Pirfenidone improves voiding function by suppressing bladder fibrosis in underactive bladder rats.

Underactive bladder (UAB), characterized by a complex set of symptoms with few treatment options, can significantly reduce the quality of life of affected people. UAB is characterized by hyperplasia and fibrosis of the bladder wall as well as decreased bladder compliance. Pirfenidone is a powerful anti-fibrotic agent that inhibits the progression of fibrosis in people with idiopathic pulmonary fibrosis. In the current study, we evaluated the efficacy of pirfenidone in the treatment of bladder fibrosis in a UAB rat model. UAB was induced by crushing damage to nerve bundles in the major pelvic ganglion. Forty-two days after surgery, 1 mL distilled water containing pirfenidone (100, 300, or 500 mg/kg) was orally administered once every 2 days for a total of 10 times for 20 days to the rats in the pirfenidone-treated groups. Crushing damage to the nerve bundles caused voiding dysfunction, resulting in increased bladder weight and the level of fibrous related factors in the bladder, leading to UAB symptoms. Pirfenidone treatment improved urinary function, increased bladder weight and suppressed the expression of fibrosis factors. The results of this experiment suggest that pirfenidone can be used to ameliorate difficult-to-treat urological conditions such as bladder fibrosis. Therefore, pirfenidone treatment can be considered an option to improve voiding function in patient with incurable UAB.

Effects of Transcranial Direct Current Stimulation on Clinical Features of Dizziness and Cortical Activation in a Patient with Vestibular Migraine.

BACKGROUND: Vestibular migraine (VM) is common migraine that occurs in patients with dizziness. Vestibular rehabilitation for managing VM generally remains unclear. Recently, it has been reported that transcranial direct current stimulation (tDCS) has positive effects in alleviating dizziness. This study investigated the effects of tDCS on dizziness and cortical activation in a patient with VM. METHODS: We recruited a male patient aged 31 years with no dizziness. The patient watched a video to induce dizziness using a virtual reality device. The study applied the intervention using tDCS for 4 weeks and measured 4 assessments: functional near-infrared spectroscopy (fNIRS), quantitative electroencephalography (qEEG), dizziness handicap inventory, and visual vertigo analog scale. RESULTS: We showed the activation in the middle temporal gyrus and inferior temporal gyrus (ITG) of the left hemisphere and in the superior temporal gyrus and ITG of the right hemisphere in the pre-intervention. After the intervention, the activation of these areas decreased. In the results of qEEG, excessive activation of C3, P3, and T5 in the left hemisphere and C4 in the right hemisphere before intervention disappeared after the intervention. CONCLUSIONS: This study indicated that tDCS-based intervention could be considered a viable approach to treating patients with vestibular dysfunction and dizziness caused by VM.

Physiotherapy strategies for functional improvement in a child with complicated hereditary spastic paraplegia: 1-year follow-up of a case report using a changing criterion design.

BACKGROUND: and Purpose: Hereditary spastic paraplegias (HSP) are a group of clinically diverse genetic disorders that share the neurologic symptom of difficulty in walking due to progressive serious muscle weakness and spasticity in the legs. This study describes a physiotherapy program for improving the functional ability of a child diagnosed with complicated HSP and reports the treatment results. METHODS: A 10-year-old boy with complicated HSP received a physiotherapy intervention that included strengthening of the leg muscles and treadmill training for 1 h per session, three to four times a week for 6 weeks. Outcome measures included sit-to-stand, 10-m walk, 1-min walk tests, and gross motor function measures (dimensions D and E). RESULTS: After the intervention, the sit-to-stand, 1-min walk, and 10-m walk test scores improved by 6.75 times, 2.57 m, and 0.05 m/s, respectively. Furthermore, the gross motor function measure dimensions D and E scores improved by 8% (46%-54%) and 5% (22%-27%), respectively. The gains in each parameter were maintained at the 3- and 6-month and 1-year follow-ups. CONCLUSION: These results suggest that structured physiotherapy programs can benefit the functional rehabilitation of children with complicated HSP.

Alternating mealtimes during pregnancy and weaning triggers behavioral changes in adult offspring.

In brief: Mealtime changes in pregnant mice revealed impaired neurobehavioral development in mouse offspring. This study is the basis for investigating diseases associated with neurobehavioral development of adult offspring of pregnant shift-working women. Abstract: Most organisms on Earth have a biological clock, and their physiological processes are regulated by a 1-day cycle. In modern society, several factors can disturb these biological clocks in humans; in particular, individuals working in shifts are exposed to stark environmental changes that interfere with their biological clock. They have a high risk of various diseases. However, there are scarce experimental approaches to address the reproductive and health consequences of shift work in the offspring of exposed individuals. In this study, considering the fact that shift workers usually have their meals during their adjusted working time, we aimed to examine the effects of a 12-h shift with usual mealtime as a plausible night work model on the neurobehavioral development of adult mouse offspring. In these offspring, early exposure to this mealtime shift differentially affected circadian rhythmic variables and total locomotor activity depending on the timing and duration of restrictive feeding. Moreover, neurobehavioral alterations such as declined short-term memory and depressive-like behavior were observed in adulthood. These results have implications for the health concerns of shift-working women and their children.

Effects of exercise and microbiota transplant on the memory of obesity-induced mice.

This study attempted to investigate the association between changes in the intestinal environment and the brain using a model that received aerobic exercise and microbiome transplantation. All mice were fed a diet containing 60% fat. For the obesity with nonexercise microbiome transplantation group, feces from donors that did not undergo exercise were administered. For the obesity with exercise microbiome trans-plantation group, feces from donors who underwent exercise were administered. Treadmill exercise started 16 weeks after the intake of the high fat feeding and continued for 24 weeks. The short-term memory and spatial learning memory were determined by step-down avoidance test and Morris water maze task, immunohistochemistry for glial fibrillary acidic protein, western blot analysis for brain-derived neurotrophic factor and tropomyosin receptor kinase B were performed in the hippocampus. Exercise was the most effective way to reduce obesity, improve memory function, suppress inflammation, and increase brain-derived neurotrophic factor expression. Intestinal microbiota transplantation was the second most effective after exercise. However, there was no significant difference in the fecal microbiota transplant group according to whether or not exercise was performed.

Exercise with 40-Hz light flicker improves hippocampal insulin signaling in Alzheimer disease mice.

We examined whether exercise is associated with hippocampus-mediated improvement in insulin signaling and cell differentiation in the triple transgenic mouse model of Alzheimer disease (3xTg AD) murine model following exposure to 40-Hz light flickering and exercise. We subjected 12-month-old 3xTg AD mice to exercise and 40-Hz light flickering for 3 months. The exercise session was proceeded for 12 consecutive weeks with gradual increase of intensity. To investigate insulin signaling proteins, western blot was conducted to detect the ratio of phosphorylated insulin receptor ß (p-IRß)/total IRß (t-IRß), phosphorylated insulin receptor substrate 1 (p-IRS-1)/total IRS-1 (t-IRS-1), phosphorylated phosphatidylinositide-3-kinase (p-PI3K)/total PI3K (t-PI3K), phosphorylated 3-phosphoinositide dependent protein kinase-1 (p-PDK1)/total PDK-1 (t-PDK1), phosphorylated protein kinase B (p-Akt)/total-Akt (t-Akt), and phosphorylated glycogen synthase kinase 3 beta (p-GSK3ß)/total GSK3ß (t-GSK3ß). Doublecortin immunohistochemistry was performed for assessing cell differentiation in the hippocampus. Treatments exerted a positive effect. The combination of exercise and 40-Hz light flickering exposure was the most effective treatment enhancing insulin signaling. Increased ratio of p-IRß/t-IRß, p-IRS-1/t-IRS-1, p-PI3K/t-PI3K, p-PDK1/t-PDK1, p-Akt/t-Akt, and p-GSK3ß/t-GSK3ß and enhanced cell differentiation were observed in the 3xTg AD with exercise under 40-Hz light flickering group. Our results indicate that exercise under 40-Hz light flickering most potently improved insulin signaling, thereby promoted cell differentiation.

Mealtime shift delays conception in mice.

The physiological processes of organisms in this rotating planet can adjust according to the time of day via built-in circadian clocks. However, more people are having different shift works, which can increase the risk of pathological conditions including altered reproductive function. Thus, circadian rhythm disturbance has become prevalent in the modern society. Specifically, epidemiological evidence has shown that shift-working women are at high risk of spontaneous abortions, irregular menstrual cycles, and low-birth-weight babies. The current study aimed to investigate the effects of circadian rhythm disturbances on the reproductive function of mice caused by dietary time shift, which is common among night-shift workers. According to the schedule of restricted feeding, the mice were classified into the free feeding, daytime feeding, and night feeding groups. The fertility indices of each group were then evaluated. Activity monitoring was performed to determine whether pregnancy delay might be attributed to mealtime shift. Moreover, the estrous cycle of female mice and the reproductive phenotype of male mice were investigated. Results showed that a 12-h mealtime shift significantly delayed successful conception, which could be attributed to a disrupted estrous cycle, in adult female mice.

Combined effects of aerobic exercise and 40-Hz light flicker exposure on early cognitive impairments in Alzheimer's disease of 3×Tg mice.

Alzheimer's disease (AD) is a progressive degenerative brain disease and the primary cause of dementia. At an early stage, AD is generally characterized by short-term memory impairment, owing to dysfunctions of the cortex and hippocampus. We previously reported that a combination of exercise and 40-Hz light flickering can protect against AD-related neuroinflammation, gamma oscillations, reduction in Aß, and cognitive decline. Therefore, we sought to extend our previous findings to the 5-mo-old 3×Tg-AD mouse model to examine whether the same favorable effects occur in earlier stages of cognitive dysfunction. We investigated the effects of 12 wk of exercise combined with 40-Hz light flickering on cognitive function by analyzing neuroinflammation, mitochondrial function, and neuroplasticity in the hippocampus in a 3×Tg-AD mouse model. Five-month-old 3×Tg-AD mice performed 12 wk of exercise with 40-Hz light flickering administered independently and in combination. Spatial learning and memory, long-term memory, hippocampal Aß, tau, neuroinflammation, proinflammatory cytokine expression, mitochondrial function, and neuroplasticity were analyzed. Aß and tau proteins levels were significantly reduced in the early stage of AD, resulting in protection against cognitive decline by reducing neuroinflammation and proinflammatory cytokines. Furthermore, mitochondrial function improved, apoptosis was reduced, and synapse-related protein expression increased. Overall, exercise with 40-Hz light flickering was significantly more effective than exercise or 40-Hz light flickering alone, and the improvement was comparable to the levels in the nontransgenic aged-match control group. Our results indicate a synergistic effect of exercise and 40-Hz light flickering on pathological improvements in the hippocampus during early AD-associated cognitive impairment.NEW & NOTEWORTHY Exercising in a 40-Hz light flicker environment was more effective than exercise or 40-Hz light flicker alone. This synergistic effect may prevent cognitive dysfunction by inhibiting Aß, tau pathway, and neuroinflammation and enhancing neuroplasticity and mitochondrial functions in the hippocampus during early Alzheimer's disease.

An Extracellular Matrix-Liposome Composite, a Novel Extracellular Matrix Delivery System for Accelerated Tissue Regeneration.

The unfolded states of fibronectin (FN) subsequently induce the formation of an extracellular matrix (ECM) fibrillar network, which is necessary to generate new substitutive tissues. Here, the authors demonstrate that negatively charged small unilamellar vesicles (SUVs) qualify as candidates for FN delivery due to their remarkable effects on the autonomous binding and unfolding of FN, which leads to increased tissue regeneration. In vitro experiments revealed that the FN-SUV complex remarkably increased the attachment, differentiation, and migration of fibroblasts. The potential utilization of this complex in vivo to treat inflammatory colon diseases is also described based on results obtained for ameliorated conditions in rats with ulcerative colitis (UC) that had been treated with the FN-SUV complex. Their findings provide a new ECM-delivery platform for ECM-based therapeutic applications and suggest that properly designed SUVs may be an unprecedented FN-delivery system that is highly effective in treating UC and inflammatory bowel diseases.

Polydeoxyribonucleotide ameliorates alcoholic liver injury though suppressing phosphatidylinositol 3-kinase/protein kinase B signaling pathway in mice.

Polydeoxyribonucleotide (PDRN), which is adenosine A2A receptor agonist, facilitates healing and inhibits inflammation and apoptosis. The effect of PDRN on alcoholic liver injury (ALI) was evaluated focusing on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. The mice were given daily oral administration of 50% ethanol at a dose of 4 g/kg during 8 weeks. After 4 weeks of alcohol intake, 200 µL of normal saline containing 8-mg/kg PDRN was intraperitoneally administered 3 times a week for 4 weeks. To determine whether the action of PDRN occurs through the adenosine A2A receptor, 8-mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX) with PDRN was treated. The concentration of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was detected. For liver histopathological score, hematoxylin and eosin staining was conducted. Enzyme-linked immunoassay was used to measure cyclic adenosine-3',5'-monophosphate (cAMP) concentration. PI3K and Akt expression was determined using Western blot analysis. In the results, PDRN treatment suppressed AST and ALT level in serum and liver tissue, and improved damaged liver tissue and decreased histological score. PDRN application inhibited the expression of phosphorylated PI3K/Akt signaling pathway. The increasing effect of PDRN on cAMP level ats as a mechanism for ALI treatment. Co-treatment of DMPX with PDRN did not reduce apoptosis, causing no improvement in liver function. As a result of this experiment, PDRN has the potential to be selected as a therapeutic agent for ALI.

Maternal Swimming Exercise During Pregnancy Improves Memory Through Enhancing Neurogenesis and Suppressing Apoptosis via Wnt/ß-Catenin Pathway in Autistic Mice.

PURPOSE: Wnt pathway is closely related to neurodevelopmental process associated with cognitive function. After administration of valproic acid to the pregnant mice, the effect of swimming exercise of pregnant mice on the memory, neuronal production, and apoptosis of pups was studied in relation with Wnt/ß-catenin signaling pathway. METHODS: On day 12 of pregnancy, mice were injected subcutaneously with 400-mg/kg valproic acid. The pregnant mice in the control with swimming exercise group and in the valproic acid injection with swimming exercise group were allowed for swimming for 30 minutes one time per a day, repeated 5 days per a week, during 3 weeks. Step-through avoidance task and Morris water maze task for memory function, immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU)-positive cells and western blot for brain-derived neurotrophic factor (BDNF), Wnt, ß-catenin, Bcl-2 related X protein (Bax), B-cell lymphoma 2 (Bcl-2), cleaved caspase-3 were carried out. RESULTS: Maternal swimming exercise during pregnancy improved memory function, increased BDNF expression, and neuronal proliferation in the valproic acid injected pups. Maternal swimming exercise during pregnancy suppressed Wnt expression and phosphorylation of ß-catenin in the valproic acid injected pups. Maternal swimming exercise inhibited Bax and cleaved caspase-3 expression and increased Bcl-2 expression in the valproic acid injected pups. CONCLUSION: Maternal swimming exercise during pregnancy improved memory function by increasing cell proliferation and inhibiting apoptosis through Wnt/ß-catenin signaling cascade activation in the valproic acid injected pups. Maternal swimming exercise during pregnancy may have a protective effect on factors that induce autism in the fetus.

Adenosine A2A receptor agonist polydeoxyribonucleotide ameliorates short-term memory impairment by suppressing cerebral ischemia-induced inflammation via MAPK pathway.

Cerebral ischemia causes tissue death owing to occlusion of the cerebral blood vessels, and cerebral ischemia activates mitogen-activated protein kinase (MAPK) and induces secretion of pro-inflammatory cytokines. Adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), suppresses the secretion of pro-inflammatory cytokines and exhibits anti-inflammatory effect. In the current study, the therapeutic effect of PDRN on cerebral ischemia was evaluated using gerbils. For the induction of cerebral ischemia, the common carotid arteries were exposed, and then aneurysm clips were used to occlude the common carotid arteries bilaterally for 7 minutes. In the PDRN-treated groups, the gerbils were injected intraperitoneally with 0.3 mL of saline containing 8 mg/kg PDRN, per a day for 7 days following cerebral ischemia induction. In order to confirm the participation of the adenosine A2A receptor in the effects mediated by PDRN, 8 mg/kg 7-dimethyl-1-propargylxanthine (DMPX), adenosine A2A receptor antagonist, was treated with PDRN. In the current study, induction of ischemia enhanced the levels of pro-inflammatory cytokines and increased phosphorylation of MAPK signaling factors in the hippocampus and basolateral amygdala. However, treatment with PDRN ameliorated short-term memory impairment by suppressing the production of pro-inflammatory cytokines and inactivation of MAPK signaling factors in cerebral ischemia. Furthermore, PDRN treatment enhanced the concentration of cyclic adenosine-3,5'-monophosphate (cAMP) as well as phosphorylation of cAMP response element-binding protein (p-CREB). Co-treatment of DMPX and PDRN attenuated the therapeutic effect of PDRN on cerebral ischemia. Based on these findings, PDRN may be developed as the primary treatment in cerebral ischemia.

Adenosine A2A Receptor Agonist Polydeoxyribonucleotide Alleviates Interstitial Cystitis-Induced Voiding Dysfunction by Suppressing Inflammation and Apoptosis in Rats.

BACKGROUND: Interstitial cystitis (IC) is a chronic disorder that indicates bladder-related pain or discomfort. Patients with IC often experience urination problems, such as urinary frequency and urgency, along with pain or discomfort in the bladder area. Therefore, new treatments based on IC etiology are needed. Polydeoxyribonucleotide (PDRN) is a biologic agonist of the adenosine A2A receptor, and PDRN has anti-inflammatory effect and inhibits apoptosis. In the current study, the effect of PDRN on cyclophosphamide-induced IC animal model was investigated using rats. METHODOLOGY: To induce the IC animal model, 75 mg/kg of cyclophosphamide was injected intraperitoneally once every 3 days for 10 days. The rats in the PDRN-treated groups were intraperitoneally injected with 0.5 mL physiological saline containing 8 mg/kg PDRN, once a day for 10 days after IC induction. RESULTS: Induction of IC by cyclophosphamide injection caused voiding dysfunction, bladder edema, and histological damage. Cyclophosphamide injection increased secretion of pro-inflammatory cytokines and enhanced apoptosis. In contrast, PDRN treatment alleviated voiding dysfunction, bladder edema, and histological damage. Secretion of pro-inflammatory cytokines and expressions of apoptotic factors were suppressed by PDRN treatment. These changes indicate that treatment with PDRN improves voiding function by ultimately promoting the repair of damaged bladder tissue. CONCLUSION: The conclusion of this experiment suggests the possibility that PDRN could be used as an effective therapeutic agent for IC.

Moderate aerobic exercise training ameliorates impairment of mitochondrial function and dynamics in skeletal muscle of high-fat diet-induced obese mice.

The purpose of this study is to determine whether moderate aerobic exercise training improves high-fat diet-induced alterations in mitochondrial function and structure in the skeletal muscle. Male 4-week-old C57BL/6 mice were randomly divided into four groups: control (CON), control plus exercise (CON + EX), high-fat diet (HFD), and high-fat diet plus exercise (HFD + EX). After obesity was induced by 20 weeks of 60% HFD, treadmill exercise training was performed at 13-16 m/min, 40-50 min/day, and 6 days/week for 12 weeks. Mitochondrial structure, function, and dynamics, and mitophagy were analyzed in the skeletal muscle fibers from the red gastrocnemius. Exercise training increased mitochondrial number and area and reduced high-fat diet-induced obesity and hyperglycemia. In addition, exercise training attenuated mitochondrial dysfunction in the permeabilized myofibers, indicating that HFD-induced decrease of mitochondrial O2 respiration and Ca2+ retention capacity and increase of mitochondrial H2 O2 emission were attenuated in the HFD + EX group compared to the HFD group. Exercise also ameliorated HFD-induced imbalance of mitochondrial fusion and fission, demonstrating that HFD-induced decrease in fusion protein levels was elevated, and increase in fission protein levels was reduced in the HFD + EX groups compared with the HFD group. Moreover, dysregulation of mitophagy induced by HFD was mitigated in the HFD + EX group, indicating a decrease in PINK1 protein level. Our findings demonstrated that moderate aerobic exercise training mitigated obesity-induced insulin resistance by improving mitochondrial function, and reversed obesity-induced mitochondrial structural damage by improving mitochondrial dynamics and mitophagy, suggesting that moderate aerobic exercise training may play a therapeutic role in protecting the skeletal muscle against mitochondrial impairments and insulin resistance induced by obesity.