Sex-dependent alterations of inflammatory factors, oxidative stress, and histopathology of the brain-gut axis in a VPA-induced autistic-like model of rats.

INTRODUCTION: In this study, we aimed to investigate the inflammatory factors, oxidative stress, and histopathological consequences of the brain-gut axis in male and female rats prenatally exposed to VPA. METHODS: Pregnant Wistar rats were randomly divided into two groups. The animals received saline, and valproic acid (VPA) (600 mg/kg, i.p.) on embryonic day 12.5 (E12.5). All offspring were weaned on postnatal day 21, and the experiments were done in male and female rats on day 60. The brain and intestine tissues were extracted to assess histopathology, inflammation, and oxidative stress. RESULTS: An increase of interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) and a decrease of interleukin-10 (IL-10) were observed in the two sexes and two tissues of the autistic rats. In the VPA-exposed animals, malondialdehyde (MDA) and protein carbonyl (PC) increased in the brain of both sexes and the intestines of only the males. The total antioxidant capacity (TAC), superoxide dismutase (SOD), and catalase (CAT) significantly decreased in both tissues of male and female autistic groups. Histopathological evaluation showed that the %apoptosis of the cortex in the autistic male and female groups was more than in controls whereas this parameter in the CA1 and CA3 was significant only in the male rats. In the intestine, histopathologic changes were seen only in the male autistic animals. CONCLUSION: The inflammatory and antioxidant factors were in line in the brain-gut axis in male and female rats prenatally exposed to VPA. Histopathological consequences were more significant in the VPA-exposed male animals.

The administration of oral mucosal mesenchymal-derived stem cells improves hepatic inflammation, oxidative stress, and histopathology following traumatic brain injury.

BACKGROUND: The inflammatory mediators produced after traumatic brain injury (TBI) are reaching peripheral organs causing organ and tissue damage, including the liver. Our study assessed the effect of intravenous (i.v.) infusion of oral mesenchymal stem cells (OMSCs) on TBI-induced liver damage by measuring liver inflammatory factors and liver oxidative stress. METHODS: Twenty-eight adult male Wistar rats were divided into four groups: 1) sham control; 2) TBI alone (TBI); 3) TBI vehicle (Veh)-control; and 4) TBI with OMSC treatment (SC). OMSCs were obtained from oral mucosa biopsies. OMSCs were administered and administered i.v. at 1 and 24 h after TBI. Within 48 h after TBI, multiple parameters were analyzed, including inflammation, oxidative stress, and histopathological changes. RESULTS: In comparison to sham controls, the TBI alone showed in liver significantly increased levels of interleukin-1ß (IL-1ß; P < 0.001), interleukin-6 (IL-6; P < 0.001), malondialdehyde (MDA; P < 0.001), and protein carbonyl (PC; P < 0.001). At the same time the TBI alone decreased the liver levels of superoxide dismutase (SOD; P < 0.001), total antioxidant capacity (TAC; P < 0.001), catalase (CAT; P < 0.001), and interleukin-10 (IL-10; P < 0.001). In comparison to the TBI alone group, the therapeutic group treated with i.v. infusion of OMSCs demonstrated significantly reduced changes of IL-1ß (P < 0.001), IL-6 (P < 0.01), MDA (P < 0.01), PC (P < 0.05), SOD (P < 0.001), TAC (P < 0.01), CAT (P < 0.01), and IL-10 (P < 0.01). Histopathological evaluation showed in TBI alone group that the total score of liver tissue injury included extensive hydropic degeneration, lobular necrosis, inflammation as well as central vein congestion with subendothelial hemorrhage increased compared the sham group (P < 0.001). Administration of OMSC showed significantly smaller increase in the injury score compared to the TBI alone group (P < 0.001). CONCLUSION: Therapy with i.v. OMSCs administration after TBI reduces liver injury, as measured by inflammation and oxidative stress. The use of OMSCs can be considered for treatment of liver injury caused by TBI.

The effect of low- and moderate-intensity interval training on cognitive behaviors of male and female rats with VPA-induced autism.

Introduction: This study was performed to evaluate the effects of low and moderate treadmill exercise for one month on social interaction, anxiety-like behaviors, and spatial learning and memory in male and female autistic rats. Methods: Pregnant rats received valproic acid (VPA) (600 mg/kg/i.p) once on gestational day 12.5 to induce autism-like symptoms in the offspring. After delivery, the offspring were divided into six main groups, each with male and female subgroups: Control (CTL, prenatal normal saline), autism (prenatal VPA), low-intensity training (LIT,normal saline + low treadmill exercise), moderate -intensity training (MIT, normal saline + moderate treadmill exercise), VPA + LIT, and VPA + MIT. On the 60th day, the offspring were tested by the elevated plus maze (EPM), open field test (OFT), social interaction test (SIT), and Morris water maze (MWM). Results: The results showed that both LIT and MIT could partly alleviate anxiety-like behaviors induced by prenatal VPA exposure in two sexes. Social impairment was observed in the autistic rats and was improved by LIT in both sexes and MIT in females. No significant change was seen in the spatial learning and memory of autistic rats by exercise. Conclusion: The findings suggest that treadmill exercise can be helpful for improving some autism-like behaviors. Further studies are needed to investigate the involved mechanisms.

Sex-related beneficial effects of exercise on cardiac function and rhythm in autistic rats.

BACKGROUND: Cardiovascular diseases are prevalent in autistic patients. As exercise is useful in the treatment of medical conditions, this study aimed to identify the effect of low-intensity endurance exercise (LIEE) and moderate-intensity endurance exercise (MIEE) on cardiovascular events in autistic rats. METHODS: Valproic acid (VPA) was administrated once on gestational day 12.5 to pregnant rats to produce autism-like symptoms in offspring. Thirty-day-old offspring were divided into 12 groups: Male-CTL, Male-VPA, Male-CTL + LIEE, Male-CTL + MIEE, Male-VPA + LIEE, Male-VPA + MIEE, Female-CTL, Female-VPA, Female-CTL + LIEE, Female-CTL + MIEE, Female-VPA + LIEE, and Female-VPA + MIEE. LIEE and MIEE were performed 5 days a week for 30 days. Twenty-four hours after the last exercise session, electrocardiogram and hemodynamic and cardiac function indices were recorded. RESULTS: The results indicated that +dp/dt max and contractility index (CI) decreased in the Female-VPA group compared to the Female-CTL group. LIEE increased these parameters in the Female-VPA + LIEE group. However, MIEE normalized CI in the Male-VPA + MIEE compared to the Male-VPA group. Tau increased in the Female-VPA group compared to the Female-CTL group and it decreased in the Female-VPA + MIEE group compared to the Female-VPA group. LIEE and MIEE recovered the reduction of heart rate and the increase in P, R, and T amplitudes in Male-VPA group. LIEE and MIEE increased heart rate variability in the Male-VPA and Female-VPA groups. CONCLUSIONS: The findings showed that LIEE and MIEE alleviated cardiac dysfunction and disturbances in heart rhythm in the autistic offspring. Exercise may be recommended as a routine program for autistic patients to prevent and treat the harmful cardiovascular consequences of autism.

Effects of varied­intensity endurance exercise training on oxidative and antioxidant factors in the liver of rats with valproic acid­induced autism.

Autism spectrum disorders are complex behavioral disorders that can be caused by exposure to valproic acid (VPA) during pregnancy. A therapeutic role for exercise training has been reported in many neurological diseases and problems, including autism. We aimed to evaluate various intensities of endurance exercise training and investigate its effects on oxidative and antioxidant factors in the liver of young males in a rat model of autism. Female rats were divided into a treatment (autism) and a control group. The autism group received VPA intraperitoneally on day 12.5 of pregnancy and the control pregnant females received saline. On the 30th day post­birth, a social interaction test was performed on the offspring to confirm autistic­like behavior. Offspring were divided into three subgroups: no exercise, mild exercise training, and moderate exercise training. Then the oxidative index of malondialdehyde (MDA) and the antioxidant indices of superoxide dismutase (SOD), total antioxidant capacity (TAC), and catalase in liver tissue were examined. The results of this study showed that both indices of sociability and social novelty decreased in the autism group. MDA levels in the liver of the autistic group increased, and moderate exercise training was shown to reduce the levels. Catalase and SOD activity as well as TAC levels decreased in the autism group, and moderate­intensity exercise training was shown to increase the values. Parameters of hepatic oxidative stress were altered in VPA­induced autism, and moderate­intensity endurance exercise training was demonstrated to have beneficial effects on hepatic oxidative stress factors by modul ating the antioxidant/oxidant ratio.

Beneficial effects of time and energy restriction diets on the development of experimental acute kidney injury in Rat: Bax/Bcl-2 and histopathological evaluation.

People's lifestyles and, especially, their eating habits affect their health and the functioning of the organs in their bodies, including the kidneys. One's diet influences the cells' responses to stressful conditions such as acute kidney injury (AKI). This study aims to determine the preconditioning effects of four different diets: energy restriction (ER) diet, time restriction (TR) eating, intermittent fasting (IF), and high-fat diet (HF) on histopathological indices of the kidney as well as the molecules involved in apoptosis during AKI. Adult male rats underwent ER, TR, IF, and HF diets for eight weeks. Then, AKI was induced, and renal function indices, histopathological indices, and molecules involved in apoptosis were measured. In animals with AKI, urinary albumin excretion, serum urea, creatinine and, Bax/Bcl-2 ratio increased in the kidney, while renal eGFR decreased. ER and TR diets improved renal parameters and prevented an increase in the Bax/Bcl-2 ratio. The IF diet improved renal parameters but had no effect on the Bax/Bcl-2 ratio. On the other hand, the HF diet worsened renal function and increased the Bax/Bcl-2 ratio. Histopathological examination also showed improved kidney conditions in the ER and TR groups and more damage in the HF group. This study demonstrated that ER and TR diets have renoprotective effects on AKI and possibly cause the resistance of kidney cells to damage by reducing the Bax/Bcl-2 ratio and improving apoptotic conditions.

The Prescription of Oral Mucosal Mesenchymal Stem Cells post-Traumatic Brain Injury Improved the Kidney and Heart Inflammation and Oxidative Stress.

Background: In the last years, mesenchymal stem cells (MSCs) have been considered as a useful strategy to treat many diseases such as traumatic brain injury (TBI). The production of inflammatory agents by TBI elicits an inflammatory response directed to other systems of body, such as the heart and the kidneys. In this study, the efficacy of oral mucosal mesenchymal stem cells (OMSCs) prescription after TBI in inflammation and oxidative stress of the heart and kidneys was evaluated. Methods: Twenty-four male rats were located in groups as follows: sham, TBI, vehicle (Veh), and stem cell (SC). OMSCs were injected intravenously 1 and 24 hours after TBI. Inflammatory, oxidative stress, and histopathological outcomes of the heart and kidney tissues were investigated 48 hours after TBI. Results: TBI caused an increase in the level of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), malondialdehyde (MDA), and carbonyl protein (PC) of the heart and kidney compared to the sham group. Superoxide dismutase (SOD), total antioxidant capacity (TAC), catalase (CAT), and interleukin-10 (IL-10) of the heart and kidney decreased after TBI. The use of OMSCs after TBI reduced the changes of these factors in both the heart and the kidney. Conclusion: Application of OMSCs after TBI can decrease inflammation and oxidative stress of the heart and kidney tissues leading to the reduction of damage. Therefore, this method can be evaluated in the TBI patients in future studies.

The effect of two types of diet on apoptosis indexes, lipid profile and histopathological outcome in acute kidney injury during exercise.

BACKGROUND: Exercise and some pre-AKI diets have been shown to improve injury, apoptosis, and lipid profile. In this study, the effect of two different diets along with exercise training on acute kidney injury (AKI) was investigated.  MATERIALS AND METHODS: Laboratory rats were randomly divided into four groups of control, standard diet + exercise, exercise + calorie restriction (CR) and exercise + time restriction (TR). Each group was divided into two subgroups of AKI and no AKI. The animals received endurance training and diet regimens before AKI. Fasting blood glucose, serum creatinine, Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2) and histopathological outcome of renal tissue as well as serum lipid profile of animals were assessed 24 h after AKI.  RESULTS: The percentage of changes in renal Bcl2 and Bax after AKI in the group with previous exercise was lower than the group without previous exercise (p < 0.01). After induction of AKI, serum lipid profile changed in non-exercised rats (p < 0.001). Also, after injury, fasting blood glucose levels increased in non-exercised rats (p < 0.05). After injury, the start of both CR and TR diets during exercise caused less change in Bcl2 and Bax of non-exercised rats compared to exercised rats (p < 0.001). CR diet along with exercise improved lipid profile, and also CR diet along exercise decreased fasting blood glucose levels (p < 0.001). Also, both the CR and TR diets during exercise caused fewer changes in histopathological outcome after AKI. CONCLUSION: Exercise alone decreased changes in apoptotic and histopathological indexes, fasting blood glucose, as well as lipid profile of rats after AKI. Reduction of apoptosis and improvement of histopathological outcome after AKI appeared more when CR and TR diets were commenced during exercise. The reduction of lipid profile changes was more pronounced in the group that received CR diet during exercise.

The Effect of Oral Mucosal Mesenchymal Stem Cells on Pathological and Long-Term Outcomes in Experimental Traumatic Brain Injury.

Background: Neuroprotective effects of stem cells have been shown in some neurologic diseases. In this study, the effect of oral mucosal mesenchymal stem cells (OMSCs) on traumatic brain injury (TBI) was evaluated in long term. Materials and Methods: TBI was induced by Marmarou's method. The number of 2 × 106 OMSCs was intravenously injected 1 and 24 h after the injury. Brain edema and pathological outcome were assessed at 24 h and 21 days after the injury. Besides, long-term neurological, motor, and cognitive outcomes were evaluated at days 3, 7, 14, and 21 after the injury. Results: OMSCs administration could significantly inhibit microglia proliferation, and reduce brain edema and neuronal damage, at 24 h and 21 days after the injury. Neurological function improvement was observed in the times evaluated in OMSCs group. Cognitive and motor function dysfunction and anxiety-like behavior were prevented especially at 14 and 21 days after the injury in the treatment group. Conclusion: According to the results of this study, OMSCs administration after TBI reduced brain edema and neuronal damage, improved neurologic outcome, and prevented memory and motor impairments and anxiety-like behavior in long term.

The effects of exercise on kidney injury: the role of SIRT1.

In patients with kidney injury, muscle mass and strength decrease with altered muscle protein synthesis and degradation along with complications such as inflammation and low physical activity. A treatment strategy to maintain muscle metabolism in kidney injury is important. One of the proposed strategies in this regard is exercise, which in addition to inducing muscle hypertrophy, reducing plasma creatinine and urea and decreasing the severity of tubal injuries, can boost immune function and has anti-inflammatory effects. One of the molecules that have been considered as a target in the treatment of many diseases is silent information regulator 1 (SIRT1). Exercise increases the expression of SIRT1 and improves its activity. Therefore, studies that examined the effect of exercise on kidney injury considering the role of SIRT1 in this effect were reviewed to determine the direction of kidney injury research in future regarding to its prevalence, especially following diabetes, and lack of definitive treatment. In this review, we found that SIRT1 can be one of renoprotective target pathways of exercise. However, further studies are needed to determine the role of SIRT1 in different kidney injuries following exercise according to the type and severity of exercise, and the type of kidney injury.

The effects of two different dietary regimens during exercise on outcome of experimental acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a syndrome characterized by rapid loss of excretory function of kidney. Both exercise and some diets have been shown to increase silent information regulator (SIRT1) expression leading to reduction of kidney injury. In this study, the effect of two different diets during exercise on kidney function, oxidative stress, inflammation and also SIRT1 in AKI was investigated. MATERIALS AND METHODS: A number of rats were randomly divided into four groups; control without exercise, control with exercise, exercise + calorie restriction (CR), and exercise + time restriction (TR). Each group was divided into two subgroups of without AKI and with AKI (six rats in each group). Endurance exercise and diets were implemented before AKI. Serum urea and creatinine, urinary albumin, kidney malondialdehyde (MDA), total antioxidant capacity (TAC), transforming growth factor (TGF-ß1), and SIRT1 levels, glomerular filtration rate (GFR) and relative kidney weight were measured before and 24 h after AKI induction. RESULTS: After induction of kidney injury, serum urea and creatinine, urinary albumin, kidney MDA and TGF-ß1 levels increased in rats with both previous exercise and no previous exercise, while GFR, and kidney TAC and SIRT1 levels significantly decreased. These changes after AKI were less in the group with previous exercise than in the group that had no exercise (p <0.001). The TR diet during exercise caused a less increase in serum urea (p <0.01) and creatinine (p <0.01), and urinary albumin (p <0.001) levels after the injury compared to the just exercise group. Also, both CR and TR diets during exercise caused less change in MDA (p <0.001) and TAC (p <0.05, p <0.001, respectively) levels compared to just exercise group. CONCLUSIONS: The results showed that exercise alone had no effect on preventing function impairment of kidney, oxidative stress, inflammation and also SIRT1 alteration following AKI, although these indexes were less among those with exercise than those without exercise. However, when the CR and TR diets were implemented during exercise, strong renoprotective effects appeared, and the protective effect of TR diet was greater.

Comparison of the effects of different dietary regimens on susceptibility to experimental acute kidney injury: The roles of SIRT1 and TGF-ß1.

OBJECTIVES: Mortality due to acute kidney injury (AKI) is high despite its reversibility, and studies on efficient treatments for accelerating the recovery of or preventing AKI are of great significance. The amount of daily calorie intake and how it is taken affect body organs and how cells respond to it. The aim of this study was to determine the effects of four types of diets: calorie restriction (CR), time-restriction eating (TR), intermittent fasting (IF), and high-fat diet (HF), on renal injury indicators in male rats. METHODS: Adult rats were placed on CR, TR, IF, and HF diets for 8 wk, after which AKI was induced in them by injection of glycerol. Renal injury indicators and biochemical parameters were measured before and after AKI induction. RESULTS: After AKI, urinary albumin excretion, urea, serum creatinine, and transforming growth factor (TGF)-ß1 increased, whereas creatinine clearance and SIRT1 decreased. CR and TR diets improved renal indicators, decreased TGF-ß1 and malondialdehyde (MDA), and increased SIRT1, total antioxidant capacity, and creatinine clearance after AKI induction. Although IF improved renal indicators, it only led to a decrease in MDA and TGF-ß1. On the other hand, the HF diet worsened renal indicators, increased TGF-ß1, and decreased SIRT1 in the kidney. Moreover, CR and TR improved metabolism indicators, and HF led to the abnormalization of these factors. CONCLUSIONS: The results of the present study showed that CR and TR can be introduced as a treatment method to prevent AKI. These diets can increase the resistance of kidney cells against injuries, possibly by increasing SIRT1, decreasing TGF-ß1, and improving antioxidant status; and they have renoprotective effects.

Multipotential and systemic effects of traumatic brain injury.

Traumatic brain injury (TBI) is one of the leading causes of disability and mortality of people at all ages. Biochemical, cellular and physiological events that occur during primary injury lead to a delayed and long-term secondary damage that can last from hours to years. Secondary brain injury causes tissue damage in the central nervous system and a subsequent strong and rapid inflammatory response that may lead to persistent inflammation. However, this inflammatory response is not limited to the brain. Inflammatory mediators are transferred from damaged brain tissue to the bloodstream and produce a systemic inflammatory response in peripheral organs, including the cardiovascular, pulmonary, gastrointestinal, renal and endocrine systems. Complications of TBI are associated with its multiple and systemic effects that should be considered in the treatment of TBI patients. Therefore, in this review, an attempt was made to examine the systemic effects of TBI in detail. It is hoped that this review will identify the mechanisms of injury and complications of TBI, and open a window for promising treatment in TBI complications.

Antidiabetic, antioxidant, and antilipid peroxidative activities of Dracocephalum polychaetum shoot extract in streptozotocin-induced diabetic rats: In vivo and in vitro studies.

CONTEXT: Dracocephalum polychaetum Bornm. (Lamiaceae) is used in folk medicine and contains antioxidant agents. OBJECTIVES: The objective of this study is to investigate the antidiabetic, antioxidant, and antilipid peroxidative properties of methanol extract of D. polychaetum aerial parts. MATERIALS AND METHODS: The effect of extract (200, 300, and 400 mg/kg, b.w.) on oral glucose tolerance test (OGTT) was investigated. Also, extract (300 mg/kg) administered orally in diabetic rats for 14 d then, serum levels of some biochemical factors were evaluated. Pancreas samples were used for the determination of malondealdehyde (MDA) level, glutathione (GSH) content, superoxide dismutase, and catalase enzyme activities. Red blood cells (RBCs) and plasma were used for MDA estimation. Pancreatic α-amylase inhibition, DPPH (1,1-diphenyl-2-picrylhydrazyl), and FRAP (ferric reducing antioxidant power) assays were done. The total flavonoid content of the extract was determined by spectrophotometry. RESULTS: Extract (300 mg/kg) decreased serum glucose level (27.1%) significantly at 120 min in OGTT. Serum levels of creatinine, triglycerides, cholesterol, alanine amino transferase and MDA levels in plasma, RBCs, and pancreas significantly decreased in treated (300 mg/kg) diabetic rats, while pancreatic GSH content, superoxide dismutase, and catalase enzymatic activities increased (p < 0.05). The IC50 values for the extract and butyl hydroxyanisole were 5.6 and 1.15 mg/mL in DPPH and 0.155 and 0.062 mg/mL in the FRAP methods, respectively. The extract had no inhibitory effect on α-amylase activity. The total amount of flavonoids of the extract was estimated to be 1.8% (g/g) on the basis of quercetin content. CONCLUSION: Dracocephalum polychaetum shoot extract has antioxidant, antihyperlipidemic, and antilipid peroxidative properties.