Search

Background High cardiorespiratory fitness (CRF) protects against age-related diseases. However, the mechanisms mediating the protective effect of high intrinsic CRF against metabolic, cardiac, and brain impairments in non-obese versus obese conditions remain incompletely understood. We aimed to identify the mechanisms through which high intrinsic CRF protects against metabolic, cardiac, and brain impairments in non-obese versus obese untrained rats. Methods Seven-week-old male Wistar rats were divided into two groups (n=8 per group) to receive either a normal diet or a high-fat diet (HFD). At weeks 12 and 28, CRF, carbohydrate and fatty acid oxidation, cardiac function, and metabolic parameters were evaluated. At week 28, behavior tests were performed. At the end of week 28, rats were euthanized to collect heart and brain samples for molecular studies. Results The obese rats exhibited higher values for aging-related parameters than the non-obese rats, indicating that they experienced obesity-induced premature aging. High baseline CRF levels were positively correlated with several favorable metabolic, cardiac, and brain parameters at follow-up. Specifically, the protective effects of high CRF against metabolic, cardiac, and brain impairments were mediated by the modulation of body weight and composition, the lipid profile, substrate oxidation, mitochondrial function, insulin signaling, autophagy, apoptosis, inflammation, oxidative stress, cardiac function, neurogenesis, blood-brain barrier, synaptic function, accumulation of Alzheimer’s disease-related proteins, and cognition. Interestingly, this effect was more obvious in HFD-fed rats. Conclusion The protective effect of high CRF is mediated by the modulation of several mechanisms. These effects exhibit greater efficacy under conditions of obesity-induced premature aging.

Abstract Background Caloric restriction and exercise are lifestyle interventions that effectively attenuate cardiometabolic impairment. However, cardioprotective effects of long-term lifestyle interventions and short-term lifestyle interventions followed by weight maintenance in prediabetes have never been compared. High cardiorespiratory fitness (CRF) has been shown to provide protection against prediabetes and cardiovascular diseases, however, the interactions between CRF, prediabetes, caloric restriction, and exercise on cardiometabolic health has never been investigated. Methods Seven-week-old male Wistar rats were fed with either a normal diet (ND; n = 6) or a high-fat diet (HFD; n = 30) to induce prediabetes for 12 weeks. Baseline CRF and cardiometabolic parameters were determined at this timepoint. The ND-fed rats were fed continuously with a ND for 16 more weeks. The HFD-fed rats were divided into 5 groups (n = 6/group) to receive one of the following: (1) a HFD without any intervention for 16 weeks, (2) 40% caloric restriction for 6 weeks followed by an ad libitum ND for 10 weeks, (3) 40% caloric restriction for 16 weeks, (4) a HFD plus an exercise training program for 6 weeks followed by a ND without exercise for 10 weeks, or (5) a HFD plus an exercise training program for 16 weeks. At the end of the interventions, CRF and cardiometabolic parameters were re-assessed. Then, all rats were euthanized and heart tissues were collected. Results Either short-term caloric restriction or exercise followed by weight maintenance ameliorated cardiometabolic impairment in prediabetes, as indicated by increased insulin sensitivity, improved blood lipid profile, improved mitochondrial function and oxidative phosphorylation, reduced oxidative stress and inflammation, and improved cardiac function. However, these benefits were not as effective as those of either long-term caloric restriction or exercise. Interestingly, high-level baseline CRF was correlated with favorable cardiac and metabolic profiles at follow-up in prediabetic rats, both with and without lifestyle interventions. Conclusions Short-term lifestyle modification followed by weight maintenance improves cardiometabolic health in prediabetes. High CRF exerted protection against cardiometabolic impairment in prediabetes, both with and without lifestyle modification. These findings suggest that targeting the enhancement of CRF may contribute to the more effective treatment of prediabetes-induced cardiometabolic impairment.

The objects of research were the fruits of apple trees of the Golden Reinders variety (rootstock M 9) grown on the basis of experimental plantings Agricultural institute, Science Academy of Abkhazia. Complex organic fertilizers have been selected as agrochemicals Antistress Chelate and Chelate Filling. The research is aimed at finding new, highly efficient and environmentally friendly agrochemicals, and also determines the development of technology for their application. It was found that the Golden Reinders variety in the humid subtropical zone accumulates from 10.6% (under control) to 11.6% (with non-root treatments) of sugars. Treatments with agrochemicals affected the main quantitative patterns in the content of mono- and disaccharides in apple fruits. The amount of fructose ranges from 6.63 g/100 g at the control to 7.52 g/100 g during treatments; glucose accumulates on average only 1.1-1.2 g/100 g, depending on the variant. Sucrose in fruits is 2.4-2.6 times more than glucose, which characterizes the ripening processes in fruits. Agrochemicals treatments have an ambiguous effect on the accumulation of organic acids. So, if there is a significant increase in malic, citric and tartaric acid during processing, then the content of lactic, succinic, oxalic and acetic acid drops. The sugar-acid index averages 13.6 units, there is a slightly acidic taste.

The quality of fruit depends largely on the growing area of the crop, the intensity of disease development, damage by pests, as well as on the treatment of plants with compounds of various chemical natures. When introducing the immunity inducers Albit® (poly-beta-hydroxybutyric acid), Immunocytophyte® (arachidonic acid ethyl ether) and Ecogel® (chitosan lactate) into apple tree protection systems, an urgent task is to study their influence on the quality of fruits. Research was conducted on apple trees (cultivars Idared and Golden Rangers) in the conditions of the Republic of Abkhazia (Gulripsh district). When treated with immunity inducers, the genotypic features of the cultivars were clearly revealed. For the susceptible Idared cultivar, it is more significant to use Ecogel®, which causes the active synthesis of soluble solids, pectin, soluble sugars, ascorbic acid, and as a result, an increase in the sugar-acid index. At the same time, a relatively resistant cultivar Golden Rangers has a similar effect when treated with Immunocytophyte®. Treatment with Albit® has the same effect on the synthesis of soluble organic acids in the fruits of the studied apple cultivars, reducing their amount. The results obtained indicate the need for a cultivar-specific approach in the application and selection of plant immunity inducers.

One of the ways to reduce pesticide load and prevent emergence of pathogen resistance can be the use of plant immunity inducers in plant protection systems. The purpose of these studies was to evaluate an efficiency of natural plant immunity inducers Albit® (poly-beta-hydroxybutyric acid), Immunocytophite® (arachidonic acid ethyl ether) and Ecogel® (chitosan lactate) in apple scab protection systems in Abkhazia. The maximum resistance of apple trees to this phytopathogen was recorded in the experimental variants with Albit® and Ecogel® application in half dosages of fungicides and in the variant of production processing (biological efficiency reached 79.4 %). Plant immunity inducers used on apple trees showed cultivar-specificity. For the four-year research period, the greatest efficiency of immunity inducers was achieved on the susceptible cultivar Idared in the second year of the experiment, while on the relatively scab-resistant cultivar Golden Rangers – it was achieved only in the third year. The greatest stability in the efficiency for a four-year period was observed for the tank mix Albit with half dosages of fungicides. Immunocytophyte® was characterized by lower inducing activity, which is associated with its activation of the jasmonate pathway for the formation of non-specific induced immunity.

Background: Chemotherapy, particularly treatment with doxorubicin (Dox), is known to cause neurotoxicity in the brain known as chemobrain. Dox administration causes neuroinflammation, mitochondrial dysfunction, and subsequent cognitive decline (1). Additionally, cancer survivors who received Dox were found to have an increased risk of developing dementia (2). Interestingly, the activation of the parasympathetic nervous system by vagus nerve stimulation (VNS) exerted neuroprotective effects on Alzheimer's disease (3). However, the neuroprotective effects of VNS against Dox‐induced chemobrain have never been investigated. Moreover, whether the therapeutic effects of VNS are achieved via stimulation of nicotinic acetylcholine receptors (AChRs) or muscarinic acetylcholine receptors (mAChRs) needs further investigation. Method: Twenty male Wistar rats were divided into sham‐operated and VNS device‐implanted groups. After 2 weeks of recovery, all sham‐operated rats were divided and received either 0.9% NSS (Control; n = 4) or 3 mg/kg Dox for 6 doses (Sham; n = 4) via intraperitoneal injection. In addition, all VNS device‐implanted rats were treated with 3 mg/kg Dox for 6 doses and then randomly divided into 3 groups to receive either 0.9% NSS (VNS; n = 4), a mAChR antagonist (atropine; 1 mg/kg/day, VNS+Atro; n = 4), or a nAChR antagonist (mecamylamine; 7.5 mg/kg/day, VNS+Mec; n = 4). At the end of treatment protocol, cognitive function was assessed using the novel object location (NOL) task. The brains were obtained for further molecular studies. Result: Dox treatment impaired cognitive performance in rats, as demonstrated by a decrease in the preference index in the NOL task (Figure A). Microglia in the CA1 region of Dox‐treated rats exhibited decreased process complexity and increased microglial volume, indicating reactivation of microglia (Figure B and C). Notably, Dox administration caused mitochondrial dysfunction in the brain, as evidenced by increased levels of mitochondrial reactive oxygen species (ROS) and mitochondrial membrane depolarization (Figure D and E). Importantly, the intervention with VNS rescued long‐term cognitive function in Dox‐treated rats by ameliorating all chemobrain pathologies (Figure A‐E). In contrast, the therapeutic effects of VNS were completely abolished by blocking either mAChRs or nAChRs using their antagonists (Figure A‐E). Conclusion: The findings suggested that VNS protected against Dox‐induced chemobrain through activations of both nAChRs and mAChRs. [ABSTRACT FROM AUTHOR]

Background: Although doxorubicin has been broadly used in treating a wide range of cancers, it frequently causes a serious neurological consequences referred to as chemobrain in cancer patients. Chemobrain shares several key pathological features with Alzheimer's disease (AD) including neuroinflammation and Tau pathology. In addition to the inhibition of acetylcholinesterase, the activation of a7nicotinic and muscarinic acetylcholine receptors (a7nAChR and mAChR) using their agonists has been considered an effective therapeutic target against dementia. However, the benefit of intervention with nAChR and mAChR agonists in DOX‐induced chemobrain has never been investigated. Method: Twenty‐five male Wistar rats were assigned to received either (0.9% NSS) or doxorubicin (3 mg/kg; 6 doses) via intraperitoneal injection. Then, doxorubicin‐treated rats were divided into 4 intervention groups to treat with either vehicle, an a7nAChR agonist (PNU‐282987; 3 mg/kg), a mAChR agonist (bethanechol; 12 mg/kg), or a combined treatment of PNU‐282987 and bethanechol via intraperitoneal injection as a concomitant treatment with doxorubicin for a period of 30 days. After completion of the treatment paradigm, cognitive function was evaluated using the novel object location task (NOLT). The hippocampal tissues were dissected to enable further investigation. Result: Systemic administration of doxorubicin impaired long‐term cognitive function in rats as shown by a decreased preference index in the NOLT (Figure A). Furthermore, doxorubicin‐treated rats exhibited neuroinflammation in the hippocampus as demonstrated by an increase in TNF‐a protein expression (Figure B) and an alteration in microglial morphology to a pro‐inflammatory amoeboid‐liked phenotype (Figure C). Notably, injection of doxorubicin markedly reduced the phosphorylation of GSK3b at Ser9 (Figure D) and upregulated the phosphorylation of Tau at Thr181 (Figure E). Also, a decline in the dendritic spine density in the CA1 region was observed in doxorubicin‐treated rats compared with the controls (Figure F). Interestingly, all AChR agonists restored cognitive function in rats in a similar manner by attenuating neuroinflammation and Tau phosphorylation while preserving dendritic spine density (Figure A‐F). Conclusion: Together, activation of AChRs by their agonists protected against the neuropathology of doxorubicin‐induced chemobrain, indicating their potential role as a novel strategy to prevent chemobrain in patients receiving chemotherapy. [ABSTRACT FROM AUTHOR]

Background: CD147, also known as extracellular matrix metalloproteinase inducer, is a key mediator of inflammatory and immune responses in various kinds of neurodegenerative disease (1). However, the role of CD147 in obesity‐induced neurodegeneration has not been previously investigated. Therefore, this study aims to investigate the alteration of CD147 expression in the hippocampus of obese rats, both with and without lifestyle modification. Method: Seven‐week‐old male Wistar rats were divided into 4 groups (n = 5 per group), including 1) rats fed with a normal diet for 28 weeks [ND], 2) rats fed with a high‐fat diet (HFD) for 28 weeks [HFD], 3) rats fed with a HFD for 12 weeks followed by 40% caloric restriction for an additional 16 weeks [HFD‐CR], or 4) rats fed with a HFD for 12 weeks followed by exercise plus HFD for an additional 16 weeks [HFD‐EX]. At the end of week 28, cognitive function was determined by a novel object location test. The rats were then euthanized on the following day for molecular studies in the hippocampus. Result: We found that hippocampal CD147 level exerted a strongly negative correlation with the level of cognitive function (Figure A). In addition, CD147 expression and its downstream consequences – p‐NFκB, MMP‐9, and TNF‐α – were upregulated in HFD‐fed rats (Figure B‐E). The HFD‐fed rats also exhibited an increase in activated microglia (CD68), along with decreased blood‐brain barrier protein (claudin‐5), dendritic spine density, and cognitive performance (Figure F‐I). Strikingly, both caloric restriction and exercise effectively reduced the expression of CD147 and its downstream consequences, as well as restored CD68, claudin‐5, dendritic spine density, and cognitive function in HFD‐fed rats (Figure B‐I). Conclusion: Our findings suggested that CD147 is one of the detrimental mediators in obesity‐induced neurodegeneration (Figure J). Interestingly, an attenuation of obesity by lifestyle modification exerts protection against cognitive impairment via CD147‐related mechanisms (Figure J). Therefore, an inhibition of CD147 is considered as a therapeutic target to prevent cognitive impairment in obese individuals. Reference 1. Kaushik DK, Hahn JN, Yong VW. EMMPRIN, an upstream regulator of MMPs, in CNS biology. Matrix Biol. 2015;44‐46:138‐46. [ABSTRACT FROM AUTHOR]

Background: D‐galactose has been widely used for an induction of premature aging in laboratory animals (1). However, it was observed that short‐term administration of D‐galactose failed to induce some aging phenomena (2). Therefore, we aimed to determine whether long‐term administration of D‐galactose could mimic natural aging of the rat's hippocampus, based on the primary, antagonistic, and integrative hallmarks of aging. Method: Seven‐week‐old male Wistar rats (n = 12) were randomly injected with either normal saline as vehicle (n = 6) or 150 mg/kg/day of D‐galactose subcutaneously for 28 weeks. Seventeen‐month‐old male Wistar rats (n = 6) were also included as the naturally aged controls. At the end of week 28 of the experiment (when the rats were 35 weeks old for D‐galactose‐induced aging and 24 months old for natural aging), all rats were sacrificed for brain collection. The, the hippocampus was examined for molecular studies. Result: Long‐term D‐galactose administration demonstrated the features of natural aging in the hippocampus of young rats. These include loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication (Figure A). In the context of cognitive function, natural aging and long‐term D‐galactose administration similarly impaired hippocampal learning and memory, as indicated by reducing the novel object location and recognition tests (Figure B, C). Conclusion: Long‐term administration of D‐galactose‐induced aging potentially mimic natural aging process of the hippocampus. These findings suggest that long‐term administration of D‐galactose is suitable for an establishment of the aging model in young animals. Reference 1. Shwe T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. Role of D‐galactose‐induced brain aging and its potential used for therapeutic interventions. Exp Gerontol. 2018;101:13‐36. 2. Cardoso A, Magano S, Marrana F, Andrade JP. D‐Galactose High‐Dose Administration Failed to Induce Accelerated Aging Changes in Neurogenesis, Anxiety, and Spatial Memory on Young Male Wistar Rats. Rejuvenation research. 2015;18(6):497‐507. [ABSTRACT FROM AUTHOR]

Background: Diet‐induced obesity can lead to develop endotoxemia and cognitive decline (1). A previous study in Alzheimer's disease model demonstrated that an increase in the colocalization of C1q, a classical complement protein, and microglia occurred, when those microglia increased synaptic engulfment, resulting in increased synaptic‐pruning process and synaptic loss (2). However, the effects of lipopolysaccharide (LPS) as endotoxin on peripheral inflammation, blood‐brain barrier(BBB) integrity, brain oxidative stress, synaptic engulfment by microglia, synaptic plasticity, and cognitive function in high‐fat diet‐induced obese rats have never been investigated. Method: Sixteen male Wistar rats were randomly assigned to receive either a normal diet (ND, n = 8) or the high‐fat diet (HFD, n = 8) for 12 weeks. All animals in each dietary group were subsequently assigned into 2 subgroups (n = 4 /subgroup) to receive either a single dose of vehicle (1 ml of 0.9% normal saline solution, intraperitoneal (i.p.) injection, or LPS (0.5 mg/kg, i.p.). After the injections for 12‐16 hours, all animals were measured for cognitive function and the blood was collected. Then, animals were sacrificed, and their brains and spleens were obtained for further investigation. Result: All HFD‐fed rats exhibited peripheral inflammation as indicated by increased spleen IL‐1β protein levels, BBB disruption as indicated by the reduction of hippocampal claudia‐5 protein levels, and increased brain oxidative stress as indicated by the increased brain malondialdehyde levels (p<0.05, Figure 1). Interestingly, LPS‐treated ND‐fed rats and vehicle‐treated HFD‐fed rats equally impaired microglial function by increasing synaptic engulfment as indicated by the increase in C1q colocalized in microglia and the decreased dendritic spine density (p<0.05, Figure 1). The results demonstrated that these parameters were aggravated in LPS‐treated HFD‐fed rats. Lastly, all HFD‐fed rats decreased the preference index of novel object location and recognition test suggesting long‐term HFD consumption caused cognitive decline (p<0.05, Figure 1). Conclusion: Long‐term HFD consumption, but not LPS alone, caused cognitive decline by increasing peripheral inflammation, disrupting BBB integrity, increasing brain oxidative stress, increasing synaptic engulfment by microglia, and decreasing synaptic plasticity. Microglia are susceptible to impair their function in response to LPS, which potentially worsen brain pathologies in obese condition. [ABSTRACT FROM AUTHOR]

Background: Trastuzumap (Trz) is effectively used for breast cancer patients to improve health status and reduce mortality rate. Nevertheless, several studies reported its adverse effect on brain toxicity. To date, the mechanisms of Trz‐induced brain toxicity are not fully understood. Metformin is a generic prescribed drug for type 2 diabetes mellitus, while in the past decade it also used for attenuating the adverse effects of chemotherapy. However, the effects of metformin on brain mitochondrial function, hippocampal microglial function, hippocampal synaptic plasticity, and cognitive function in Trz‐induced brain toxicity have never been investigated. Method: Eighteen male Wistar rats were randomly divided into two groups; control group (0.9% NSS, intraperitoneal (i.p.) injection, n = 8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n = 16). Then, Trz‐treated rats were divided into two subgroups (n = 6/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or metformin (250 mg/kg/day for 7 days, daily via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation. Result: Trz‐treated rats demonstrated an increase of mitochondrial ROS production, increased mean fluorescence intensity of ionized calcium binding adaptor molecule 1 (Iba1), decreased hippocampal dendritic spine density, decreased preferent index in novel object location (NOL) and novel object recognition (NOR) test (p<0.05, Figure 1A‐F). Metformin‐treated in Trz‐rats reversed the adverse effect of Trz by attenuated mitochondrial ROS production, decreased mean fluorescence intensity of Iba1, increased hippocampal dendritic spine density, as well as increased preferent index in NOL and NOR test (p<0.05, Figure 1A‐F). Conclusion: Trz‐induced brain toxicity as indicated by brain mitochondrial dysfunction, decreased hippocampal microglial function, impaired hippocampal synaptic plasticity, and cognitive dysfunction, while metformin alleviated those deleterious effects. The findings in this study emphasize the roles of metformin against Trz‐induced brain toxicity and strengthen [ABSTRACT FROM AUTHOR]

Background: High cardiorespiratory fitness (CRF) and behavioral modification exert a neuroprotective effect in obese condition. However, the interplay between CRF, obesity, and behavioral modification has never been identified. Therefore, this study investigated whether high CRF level provides the neuroprotective effect in obese rats receiving either caloric restriction or exercise. Method: Seven‐week‐old male Wistar rats were fed with either a normal diet (ND; n = 5) or a high‐fat diet (HFD; n = 25) to induce obesity for 12 weeks. At the end of week 12, baseline CRF was measured. The ND‐fed rats were continuously fed with a ND for an additional 16 weeks. The HFD‐fed rats were randomly assigned into 5 groups (n = 5/group) to receive either 1) a HFD without intervention for 16 weeks, 2) 40% caloric restriction for 6 weeks followed by an ad libitum ND for 10 weeks (short‐term caloric restriction followed by weight maintenance), 3) 40% caloric restriction for 16 weeks (long‐term caloric restriction), 4) a HFD plus an exercise for 6 weeks followed by a ND without exercise for 10 weeks (short‐term exercise followed by weight maintenance), or 5) a HFD plus an exercise for 16 weeks (long‐term exercise). At the end of interventions (week 28), CRF and cognitive function were determined. After that, the rats were euthanized for molecular studies in the brain. Result: There was a significantly positive correlation between running distance at week 12 and week 28 (Figure A), indicating that CRF is highly intrinsic factor. When compared to the ND‐fed rats, CRF level was lower in the obese rats at week 12 (Figure B). At week 28, all types of behavioral modification significantly increased the CRF level in obese rats (Figure C). Interestingly, high baseline CRF level demonstrated a significant correlation with favorable brain profiles at follow‐up in obese rats, both with and without behavioral modification (Figure D). Conclusion: Regardless of behavioral modification, high CRF exerts a neuroprotective effect against obesity. Hence, targeting on an enhancement of CRF may provide the better effective therapy for obesity‐induced neuronal impairment. [ABSTRACT FROM AUTHOR]

Background: Chemobrain has recently gained attention as a serious neurobehavioral consequence of chemotherapy in cancer patients. Even well‐recognized among conventional chemotherapeutic agents, trastuzumab (TRZ), an oncogene‐targeted therapy for treating breast cancer, has been shown to intricately caused symptoms of chemobrain elicited by impaired cerebral glucose metabolism and long‐term cognitive function. Noticeably, the inhibition of acetylcholinesterase using donepezil (DPZ), a medication widely used to treat Alzheimer's disease (AD), possesses several pleiotropic effects including mitochondrial protection and immunomodulation. However, the mechanistic insights regarding the pathophysiology and therapeutic benefit of DPZ have never been holistically determined in a rat model of TRZ‐induced chemobrain. Method: Fifteen male Wistar rats were randomized to receive either a 0.9% normal saline solution (Control; n=5) or 4 mg/kg of TRZ via intraperitoneal injection for 7 consecutive days. Then, TRZ‐treated rats were subdivided into 2 groups to receive either drinking water (TRZ, n=5) or 5 mg/kg of DPZ (TRZ+DPZ; n=5) via oral gavage as co‐treatment with TRZ for 7‐day duration. After cessation of the treatment paradigm, cognitive performance was assessed using the novel object location task (NOLT). The brain tissues were obtained for further molecular investigation. Result: TRZ‐treated rats showed impaired long‐term spatial memory as demonstrated by a reduction of preference index in the NOLT (Figure A). Systemic TRZ administration compromised mitochondrial anti‐oxidant capacity (Figure B) and potentiated the activation of mitochondrial‐fission related protein. Furthermore, the upregulation of neuroinflammation was observed in TRZ‐treated rats presented by increased TNF‐α mRNA level (Figure C) and microglial morphological changes into neurotoxic amoeboid‐shaped (Figure D). Additionally. Administration of TRZ triggered the phosphorylation of Tau protein (Figure E) and reduced dendritic spine density in CA1 region (Figure F). Strikingly, co‐administration with DPZ effectively rescued cognitive performance of TRZ‐treated rats by improving mitochondrial anti‐oxidant capacity, reducing mitochondrial fission, mitigating neuroinflammation and microglial polarization, attenuating Tau hyperphosphorylation, and preserving dendritic spine density (Figure A‐F). Conclusion: These findings suggested that DPZ exerted neuroprotective effects against TRZ‐induced chemobrain. Our findings pave the way for parasympathetic activation using DPZ as a therapeutic approach in the prevention of chemobrain in patients who received chemotherapy in the future. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy can increase survival rate of cancer patients. One of the chemotherapeutic drugs for breast cancer patients is trastuzumap (Trz). Chemotherapy not only helps to kill cancers, but it also causes several adverse effects in the patients, particularly in the brain, known as chemobrain. Chemobrain has been characterized by cognitive decline with brain mitochondrial dysfunction, hippocampal microglial activation, and loss of dendritic spines. Although several types of chemotherapy induce chemobrain, Trz‐induced chemobrain are not clearly elucidated. Ranolazine, a drug that is commonly used to treat the patients with chronic angina, shows benefits on cognitive function in doxorubicin‐induced chemobrain. However, the effects of ranolazine on brain mitochondrial function, hippocampal microglial function, hippocampal dendritic spines, and cognitive function in Trz‐induced chemobrain have never been investigated. Methods: Eighteen male Wistar rats were randomly divided into two groups including control group (0.9% NSS, intraperitoneal (i.p.) injection, n=8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n=16). All Trz‐treated rats were randomly divided into two subgroups (n=8/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or ranolazine (305 mg/kg/day, daily via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation. Results: The results demonstrated that vehicle‐treated Trz‐rats significantly increased brain mitochondrial ROS production, increased brain mitochondrial membrane potential change, and increased brain mitochondrial swelling, suggesting brain mitochondrial dysfunction (p<0.05, Figure 1). These parameters were attenuated in ranolazine‐treated Trz‐rats (p<0.05, Figure 1). In addition, the microglial activation was found in vehicle‐treated Trz‐rats as indicated by increased the number of microglial cells, which was suppressed by the ranolazine treatment (p<0.05, Figure 1). Consistently, the dendritic spine density decreased in vehicle‐treated Trz‐rats, leading to cognitive decline (p<0.05, Figure 1). Ranolazine‐treated Trz‐rats showed an increase in dendritic spine density, resulting in the improvement of cognitive function (p<0.05, Figure 1). Conclusions: All findings suggest that ranolazine effectively ameliorated cognitive decline in rats with Trz‐induced chemobrain. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for better preventing chemobrain in the future. [ABSTRACT FROM AUTHOR]

Background: Trastuzumap (Trz) has been shown to significantly increase the survival rate in human epidermal growth factor receptor (HER2)‐positive breast cancer patients, whereas it also causes neuroinflammation, leading to cognitive impairment, as called "chemobrain". The exact mechanisms of Trz‐induced chemobrain are not fully understood. Melatonin, a hormone derived from the amino acid tryptophan, has been shown to have the neuroprotection in several pathological conditions. However, the effects of melatonin on brain mitochondrial function, microglial morphology, synaptic plasticity, and cognitive function in Trz‐induced chemobrain have never been investigated. Method: Eighteen male Wistar rats were randomly divided into two groups including control group (0.9% NSS, intraperitoneal (i.p.) injection, n=8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n=16). All Trz‐treated rats were randomly divided into two subgroups (n=8/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or melatonin (10 mg/kg/day, via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation. Result: Trz‐treated rats displayed significantly impaired brain mitochondrial function as indicated by increased ROS production, brain mitochondrial membrane potential change, and brain mitochondrial swelling. These parameters were attenuated in melatonin‐treated Trz‐rats (p<0.05, Figure 1). Consistently, Trz administration decreased microglial complexity, as measured by Sholl analysis, which was ameliorated by melatonin treatment (p<0.05, Figure 1). In addition, the results demonstrated that hippocampal plasticity as indicated by dendritic spine density significantly decreased in Trz‐rats, resulting in cognitive dysfunction as indicated by reducing preferent index of novel object location (NOL) and novel object recognition (NOR) test (p<0.05, Figure 1). Melatonin‐treated Trz‐rats improved hippocampal plasticity by increased dendritic spine density, leading to the improvement of cognition by increased preferent index of NOL and NOR (p<0.05, Figure 1). Conclusion: These findings suggest that melatonin effectively ameliorated cognitive dysfunction in rats with Trz‐induced chemobrain. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for better preventing chemobrain in the future. [ABSTRACT FROM AUTHOR]

Background: Previous studies demonstrated that CRF predicts brain aging as indicated by higher brain volume, greater white matter integrity, and lower risk of dementia mortality in people with higher CRF level. However, mechanisms that mediate the predictive effect of CRF on brain aging have never been holistically determined in both normal condition and obesity‐induced premature aging. Method: Seven‐week‐old male Wistar rats received either a normal diet (ND; n=6) or a high‐fat diet (HFD; n=6) for 28 weeks. At week 12 and 28, rats were run on a treadmill to measure CRF level, and fasting blood was also collected for metabolic parameters. At week 28, open field, novel object location, and novel object recognition tests were conducted. At the end of week 28, brain tissues were then obtained after sacrifice. Result: From week 12 to 28, all rats developed aging as indicated by decreased CRF level, insulin resistance, and dyslipidemia. Compared to ND‐fed rats, HFD‐fed rats exhibited obesity‐induced premature brain aging as indicated by mitochondrial dysfunction, increased oxidative stress and inflammation, increased apoptosis, blood brain barrier breakdown, synaptic dysfunction, impaired neurogenesis, increased Alzheimer's disease markers, and cognitive dysfunction. In both groups of rats, CRF level at week 12 revealed positive correlations with several brain parameters at week 28, including metabolism, mitochondrial fusion, autophagy, antioxidative capacity, synapse, and neurogenesis, while a negative correlation between CRF level at week 12 and brain oxidative stress at week 28 was observed (Table 1). Only in ND‐fed rats, CRF level at week 12 was negatively correlated with brain apoptosis and anxiety‐like behavior at week 28 (Table 1). Only in HFD‐fed rats, CRF level at week 12 was positively correlated with brain insulin signaling, mitophagy, blood brain barrier, and cognition at week 28, whereas there was a negative correlation between CRF level at week 12 and Alzheimer's disease markers at week 28 (Table 1). Conclusion: High CRF level attenuates aging‐induced brain pathology, resulting in mitigating cognitive impairment. Interestingly, these effects of CRF become highly potent in obesity‐induced premature aging since greater number of brain parameters that correlated with CRF level was observed in HFD‐fed rats. [ABSTRACT FROM AUTHOR]

Background: Chemobrain has recently been recognized as the most common neurological consequences following chemotherapy, particularly doxorubicin (Dox) treatment. In addition, the incidence of Alzheimer's disease (AD) increases in response to chemotherapy. Dox administration induced cognitive impairment via brain oxidative stress, neuroinflammation, mitochondrial dysfunction, cholinergic deficits, and cumulating neuronal apoptosis. Notably, donepezil (DPZ), an acetylcholinesterase inhibitor, has been proven to effectively attenuate various neuropathological conditions, particularly AD. However, the mechanistic insight regarding the protective effects of DPZ on cognition and brain pathologies in rats with doxorubicin‐induced chemobrain has never been determined. Method: Fifteen male Wistar rats were randomized to receive either a 0.9% normal saline solution (Control; n=5) or 3 mg/kg Dox for 6 doses via intraperitoneal injection. Then, Dox‐treated rats were divided into 2 groups to receive either vehicle (Dox, n=5) or DPZ (5 mg/kg: Dox+DPZ; n=5) orally, starting at 1st day of Dox for a 30‐day duration. After completion of the treatment paradigm, cognitive function was evaluated using the novel object location (NOL) task. The brains were obtained for further molecular investigation. Result: Dox‐treated rats exhibited impaired cognitive performance as presented by a decline in preference index in the NOL test. Loss of dendritic spines was observed following Dox treatment. Dox‐treated rats showed brain mitochondrial dysfunction as indicated by increased mitochondrial reactive oxygen species (ROS) production (Figure 1) and imbalanced mitochondrial dynamics. Additionally, Dox induced neuroinflammation as demonstrated by increased TNF‐α mRNA expression, together with enhanced microglial activation (Figure 1). Interestingly, Dox‐treated rats developed potential amyloid lesions (Figure 1) and disrupted neurogenesis in the hippocampus which in turn led to neuronal cell death through both apoptosis and necroptosis. Strikingly, DPZ co‐treatment completely restored cognitive function (Figure 1) by reducing dendritic spine loss, improving mitochondrial function, balancing mitochondrial dynamics, ameliorating neuroinflammation, decreasing Alzheimer's related proteins, preserving neurogenesis, and inhibiting apoptosis and necroptosis. Conclusion: These findings suggested that DPZ provided neuroprotection against Dox‐induced chemobrain, which could be used for the therapeutic approach to prevent chemobrain in patients who received chemotherapy in the future. [ABSTRACT FROM AUTHOR]

Background: Doxorubicin (Dox), the common therapeutic regimen for breast cancer treatment, has been shown the toxicity to the brain, known as "chemotherapy‐induced cognitive impairment or chemobrain". However, the mechanisms of doxorubicin‐induced chemobrain are not fully understood. Melatonin, metformin, and ranolazine have been shown the neuroprotective effects on mitochondrial function and cognition in several pathological conditions. However, the effects of melatonin, metformin, and ranolazine on peripheral oxidative stress, brain mitochondrial function, synaptic plasticity, and cognitive function in Dox‐induced chemobrain has never been investigated. Methods: Forty male Wistar rats were randomly divided into two groups including control group (0.9% NSS, intraperitoneal (i.p.) injection, n=8) and Dox‐treated group (3 mg/kg for 6 doses, i.p. injection, n=32). All Dox‐treated rats were randomly divided into four subgroups (n=8/ subgroup) to receive either vehicle (0.9% NSS, daily oral gavage feeding), melatonin (10 mg/kg/day, oral gavage feeding), metformin (250 mg/kg/day, oral gavage feeding), or ranolazine (305 mg/kg/day, oral gavage feeding). Each drug was continuously given by starting at the 1st day of Dox for 30 days. At the end of experimental protocol, cognitive function was tested, and brains were obtained for further molecular investigation. Results: Dox‐treated rats significantly increased peripheral oxidative stress as indicated by increased serum malondialdehyde level, which were equally decreased by treatment with melatonin, metformin, and ranolazine (p<0.05, Figure 1). Moreover, brain mitochondrial dysfunction was demonstrated by increasing brain mitochondrial ROS production, membrane potential change, and swelling (p<0.05, Figure 1). These parameters were equally attenuated by all treatments. Consistently, Dox‐treated rats showed synaptic dysplasticity, as indicated by decreasing dendritic spine density, which was attenuated by all treatments. Interestingly, melatonin, metformin, and ranolazine improved cognitive function in Dox‐treated rats by increasing preference index of object in novel location and novel object in novel object location and recognition test (p<0.05, Figure 1). Conclusions: These findings suggest that melatonin, metformin, and ranolazine effectively ameliorate cognitive decline in rats with Dox‐induced chemobrain. The novel findings obtained from the present study provides the therapeutic strategies which can be translated into clinical settings for better preventing chemobrain in the future. [ABSTRACT FROM AUTHOR]

Exercise and caloric restriction improve skeletal muscle metabolism. However, the benefits of exercise and caloric restriction on skeletal muscle metabolism in aging have never been compared. Seven-week-old male Wistar rats ( n = 24) were divided into 4 groups ( n = 6 per group) to receive either normal saline solution for 28 weeks, 150 mg/kg/day of D-galactose for 28 weeks to induce premature aging, 150 mg/kg/day of D-galactose for 28 weeks plus exercise for 16 weeks (week 13-28), or 150 mg/kg/day of D-galactose for 28 weeks plus 30% caloric restriction for 16 weeks (week 13-28). The 17-month-old rats ( n = 6) were also injected with normal saline solution for 28 weeks as the naturally aged controls. At the end of week 28, total walking distance and fatty acid and carbohydrate oxidation during physical activity were determined. Then, all rats were euthanized for the collection of blood and tibialis anterior muscle. The results showed that D-galactose successfully mimicked the natural aging of skeletal muscle. Exercise and caloric restriction equally improved carbohydrate oxidation during physical activity and myogenesis. However, exercise was superior to caloric restriction in terms of improving fatty acid oxidation and oxidative phosphorylation. Interestingly, caloric restriction decreased oxidative stress, whereas exercise increased oxidative stress of skeletal muscle. All of these findings indicated that the benefits of exercise and caloric restriction on skeletal muscle metabolism during aging were different, and therefore the combination of exercise and caloric restriction might provide greater efficacy in ameliorating skeletal muscle aging.

Aims: To investigate whether transient dietary restriction or aerobic exercise in young adulthood exert long-lasting protection against brain aging later in life., Main Methods: Seven-week-old male Wistar rats were divided into 2 groups and given either normal saline as a vehicle (n = 8) or 150 mg/kg/day of D-galactose (n = 40) for 28 weeks, the D-galactose being used to induce aging. At week 13 of the experiment, D-galactose-treated rats were further divided into 5 groups, 1) no intervention, 2) transient dietary restriction for 6 weeks (week 13-18), 3) transient exercise for 6 weeks (week 13-18), 4) long-term dietary restriction for 16 weeks (week 13-28), and 5) long-term exercise for 16 weeks (week 13-28). At the end of week 28, cognitive function was examined, followed by molecular studies in the hippocampus., Key Findings: Our results showed that either long-term dietary restriction or aerobic exercise effectively attenuated cognitive function in D-galactose-treated rats via the attenuation of oxidative stress, cellular senescence, Alzheimer's-like pathology, neuroinflammation, and improvements in mitochondria, brain metabolism, adult neurogenesis, and synaptic integrity. Although transient interventions provided benefits in some brain parameters in D-galactose-treated rats, an improvement in cognitive function was not observed., Significance: Our findings suggested that transient lifestyle interventions failed to exert a long-lasting protective effect against brain aging. Hence, novel drugs mimicking the neuroprotective effect of long-term dietary restriction or exercise and the combination of the two since young age appear to be more appropriate treatments for the elderly who are unable to engage in long-term dietary restriction or exercise., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We investigated whether weight maintenance following short-term caloric restriction or exercise exerted neuroprotective effects on obesity induced by a high-fat diet. We also sought to identify whether the neuroprotective effects of higher untrained fitness persisted in the obese condition, both with and without caloric restriction or exercise. Male Wistar rats were fed with either a normal diet (ND) or a high-fat diet (HFD) for 12 weeks. At week 12, untrained fitness and blood metabolic parameters were measured. The ND-fed rats continuously received a ND for 16 additional weeks. HFD-fed rats were randomly assigned to 5 groups as of the followings: 1) an additional 16 weeks of HFD without intervention, 2) 10-week weight maintenance following 6-week short-term caloric restriction, 3) long-term caloric restriction (16 weeks), 4) 10-week weight maintenance following 6 weeks of HFD plus short-term exercise, and 5) HFD plus long-term exercise (16 weeks). Untrained fitness, blood metabolic parameters, and behavioral tests were then determined. Thereafter, the rats were euthanized for molecular studies. Our results demonstrated that long-term caloric restriction had the greatest systemic metabolic benefit among all interventions. Long-term caloric restriction and exercise equally attenuated HFD-induced cognitive impairment by improving synaptic function, blood-brain barrier integrity, mitochondrial health, and neurogenesis, and reducing oxidative stress, neuroinflammation, apoptosis, and Alzheimer's-related pathology. Weight maintenance following short-term caloric restriction showed no benefit to neurogenesis. Weight maintenance following short-term exercise exerted no benefit on synaptic function, neuronal insulin signaling and metabolism, autophagy, and neurogenesis. Interestingly, we found that higher untrained fitness level at week 12 showed positive correlations with more favorable brain profiles at week 28 in HFD-fed rats, both with and without caloric restriction or exercise. All of these findings suggested that higher untrained fitness exerts neuroprotection in HFD-induced obesity independently of caloric restriction or exercise. Therefore, targeting enhancement of untrained fitness may lead to more effective treatment of neurodegeneration in obese condition., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We aimed to investigate the effect of chronic D-galactose exposure on the mimicking of natural aging processes based upon the hallmarks of aging. Seven-week-old male Wistar rats (n = 12) were randomly assigned to receive either normal saline solution as a vehicle (n = 6) or 150 mg/kg/day of D-galactose subcutaneously for 28 weeks. Seventeen-month-old rats (n = 6) were also included as the chronologically aged controls. At the end of week 28 of the experiment (when the rats reach 35 weeks old and 24 months old), all rats were sacrificed for brain and heart collection. Our results showed that chronic D-galactose exposure mimicked natural aging characteristics of the brain and the heart in terms of deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and functional impairment. All of which highlight the potential of D-galactose as a substance for inducing brain and cardiac aging in animal experiments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Doxorubicin (DOX), an effective, extensively used chemotherapeutic drug, can cause cognitive deterioration in cancer patients. The associated debilitating neurological sequelae are referred to as chemobrain. Our recent work demonstrated that Dox treatment resulted in an imbalance in mitochondrial dynamics, ultimately culminating in cognitive decline in rats. Therefore, in this study, we aim to explore the therapeutic efficacy of a pharmacological intervention, which modulates mitochondrial dynamics using a potent mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promoter (M1) against Dox-induced chemobrain. In the study, male Wistar rats were randomly assigned to receive either normal saline solution or six doses of Dox (3 mg·kg -1 ) via intraperitoneal injection. Then, the Dox-treated rats were intraperitoneally given either 1% DMSO as the vehicle, Mdivi-1 (1.2 mg·kg -1 ), M1 (2 mg·kg -1 ), or a combined treatment of Mdivi-1 and M1 for 30 consecutive days. Long-term learning and memory were evaluated using the novel object location task and novel object recognition task. Following euthanasia, the rat brains were dissected to enable further molecular investigation. We demonstrated that long-term treatment with mitochondrial dynamic modulators suppressed mitochondrial fission in the hippocampus following Dox treatment, leading to an improvement in brain homeostasis. Mitochondrial dynamic modulator treatments restored cognitive function in Dox-treated rats by attenuating neuroinflammation, decreasing oxidative stress, preserving synaptic integrity, reducing potential Alzheimer's related lesions, and mitigating both apoptosis and necroptosis following Dox administration. Together, our findings suggested that mitochondrial dynamics modulators protected against Dox-induced cognitive impairment by rebalancing mitochondrial homeostasis and attenuating both oxidative and inflammatory insults., (© 2022 Federation of European Biochemical Societies.)

Backgruound: High cardiorespiratory fitness (CRF) protects against age-related diseases. However, the mechanisms mediating the protective effect of high intrinsic CRF against metabolic, cardiac, and brain impairments in non-obese versus obese conditions remain incompletely understood. We aimed to identify the mechanisms through which high intrinsic CRF protects against metabolic, cardiac, and brain impairments in non-obese versus obese untrained rats., Methods: Seven-week-old male Wistar rats were divided into two groups (n=8 per group) to receive either a normal diet or a highfat diet (HFD). At weeks 12 and 28, CRF, carbohydrate and fatty acid oxidation, cardiac function, and metabolic parameters were evaluated. At week 28, behavior tests were performed. At the end of week 28, rats were euthanized to collect heart and brain samples for molecular studies., Results: The obese rats exhibited higher values for aging-related parameters than the non-obese rats, indicating that they experienced obesity-induced premature aging. High baseline CRF levels were positively correlated with several favorable metabolic, cardiac, and brain parameters at follow-up. Specifically, the protective effects of high CRF against metabolic, cardiac, and brain impairments were mediated by the modulation of body weight and composition, the lipid profile, substrate oxidation, mitochondrial function, insulin signaling, autophagy, apoptosis, inflammation, oxidative stress, cardiac function, neurogenesis, blood-brain barrier, synaptic function, accumulation of Alzheimer's disease-related proteins, and cognition. Interestingly, this effect was more obvious in HFD-fed rats., Conclusion: The protective effect of high CRF is mediated by the modulation of several mechanisms. These effects exhibit greater efficacy under conditions of obesity-induced premature aging.

Doxorubicin (Dox), a powerful chemotherapeutic agent, has been shown to cause cardiotoxicity and neurotoxicity. Ranolazine, a drug that is commonly used to treat patients with chronic angina, has been shown to reduce toxicity from Dox therapy. Therefore, the present study aims to investigate the mechanisms behind the protective effects of ranolazine on the heart and brain in Dox-treatment. Twenty-four male Wistar rats received 6 doses of either 0.9% normal saline (0.9% NSS, i.p., n = 8) or Dox (3 mg/kg, i.p., n = 16). All Dox-treated rats were assigned into 2 groups to receive vehicle (0.9% NSS, orally; n = 8) or ranolazine (305 mg/kg/day, orally; n = 8) for 30 consecutive days. Following the treatments, left ventricular (LV) function and cognition were determined. Animals were euthanized, then the heart and brain were collected for further analysis. Dox induced systemic oxidative stress/inflammation, and cardiac injury evidenced by mitochondrial dysfunction, mitochondrial dynamic imbalance, and apoptosis, resulting in LV dysfunction. Ranolazine significantly improved LV function via attenuating cardiac injury. Dox also caused brain pathologies as indicated by increased brain inflammation, impaired blood-brain barrier integrity, brain mitochondrial dysfunction, microglial dysmorphology, hippocampal dysplasticity, and increased apoptosis, resulting in cognitive decline. Ranolazine exerted neuroprotective effects by suppressing brain pathologies and restoring cognitive function. These findings suggest that ranolazine has a potential role in cardio- and neuro-protection against chemotherapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mitochondrial abnormalities in the brain are considered early pathological changes in neurogenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). The mitochondrial dysfunction in the brain can be induced by toxic proteins, including amyloid-beta (Aβ), phosphorylated tau, alpha-synuclein (α-syn) and mutant huntingtin (mtHTT). These proteins cause mitochondrial genome damage, increased oxidative stress, decreased mitochondrial membrane permeability, and diminished ATP production. Consequently, synaptic dysfunction, synaptic loss, neuronal apoptosis, and ultimately cognitive impairment are exhibited. Therefore, the restoration of mitochondrial abnormalities in the brain is an alternative intervention to delay the progression of neurodegenerative diseases in addition to reducing the level of toxic proteins, especially Aβ, and restored synaptic dysfunction by interventions. Here we comprehensively review mitochondrial alterations in the brain of neurodegenerative models, specifically AD, PD and HD, from both in vitro and in vivo studies. Additionally, the correlation between mitochondrial changes, cognitive function, and disease progression from in vivo studies is described. This review also summarizes interventions that possibly attenuate mitochondrial abnormalities in AD, PD and HD models from both in vitro and in vivo studies. This may lead to the introduction of novel therapies that target on brain mitochondria to delay the progression of AD, PD and HD., (Copyright © 2020 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)