Protective effects of 17-ß-estradiol on liver injury: The role of TLR4 signaling pathway and inflammatory response.

Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERß) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1ß, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.

Caloric and time restriction diets improve acute kidney injury in experimental menopausal rats: role of silent information regulator 2 homolog 1 and transforming growth factor beta 1.

BACKGROUND: Estrogen has a protective impact on acute kidney injury (AKI); moreover, reducing the daily intake of calories impedes developing diseases. The present study aimed to determine the effects of calorie restriction (CR) and time restriction (TR) diets on the expression of silent information regulator 2 homolog 1 (SIRT1), transforming growth factor beta 1 (TGF-ß1), and other indicators in the presence and absence of ovaries in AKI female rats. METHODS: The female rats were divided into two groups, ovariectomized (OVX) and sham, and were placed on CR and TR diets for eight weeks; afterward, AKI was induced by injecting glycerol, and kidney injury indicators and biochemical parameters were measured before and after AKI. RESULTS: After AKI, the levels of urine albumin excretion rate, urea, and creatinine in serum, and TGF-ß1 increased, while creatinine clearance and SIRT1 decreased in kidney tissue. CR improved kidney indicators and caused a reduction in TGF-ß1 and an increase in SIRT1 in ovary-intact rats. Moreover, CR prevented total antioxidant capacity (TAC) decrease and malondialdehyde (MDA) increase resulting from AKI. Before AKI, an increase in body weight, fasting blood sugar (FBS), low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol (TC), and a decrease in high-density lipoprotein (HDL) were observed in OVX rats compared to sham rats, but CR prevented these changes. The effects of TR were similar to those of CR in all indicators except for TGF-ß1, SIRT1, urea, creatinine, and albumin. CONCLUSION: The present study indicated that CR is more effective than TR in preventing AKI, probably by increasing SIRT1 and decreasing TGF-ß1 in ovary-intact animals.

Changes in the hippocampal level of tau but not beta-amyloid may mediate anxiety-like behavior improvement ensuing from exercise in diabetic female rats.

BACKGROUND: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. METHODS: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of VMax, 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aß) and Tau were also assessed using Western blot. RESULTS: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. CONCLUSIONS: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.

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 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.

Autophagy in combination therapy of temozolomide and IFN-γ in C6-induced glioblastoma: role of non-coding RNAs.

Aim: We predicted the modulation of autophagy and apoptosis in response to temozolomide (TMZ) and IFN-γ based on changes in the expression of non-coding RNAs in C6-induced glioblastoma (GBM). Materials & methods: Each rat received an intraperitoneal injection of TMZ (7.5 mg/kg) and/or IFN-γ (50,000 IU). Results: The reduced expression of H19 and colorectal neoplasia differentially expressed (CRNDE) was associated with a reduction in autophagy in response to TMZ, IFN-γ and TMZ + IFN-γ therapy, whereas the decreased level of miR-29a (proapoptotic miRNA) was associated with an increase in apoptosis. Conclusion: It appears that H19 promotes switching from autophagy to apoptosis in response to combination therapy of TMZ and IFN-γ through the miR-29a/autophagy-related protein 9A (ATG9A) pathway in C6-induced GBM.

Temozolomide (TMZ) is a drug for people with brain cancer. It can make it hard for patients to learn and think, and it can also make the drug stop working, which lets the tumor keep growing. Researchers are looking for other drugs or things that can be taken with TMZ to stop this from happening. In this study, we used a protein called interferon (IFN), which helps fight cancer. We gave mice with brain cancer both TMZ and IFN, and saw that the tumor cells died and the tumor got smaller. We also looked at how IFN and TMZ changed the genetic material of the mouse brain, called RNA. But we need to test this on people to be sure it works.

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.

Investigating the effect of myricetin against arsenic-induced cardiac toxicity in rats.

Arsenic intoxication is a serious health hazard worldwide. Its toxicity is associated with several disorders and health problems in humans. Recent studies revealed that myricetin has various biological effects, including anti-oxidation. The aim of this study is to investigate the protective effect of myricetin against arsenic-induced cardiotoxicity in rats. Rats were randomized to one of the following groups: control, myricetin (2 mg/kg), arsenic (5 mg/kg), myricetin (1 mg/kg) + arsenic, and myricetin (2 mg/kg) + arsenic. Myricetin was given intraperitoneally 30 min before arsenic administration (5 mg/kg for 10 days). After treatments, the activity of lactate dehydrogenase (LDH) and the levels of aspartate aminotransferase (AST), creatine kinase myocardial band (CK-MB), lipid peroxidation (LPO), total antioxidant capacity (TAC), and total thiol molecules (TTM) were determined in serum samples and cardiac tissues. Also, histological changes in cardiac tissue were evaluated. Myricetin pretreatment inhibited arsenic-induced increase in LDH, AST, CK-MB, and LPO levels. Pretreatment with myricetin also enhanced the decreased TAC and TTM levels. In addition, myricetin improved histopathological alterations in arsenic-treated rats. In conclusion, the results of the present study demonstrated that treatment with myricetin prevented arsenic-induced cardiac toxicity at least in part by decreasing oxidative stress and restoring the antioxidant system.

Ameliorating age-dependent effects of resveratrol on VPA-induced social impairments and anxiety-like behaviors in a rat model of neurodevelopmental disorder.

Although anxiety disorders, as well as difficulties in social interaction, are documented in children with autism spectrum disorder (ASD) as a neurodevelopmental disorder, the effectiveness of potential therapeutic procedures considering age and sex differences is under serious discussion. The present study aimed to investigate the effect of resveratrol (RSV) on anxiety-like behaviors and social interaction in juvenile and adult rats of both sex in a valproic acid (VPA)-induced autistic-like model. Prenatal exposure to VPA was associated with increased anxiety, also causing a significant reduction in social interaction in juvenile male subjects. Further administration of RSV attenuated VPA-induced anxiety symptoms in both sexes of adult animals and significantly increased the sociability index in male and female juvenile rats. Taken together, it can be concluded that treatment with RSV can attenuate some of the harsh effects of VPA. This treatment was especially effective on anxiety-like traits in adult subjects of both sexes regarding their performance in open field and EPM. We encourage future research to consider the sex and age-specific mechanisms behind the RSV treatment in the prenatal VPA model of autism.

Characterization of prevalent tyrosine kinase inhibitors and their challenges in glioblastoma treatment.

Glioblastoma multiforme (GBM) is a highly aggressive malignant primary tumor in the central nervous system. Despite extensive efforts in radiotherapy, chemotherapy, and neurosurgery, there remains an inadequate level of improvement in treatment outcomes. The development of large-scale genomic and proteomic analysis suggests that GBMs are characterized by transcriptional heterogeneity, which is responsible for therapy resistance. Hence, knowledge about the genetic and epigenetic heterogeneity of GBM is crucial for developing effective treatments for this aggressive form of brain cancer. Tyrosine kinases (TKs) can act as signal transducers, regulate important cellular processes like differentiation, proliferation, apoptosis and metabolism. Therefore, TK inhibitors (TKIs) have been developed to specifically target these kinases. TKIs are categorized into allosteric and non-allosteric inhibitors. Irreversible inhibitors form covalent bonds, which can lead to longer-lasting effects. However, this can also increase the risk of off-target effects and toxicity. The development of TKIs as therapeutics through computer-aided drug design (CADD) and bioinformatic techniques enhance the potential to improve patients' survival rates. Therefore, the continued exploration of TKIs as drug targets is expected to lead to even more effective and specific therapeutics in the future.

High-Intensity Interval Training-Induced Hippocampal Molecular Changes Associated with Improvement in Anxiety-like Behavior but Not Cognitive Function in Rats with Type 2 Diabetes.

(1) Background: Exercise exerts many neuroprotective effects in diabetes-induced brain disorders. In this study, we investigated the effect of high-intensity interval training (HIIT) on brain molecular changes and cognitive and anxiety-like behaviors in rats with type 2 diabetes. (2) Methods: Twenty-eight adult male rats were divided into four groups (n = 7): control (C), exercise + control (C+EX), diabetes (DM), and diabetes + exercise (DM+EX). Diabetes was induced using a two-month high-fat diet and a single dose of streptozotocin (35 mg/kg) in the DM and DM+EX groups. After, the C+EX and DM+EX groups performed HIIT for eight weeks (five sessions per week, running at 80-100% of VMax, 4-10 intervals) on a motorized treadmill. Then, the elevated plus maze (EPM) and open field test (OFT) were performed to evaluate anxiety-like behaviors. The Morris water maze (MWM) and shuttle box were used to assess cognitive function. The hippocampal levels of beta-amyloid and tau protein were also assessed using Western blot. (3) Results: The hippocampal levels of beta-amyloid and tau protein were increased in the DM group, but HIIT restored these changes. While diabetes led to a significant decrease in open arm time percentage (%OAT) and open arm enters percentage (%OAE) in the EPM, indicating anxiety-like behavior, HIIT restored them. In the OFT, grooming was decreased in diabetic rats, which was restored by HIIT. No significant difference between groups was seen in the latency time in the shuttle box or for learning and memory in the MWM. (4) Conclusions: HIIT-induced hippocampal molecular changes were associated with anxiety-like behavior improvement but not cognitive function in rats with type 2 diabetes.

The effect of gallic acid on memory and anxiety-like behaviors in rats with bile duct ligation-induced hepatic encephalopathy: Role of AMPK pathway.

Objective: Hepatic encephalopathy (HE) is a serious neurological syndrome which is caused by acute and chronic liver diseases. In this study, the effect of gallic acid (GA) as an activator of AMP-activated protein kinase (AMPK) on memory and anxiety-like behaviors in rats with HE caused by bile duct ligation (BDL) was investigated. Materials and Methods: The rats were randomly divided into the following eight groups (n=7): sham; BDL; BDL+GA 20 mg/kg; BDL+GA 30 mg/kg; sham+dorsomorphin or compound C (CC) (as AMPK inhibitors); BDL+CC; BDL+GA 20 mg/kg+CC; and BDL+GA 30 mg/kg+CC. The rats received GA once daily by gavage for four weeks, and dorsomorphin 6.2 µg per rat was administered on a daily basis via bilateral intraventricular injection for four weeks. Behavioral tests including novel object recognition (NOR), open field and Morris water maze (MWM) were used to evaluate anxiety and memory in the rats. Results: Examining some parameters of NOR and MWM tests showed that memory performance was significantly reduced in the BDL versus the sham group, and in the BDL+CC versus the sham+CC group (p<0.05). GA intake improved memory in the GA-receiving groups compared with the BDL and BDL+CC groups (p<0.05). Examining some parameters of open field test showed that anxiety was significantly increased in the BDL versus the sham group, and the BDL+CC versus the sham+CC group (p<0.05). GA intake reduced anxiety in GA-receiving groups compared with the BDL+BDL+CC group (p<0.05). Conclusion: GA was effective in improving cognitive and anxiety-like behaviors through activating AMPK.

Spiritual Well-being in Patients with Chronic Diseases: A Systematic Review and Meta-analysis.

As a significant health challenge, chronic disease can have critical spiritual consequences for patients. Therefore, the study of spiritual well-being as an aspect of health is essential but has been less considered with regard to chronic diseases. Thus, this systematic review and meta-analysis were conducted to investigate spiritual well-being in patients with chronic diseases. For this purpose, in the initial search that was performed of valid databases, a total of 615 descriptive studies published between 2000 and 2018 were found. After carefully assessing these, only 24 studies were included in the review. Overall, the spiritual well-being of 3289 patients with chronic disease was investigated. This study showed that the total mean score of the spiritual well-being of patients with chronic diseases was 86.65 (P < 0.001, 95%, CI: 80.34-92.96), indicating a moderate level of spiritual well-being in these patients. Thus, patients with chronic diseases are recommended to consider spiritual consultation programs.

Combination therapy with interferon-gamma as a potential therapeutic medicine in rat's glioblastoma: A multi-mechanism evaluation.

BACKGROUND: This study assessed the effects of single or combined administration of temozolomide (TMZ) and interferon-gamma (IFN-ᵞ) on anxiety-like behaviors, balance disorders, learning and memory, TNF-α, IL-10, some oxidant and antioxidants factors with investigating the toll-like receptor-4 (TLR4) and p-CREB signaling pathway in C6-induced glioblastoma of rats. METHODS: 40 male Sprague-Dawley rats bearing intra-caudate nucleus (CN) culture medium or C6 inoculation were randomly divided into five groups as follows: Sham, Tumor, TMZ, IFN-ᵞ and a TMZ + IFN-ᵞ combination. The open-field test (OFT), elevated plus maze (EPM), rotarod, and passive avoidance test (PAT) were done on days 14-17. On day 17 after tumor implantation, brain tissues were extracted for histopathological evaluation. TNF-α, IL-10, SOD, GPX, TAC, MDA, the protein level of TLR4 and p-CREB was measured. RESULTS: Combination therapy inhibited the growth of the tumor. Treatment groups alleviated tumor-induced anxiety-like behaviors and improved imbalance and memory impairment. SOD, GPX, and TAC decreased in the tumor group. The combination group augmented GPX and TAC. MDA decreased in treatment groups. TMZ, IFN-ᵞ reduced tumor-increased TNF-α and IL-10 level. The combination group declined TNF-α level in serum and IL-10 level in serum and brain. Glioblastoma induced significant upregulation of TLR4 and p-CREB in the brain which inhibited by IFN-ᵞ and TMZ+ IFN-ᵞ. CONCLUSION: The beneficial effects of TMZ, IFN-ᵞ, and TMZ+ IFN-ᵞ on neurocognitive functioning of rats with C6-induced glioblastoma may be mediated via modulating oxidative stress, reduced cytokines, and the downregulation of expression of TLR4 and p-CREB. Combination treatment appears to be more effective than single treatment.

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.

Protective effects of combining SERMs with estrogen on metabolic parameters in postmenopausal diabetic cardiovascular dysfunction: The role of cytokines and angiotensin II.

INTRODUCTION: The beneficial effects of the administration of selective estrogen receptor modulators (SERMs) and estrogen (E2), alone or in combination with each other, have been reported in postmenopausal diabetic cardiovascular dysfunction. In the present study, we determined the mechanism of action of SERMs and E2 on inflammatory balance, angiotensin II (Ang II) serum levels, and glycemic profile in a postmenopausal diabetic rat model. METHODS: Ovariectomized rats with type 2 diabetes received daily SERMs (tamoxifen and raloxifene) and E2 for one month. After treatment, cardiovascular risk indices, glycemic profile, and serum Ang II, TNF-α and IL-10 levels were measured. RESULTS: Type 2 diabetes caused an abnormal glycemic profile, which was exacerbated by ovariectomy. All treatments inhibited the effects of diabetes and ovariectomy on the glycemic profile, with combined treatments (SERMs + E2) showing stronger effects. Cardiovascular risk indices that became abnormal by diabetes and worsened by ovariectomy were improved in all treatment modalities. Also, combined treatment reduced serum Ang II, TNF-α, and the ratio of TNF-α to IL-10, indicating an improvement in inflammatory balance. CONCLUSION: Our study showed the administration of SERMs and E2, alone or in combination, could be an effective alternative in the treatment of menopausal diabetes, and generally, the beneficial effects of combined treatments were more effective than the effects of E2 or SERMs alone. It appears that E2 or SERMs benefit the cardiovascular system by improving inflammatory balance and reducing Ang II levels.

Early postnatal handling alters social behavior, learning, and memory of pre- and postnatal VPA-induced rat models of autism in a context-based manner.

Early life events are known to greatly affect brain development, cortical neurogenesis, and Hypothalamic-pituitary-adrenal activity. Mainly characterized by impairment in social communication, language, and cognitive development, autism spectrum disorder (ASD) refers to a class of neuropsychiatric disorders with numerous genetic and environmental risk factors. In the early handling (EH) method, daily separation of infants from their mother, physical touching, and exposure to a new environment occur. Here, we studied the effect of EH on Social interaction, learning, and memory in rats exposed pre-or post-natally to valproic acid (VPA). Gestational VPA exposure (600 mg/kg) led to some severe autistic-like traits, more notable in the social behavior of the male sex, along with unchanged to partially altered spatial learning and memory function and reduced avoidance memory. In comparison, while causing a sex-dependent increase in spatial memory, subcutaneous injection of VPA (400 mg/kg) in infancy resulted in limited adverse autistic features, including a decrease in males' social preference, as well as reduced avoidance memory. The results indicated that neonatal handling significantly improved multiple social behavior and memory deficits in prenatally injected rats. In contrast, EH in rats receiving postnatal VPA elicited a restricted advantage on social novelty tendency; while negatively affecting some other social behavior criteria and spatial learning of males and encouraging sex-dependent repetitive behaviors in the social setting. The controversial influence of postnatal handling on juvenile rats of postnatal VPA treatment vs. prenatal VPA treatment opens up the potential for future research on the context-based consequence of early-life handling stress using different behavioral tasks and to benefit therapeutic procedures through understanding the sex- and age-specific neurobiology of short-term environmental manipulation in animal models of autism.

The effect of early handling on anxiety-like behaviors of rats exposed to valproic acid pre-and post-natally.

INTRODUCTION: Autism spectrum disorder (ASD) is a complex, behaviorally defined disorder of the immature brain as a result of genetic and environmental risk factors, such as prenatal exposure to valproic acid (VPA). This syndrome is known for its high prevalence. On the other hand, postnatal manipulations have been shown to affect brain development, cortical neuroscience, and pituitary-adrenal activity. In early handling (EH) procedure, pups are removed from their mother on a daily basis from birth to lactation, are physically touched, and exposed to the (a) new environment. In the present study, the effect of EH on anxiety-like behaviors in rats exposed pre- and post-natally to valproic acid was investigated. METHODS: Pregnant Wistar rats were randomly separated into six groups which are prenatal saline, Prenatal VPA, Prenatal VPA + EH and postnatal saline, Postnatal VPA, Postnatal VPA + EH. VPA administration was performed either on ED12.5 (600 mg/kg, i.p.) or PD 2-4 (400 mg/kg, s.c.). In the groups receiving EH, pups underwent physical handling from PD 1 to 21. On postnatal day 21 all offspring were weaned and the behavioral tests were performed on 30 and 31 days of age. Elevated plus maze and open field tests were used to investigate anxiety-like behaviors. RESULTS: The results revealed that intraperitoneal injection of valrpoic acid (600 mg.kg) during pregnancy significantly reduced OAT% in males (p < 0.01) and females in a non-significant manner (p > 0.05). In comparison, rearing counts of prenatal VPA groups significantly increased in female sex (p < 0.05) in the EPM test. Following postnatal VPA administration (400 mg/kg), decrease in the time spent in central zone occurred in female rats in the open filed (p < 0.05), as well as a significant increase in the number of grooming of the male sex (p < 0.05). Applying Early Handling to male and female Wistar rats receiving prenatal VPA significantly reversed the OAT% fall (p < 0.05). EH in postnatally VPA exposed animals significantly decreased the OAT% and OAE% criteria, while increasing the locomotor activity of the female sex (p < 0.05). Compared with the postnatal VPA group, no significant change was reported in the EPM performance of postnatal VPA + EH group in neither of sexes (p > 0.05). CONCLUSION: The findings of this study suggest that injections of valproic acid during pregnancy lead to anxiety-like behaviors in male offspring, which EH can improve (attenuate) to some extent. VPA injections on the second to the fourth day of infancy did not have a profound effect on anxiety level. Further behavioral studies need to be performed using other devices to investigate anxiety-like behaviors and to determine the mechanisms involved in these behaviors.

The combination of fluoxetine and environmental enrichment reduces postpartum stress-related behaviors through the oxytocinergic system and HPA axis in mice.

Gestational stress can increase postpartum depression in women. To treat maternal depression, fluoxetine (FLX) is most commonly prescribed. While FLX may be effective for the mother, at high doses it may have adverse effects on the fetus. As environmental enrichment (EE) can reduce maternal stress effects, we hypothesized that a subthreshold dose of FLX increases the impact of EE to reduce anxiety and depression-like behavior in postpartum dams exposed to gestational stress. We evaluated this hypothesis in mice and to assess underlying mechanisms we additionally measured hypothalamic-pituitary-adrenal (HPA) axis function and brain levels of the hormone oxytocin, which are thought to be implicated in postpartum depression. Gestational stress increased anxiety- and depression-like behavior in postpartum dams. This was accompanied by an increase in HPA axis function and a decrease in whole-brain oxytocin levels in dams. A combination of FLX and EE remediated the behavioral, HPA axis and oxytocin changes induced by gestational stress. Central administration of an oxytocin receptor antagonist prevented the remediating effect of FLX + EE, indicating that brain oxytocin contributes to the effect of FLX + EE. These findings suggest that oxytocin is causally involved in FLX + EE mediated remediation of postpartum stress-related behaviors, and HPA axis function in postpartum dams.