into the five groups: Standard cage (SC), SI, EE, SI + SC, and SI + EE group. For each group, eight rats were housed, either grouped or isolated, in a standard or 3-week EE, respectively. Morris water maze test (MWMT) was used for measuring the learning and memory function. Elevated plus maze (EPM) and open field (OF) were used for the evaluation of anxiety behavior. Blood corticosterone level was evaluated by the ELISA method. The expression levels of genes were measured by the RT-PCR method. RESULTS: Results showed that EE increased memory performance in the SI group (p < 0.05). SI caused anxiety while EE improved anxiety behavior (p < 0.05). There was no significant difference between the groups in the OF test. Corticosterone levels did not change between groups. BDNF expression level was downregulated in EE and SI + SC compared with the SC group (respectively; p = 0.012; p = 0.011). NR2A, NR2B, and cFos expression levels did not change between groups significantly. CONCLUSIONS: SI impaired memory performance while EE has beneficial effects on memory in socially isolated rats. EE alone was insufficient to cause alterations in the memory performance. The therapeutic effects of EE became strengthened while applied together with stress protocol. Together with improving the effectiveness of memory function, EE has the potential to decrease anxiety behavior. EE seemed to be the reason for decreasing in BDNF.

Living with female rats exposed to restraint stress during pregnancy caused depressive-like behavior in male rats and stress-induced apoptosis.

OBJECTIVE: Maternal mood disorders such as postpartum depression (PPD) can negatively affect the lives not only of mothers but also of partners. The purpose of this study investigates emotional behavior and hippocampal apoptosis alterations of the male live with a postpartum depressed female. METHODS: Pregnant rats in the stress group were exposed to restraint stress (RS). The male rats who shared the same cages were not exposed to RS. To explain the consequences of depressive-like behavior and anxiety, animals were exposed to the forced swim test (FST), open-field test (OFT), and elevated plus maze (EPM). The apoptotic cell number was detected by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP biotin nick-end labeling (TUNEL) staining. RESULTS: According to FST, PPD caused more immobility, reduced swimming, and climbing compared to control groups in the stressed female and male (p < 0.05). For the crossing number of squares in the center area, the main effect of the group was significant (p < 0.05). Stressed groups have a higher crossing number of squares in the center area compared to control groups. In the OFT, there was a significant increase in the time spent in the center area in the stress female and male group compared to the control female and male group (p < 0.05). For the EPM, time spent in the close arms was increased in the control male and stress male compared to the stress female group (p < 0.05). Female and male rats with PPD demonstrated apoptosis in neuron and glial cells in the hippocampus. CONCLUSIONS: The present study demonstrates that RS results in PPD in females. Furthermore, it implicates RS as a potential risk factor for the development of postpartum mood disorder in males. Most of the studies on paternal PPD have been done by using self-report questionnaires. Studies on physiological and hormonal changes during the postpartum period among fathers would provide information on biological factors of depression.

Mild regular treadmill exercise ameliorated the detrimental effects of acute sleep deprivation on spatial memory.

Vulnerable areas like the hippocampus are sensitive to insults such as sleep deprivation (SD); they are also susceptible to environmental enrichment. Much evidence is accumulating that chronic sleep deprivation causes alterations in the hippocampus that responsible for spatial memory. However, there is conflicting about the differences between acute and chronic SD results. The purpose of this study was to determine the protective effects of mild treadmill exercise on acute SD rats. Four groups were created as control, exercise, sleep deprivation, exercise + sleep deprivation. Multiple platforms method was used to induce REM sleep deprivation (RD) for 48 h. The exercise was applied fivedaysperweekforfour weeks(5 × 4). For the first and second weeks, the length of the exercise was 15 min in two sessions (5 min interval) followed by 15 min in three, 15 min in four sessions. Morris water maze (MWM) was used as a spatial memory test. Gene level was determined by using the qPCR technique. Malondialdehyde (MDA) content in the hippocampus was measured as an extent of peroxidative damage to lipids by using the ELISA method. 48 h RD impaired long-term spatial memory significantly. Mild, regular treadmill exercise ameliorated the detrimental effects of acute sleep deprivation on memory. There was no significant difference in MDA between groups. Hippocampal gene expression did not show any changes in all groups. Lack of correlation between memory impairment and levels of genes in the hippocampus is likely to be related to the differences in behavioral and genetic mechanisms.

Perifosine and vitamin D combination induces apoptotic and non-apoptotic cell death in endometrial cancer cells.

Endometrial cancer is the most common cancer of the female reproductive system. Combination treatment with specific agents has been widely used as a targeted therapy for cancer. In this study, we aimed to investigate the anti-proliferative and apoptotic effects of varying concentrations of perifosine and vitamin D on the human endometrial cancer cell line (HEC-1A). HEC-1A cells were exposed to perifosine (10 µM, 30 µM), vitamin D (50 nM, 200 nM) and combinations of both for 48 h and 72 h. Monitoring of cell proliferation in a time-dependent manner was performed with the xCELLigence RTCA DP system. The levels of BCL2, BAX and P53 mRNA expression were examined using RT-qPCR. Apoptosis was determined using Annexin V, which were followed by flow cytometry analysis. Ultra-structural morphology of cells was analyzed by transmission electron microscopy (TEM) for 72 h. The anti-proliferative and apoptotic effects of the perifosine+vitamin D combination (30 µM + 200 nM at 48 h and 10 µM + 200 nM at 72 h) on HEC-1A cells were higher than in perifosine and vitamin D alone. It was observed that perifosine has increased the expression of BAX mRNA in HEC-1A cells in a dose-dependent manner. While perifosine+vitamin D combinations increased P53 mRNA expression in HEC-1A cells we did not find any significant change in BCL2, BAX mRNA expression levels. In TEM examinations of HEC-1A cells, perifosine appeared to lead autophagic cell death, whereas vitamin D caused paraptosis-like cell death and combination of perifosine+vitamin D caused apoptotic and non-apoptotic (paraptotic, autophagic and necrotic) cell death. Therefore, it is considered that the combination of both drugs in the treatment of endometrial cancer might be an alternative and effective treatment option through activating the apoptotic and non-apoptotic cell death mechanisms in cancer cells.

Caffeine as a potential arousal enhancer: altered NMDA subunit gene expression without improving cognitive performance in REM sleep deprived rats.

Caffeine is one of the most extensively consumed stimulants in the world and has been suggested to induce wakefulness by antagonizing the function of the adenosine A2A receptor. Therefore, we investigated the effects of chronic caffeine consumption on learning and memory in the REM sleep-deprived rats.Male Wistar rats (n = 50), were randomly assigned into 5 groups: Control (C), Caffeine (Cf), Pedestal Control (PC), Sleep Deprivation (SD), Sleep Deprivation and Caffeine (SD + Cf). Sleep deprivation procedure was applied as the flower-pot technique. SD and SD + Cf groups were deprived for 18 hours in a day for 21 days. Caffeine was administered daily in drinking water (0.3 g/L) for 5 weeks. For evaluated learning and memory function, Morris Water Maze Test (MWM) was used. Fluidigm Access Array was used for Grin2a, Grin2b, BDNF, cdk5/cdk5r1, CaMKIIa genes expression in the hippocampus. Distance moved and escape latency were decreased through trial days (p<0.05). However, there is no significant difference between groups for time spent in targeted quadrant during probe test for memory performance. Grin2a up-regulation was found in Cf and SD+Cf (p<0.05), and cdk5r1 increased in Cf and PC control (p<0.05). Also, BDNF up-regulation was found in PC group. Grin2b, Cdk5, CaMKIIa expression levels were not changed significantly. We showed chronic caffeine altered some of the hippocampal genes without changing learning and memory in REM sleep deprived rats. Chronic consumption of caffeine caused up-regulation in Grin2a that subunit of NMDA receptor. We supposed that chronic caffeine consumption maintained arousal without affecting learning and memory performance.

Long term treadmill exercise performed to chronic social isolated rats regulate anxiety behavior without improving learning.

AIM: The type and duration of exposure to stress is an important influence on emotional and cognitive functions. Learning is the adaptive response of the central nervous system that occurs in hippocampus which affects from environmental factors like exercise. In this study, we investigated effects of long term treadmill exercise on learning and behavior on chronic social isolated rat. MAIN METHODS: Male Wistar rats (n = 32) randomly assigned into four groups: control, exercised, social isolation, social isolation + exercise during postnatal days (PNDs) 21-34. Social isolation protocol was applied during 14 days by placing rat in a cage one by one. Rats were exercised during 5 days, days were chosen randomly for overall 4 weeks (20, 30, 50, 60 min respectively). Finally, learning performance was evaluated by Morris water maze (MWM). Anxiety behavior was evaluated by Open field and elevated plus maze test. At the end of learning and behavior tests, the rats were decapitated to collect blood samples via intracardiac puncture and corticosterone analysis was performed with ELISA method. KEY FINDINGS: Animal weights and water consumption did not change significantly but food intake differed among groups. Corticosterone level did not change between groups. The frequency of entering to the target quadrant increased in exercised rat significantly. However, there was no difference in learning and memory in rats. Treadmill exercise reduced anxiety behavior significantly. SIGNIFICANCE: Taken together these findings may point out that, long term treadmill exercise did not change learning and memory but reduced anxiety level of rat without changing corticosterone level.

Role of rho-kinase (ROCK) in tonic but not phasic contraction in the frog stomach smooth muscle.

AIMS: Rho/Rho-kinase (ROCK) signaling has extensively been shown to take part in mammalian smooth muscle contractions in response to diverse agents yet its role in the contraction of amphibian smooth muscle has not been investigated. Therefore, we aimed to explore any role of this pathway in the contractions of frog stomach smooth. MAIN METHODS: The strips were prepared and suspended in organ baths filled with Ringer solution. Changes in the circular strips of the frog stomach muscle length were recorded isotonically with a force transducer in organ baths. KEY FINDINGS: Carbachol (CCh) exerted both phasic and tonic contractions. In contrast, atropin abolished all types of contractions by CCh. The phasic contractions were suppressed by a Ca2+ channel blocker, nifedipine but not by the ROCK inhibitor, Y-27632. However, the tonic contractions were markedly attenuated by Y-27632. Selective M1 receptor blocker, pirenzepin, selective M3 receptor blocker and DAMP had no effects on CCh-elicited contractions. On the other hand, selective M2 receptor blocker, AF-DX suppressed all types of contractile activity by CCh. SIGNIFICANCE: These data suggest that M2 receptor activation could mainly mediate CCh-induced phasic and tonic contractions, and ROCK seems to be involved in the CCh-induced tonic but not phasic contractions of the frog stomach smooth muscle.

Developmental Control and Plasticity of Fruit and Seed Dimorphism in Aethionema arabicum.

Understanding how plants cope with changing habitats is a timely and important topic in plant research. Phenotypic plasticity describes the capability of a genotype to produce different phenotypes when exposed to different environmental conditions. In contrast, the constant production of a set of distinct phenotypes by one genotype mediates bet hedging, a strategy that reduces the temporal variance in fitness at the expense of a lowered arithmetic mean fitness. Both phenomena are thought to represent important adaptation strategies to unstable environments. However, little is known about the underlying mechanisms of these phenomena, partly due to the lack of suitable model systems. We used phylogenetic and comparative analyses of fruit and seed anatomy, biomechanics, physiology, and environmental responses to study fruit and seed heteromorphism, a typical morphological basis of a bet-hedging strategy of plants, in the annual Brassicaceae species Aethionema arabicum Our results indicate that heteromorphism evolved twice within the Aethionemeae, including once for the monophyletic annual Aethionema clade. The dimorphism of Ae. arabicum is associated with several anatomic, biomechanical, gene expression, and physiological differences between the fruit and seed morphs. However, fruit ratios and numbers change in response to different environmental conditions. Therefore, the life-history strategy of Ae. arabicum appears to be a blend of bet hedging and plasticity. Together with the available genomic resources, our results pave the way to use this species in future studies intended to unravel the molecular control of heteromorphism and plasticity.