Inhibition of TLR4, NF-κB, and INOS pathways mediates ameliorative effect of syringic acid in experimental ulcerative colitis in rats.

OBJECTIVE: Numerous therapeutics and pharmacological properties have been reported in syringic acid (SA). In this study, we aimed to evaluate effect of SA in ulcerative colitis (UC) in rats considering effect on TLR4, NF-κB, and INOS pathways. MATERIALS AND METHODS: 48 Wistar rats were randomly designated into six groups (n = 8). UC was induced via intra-rectal administration of 7% acetic acid (0.8 ml). SA at doses of 10, 25, 50 mg/kg was administrated through gavage, and dexamethasone (2 mg/kg) administrated intra-peritoneally for 5 consecutive days. The macroscopic and histopathological damages as well as expression of inflammatory and apoptotic genes along with superoxide dismutase (SOD) and catalase (CAT) activities, total antioxidant capacity (TAC), nitric oxide (NO), and malondialdehyde (MDA) levels in the colon tissue were assessed. RESULTS: UC led to an increase in the apoptotic and inflammatory genes, NO and MDA levels as well as decrease in TAC level, and SOD and CAT activities (p < 0.05). UC also caused severe damage, edema, inflammation, and necrosis in the colon. SA significantly reduced gene expressions of INOS, TLR4, IL-6, IL-1ß, NF-κB, Caspase-3, Caspase-8, and Bax. SA ameliorated negative macroscopic and histopathologic effects of UC. SA significantly reduced MDA and NO levels, and increased TAC level and CAT activity in the colon tissue in comparison to the UC rats without treatment (p < 0.05). CONCLUSION: SA via attenuation of the TLR4-NF-κB, NF-κB-INOS-NO pathways, oxidative stress, inflammation, and apoptosis of UC in rats.

Possible involvement of L-arginine-nitric oxide pathway in the antidepressant activity of Auraptene in mice.

BACKGROUND: Depression is one of the most common mental illnesses worldwide. Nitric oxide (NO) is involved in the pathophysiology of depression. Auraptene (a coumarin derivative) has been shown to possess pharmacological effects on neurological diseases. PURPOSE: The present study aimed to investigate the possible role of the NO pathway in Auraptene antidepressant effects in male mice. METHODS: Behavioral tests were used to assess depression-like behaviors. The mice received Auraptene at 10, 30, and 100 mg/kg, the combination of the sub-effective (ineffective) dose of Auraptene (10 mg/kg) and L-NAME, and the combination of the effective dose of Auraptene (30 mg/kg) and L-arginine. Finally, OFT, TST, FST, brain, serum MDA level, antioxidant capacity, hippocampus, and serum NO level were measured. RESULTS: The data analysis showed that Auraptene (30 mg/kg) improved depression-like behaviors. Auraptene (30 mg/kg) also significantly reduced serum NO levels (P < 0.05) and significantly increased serum MDA (10 mg/kg, P < 0.05). Auraptene at 30 mg/kg also increased serum antioxidant capacity (P < 0.01). Co-administration of L-NAME and the sub-effective dose of Auraptene enhanced the effects of Auraptene. However, co-administration of the effective dose of Auraptene and L-arginine reduced the impacts of Auraptene. CONCLUSIONS: The results showed that Auraptene causes antidepressant effects in a dose-dependent manner and acts as a prooxidant at 100 mg/kg, and exacerbates oxidative stress. The antidepressant effects of this active molecule are exerted by reducing the NO level in the hippocampus and serum, increasing the antioxidant capacity, and reducing the MDA level in the serum.

Effect of Curcuma zedoaria hydro-alcoholic extract on learning, memory deficits and oxidative damage of brain tissue following seizures induced by pentylenetetrazole in rat.

BACKGROUND: Previous studies have shown that seizures can cause cognitive disorders. On the other hand, the Curcuma zedoaria (CZ) has beneficial effects on the nervous system. However, there is little information on the possible effects of the CZ extract on seizures. The aim of this study was to investigate the possible effects of CZ extract on cognitive impairment and oxidative stress induced by epilepsy in rats. METHODS: Rats were randomly divided into different groups. In all rats (except the sham group), kindling was performed by intraperitoneal injection of pentylenetetrazol (PTZ) at a dose of 35 mg/kg every 48 h for 14 days. Positive group received 2 mg/kg diazepam + PTZ; treatment groups received 100, 200 or 400 mg/kg CZ extract + PTZ; and one group received 0.5 mg/kg flumazenil and CZ extract + PTZ. Shuttle box and Morris Water Maze tests were used to measure memory and learning. On the last day of treatments PTZ injection was at dose of 60 mg/kg, tonic seizure threshold and mortality rate were recorded in each group. After deep anesthesia, blood was drawn from the rats' hearts and the hippocampus of all rats was removed. RESULTS: Statistical analysis of the data showed that the CZ extract significantly increased the tonic seizure threshold and reduced the pentylenetetrazol-induced mortality and the extract dose of 400 mg/kg was selected as the most effective dose compared to the other doses. It was also found that flumazenil (a GABAA receptor antagonist) reduced the tonic seizure threshold compared to the effective dose of the extract. The results of shuttle box and Morris water maze behavioral tests showed that memory and learning decreased in the negative control group and the CZ extract treatment improved memory and learning in rats. The CZ extract also increased antioxidant capacity, decreased MDA and NO in the brain and serum of pre-treated groups in compared to the negative control group. CONCLUSION: It is concluded that the CZ extract has beneficial effects on learning and memory impairment in PTZ-induced epilepsy model, which has been associated with antioxidant effects in the brain or possibly exerts its effects through the GABAergic system.

Trigonelline through the Attenuation of Oxidative Stress Exerts Antidepressant- and Anxiolytic-Like Effects in a Mouse Model of Maternal Separation Stress.

Depression and anxiety are common psychiatric disorders accounting for social and economic burdens. Previous studies have shown that oxidative stress and oxidant/antioxidant imbalance are involved in the pathophysiology of psychiatric disorders. Experiencing early-life adversities (like maternal separation [MS] stress) provoked psychiatric disorders. Trigonelline (TRG) is a pyridine alkaloid that has various pharmacological effects including hypoglycemic, neuroprotective and memory-improving properties. To investigate the antidepressant- and anxiolytic-like effects of TRG focusing oxidative stress, we applied the MS paradigm to male mice at postnatal day (PND) 2-14 (3 h daily, 9-12 a.m.) and investigated the behaviors at PND 45-47. Using valid behavioral tests including a forced swimming test (FST), splash test, open field test (OFT) and elevated plus maze (EPM), we investigated behavioral modifications. Additionally, we examined the effects of MS and TRG treatment on the level of malondialdehyde (MDA), nitric oxide (NO) and also antioxidant capacity in the brain and serum. Our results showed that MS provoked depressive- and anxiety-like behaviors in the FST, OFT, EPM and splash test, which are associated with an increase in MDA and NO levels as well as a decrease in antioxidant capacity in the brain and serum samples. Findings determined that TRG significantly reversed the negative effects of MS on behavior that is accompanied by a decrease in MDA and NO as well as an increase in antioxidant capacity. Findings of the present study showed that beneficial effects of TRG may be, at least partially, mediated via the reduction of oxidative stress and an increase of antioxidant capacity.

Ruta graveolens and rutin, as its major compound: investigating their effect on spatial memory and passive avoidance memory in rats.

Context: There are numerous pharmacological activities for Ruta graveolens and its bioactive constituent, rutin, on learning and memory.Objective: This study aimed to examine the effect of R. graveolens and rutin on memory in rats.Materials and methods: In this study animals were treated with the hydroalcholic extract of R. graveolens and rutin by IP injection for 10 days. Behavioural and biochemical tests as well as HPLC analysis and antioxidant activity of extract have been evaluated.Results: R. graveolens extract and rutin significantly increased learning and improved spatial memory, as well as secondary latency; moreover, there were significant increases in the serum and brain antioxidant capacity as well as the level of TBARS in serum and brain tissues. Results also showed that R. graveolens has significant DPPH radical scavenging effect (IC50: 159.17 ± 1.56 µg/mL). The HPLC analysis of extract showed that caffeic acid (19.92 ± 0.01), rutin (40.15 ± 0.01), and apigenin (0.84 ± 0.01) mg/g of dry extract are the main components of the extract.Discussion and conclusion: Regarding the effects of R. graveolens extract and rutin on animal brain cells, memory function, and learning, additional studies, including clinical trials, might be beneficial in producing natural supplementary drugs from this herb.

Resocialization mitigates depressive behaviors induced by social isolation stress in mice: Attenuation of hippocampal neuroinflammation and nitrite level.

BACKGROUND AND AIM: Social isolation stress (SIS) is a stressor known to trigger depressive behaviors. Psychiatric disorders are associated with neurobiological changes, such as neuroinflammation and an increase in nitric oxide (NO) signaling. Despite the well-established detrimental effects of SIS and the involvement of neuroinflammation and NO in depression, potential management strategies, especially resocialization, remain insufficiently explored. Our aim was to elucidate the effects of resocialization on depressive behaviors in socially isolated mice, with a focus on the possible involvement of neuroinflammation and nitrite in the hippocampus (HIP). METHODS: We utilized 24 Naval Medical Research Institute male mice, maintained under both social and isolation conditions (SC and IC). After the isolation period, the mice were divided into two groups of eight, including the SIS group and a resocialized group. The SC group was kept without exposure to isolation stress. We conducted the open-field test, forced swimming test, and splash test to evaluate depressive behaviors. Additionally, nitrite levels, as well as the gene expression of interleukin (IL)-1ß, tumor necrosis factor (TNF), and toll-like receptor 4 (TLR4) in the HIP, were measured. RESULTS: The study found that resocialization significantly reduces depressive behaviors in SIS mice. The results suggest that the antidepressive effects of resocialization may be partially due to the modulation of the neuroinflammatory response and nitrite levels in the HIP. This is supported by the observed decrease in hippocampal gene expression of IL-1ß, TLR4, and TNF, along with a reduction in nitrite levels following resocialization. CONCLUSION: These insights could pave the way for new management strategies for depression, emphasizing the potential benefits of social interactions.

Anethole as a promising antidepressant for maternal separation stress in mice by modulating oxidative stress and nitrite imbalance.

The occurrence of major depressive disorder is widespread and can be observed in individuals belonging to all societies. It has been suggested that changes in the NO pathway and heightened oxidative stress may play a role in developing this condition. Anethole is a diterpene aromatic compound found in the Umbelliferae, Apiaceae, and Schisandraceae families. It has potential pharmacological effects like antioxidant, anxiolytic, analgesic, anti-inflammatory, antidiabetic, gastroprotective, anticancer, estrogenic, and antimicrobial activities. This study aimed to investigate the potential antidepressant properties of Anethole in a mouse model experiencing maternal separation stress while also examining its impact on oxidative stress and nitrite levels. The research involved the participation of 40 male NMRI mice, separated into five distinct groups to conduct the study. The control group was administered 1 ml/kg of normal saline, while the MS groups were given normal saline and Anethole at 10, 50, and 100 mg/kg doses. The study comprised various behavioural tests, including the open field test (OFT), forced swimming test (FST), and splash test, to assess the effects of Anethole on the mice. In addition to the behavioural tests, measurements were taken to evaluate the total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels in the hippocampus of the mice. According to the findings, maternal separation stress (MS) led to depressive-like conduct in mice, including a rise in immobility duration during the FST and a reduction in the duration of grooming behaviour in the splash test. Additionally, the results indicated that MS correlated with an increase in the levels of MDA and nitrite and a reduction in the TAC in the hippocampus. However, the administration of Anethole resulted in an increase in grooming activity time during the splash test and a decrease in immobility time during the FST. Anethole also exhibited antioxidant characteristics, as demonstrated by its ability to lower MDA and nitrite levels while increasing the TAC in the hippocampus. The results suggest that Anethole may have an antidepressant-like impact on mice separated from their mothers, likely partly due to its antioxidant properties in the hippocampus.

Maternal separation stress through triggering of the neuro-immune response in the hippocampus induces autistic-like behaviors in male mice.

Autism spectrum disorder (ASD) is the fastest-growing neurodevelopmental disease throughout the world. Neuro-immune responses from prenatal to adulthood stages of life induce developmental defects in synaptic signaling, neurotransmitter imbalance, and even structural changes in the brain. In this study, we aimed to focus on the possible role of neuroinflammatory response in the hippocampus in development of the autistic-like behaviors following maternal separation (MS) stress in mice. To do this, mice neonates daily separated from their mothers from postnatal day (PND) 2 to PND 14 for 3 h. During PND45-60, behavioral tests related to autistic-like behaviors including three-chamber sociability, Morris water maze (MWM), shuttle box, resident-intruder, and marble burying tests were performed. Then, hippocampi were dissected out, and the gene expression of inflammatory mediators including TNF-α, IL-1ß, TLR4, HMGB1, and NLRP3 was assessed in the hippocampus using RT-PCR. Results showed that MS mice exerted impaired sociability preference, repetitive behaviors, impaired passive avoidance, and spatial memories. The gene expression of inflammatory mediators significantly increased in the hippocampi of MS mice. We concluded that MS stress probably via activating of the HMGB1/TLR4 signaling cascade in the hippocampus induced autistic-like behaviors in mice.

Gut-brain barrier dysfunction bridge autistic-like behavior in mouse model of maternal separation stress: A behavioral, histopathological, and molecular study.

Autism spectrum disorder (ASD) is a fast-growing neurodevelopmental disorder throughout the world. Experiencing early life stresses (ELS) like maternal separation (MS) is associated with autistic-like behaviors. It has been proposed that disturbance in the gut-brain axis-mediated psychiatric disorders following MS. The role of disruption in the integrity of gut-brain barrier in ASD remains unclear. Addressing this knowledge gap, in this study we aimed to investigate role of the gut-brain barrier integrity in mediating autistic-like behaviors in mouse models of MS stress. To do this, mice neonates are separated daily from their mothers from postnatal day (PND) 2 to PND 14 for 3 hours. During PND58-60, behavioral tests related to autistic-like behaviors including three-chamber sociability, shuttle box, and resident-intruder tests were performed. Then, prefrontal cortex (PFC), hippocampus, and colon samples were dissected out for histopathological and molecular evaluations. Results showed that MS is associated with impaired sociability and social preference indexes, aggressive behaviors, and impaired passive avoidance memory. The gene expression of CLDN1 decreased in the colon, and the gene expression of CLDN5, CLDN12, and MMP9 increased in the PFC of the MS mice. MS is associated with decrease in the diameter of CA1 and CA3 areas of the hippocampus. In addition, MS led to histopathological changes in the colon. We concluded that, probably, disturbance in the gut-brain barrier integrities mediated the autistic-like behavior in MS stress in mice.

Sinapinic acid as a potential therapeutic agent for epilepsy through targeting NMDA receptors and nitrite level.

Epilepsy, a widespread neural ailment considered by prolonged neuronal depolarization and repetitive discharge, has been linked to extreme stimulus of N-methyl-D-aspartate receptors (NMDARs). Despite the availability of approved anti-seizure medications (ASMs) in many developed nations, approximately 30% of epilepsy patients continue to experience drug-resistant seizures. Thus, a growing interest in discovering natural compounds as potential sources for new medications is growing. Sinapinic acid, a natural derivative of cinnamic acid found in food sources, is known for its neuroprotective properties. This study investigated how sinapinic acid interacts with NMDA receptors and its potential role in providing anticonvulsant effects. Male mice were randomly allocated into nine groups: a control group receiving normal saline (1 ml/kg), groups treated with sinapinic acid at doses of 1, 3, and 10 mg/kg, a group treated with diazepam at 10 mg/kg, a group treated with an NMDA agonist at 75 mg/kg, a group treated with an NMDA antagonist at 0.5 mg/kg, a group receiving the ineffective dose of sinapinic acid (1 mg/kg) along with the NMDA antagonist, and a group receiving the effective dose of sinapinic acid (10 mg/kg) along with the NMDA agonist. Sinapinic acid and other treatments were administered intraperitoneally 30 min prior to inducing seizures with PTZ injection. Seizure onset time was recorded following PTZ injection. Blood and brain samples were collected after anesthesia to determine serum and brain nitrite levels. Real-time PCR assessed NMDAR gene expression in the prefrontal cortex (PFC). Data were analyzed using Prism software. The time seizures began was notably extended in groups treated with sinapinic acid at doses of 3 and 10 mg/kg compared to those treated with saline (P < 0.05). Additionally, in the receiving group of an ineffective dose of sinapinic acid alongside ketamine, the beginning of seizure time was significantly prolonged compared to the group that received the ineffective dose of sinapinic acid alone (P < 0.05). Serum and prefrontal cortex (PFC) nitrite levels were significantly lower in mice treated with sinapinic acid at doses of 1, 3, and 10 mg/kg compared to the saline-treated group (P < 0.05). The gene expression of the NMDAR NR2B subunit in the PFC was decreased in groups treated with sinapinic acid at 1 and 10 mg/kg compared to the saline-treated group. Furthermore, co-administration of sinapinic acid (10 mg/kg) with NMDA resulted in significantly lower NR2A gene expression than the group treated with 10 mg/kg of sinapinic acid alone. Conversely, co-administration of ketamine with sinapinic acid (1 mg/kg) significantly increased NR2B subunit gene expression compared to the group treated with sinapinic acid at 1 mg/kg alone. Sinapinic acid showed anticonvulsant effects through reduced serum and PFC nitrite and modulation of glutamatergic signaling.

Acute oral toxicity assessment of galbanic acid in albino rat according to OECD 425 TG.

In spite of the broad biological and also anticarcinogenic effects which have been reported for galbanic acid in various studies, its toxic effects are not still well characterized. The study was accomplished to evaluate the acute oral toxicity of galbanic acid pursuant to Organisation for Economic Co-operation and Development (OECD) TG No. 425. Female rats were received asafoetida extract and galbanic acid in distilled water by oral gavage. According to the existing information, limit test was done for aqueous extract of asafoetida and main test was done for galbanic acid. The animals were monitored for 2 weeks. Then under general anesthesia, the blood samples were obtained from the heart for biochemical and hematological assessment and the vital organs of rats were isolated for pathological evaluation. The results showed that although the Median lethal dose (LD50) of asafoetida extract was above the 2000 mg/kg body weight, the galbanic acid estimated LD50 was 310.2 mg/kg. There was no considerable change in body weight of vehicle and extract treated animals but in galbanic acid treated animals, the body weights were not normally increased. A significant rise was observed in high-density lipoprotein (HDL), (aspartate aminotransferase) AST and (alanine aminotransferase) ALT levels as well as in white blood cells (WBC), platelet and lymphocytes counts in galbanic acid group compared to vehicle and extract groups. Based on the obtained results, we suggest that although the asafoetida aqueous extract could be categorized as group 5 (LD50 > 2000 mg/kg), but galbanic acid estimated LD50 is about 310.2 mg/kg and toxicity signs also appeared in lung, liver enzymes and complete blood count (CBC) of galbanic acid treated animals.

Chronic stress but not acute stress decreases the seizure threshold in PTZ-induced seizure in mice: role of inflammatory response and oxidative stress.

Seizure is paroxysmal abnormal electrical discharges in the cerebral cortex. Inflammatory pathways and oxidative stress are involved in the pathophysiology of seizures. Stress can induce an oxidative stress state and increase the production of inflammatory mediators in the brain. We investigated the effects of acute and chronic stresses on the seizure threshold in pentylenetetrazol (PTZ)-induced seizures in mice, considering oxidative stress and inflammatory mediators in the prefrontal cortex. In this study, 30 male Naval Medical Research Institute (NMRI) mice were divided into 3 groups, including acute stress, chronic stress, and control groups. PTZ was used for the induction of seizures. The gene expression of inflammatory markers (IL-1ß, TNF-α, NLRP3, and iNOS), malondialdehyde (MDA) level, nitrite level, and total antioxidant capacity (TAC) were assessed in the prefrontal cortex and serum. Our results showed that stress could increase the expression of inflammatory cytokines genes and oxidative stress in the prefrontal cortex of the brain and serum following PTZ-induced seizures, which is associated with increased seizure sensitivity and decreased the seizure threshold. The effects of chronic stress were much more significant than acute stress. We concluded that the effects of chronic stress on seizure sensitivity and enhancement of neuroinflammation and oxidative stress are much greater than acute stress.

Protective effects of vanillic acid on autistic-like behaviors in a rat model of maternal separation stress: Behavioral, electrophysiological, molecular and histopathological alterations.

Compounds derived from herbs exhibit a range of biological properties, including anti-inflammatory, antioxidant, and neuroprotective properties. However, the exact mechanism of action of these compounds in various neurological disorders is not fully discovered yet. Herein, the present work detected the effect of Vanillic acid (VA), a widely-used flavoring agent derived from vanillin, on autistic-like behaviors to assess the probable underlying mechanisms that mediate behavioral, electrophysiological, molecular, and histopathological alterations in the rat model of maternal separation (MS) stress. Maternal separated rats were treated with VA (25, 50, and 100 mg/kg interperitoneally for 14 days). In addition, anxiety-like, autistic-like behaviors, and learning and memory impairment were evaluated using various behavioral tests. Hippocampus samples were assessed histopathologically by H&E staining. Levels of malondialdehyde (MDA) and antioxidant capacity (by the FRAP method), as well as nitrite levels, were measured in brain tissue. Moreover, gene expression of inflammatory markers (IL-1ß, TLR-4, TNF-α, and NLRP3) was evaluated in the hippocampus. Electrophysiological alterations were also estimated in the hippocampus by long-term potentiation (LTP) assessments. Results showed that VA reversed the negative effects of MS on behavior. VA increased the diameter and decreased the percentage of dark neurons in the CA3 area. Accordingly, VA decreased MDA and nitrite levels and increased the antioxidant capacity in brain samples and decreased the expression of all inflammatory genes. VA treated rats showed significant improvements in all LTP parameters. This study provided evidence suggesting a possible role for VA in preventing autism spectrum disorder (ASD) by regulating immune signaling.

The nephrotoxicity of Aristolochia rotunda L. in rats: Mitochondrion as a target for renal toxicity of Aristolochic acids-containing plants.

In recent years, there has been a growing trend in the usage of traditional medicine and herbal treatments. However, the misconception that they are completely safe resulted in irreversible complications and damages. The present study was conducted to investigate the potential renal toxicity of a commonly used drug in Iran's traditional medicine and pharmacy, known as Zaravand Gerd or Nokhod Alvand (Aristolochia rotunda L.). In Iranian traditional medicine, Zaravand Gerd is used as a remedy for respiratory system ailments, back pain, anxiety, headache and septic wounds. Fifty-six male rats were divided into seven groups (n = 8). The first group served as the control and received normal saline, while the second to seventh groups were administered varying doses of the aqueous extract of Zaravand Gerd (0.1, 0.5, 1.25, 2.5, and 5 g/kg) for a period of three weeks. Various parameters were measured to evaluate the potential kidney damage caused by the extract, including serum creatinine and BUN levels, as well as urine protein and glucose levels, which were analyzed using an autoanalyzer. Additionally, kidney tissue samples were examined pathologically, and mitochondria from the kidney tissue were isolated to assess mitochondrial parameters. The results of this study revealed that high doses of Zaravand Gerd extract led to a significant increase in urinary glucose and protein excretion compared to the control group. Pathological examination of the isolated kidney tissues indicated that the concentrations of 2.5 and 5 g/kg of Zaravand Gerd extract resulted in kidney damage and dilation of proximal convoluted tubules. Furthermore, the study demonstrated that high doses of the extract (2.5 and 5 g/kg) caused damage to the mitochondria. Based on the findings of this study, it can be concluded that the administration of high doses of Zaravand Gerd extract, which are not commonly used in traditional medicine, can have toxic effects on the kidneys in rats as an animal model. These results highlight the importance of considering the potential risks associated with herbal medicines and the necessity of usage based on scientific evidence.

Combined treatment with Alhagi maurorum and docetaxel inhibits breast cancer progression via targeting HIF-1α/VEGF mediated tumor angiogenesis in vivo.

Breast cancer is a challenging disease and leading cause of cancer death in women. There is no effective agent for metastatic breast cancer after surgery and chemotherapy. Alhagi maurorum (A.m) has been reported to exhibit an anticancer effect on various types of cancer cells in vitro. This study aimed to examine the suppressive effect of A.m alone and combined with docetaxel (DTX) on the breast cancer growth in mice models and the possible underlying mechanisms. In the present study, the mice were inoculated subcutaneously with the injections of 4T1 cells. Then, A.m, DTX, and their combination were administered intraperitoneally. The expressions of ß-catenin (ß-cat), FZD7, MMP2, HIF1-α, and VEGF A (vascular endothelial growth factor A) were investigated using RT-PCR method. Also, plasma alkaline phosphatase (ALP), alanine aminotransferase (GPT or ALT), aspartate transaminase (GOT or AST), serum creatinine, and urea were examined, and histological analyses of the tissues were conducted. The results demonstrated that A.m (500 mg/kg) combined with DTX significantly decreased the expression of ß-cat, MMP2, and FZD7 as compared with the negative control group and monotherapies. Also, the mRNA levels of HIF1-α and VEGF A were suppressed significantly by DTX + A.m (500 mg/kg). Tumor weights and sizes were significantly lower and tumor inhibition rate was significantly higher in the DTX + A.m group. The A.m 500 mg/kg + DTX also suppressed the serum GPT level in tumor-bearing mice and decreased the serum urea level. Taken together, our findings suggest that DTX combined with A.m at an optimal dose of 500 mg/kg as the optimal dose can inhibit ß-cat, FZD7, MMP2, and breast cancer growth via interrupting HIF-1α/VEGF signaling and might be used as a promising antiangiogenic agent for breast cancer treatment.

Effect of White Tea (Camellia sinensis) Extract on Skin Wound Healing Process in Rats.

BACKGROUND: White tea (Camellia sinensis) has anti-inflammatory and antioxidant properties and a protective effect against wrinkles, sunburn and UV damages on the skin. Thus, we aimed to evaluate the effect of white tea extract on the healing process of skin wounds in rats. METHODS: This study was done in the Research Center of Shahrekord University of Medical Sciences, Shahrekord, Iran in 2019. Excisional skin wounds were created on five groups of healthy male Wistar rats (200-250 g, n=21) including control group, Eucerin-treated group, white tea 5% ointment (Eucerin) treated group, gel-treated group, white tea 5% gel treated group. Treatment was begun on day 1 and repeated every day at the same time until day 15. Pathologic samples were taken on days 4, 7 and 15 for histopathological examinations. Kruskal-Wallis test was used to analyze data by SPSS. Statistical significance was defined as P<0.05. RESULTS: Wound closure rate of control group was more than other groups on day 4 (P<0.05). On day 7, reepithelisation and granulation tissue of control group were more than white tea 5% ointment-treated and its inflammation was less than others (P<0.05). Neo-vascularization of white tea 5% ointment-treated group was more than control group on days 4 and 15 (P<0.05). On day 4, intact mast cells of control group were more than white tea treated groups (P<0.05). Degranulated mast cells of white tea 5% gel treated group was significantly (P<0.05) more than control group on days 4 and 15. CONCLUSION: Five percent white tea extract could not help the skin wound healing process.

Limonene through Attenuation of Neuroinflammation and Nitrite Level Exerts Antidepressant-Like Effect on Mouse Model of Maternal Separation Stress.

METHODS: Mice were randomly divided into experimental groups as follows: the control group received normal saline and MS groups received normal saline, limonene (10 and 20 mg/kg), L-NAME (10 mg/kg), L-arginine (L-arg) (75 mg/kg), limonene (10 mg/kg) plus L-NAME, and limonene (20 mg/kg) plus L-arg. Behavioral tests including the forced swimming test (FST), open field test (OFT), and splash test were performed. Finally, serum and hippocampal nitrite levels as well as the expression of inflammatory genes (IL-1ß and TNF-α) in the hippocampus were measured. RESULTS: We showed that MS caused depressive-like behavior. Treatment of MS mice with limonene reduced the duration of immobility time in FST and increases the grooming activity time in the splash test. Limonene also reduces serum and brain nitrite levels and reduces the expression of IL-1ß and TNF-α in the hippocampus. We found that L-NAME potentiated the effects of a subeffective dose of limonene. CONCLUSION: We concluded that the antidepressant-like effects of limonene are probably mediated through inhibition of neuroinflammation and attenuation of nitrite levels in the hippocampus.

Diosmetin Mitigates Cognitive and Memory Impairment Provoked by Chronic Unpredictable Mild Stress in Mice.

MATERIALS AND METHODS: In the present experimental study, male NMRI mice were exposed to chronic unpredictable mild stress (CUMS) paradigm for 35 days. Diosmetin (at doses of 10, 20, and 40 mg/kg. i.p.) or diosmetin solvent (normal saline + DMSO, 1 ml/kg; i.p.) was administered 30 min before stress induction. After 28 days, memory and cognitive performance were assessed by shuttle box and novel object recognition tests. Finally, antioxidant capacity (FRAP) and malondialdehyde (MDA) level of serum and brain, and serum corticosterone level were evaluated. RESULTS: Behavioral tests showed that CUMS significantly reduced the secondary latency in passive avoidance memory test and diagnosis index in novel object recognition test compared to the control group (P < 0.001), whereas treatment with diosmetin (20 and 40 mg/kg) significantly improved memory performance in the two tests (P < 0.001). In addition, diosmetin (40 mg/kg) could pronouncedly suppress increase in serum corticosterone levels, reduction in antioxidant capacity, and production of excess MDA caused by CUMS compared to the control group (P < 0.01, P < 0.001, and P < 0.001, respectively). CONCLUSION: Chronic stress can impair memory and cognition and treatment with diosmetin can partly improve this disorder in male mice by increasing the antioxidant capacity of brain tissue and serum and improving serum corticosterone levels.

Therapeutic Effects of Oleuropein in Improving Seizure, Oxidative Stress and Cognitive Disorder in Pentylenetetrazole Kindling Model of Epilepsy in Mice.

Prolonged epileptic seizures are the cause of neuronal death and brain damage. Lesions in different regions of the brain can lead to memory loss and cognitive disorders. It is therefore essential to seek out new neuroprotective drugs. Our aim was to investigate the therapeutic effects of oleuropein in improving seizure, oxidative stress, and cognitive disorder in pentylenetetrazole (PTZ) kindling model of epilepsy in mice. Mice were randomized to four groups; negative control group intraperitoneally receiving PTZ for 10 days, oleuropein group receiving oleuropein (20 mg/kg) 30 min before PTZ administration, positive control group receiving diazepam 30 min before PTZ administration and flumazenil group receiving flumazenil and then oleuropein 30 min before PTZ administration. Epilepsy severity was investigated after final administration of PTZ. Then hippocampal tissues were removed and stored at -70 °C until measurements of the interleukin-1 (IL-1) and glutamate transporter 1 (GLT-1) gene expression were conducted. Oleuropein treatment caused a significant increase in seizure latency and a significant decrease in total frequencies of head ticks, head and upper limbs seizures, the whole body seizures, frequent spinning and jumping and tonic seizures in PTZ receiving mice. IL-1 expression decreased in oleuropein group and GLT-1 levels did not change significantly in this group. Oleuropein treatment caused significant improvement of passive avoidance memory in PTZ receiving mice in shuttle box. Oleuropein can decrease PTZ-induced seizures and memory disorders due to its antioxidant and anti-inflammatory properties and is thus recommended to be used for production of anti-epileptic drugs.

Effect of hydroalcoholic Allium atroviolaceum L. on the pathology of testicular tissue in cyclophosphamide-treated mice.

BACKGROUND: The most important side effects of Cyclophosphamide, as an anticancer broad-spectrum drug, are the negative effects on the reproduction and fertility because of oxidative stress. Considering the antioxidant properties of medicinal plants, especially those of the Allium genus, this paper studied the effect of hydroalcoholic extract of Allium atroviolaceum L. on the pathology of testicular tissue in CP-treated mice. METHODS: Groups of this experimental study consisted of normal saline recipients; three groups receiving A. atroviolaceum extract at 50, 100, 200 mg/kg; three groups receiving A. atroviolaceum extract at 50, 100, and 200 mg/g and 6.6 mg/kg of Cyclophosphamide; and a group given Cyclophosphamide at 1.6 mg/kg. All injections were performed intra-peritoneally. After 30 days, the testicular histological profile as well as the number of spermatozoa, the number of primary and round spermatocytes, and the number of spermatogonia were investigated. RESULTS: Cyclophosphamide treatment significantly reduced the lumen diameter, the seminiferous tubule diameter, the epithelial thickness, as well as decreased the quantity of spermatozoa and round and primary spermatocytes compared to the control group. Cyclophosphamide groups treated with A. atroviolaceum extract at 50, 100 and 200 mg/kg in a significant manner improved these variables (P < 0.001). CONCLUSION: A. atroviolaceum extract can significantly improve Cyclophosphamide-induced toxicity and pathological process on testicular tissue. It seems that this plant, with high antioxidant capacity, can be considered a complementary therapy for Cyclophosphamide to prevent undesirable effects on the reproductive system.