Treadmill exercise ameliorates chemotherapy-induced memory impairment through Wnt/ß-catenin signaling pathway.

Doxorubicin (DOX) is a widely used chemotherapy drug for various cancers and it is known to induce cognitive impairment. The aim of this study was to investigate the effect of treadmill exercise on chemotherapy-induced memory impairment. We assessed whether DOX affects inflammation, mitochondrial Ca2+ retention capacity, and Wnt/ß-catenin signaling. Male Sprague-Dawley rats were divided into control group, exercise group, DOX-injection group, and DOX-injection and exercise group. To create a DOX-induced memory impairment model, animals were injected intraperitoneally with DOX (2 mg/kg) dissolved in saline solution once a week for 4 weeks. Treadmill exercise was performed once a day, 5 days a week, for 8 consecutive weeks. Short-term memory was determined using the step-down avoidance test. Western blot was performed for the proinflammatory cytokines, Wnt/ß-catenin signaling, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) in the hippocampus. Mitochondrial Ca2+ retention capacity in the hippocampus was also measured. DOX-injection rats showed deterioration of short-term memory along with decreased expression of BDNF and TrkB in the hippocampus. Levels of the proinflammatory cytokines, tumor necrosis factor-α and interleukin-6, were increased in the DOX-injection rats. Wnt/ß-catenin signaling was activated and mitochondrial Ca2+ retention capacity was decreased in the DOX-injection rats. However, treadmill exercise alleviated short-term memory impairment, decreased proinflammatory cytokines, increased BDNF and TrkB expression, and enhanced mitochondrial Ca2+ retention capacity. Treadmill exercise restorated Wnt/ß-catenin signaling pathway. This study demonstrated that treadmill exercise can be used for patients undergoing chemotherapy with DOX.

Study on the pathogenesis of liver injury caused by alcohol and drugs.

In the present study, alcohol, lipopolysaccharide (LPS), and carbon tetrachloride (CCL4) were administered to experimental mice. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 concentrations, and collagen type 1alpha (COL-1A) and fibronectin expressions were measured to evaluate pathophysiology of liver injury. Levels of ALT and AST were significantly increased by alcohol treatment. Alcohol with LPS treatment increased ALT and AST levels more than alcohol alone treatment, but it was not statistically significant. Alcohol with CCL4 treatment significantly increased ALT and AST levels more than alcohol alone treatment. Alcohol with LPS and CCL4 treatment significantly increased ALT and AST levels more than alcohol with CCL4 treatment. Concentrations of TNF-α, IL-1ß, and IL-6 were significantly enhanced by alcohol treatment. Alcohol with LPS treatment significantly enhanced concentrations of TNF-α, IL-1ß, and IL-6 more than alcohol alone treatment. Alcohol with CCL4 treatment significantly enhanced TNF-α, IL-1ß, and IL-6 concentrations more than alcohol alone treatment. Alcohol with LPS and CCL4 treatment increased TNF-α, IL-1ß, and IL-6 concentrations more than alcohol with CCL4 treatment, but it was not statistically significant. COL-1A and fibronectin expressions were significantly increased by alcohol treatment. Alcohol with LPS treatment significantly increased COL-1A and fibronectin expressions more than alcohol alone treatment. Alcohol with CCL4 treatment significantly increased COL-1A and fibronectin expressions more than alcohol alone treatment. Alcohol with LPS and CCL4 treatment increased COL-1A and fibronectin expressions more than alcohol with CCL4 treatment, but it was not statistically significant.

Development of Folate-Functionalized PEGylated Zein Nanoparticles for Ligand-Directed Delivery of Paclitaxel.

In this study, we investigated the active targeted delivery of a hydrophobic drug, paclitaxel (PTX), via receptor-mediated endocytosis by folate receptors expressed on cancer cells using a protein-based nanoparticle system. PTX was loaded on zein nanoparticles and conjugated with folate (PTX/Zein-FA) to estimate its chemotherapeutic efficacy in folate receptor-expressing KB cancer cells. PTX/Zein-FA nanoparticles were successfully developed, with a nanoparticle size of ~180 nm and narrow polydispersity index (~0.22). Accelerated release of PTX in an acidic environment was observed for PTX/Zein-FA. An in vitro cellular study of PTX/Zein-FAs in KB cells suggested that PTX/Zein-FA improved the cytotoxic activity of PTX on folate receptors overexpressed in cancer cells by inducing proapoptotic proteins and inhibiting anti-apoptotic proteins. In addition, PTX/Zein-FA exhibited anti-migratory properties and could alter the cell cycle profile of KB cells. A549 cells, which are folate receptor-negative cancer cells, showed no significant enhancement in the in vitro cellular activities of PTX/Zein-FA. We describe the antitumor efficacy of PTX/Zein-FA in KB tumor-bearing mice with minimum toxicity in healthy organs, and the results were confirmed in comparison with free drug and non-targeted nanoparticles.

Tailored Black Phosphorus for Erythrocyte Membrane Nanocloaking with Interleukin-1α siRNA and Paclitaxel for Targeted, Durable, and Mild Combination Cancer Therapy.

Several therapeutic nanosystems have been engineered to remedy the shortcomings of cancer monotherapies, including immunotherapy (stimulating the host immune system to eradicate cancer), to improve therapeutic efficacy with minimizing off-target effects and tumor-induced immunosuppression. Light-activated components in nanosystems confer additional phototherapeutic effects as combinatorial modalities; however, systemic and thermal toxicities with unfavorable accumulation and excretion of nanoystem components now hamper their practical applications. Thus, there remains a need for optimal multifunctional nanosystems to enhance targeted, durable, and mild combination therapies for efficient cancer treatment without notable side effects. Methods: A nanosystem constructed with a base core (poly-L-histidine [H]-grafted black phosphorus [BP]) and a shell (erythrocyte membrane [EM]) is developed to offer a mild photoresponsive (near-infrared) activity with erythrocyte mimicry. In-flight electrostatic tailoring to extract uniform BP nanoparticles maintains a hydrodynamic size of <200 nm (enabling enhanced permeability and retention) after EM cloaking and enhances their biocompatibility. Results: Ephrin-A2 receptor-specific peptide (YSA, targeting cancer cells), interleukin-1α silencing small interfering RNA (ILsi, restricting regulatory T cell trafficking), and paclitaxel (X, inducing durable chemotherapeutics) are incorporated within the base core@shell constructs to create BP-H-ILsi-X@EM-YSA architectures, which provide a more intelligent nanosystem for combination cancer therapies. Conclusion: The in-flight tailoring of BP particles provides a promising base core for fabricating <200 nm EM-mimicking multifunctional nanosystems, which could be beneficial for constructing smarter nanoarchitectures to use in combination cancer therapies.

Regulatory T Cells Tailored with pH-Responsive Liposomes Shape an Immuno-Antitumor Milieu against Tumors.

Cell-based delivery platforms have received great interest in recent years and have been indicated as a promising strategy for cancer immunotherapy. Despite their wide applications in the clinical and preclinical stages, their concomitant viability and efficacy remain major issues. Herein, a strategy for harnessing regulatory T (Treg) cells is developed as an actively targeting drug-delivery system to transport drug-loaded liposomes to the desired tumor sites via conjugating liposomes on the surface of Treg cells. Under the guidance of tumor-oriented chemokines, liposome-anchored Treg cells can be leveraged to migrate and infiltrate the acidic tumor microenvironment, where pH-sensitive liposomes release the loaded cargos [comprising interleukin-2, programmed cell death ligand 1 antibody (PD-L1), and imiquimod], provoke dramatic dendritic cell maturation, block the PD-1/PD-L1 immune-checkpoint, elevate the frequency of infiltrating CD8+ effector T cells, and collectively contribute to potent inhibition of in situ and metastatic tumors. Here, the findings suggest a potential approach that offers a simple, robust, and safe insight into the tuning of Treg cells as an encouraging vector for augmenting cancer immunotherapy.

Impact of Several Types of Stresses on Short-term Memory and Apoptosis in the Hippocampus of Rats.

PURPOSE: Stress has a deteriorating effect on hippocampal function. It also contributes to symptom exacerbation in many disease states, including overactive bladder and interstitial cystitis/bladder pain syndrome. We investigated the effects of various types of stresses (restraint, noise, and cold) on short-term memory and apoptosis in relation with corticotropin-releasing factor (CRF) expression. METHODS: Rats in the restraint stress group were restrained in a transparent Plexiglas cylinder for 60 minutes twice daily. Rats in the noise stress group were exposed to the 120 dB supersonic machine sound for 60 minutes twice daily. Rats in the cold stress group were placed in a cold chamber at 4℃ for 60 minutes twice daily. Each stress was applied for 10 days. A step-down avoidance test for short-term memory, immunohistochemistry for caspase-3 expression, and western blot analysis for Bax and Bcl-2 expressions were conducted. RESULTS: Latency time was decreased and CRF expression in the hippocampal dentate gyrus and hypothalamic paraventricular nucleus were increased in all of the stress groups. The number of caspase-3-positive cells in the hippocampal dentate gyrus was increased and the expressions of Bax and Bcl2 in the hippocampus were decreased in all of the stress groups. CONCLUSIONS: All of the stress groups experienced short-term memory impairment induced by apoptosis in the hippocampus. The present results suggest the possibility that these stresses affecting the impairment of short-term memory may also induce functional lower urinary tract disorders.

Swimming: effects on stress urinary incontinence and the expression of nerve growth factor in rats following transabdominal urethrolysis.

PURPOSE: Stress urinary incontinence (SUI) commonly occurs in women, and it has an enormous impact on quality of life. Surgery, drugs, and exercise have been recommended for the treatment of this disease. Among these, exercise is known to be effective for the relief of symptoms of SUI; however, the efficacy and underlying mechanisms of the effect of exercise on SUI are poorly understood. We investigated the effect of swimming the symptom of SUI in relation to the expression of nerve growth factor (NGF) in rats. METHODS: Transabdominal urethrolysis was used to induce SUI, in Sprague-Dawley rats. The experimental groups were divided into the following three groups: sham-operation group, transabdominal urethrolysis-induced group, and transabdominal urethrolysis-induced and swimming group. The rats in the swimming group were forced to swim for 30 minutes once daily starting 2 weeks after SUI induction and continuing for 4 weeks. For this study, determination of abdominal leak point pressure and immunohistochemistry for NGF in the urethra and in the neuronal voiding centers (medial preoptic nucleus [MPA], ventrolateral periaqueductal gray [vlPAG], pontine micturition center [PMC], and spinal cord [L4-L5]) were performed. RESULTS: Transabdominal urethrolysis significantly reduced the abdominal leak point pressure, thereby contributing to the induction of SUI. Abdominal leak point pressure, however, was significantly improved by swimming. The expression of NGF in the urethra and in the neuronal voiding centers (MPA, vlPAG, PMC, and L4-L5) relating to micturition was enhanced by the induction of SUI. Swimming, however, significantly suppressed SUI-induced NGF expression. CONCLUSIONS: Swimming alleviated symptoms of transabdominal urethrolysis-induced SUI, as assessed by an increase in abdominal leak point pressure. The underlying mechanisms of these effects of swimming might be ascribed to the inhibitory effect of swimming on NGF expression.

Pep-1 Peptide-modified liposomal carriers for intracellular delivery of gold nanoparticles.

A Pep-1 peptide-modified liposomal (Pep1-Lipo) carrier system was investigated to increase the intracellular delivery of gold nanoparticles (Au NPs). Au NPs with a mean diameter of 13 nm were successfully encapsulated into the inner aqueous compartment of the novel carrier using an ethanol injection technique, reserving the distinctive optical characteristics of the surface plasmon resonance peak around 530 nm. The Au NP-loaded liposomal carrier was physically characterized as 150-170 nm in size and 45 mV in zeta potential. Dark field microscopic observation demonstrated that in vitro cellular association and/or translocation of the nanoprobes into the cells was increased by Pep1-Lipo carriers compared to bare Au NPs. In conclusion, this novel liposomal formulation is a promising platform for the intracellular delivery of metallic nanoprobes including Au NPs.

Treadmill exercise inhibits traumatic brain injury-induced hippocampal apoptosis.

Traumatic brain injury (TBI) occurs when an outside force impacts the brain. The main problem associated with TBI is neuronal cell death of the brain, and the outcome of TBI ranges from complete recovery to permanent disability, and sometimes death. Physical exercise is known to ameliorate neurologic impairment induced by various brain insults. In the present study, we investigated the effects of treadmill exercise on short-term memory and apoptosis in the hippocampus following TBI in rats. TBI was induced by an electromagnetic-controlled cortical impact. The rats in the exercise group were forced to run on a treadmill for 30min once daily for 10 consecutive days, beginning 2days after induction of TBI. For the current study, a step-down avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, Western blot for Bcl-2 and Bax, and immunohistochemistry for caspase-3 were conducted. The present results revealed that TBI impaired short-term memory, and increased DNA fragmentation and caspase-3 expression in the hippocampus. Induction of TBI also enhanced expression of pro-apoptotic factor Bax protein and suppressed expression of anti-apoptotic factor Bcl-2 protein in the hippocampus. Treadmill exercise alleviated short-term memory impairment, and decreased DNA fragmentation and caspase-3 expression in the hippocampus. In addition, treadmill exercise remarkably suppressed expression of Bax protein and slightly increased expression of Bcl-2 protein in TBI-induced rats. The present study showed that treadmill exercise might overcome TBI-induced apoptotic neuronal cell death, thus facilitating recovery following TBI.

Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus.

Aging leads to functional changes in the hippocampus, and consequently induces cognitive deficits, such as failure of memory. Neurogenesis in the hippocampal dentate gyrus continues throughout life, but steadily declines from early adulthood. Apoptosis occurs under various pathologic and physiologic conditions, and excessive apoptotic cell death can cause a number of functional disorders in humans. Apoptosis in the hippocampus also disturbs cognitive functions. In this study, we examined the effect of treadmill exercise on memory in relation to neurogensis and apoptosis in the hippocampal dentate gyrus of old-aged rats. The present results showed that loss of memory by aging was associated with a decrease in neurogenesis and an increase in apoptosis in the hippocampal dentate gyrus. Treadmill exercise improved short-term and spatial memories by enhancing neurogenesis and suppressing apoptosis in the hippocampal dentate gyrus of old-aged rats. In the present study, we showed that treadmill exercise is a very useful strategy for preventing failure of memory in the elderly.

Effects of treadmill exercise on memory and c-Fos expression in the hippocampus of the rats with intracerebroventricular injection of streptozotocin.

Alzheimer's disease is a progressive neurodegenerative disease clinically characterized by dementia and neurobehavioral deterioration. Hippocampal neurons are vulnerable to injury induced by Alzheimer's disease. The immediate early gene c-Fos has been used as a marker of neuronal activity. In the present study, we investigated the effects of treadmill exercise on long-term memory capacity and c-Fos expression in the hippocampus of rats with Alzheimer's disease. The rat model of Alzheimer's disease used in the present study was induced by the intracerebroventricular (ICV) injection of streptozotocin (STZ) using a stereotaxic instrument. The rats in the exercise group were forced to run on a treadmill for 30 min once daily for 14 consecutive days starting at 3 days after the ICV injection of STZ. The results of the present study showed that ICV injection of STZ impaired long-term memory capacity and decreased the number of c-Fos-positive cells in several regions of the rat hippocampus. However, treadmill exercise alleviated long-term memory deficits and enhanced c-Fos expression in the rats with ICV injection of STZ. The results of the present study showed that treadmill exercise could be a useful strategy for treating several neurodegenerative diseases.

Effect of postnatal treadmill exercise on c-Fos expression in the hippocampus of rat pups born from the alcohol-intoxicated mothers.

Maternal alcohol-intoxication during pregnancy exerts detrimental effects on fetal development and is known to influence learning ability and memory capability by altering neuronal activity in the hippocampus. c-Fos expression represents neuronal activity and plays a crucial role in the brain development. Physical exercise is known to enhance neuronal plasticity and activity. In the present study, we investigated the influence of postnatal treadmill running on the c-Fos expression in the hippocampus of rat pups born from the alcohol-intoxicated mothers. The results obtained show that maternal alcohol-intoxication suppressed c-Fos expression in the hippocampus of rat pups and that postnatal treadmill exercise enhanced c-Fos expression in the hippocampus of these rat pups. The present study suggests that exercise should be considered as a therapeutic means of countering the effects of maternal alcohol-intoxication, and that it may provide a useful strategy for enhancing the neuronal activity of children born from the mothers who abuse alcohol during pregnancy.