Lung molecular and histological changes in type 2 diabetic rats and its improvement by high-intensity interval training.

BACKGROUND: Type 2 diabetes (T2D) leads to serious respiratory problems. This study investigated the effectiveness of high-intensity interval training (HIIT) on T2D-induced lung injuries at histopathological and molecular levels. METHODS: Forty-eight male Wistar rats were randomly allocated into control (CTL), Diabetes (Db), exercise (Ex), and Diabetes + exercise (Db + Ex) groups. T2D was induced by a high-fat diet plus (35 mg/kg) of streptozotocin (STZ) administration. Rats in Ex and Db + Ex performed HIIT for eight weeks. Tumor necrosis factor-alpha (TNFα), Interleukin 10 (IL-10), BAX, Bcl2, Lecithin, Sphingomyelin (SPM) and Surfactant protein D (SPD) levels were measured in the bronchoalveolar lavage fluid (BALF) and malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were measured in lung tissue. Lung histopathological alterations were assessed by using H&E and trichrome mason staining. RESULTS: Diabetes was significantly associated with imbalance in pro/anti-inflammatory, pro/anti-apoptosis and redox systems, and reduced the SPD, lecithin sphingomyelin and alveolar number. Performing HIIT by diabetic animals increased Bcl2 (P < 0.05) and IL10 (P < 0.01) levels as well as surfactants components and TAC (P < 0.05) but decreased fasting blood glucose (P < 0.001), TNFα (P < 0.05), BAX (P < 0.05) and BAX/Bcl2 (P < 0.001) levels as well as MDA (P < 0.01) and MDA/TAC (P < 0.01) compared to the diabetic group. Furthermore, lung injury and fibrosis scores were increased by T2D and recovered in presence of HIIT. CONCLUSION: These findings suggested that the attenuating effect of HIIT on diabetic lung injury mediated by reducing blood sugar, inflammation, oxidative stress, and apoptosis as well as improving pulmonary surfactants components.

Protective effects of calorie restriction and 17-ß estradiol on cardiac hypertrophy in ovariectomized obese rats.

Obesity and menopause lead to cardiovascular diseases. Calorie restriction (CR) can modulate estrogen deficiency and obesity-related cardiovascular diseases. The protective effects of CR and estradiol on cardiac hypertrophy in ovariectomized obese rats were explored in this study. The adult female Wistar rats were divided into sham and ovariectomized (OVX) groups that received a high-fat diet (60% HFD) or standard diet (SD) or 30% CR for 16 weeks, and then, 1mg/kg E2 (17-ß estradiol) was injected intraperitoneally every 4 days for four weeks in OVX-rats. Hemodynamic parameters were evaluated before and after each diet. Heart tissues were collected for biochemical, histological, and molecular analysis. HFD consumption led to weight gain in sham and OVX rats. In contrast, CR and E2 led to body weight loss in these animals. Also, heart weight (HW), heart weight/body weight (HW/BW) ratio, and left ventricular weight (LVW) were enhanced in OVX rats that received SD and HFD. E2 reduced these indexes in both diet conditions but reduction effects of CR were seen only in HFD groups. HFD and SD feeding increased hemodynamic parameters, ANP (atrial natriuretic peptide) mRNA expression, and TGF-ß1(transforming growth factor-beta 1) protein level in the OVX animals, while CR and E2 reduced these factors. Cardiomyocyte diameter and hydroxyproline content were increased in the OVX-HFD groups. Nevertheless, CR and E2 decreased these indicators. The results showed that CR and E2 treatment reduced obesity-induced-cardiac hypertrophy in ovariectomized groups (20% and 24% respectively). CR appears to have almost as reducing effects as estrogen therapy on cardiac hypertrophy. The findings suggest that CR can be considered a therapeutic candidate for postmenopausal cardiovascular disease.

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 effects of postnatal erythropoietin and nano-erythropoietin on behavioral alterations by mediating K-Cl co-transporter 2 in the valproic acid-induced rat model of autism.

In this study, based on the excitatory/inhibitory imbalance theory of autism, the time window of GABA switch, the role of K-Cl co-transporter 2 (KCC2) in adjustment GABA switch, and brain permeability to erythropoietin (EPO), the effects of postnatal -EPO and- nano- erythropoietin (NEPO) have been evaluated in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism at gestational day (GD) 12.5 (600 mg/kg). Male offsprings were injected with EPO and NEPO in a clinically proper postnatal dosing regimen on postnatal days (PND) 1-5, and autistic-like behaviors were tested at the end of the first month. Then animals were sacrificed, and neuron morphology and KCC2 expression were examined by Nissl staining and Western blot. According to our findings, high-dose NEPO improved autism-associated phenotypes. Neuroprotective effects of EPO and NEPO have been shown in the hippocampus. Postnatal NEPO treatment reversed KCC2 expression abnormalities induced by prenatal VPA. Our results might support the role of KCC2 in ASD and the excitatory/inhibitory imbalance hypothesis. We suggested Nano- erythropoietin and other KCC2 interventions as a new approach to the early treatment and prevention of autism.

Effects of Nicotine Administration in an Enriched Environment on the Behavior of Male MK-801-Exposed Rats.

Background: Smoking is more common in patients with schizophrenia than in healthy populations. Some controversial hypotheses connect the disease with the high prevalence of smoking. Moreover, environmental factors affect the severity of the positive and negative symptoms of schizophrenia. The current study aimed to assess the effect of enriched environment (EE) and nicotine on the MK-801 animal model of schizophrenia. Methods: Male Wistar rat pups randomly received saline or MK-801 (dose:1 mg/kg) for five days from the sixth postnatal day (P) until the tenth. The pups were placed in EE or standard cages (SCs) after weaning (P21). Morris water maze (MWM) was used to assess spatial learning and memory. The rats received 0.6 mg/kg nicotine twice for three days at the end of the second month and were examined in an open-field box and three-chamber social interaction test. Findings: MK-801 rats' behaviors were the same as those of the saline rats when they were exposed to nicotine. No positive effects of EE were observed when the animals were exposed to nicotine. Conclusion: The results suggested that nicotine decreased schizophrenia-like symptoms and covered the positive effects of EE.

Effects of caloric and time restriction diets on kidney health in rat model of postmenopausal acute kidney injury: An apoptosis and histopathological study.

Objectives: Lifestyle and eating habits affect the health and function of the body's organs, including the kidneys. The current study was carried out to determine the effects of two types of diet programs, including time restriction (TR) and calorie restriction (CR) on the histopathological changes and apoptotic molecules during acute kidney injury (AKI) in postmenopausal rats. Materials and Methods: In this study the female rats were divided into two groups of ovariectomized (OVX) and ovary-intact (sham), then they were placed on TR and CR diets for 8 weeks; afterward, AKI was induced by injection of glycerol. Functional indices, histopathological changes, Bax, and Bcl2 were measured before and after AKI. Results: After AKI, creatinine, serum urea, urinary albumin excretion, kidney tissue Bax, and Bax/Bcl2 ratio increased, while glomerular filtration rate (GFR) and kidney tissue Bcl2 decreased compared with before AKI. Histopathological indices (inflammation, cellular necrosis, cell vacuolization, tubular dilatation, intratubular cast, and congestion) also confirmed renal injury. TR and CR diets improved renal injury indices and prevented an increase in the Bax/Bcl2 ratio. However, in some indices, the effects of two diets on OVX animals were not observed. In addition, none of the diets could decrease kidney weight/body weight ratio (KW/BW). The histopathological finding also showed improvement of renal status in both groups, especially in the CR diet. Conclusion: The results indicated that TR and CR diets had renoprotective effects against AKI by reducing the Bax/Bcl2 ratio and improving apoptosis. The effects of CR were more than TR.

Exercise Training Attenuates Cardiac Vulnerability and Promotes Cardiac Resistance to Isoproterenol-Induced Injury Following Hookah Smoke Inhalation in Male Rats: Role of Klotho and Sirtuins.

Hookah smoking is on the rise around the world. Present study investigated the heart resistance to harmful stress following long-term waterpipe tobacco smoking (WTS) and moderate-intensity exercise training intervention in male Wistar rats. Animals were randomly divided into a non-ischemic heart control group and four ischemic heart groups including ISO (isoproterenol-treated), Ex + ISO (subjected to exercise plus ISO), S + ISO (exposed to hookah smoke plus ISO), and Ex + S + ISO (subjected to exercise along with hookah smoke plus ISO). After eight weeks of training and WTS, heart ischemia induced by isoproterenol injections. Then, cardiac functional indices and some biochemical and histopathological parameters were assessed. WTS + ISO reduced systolic pressure, ± dP/dt max, and contractility indices (P < 0.001 vs. ISO group) and increased end diastolic pressure and Tau index (P < 0.001 vs. ISO) of the left ventricle. Also, WTS + ISO was associated with an increase in Bax protein level and Bax/Bcl-2 ratio (P < 0.05 and P < 001, respectively, vs. ISO group) as apoptotic markers of heart tissue. Hookah smoke significantly decreased SIRT1 (P < 0.05 and P < 0.001, respectively, vs. ISO) and klotho (P < 0.01 and P < 0.001, respectively, vs. ISO) in serum and heart, and SIRT3 and pS9-GSK-3ß (P < 001 and P < 0.05, respectively, vs. ISO) in heart tissue. Combination of exercise with WTS prevented the hookah smoke-induced alterations in apoptotic markers, cardiac functional indices, and SIRT1, SIRT3, klotho, and pS9-GSK-3ß proteins. The findings demonstrated that hookah smoke inhalation intensifies ventricular dysfunction and decreases heart resistance to harmful stresses. Moderate-intensity exercise training attenuated these complications partly through recovering the klotho and sirtuins levels and apoptosis-survival balancing.

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.

Involvement of Sirtuins and Klotho in Cardioprotective Effects of Exercise Training Against Waterpipe Tobacco Smoking-Induced Heart Dysfunction.

Despite its negative effect on the cardiovascular system, waterpipe smoking (WPS) is currently popular worldwide, especially among youth. This study investigated the effects of moderate endurance exercise on heart function of rats exposed to WPS and its possible mechanism. The animals were randomly divided into four groups: control group (CTL), the exercise group (Ex) which trained for 8 weeks, the waterpipe tobacco smoking group (S) exposed to smoke inhalation (30 min per day, 5 days each week, for 8 weeks), and the group that did exercise training and received waterpipe tobacco smoke inhalation together (Ex + S). One day after the last session of Ex and WPS, cardiac pressures and functional indices were recorded and calculated. The levels of SIRT1, SIRT3, Klotho, Bax, and Bcl-2 in the serum and heart, the expression of phosphorylated GSK3ß of heart tissue, and cardiac histopathological changes were assessed. WPS reduced systolic pressure, +dP/dt max, -dP/dt max, and heart contractility indices (P < 0.001 vs. CTL) and increased cardiac tissue lesions (P < 0.05 vs. CTL) and end diastolic pressure and Tau index (P < 0.001 vs. CTL) of the left ventricle. Exercise training normalized the left ventricular end diastolic pressure, +dP/dt max, and contractility index. Also, exercise improved the levels of SIRT1, SIRT3, Klotho, and Bcl-2 and reduced Bax level in the heart. The findings showed that WPS causes left ventricular dysfunction. Moderate exercise prevented WPS-induced heart dysfunction partly through its anti-apoptotic features and activation of the sirtuins and Klotho pathways.

Activators of SIRT1 in the kidney and protective effects of SIRT1 during acute kidney injury (AKI) (effect of SIRT1 activators on acute kidney injury).

Acute kidney injury (AKI) is a complex disorder and a clinical condition characterized by acute reduction in renal function. If AKI is not treated, it can lead to chronic kidney disease, which is associated with a high risk of death. SIRT1 (silent information regulator 1) is an NAD-dependent deacetylase. This enzyme is responsible for the processes of DNA repair or recombination, chromosomal stability, and gene transcription. This enzyme also plays a protective role in many diseases, including AKI. In this study, we review the mechanisms that mediate the protective effects of SIRT1 on AKI, including SIRT1 activators.

Renoprotective effects of estrogen on acute kidney injury: the role of SIRT1.

Acute kidney injury (AKI) is a common syndrome associated with high morbidity and mortality, despite progress in medical care. Many studies have shown that there are sex differences and different role of sex hormones particularly estrogens in kidney injury. In this regard, the incidence and rate of progression of kidney diseases are higher in men compared with women. These observations suggest that female sex hormone may be renoprotective. Silent information regulator 2 homolog 1 (SIRT1) is a histone deacetylase, which is implicated in multiple biologic processes in several organisms. In the kidneys, SIRT1 inhibits renal cell apoptosis, inflammation, and fibrosis. Studies have reported a link between SIRT1 and estrogen. In addition, SIRT1 regulates ERα expression and inhibition of SIRT1 activity suppresses ERα expression. This effect leads to inhibition of estrogen-responsive gene expression. In this text, we review the role of SIRT1 in mediating the protective effects of estrogen in the onset and progression of AKI.

Effects of extremely low-frequency pulsed electromagnetic fields (ELF-PEMFs) on glioblastoma cells (U87).

The impact of extremely low-frequency pulsed electromagnetic fields (ELF-PEMFs) at various frequencies and amplitudes was investigated on cell cycle, apoptosis and viability of the Glioblastoma Multiforme (GBM) cell line (U87), in vitro. The GBM is a malignant brain tumor with high mortality in humans and poorly responsive to the most common type of cancer treatments, such as surgery, chemotherapy and radiation therapy. U87 cells with five experimental groups (I-V) were exposed to various ELF-PEMFs for 2, 4 and 24 h, as follows: (I) no exposure, control; (II) 50 Hz 100 ± 15 G; (III) 100 Hz 100 ± 15 G; (IV) 10 Hz 50 ± 10 G; (V) 50 Hz 50 ± 10 G. The morphology properties, cell viability and gene expression of proteins involved in cell cycle regulation (Cyclin-D1 and P53) and apoptosis (Caspase-3) were investigated. After 24 h, the cell viability and Cyclin-D1 expression increased in Group II (30%, 45%), whereas they decreased in Groups III (29%, 31%) and IV (21%, 34%); P53 and Caspase-3 elevated only in Group III; and no significant difference was observed in Group V, respectively, compared with the control (p < 0.05). The data suggest that the proliferation and apoptosis of human GBM are influenced by exposure to ELF-PEMFs in different time-dependent frequencies and amplitudes. The fact that some of the ELF-PEMFs frequencies and amplitudes favor U87 cells proliferation indicates precaution for the use of medical devices related to the MFs on cancer patients. On the other hand, some other ELF-PEMFs frequencies and intensities arresting U87 cells growth could open the way to develop novel therapeutic approaches.

Prior regular exercise reverses the decreased effects of sleep deprivation on brain-derived neurotrophic factor levels in the hippocampus of ovariectomized female rats.

Previous studies indicated that brain-derived neurotrophic factor (BDNF) is the main candidate to mediate the beneficial effects of exercise on cognitive function in sleep deprived male rats. In addition, our previous findings demonstrate that female rats are more vulnerable to the deleterious effects of sleep deprivation on cognitive performance and synaptic plasticity. Therefore, the current study was designed to investigate the effects of treadmill exercise and/or sleep deprivation (SD) on the levels of BDNF mRNA and protein in the hippocampus of female rats. Intact and ovariectomized (OVX) female Wistar rats were used in the present experiment. The exercise protocol was four weeks treadmill running and sleep deprivation was accomplished using the multiple platform method. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblot analysis were used to evaluate the level of BDNF mRNA and protein in the rat hippocampus respectively. Our results showed that protein and mRNA expression of BDNF was significantly (p<0.05) decreased after 72 h SD in OVX rats in compared with other groups. Furthermore, sleep deprived OVX rats under exercise conditions had a significant (p<0.05) up-regulation of the BDNF protein and mRNA in the hippocampus. These findings suggest that regular exercise can exert a protective effect against hippocampus-related functions and impairments induced by sleep deprivation probably by inducing BDNF expression.

Ginger (Zingiber officinale Roscoe) prevents the development of morphine analgesic tolerance and physical dependence in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments such as opiates withdrawal-induced disorders. However, its influences on opioid tolerance and dependence have not yet been clarified. MATERIALS AND METHODS: Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10 mg/kg, i.p.) twice daily for 8 days. To develop morphine dependence, rats given escalating doses of chronic morphine. To determine the effect of ginger on the development of morphine tolerance and dependence, different doses of ginger were administrated before morphine. The tail-flick and naloxone precipitation tests were used to assess the degree of tolerance and dependence, respectively. RESULTS: Our results showed that chronic morphine-injected rats displayed tolerance to the analgesic effect of morphine as well as morphine dependence. Ginger (50 and 100 mg/kg) completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with 100 and 150 mg/kg attenuated almost all of the naloxone-induced withdrawal sings which include weight lose, abdominal contraction, diarrhea, petosis, teeth chattering, and jumping. In addition, morphine-induced L-type calcium channel over-expression in spinal cord was reversed by 100 mg/kg ginger. CONCLUSION: The data indicate that ginger extract has a potential anti-tolerant/anti-dependence property against chronic usage of morphine.