Gender-related variation expressions of neuroplastin TRAF6, GluA1, GABA(A) receptor, and PMCA in cortex, hippocampus, and brainstem in an experimental epilepsy model.

Epileptic seizures are seen as a result of changing excitability balance depending on the deterioration in synaptic plasticity in the brain. Neuroplastin, and its related molecules which are known to play a role in synaptic plasticity, neurotransmitter activities that provide balance of excitability and, different neurological diseases, have not been studied before in epilepsy. In this study, a total of 34 Sprague-Dawley male and female rats, 2 months old, weighing 250-300 g were used. The epilepsy model in rats was made via pentylenetetrazole (PTZ). After the completion of the experimental procedure, the brain tissue of the rats were taken and the histopathological changes in the hippocampus and cortex parts and the brain stem were investigated, as well as the immunoreactivity of the proteins related to the immunohistochemical methods. As a result of the histopathological evaluation, it was determined that neuron degeneration and the number of dilated blood vessels in the hippocampus, frontal cortex, and brain stem were higher in the PTZ status epilepticus (SE) groups than in the control groups. It was observed that neuroplastin and related proteins TNF receptor-associated factor 6 (TRAF6), Gamma amino butyric acid type A receptors [(GABA(A)], and plasma membrane Ca2+ ATPase (PMCA) protein immunoreactivity levels increased especially in the male hippocampus, and only AMPA receptor subunit type 1 (GluA1) immunoreactivity decreased, unlike other proteins. We believe this may be caused by a problem in the mechanisms regulating the interaction of neuroplastin and GluA1 and may cause problems in synaptic plasticity in the experimental epilepsy model. It may be useful to elucidate this mechanism and target GluA1 when determining treatment strategies.

Evaluation of the anticarcinogenic effects of Rutin on brain tissue in mice with Ehrlich ascites carcinoma by micro-computed tomography and histological methods.

BACKGROUND: Studies for new treatment strategies on cancer continue, and new searches continue in the diagnosis and evaluation of cancer. This study examined the possible anticarcinogenic effect of Rutin on the brain tissues of male mice with Ehrlich ascites carcinoma (EAC). MATERIAL AND METHODS: We used micro-computed tomography (micro-CT) and histologically Hematoxylin&Eosin (H&E) staining methods for evaluation. RESULTS: In the evaluation results, we saw a significant decrease in the brain volume of the tumor group to the control group. The difference in volume between the Rutin treatment group and the control group was not significant. In the brain tissues of the tumor group, numerous degenerated neurons characterized by pericellular/perivascular space expansion, cell swelling, or expansion were detected in the cortex and hippocampus regions. We showed a reduction in the damage rate in the Rutin treated group. CONCLUSION: As a result, Rutin was found to have an anticarcinogenic effect. In addition to the classical histological evaluation, we used a newer method, micro-CT, in our study. We believe that this study has important results both in terms of its originality and adding new information to the literature.

Trans Species RNA Activity: Sperm RNA of the Father of an Autistic Child Programs Glial Cells and Behavioral Disorders in Mice.

Recently, we described the alteration of six miRNAs in the serum of autistic children, their fathers, mothers, siblings, and in the sperm of autistic mouse models. Studies in model organisms suggest that noncoding RNAs participate in transcriptional modulation pathways. Using mice, approaches to alter the amount of RNA in fertilized eggs enable in vivo intervention at an early stage of development. Noncoding RNAs are very numerous in spermatozoa. Our study addresses a fundamental question: can the transfer of RNA content from sperm to eggs result in changes in phenotypic traits, such as autism? To explore this, we used sperm RNA from a normal father but with autistic children to create mouse models for autism. Here, we induced, in a single step by microinjecting sperm RNA into fertilized mouse eggs, a transcriptional alteration with the transformation in adults of glial cells into cells affected by astrogliosis and microgliosis developing deficiency disorders of the 'autism-like' type in mice born following these manipulations. Human sperm RNA alters gene expression in mice, and validates the possibility of non-Mendelian inheritance in autism.

Protective role of olive oil extract of propolis on short and long-term administration of tamoxifen in rats.

Tamoxifen (TAM) is an antiestrogenic agent used for adjuvant treatment in estrogen receptor-positive breast cancers in the pre/post-menopausal period. This study, it was aimed to determine the effect of olive oil extract of propolis (OEP) on short and long-term administration of TAM in rats. Wistar albino rats were divided into groups with eight animals in each. Groups: control, OEP, TAM, and OEP + TAM. At the end of the experiment, oxidative stress tests were performed with Enzyme-Linked ImmunoSorbent Assay (ELISA) on blood and tissue samples (liver, kidney, and ovary) taken from rats. After single-dose TAM administration, there was a significant increase in red blood cell, hematocrit, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration levels compared to the control group, a decrease in low-density lipoprotein (LDL) value, a significant increase in liver enzymes and fasting glucose values was detected compared with the control and propolis groups. A normalizing effect was observed in the group given OEP and TAM combined. The increase in Malondialdehyde (MDA) and the decrease in enzyme activities in tissues are also noteworthy. Propolis application reduced the tissue damage caused by TAM. In addition, improved cytokine levels, which increased with TAM administration. It has been concluded that OEP can be given in supportive treatment, as it improves hematological and antioxidant parameters in TAM treatment.

Linagliptin in combination with insulin suppresses apoptotic unfolded protein response in ovaries exposed to type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is one of the main causes of ovarian atresia, but its molecular effect on the ovaries is not fully understood. Accumulating evidence suggests that T1DM causes excessive endoplasmic reticulum (ER) stress and insufficient adaptive unfolded protein response that triggers proapoptotic signaling pathways in ovarian tissue. In addition, problems such as amenorrhea and infertility, which are frequently seen in women with T1DM, continue despite the intensification of insulin therapy and improvement of metabolic control. Therefore new, and adjunctive treatments for women with T1DM need to be explored. We aimed to examine how the use of linagliptin, which has blood sugar-lowering effects and high antioxidant activity, together with insulin affects the expression levels of proteins and genes that play a role in ER stress in type 1 diabetic mouse ovaries. Eighty-four Balb/C 6-week-old female mice were randomly divided into seven groups: control, vehicle, diabetes + insulin, diabetes + linagliptin, diabetes + linagliptin + insulin, diabetes + TUDCA, and diabetes + TUDCA + insulin. TUDCA (an inhibitor of ER stress) groups are positive control groups created to compare linagliptin groups in terms of ER stress. Linagliptin and TUDCA were given by oral gavage and 1U insulin was administered subcutaneously for 2 weeks. A significant decrease was observed in the MDA and NOX1 levels and the number of atretic follicles in the ovaries of the diabetes + linagliptin + insulin group compared to the diabetes + insulin group. The use of linagliptin and insulin increased the expression of pro-survival XBP1s transmembrane protein and decreased the expression of proapoptotic ATF4, pJNK1/2, cleaved caspase 12, and cleaved caspase 3 in mouse ovaries. Our study provides new therapeutic evidence that linagliptin administered in addition to insulin induces ER stress mechanism-dependent survival in ovaries with type 1 diabetes.

The effect of Cornus mas extract on nicotine-induced oxidative stress and intratesticular damage in male rats.

The role of oxidative stress in disease pathogenesis has been extensively investigated. Researchers have gathered sufficient evidence related to oxidative stress-mediated intratesticular damage. The aim of this was study to evaluate the effects of Cornus Mas (CM) extract on intratesticular changes in rats exposed to nicotine. Thirty Wistar albino rats were divided into four groups. The groups and the administrated agents for 35 days were as follows; Control group (n=6): 0.9% saline, intraperitoneally; Nicotine group (n=7): 4 mg/kg nicotine, subcutaneous; CM group (n=7): 1000 mg/kg CM extract in 0.5 ml saline, via gavage; Nicotine + CM Group (n=8): 4 mg/kg Nicotine, subcutaneous + 1000 mg/kg CM extract via gavage. One rat each from the groups Nicotine and CM died.  In spermatogenetic and histopathological examination, significant positive changes were detected in nicotine + CM group regarding seminal parameters, apoptotic cells, Factor VIII and Johnsen score as compared to nicotine group. Oxidative stress markers were higher in nicotine group as compared to the control group. OSI and MDA levels were found to be reduced in nicotine + CM group than nicotine group. Nicotine induced a significant increase in TNF-α and IL-6 levels compared to the control group; however, CM effectively counteracted this increase. We have shown that nicotine increases testicular damage, causes apoptosis of testicular cells and adversely affects spermatogenesis by increasing inflammation. We concluded that CM extract exerted beneficial effects on spermatogenesis and minimized testicular parenchymal damage, apoptosis and angiogenesis. Rapidly increasing understanding of the complexity of oxidative stress in intratesticular is the key to unlocking the potential of ROS-targeting therapies.

Can endoplasmic reticulum stress observed in the PTZ-kindling model seizures be prevented with TUDCA and 4-PBA?

Epilepsy is a chronic neurological disease with recurrent seizures. Increasing evidence suggests that endoplasmic reticulum (ER) stress may play a role in the pathogenesis of epilepsy. We aimed to investigate the effects of Tauroursodeoxycholic acid (TUDCA) and 4-phenyl-butyric acid (4-PBA), which are known to suppress ER stress, on developed seizures in terms of markers of ER stress, oxidative stress, and apoptosis. The pentylenetetrazole (PTZ) kindling model was induced in Wistar albino rats (n = 48) by administering 35 mg/kg PTZ intraperitoneally (I.P.) every other day for 1 month. TUDCA and 4-PBA were administered via I.P. at a dose of 500 mg/kg dose. ER stress, apoptosis, and oxidative stress were determined in the hippocampus tissues of animals in all groups. Immunohistochemistry, qRT-PCR, ELISA, and Western Blot analyzes were performed to determine the efficacy of treatments. Expressions of ATF4, ATF6, p-JNK1/2, Cleaved-Kaspase3, and Caspase12 significantly increased in PTZ-kindled seizures compared to the control group. Increased NOX2 and MDA activity in the seizures were measured. In addition, stereology analyzes showed an increased neuronal loss in the PTZ-kindled group. qRT-PCR examination showed relative mRNA levels of CHOP. Accordingly, TUDCA and 4-PBA treatment suppressed the expressions of ATF4, ATF6, Cleaved-Caspase3, Kaspase12, NOX2, MDA, and CHOP in TUDCA + PTZ and 4-PBA + PTZ groups. ER stress-induced oxidative stress and apoptosis by reducing neuronal loss and degeneration were also preserved in these groups. Our data show molecularly that TUDCA and 4-PBA treatment can suppress the ER stress process in epileptic seizures.

The increase in c-fos expression in epileptic seizures is inhibited by magnetic field application, but not KCa1.1 channel expression.

The aim of this study was to understand the expression of big potassium (BK, KCa1.1) channels in epileptic seizures under magnetic field application. Forty Wistar albino adult male rats were divided into five groups (n = 8). First group rats were control group. Pentylenetetrazole (PTZ) administrated to second group rats to induce the seizures with 35 mg/kg intraperitoneally injection every two days. Levetiracetam (LEV) i.p. at a dose of 108 mg/kg was given to third group rats as positive control group (PC) before 20 minutes PTZ administration. Pulsed magnetic field with 1.5 mT was exposed to the fourth group rats for 3 hours a day for 1 month as magnetic field (MF) group. 1.5 mT pulsed magnetic field was exposed to the fifth group rats for 3 hours a day for 1 month in addition to PTZ administration (PTZ+MF). KCa1.1 not changed in hippocampus of PTZ rats while increased in frontal cortex and pons for PTZ group but not changed with magnetic field exposure. KCa1.1 increased in heart of PTZ animals and turned back to mean control values with magnetic field exposure. Suppressing the expected increase of c-fos protein expression in seizures with magnetic field application but not being able to change the KCa1.1 expression shows that new studies can be done by increasing the frequency of 1.5 mT magnetic field.

Evaluation of linagliptin and insulin combined therapy on unfolded protein response in type 1 diabetic mouse heart.

The aim of this study is to reveal the effects of the use of linagliptin, a DPP-4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT-PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p-JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts.

Intermediate filament proteins are reliable immunohistological biomarkers to help diagnose multiple tissue-specific diseases.

Cytoskeletal networks are proteins that effectively maintain cell integrity and provide mechanical support to cells by actively transmitting mechanical signals. Intermediate filaments, which are from the cytoskeleton family and are 10 nanometres in diameter, are unlike actin and microtubules, which are highly dynamic cytoskeletal elements. Intermediate filaments are flexible at low strain, harden at high strain and resist breaking. For this reason, these filaments fulfil structural functions by providing mechanical support to the cells through their different strain-hardening properties. Intermediate filaments are suitable in that cells both cope with mechanical forces and modulate signal transmission. These filaments are composed of fibrous proteins that exhibit a central α-helical rod domain with a conserved substructure. Intermediate filament proteins are divided into six groups. Type I and type II include acidic and basic keratins, type III, vimentin, desmin, peripheralin and glial fibrillary acidic protein (GFAP), respectively. Type IV intermediate filament group includes neurofilament proteins and a fourth neurofilament subunit, α-internexin proteins. Type V consists of lamins located in the nucleus, and the type VI group consists of lens-specific intermediate filaments, CP49/phakinin and filen. Intermediate filament proteins show specific immunoreactivity in differentiating cells and mature cells of various types. Various carcinomas such as colorectal, urothelial and ovarian, diseases such as chronic pancreatitis, cirrhosis, hepatitis and cataract have been associated with intermediate filaments. Accordingly, this section reviews available immunohistochemical antibodies to intermediate filament proteins. Identification of intermediate filament proteins by methodological methods may contribute to the understanding of complex diseases.

Tauroursodeoxycholic Acid (TUDCA) Regulates Inflammation and Hypoxia in Autonomic Tissues of Rats with Seizures.

Inflammation and hypoxia have an effect on the molecular mechanism of cardiovascular and respiratory pathologies accompanying seizures. Against this, Tauroursodeoxycholic Acid (TUDCA) can regulate oxidative stress, inflammation and cellular survival by suppressing endoplasmic reticulum (ER) stress. We evaluated the expression changes of NF-κB p65, TNF-α, HIF1α and Kir6.2 proteins associated with seizures in brain stem, heart and lung tissues representing the autonomous network. Additionally, we examined the protective effects of TUDCA administration against damage caused by seizures in terms of immunohistochemistry and pathology. 4 groups of Wistar Albino male rats (250-300 g, n=32) were formed as control, pentylenetetrazole (PTZ), TUDCA and PTZ+TUDCA. The epilepsy kindling model was created by intraperitoneal (i.p.) injection of PTZ chemical (35 mg/kg, every 2 days) for one month. TUDCA (500 mg/kg; every 2 days) treatment was given intraperitoneally 30 minutes before seizures for 1 month. Brain stem, heart (atria, ventricle) and lung tissues of rats were isolated. NF-κB p65, TNF-α, HIF1α and Kir6.2 proteins in the obtained tissues were evaluated by immunohistochemical staining. The immunoreactivity of the investigated proteins in the brainstem heart and lung tissues of rats with chronic PTZ administration was significantly increased. Recurrent seizures led to accumulation of inflammatory cells in tissues, hemorrhage, vasodilation, and apoptosis. Following TUDCA administration, expression of NF-κB p65, TNF-α and Kir6.2 was significantly reduced in all tissues (except the atrium of the heart) compared to control rats. HIF-1α levels were significantly suppressed in ventricular and lung tissues of epileptic rats given TUDCA. However, TUDCA pretreatment improved histopathological changes due to chronic seizures and partially reduced apoptosis. We showed that epileptic seizures may cause tissue damage with the development of inflammatory and hypoxic conditions in the brainstem and organs that represent the autonomic network. TUDCA therapy could be an effective agent in the treatment of cardiac and respiratory problems associated with seizures.

Heterozygous Cc2d1a mice show sex-dependent changes in the Beclin-1/p62 ratio with impaired prefrontal cortex and hippocampal autophagy.

Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders characterized by repetitive behaviors, lack of social interaction and communication. CC2D1A is identified in patients as an autism risk gene. Recently, we suggested that heterozygous Cc2d1a mice exhibit impaired autophagy in the hippocampus. We now report the analysis of autophagy markers (Lc3, Beclin and p62) in different regions hippocampus, prefrontal cortex, hypothalamus and cerebellum, with an overall decrease in autophagy and changes in Beclin-1/p62 ratio in the hippocampus. We observed sex-dependent variations in transcripts and protein expression levels. Moreover, our analyses suggest that alterations in autophagy initiated in Cc2d1a heterozygous parents are variably transmitted to offspring, even when the offspring's genotype is wild type. Aberration in the autophagy mechanism may indirectly contribute to induce synapse alteration in the ASD brain.

Toxicity of Propylene Glycol Extract of Propolis on Central Nervous System and Liver in Pregnant and Neonatal Rats.

BACKGROUND: Propolis has become one of the most preferred supplements due to its beneficial biological properties. Organic (water and vegetable oils) and chemical (ethyl alcohol, propylene glycol, and glycerol) solvents are used for propolis extraction. However, the effects of these chemicals on health should be taken into account. OBJECTIVES: In this study, the effects of propolis extracts on health were evaluated. METHODS: 32 pregnant Wistar albino rats and 64 neonatal/young adults were given three different extractions of propolis (propylene glycol, water, and olive oil). Histopathological analyses were performed on the liver and brain, and blood samples were taken from the hearts of rats. RESULTS: Histopathological scoring showed that the intensity of pycnotic hepatocyte, sinusoidal dilatation, and bleeding was high in liver samples of pregnant and baby rats given propylene glycol extract of propolis (p<0.05). Propylene glycol extract caused dilatation of blood vessels and apoptosis of neurons in brain tissue. The histopathological score was significantly lower in liver and brain tissues of rats treated with water and olive oil extract compared to propylene propolis groups (p<0.05). Liver enzyme levels in the blood increased in propylene propolis rats (p<0.05). CONCLUSION: Histopathological changes and biochemical alterations may indicate that propylene glycol extracts of propolis are more toxic than olive oil and water extracts. Therefore, olive oil and water extracts of propolis are more reliable than propylene glycol extract in pregnant and infant rats.

Immunoreactivity of Kir3.1, muscarinic receptors 2 and 3 on the brainstem, vagus nerve and heart tissue under experimental demyelination.

AIMS: Demyelination affects the propogation of neuronal action potential by slowing down the progression. This process results in a neuro-impairment like Multiple Sclerosis (MS). Evidence show that MS also contributes to involvement of the autonomic system. In the molecular approach to this involvement, we aimed to observe muscarinic ACh receptor 2-3 (mAChR2-3), and inwardly rectifying potassium channel 3.1 (Kir3.1) immunoreactivities on the brainstem, vagus nerve, and heart under cuprizone model. MAIN METHODS: Wistar albino rats were randomly divided into 8 groups; duplicating 4 groups as male and female: control groups (n = 3 +3), Cuprizone groups (n = 12 +12), sham groups (n = 4 +4), and carboxy-methyl-cellulose groups (n = 3 +3). Cuprizone-fed rats underwent demyelination via Luxol fast blue (LFB) staining of the hippocampus (Gyrus dentatus and Cornu Ammonis) and cortex. Immunohistochemistry analysis followed to the pathologic measurement of the brainstem, vagus nerve, and heart for mAChR2, mAChR3 and Kir3.1 proteins KEY FINDINGS: A significant demyelination was observed in the hippocampus and cortex tissues of rats in the female and male cuprizone groups. Myelin basic protein immunoreactivity demonstrated that cuprizone groups, in both males and females, had down-regulation in the hippocampus and cortex areas. The weights of the cuprizone-fed rats significantly decreased over six weeks. Dilated blood vessels and neuronal degeneration were severe in the hippocampus and cortex of the cuprizone groups. In the female cuprizone group, expression of mAChR2 and mAChR2 was significantly increased in the brainstem, atrium/ventricle of heart, and left/right sections of vagus nerve. Kir3.1 channels were also up-regulated in the left vagus nerve and heart sections of the female cuprizone group SIGNIFICANCE: Especially in our data where female-based significant results were obtained reveal that demyelination may lead to significant mAChR2, mAChR3 and Kir3.1 changes in brainstem, vagus nerve, and heart. A high immunoreactive response to demyelination at cholinergic centers may be a new target.

Evaluation of the protective role of resveratrol against sepsis caused by LPS via TLR4/NF-κB/TNF-α signaling pathways: Experimental study.

The development and progression of sepsis are multifactorial and influence the immunological, endocrine, and cardiovascular systems of the body. Our knowledge of the key mechanisms involved in the pathogenesis of sepsis has expanded exponentially, yet this still needs to be translated into effective targeted therapeutic regimes. In the present study, we aimed to determine whether resveratrol has positive effects in the experimental sepsis rat model. Twenty-eight male Spraque-Dawley rats were randomly divided into four groups (n = 7) as follows: control, lipopolysaccharide (LPS) (30 mg/kg dose), resveratrol, and LPS and resveratrol. After the experiment, liver and kidney tissues were collected for histopathological evaluation, blood serums were collected to measure malondialdehyde levels with enyzme-linked immunosorbent assay, and Toll-like receptor-4 (TLR4), tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB) immunoreactivity density was evaluated immunohistochemically. In addition, messenger RNA expression levels for TLR4, TNF-α, NF-κB, interleukin-1ß, and interleukin 6 were measured. In addition, the damage observed in liver and kidney tissue was determined by AgNOR (argyrophilic nucleolar organizer regions) staining. LPS application caused severe tissue damage, oxidative stress, and increased the expressions of proinflammatory proteins and genes we evaluated, while resveratrol application eliminated these negativities. Resveratrol has been proven to suppress the TLR4/NF-κB/TNF-α pathway, a possible therapeutic signaling pathway that is important in initiating the inflammatory response in an animal model of sepsis.

Determination of Rutin's antitumoral effect on EAC solid tumor by AgNOR count and PI3K/AKT/mTOR signaling pathway.

Rutin is one of the flavonoids found in fruits and vegetables. The PI3K/AKT/mTOR signaling pathway is critical for the life cycle at the cellular level. In current study, we purposed to demonstrate the antitumoral effect of rutin at different doses through the mTOR-signaling pathway and argyrophilic nucleolar regulatory region. EAC cells were injected subcutaneously into the experimental groups. 25 and 50 mg/kg Rutin were injected intraperitoneally to the animals with solid tumors for 14 days. Immunohistochemical, Real-time PCR and AgNOR analyzes were actualized on the taken tumors. When the rutin given groups and the tumor group were compared, the tumor size increase was detected to be statistically significant (p < 0.05). In immunohistochemical analysis, a significant decrease was encountered in the AKT, mTOR, PI3K and F8 expressions especially in the groups administered 25 mg Rutin, in comparison with the control group (p < 0.05). AgNOR area/nuclear area (TAA/NA) and average AgNOR number were determineted, and statistically important differences were detected between the groups in terms of TAA/NA ratio (p < 0.05). There were significant statistical differences between the mRNA quantity of the PI3K, AKT1 and mTOR genes (p < 0.05). In the in vitro study, cell apoptosis was evaluated with different doses of annexin V and it was determined that a dose of 10 µg/mL Rutin induced apoptosis (p < 0.05). In our study, it was demonstrated in vivo and in vitro that Rutin has an anti-tumor effect on the development of solid tumors formed by both EAC cells.

Detection of melatonin protective effects in sepsis via argyrophilic nucleolar regulatory region-associated protein synthesis and TLR4/NF-κB signaling pathway.

In this study, the protective effect of melatonin was investigated in lipopolysaccharide induced sepsis model. Twenty-eight rats were randomly divided: Control, Melatonin, LPS and LPS + Melatonin. After LPS application, surgically remove kidney and liver tissues. The level of malondialdehyde (MDA) an oxidative stress marker and the immunoreactivity of Toll-like receptor-4 (TLR4), tumor necrosis factor-α (TNF-α), and transcription factor NF-κB were evaluated immunohistochemically. Expression levels for TLR4, TNF-α, NF-kB, IL-1ß (interleukin 1 beta), and IL-6 (interleukin 6) were evaluated. Additionally, Argyrophilic NOR staining was performed in tissues. Vacuolization and inflammation were more intense in the kidney and liver sections in the LPS group compared to the other groups. It was observed that vacuolization and inflammation were decreased in LPS + Melatonin applied groups. It was determined that glomerular damage was increased in the LPS and LPS-melatonin groups, but the damage rate LPS-Melatonin group was decrease in the LPS group. It was determined that the MDA level in tissues of the LPS group was importantly increased compared to other groups. Additionally, TAA/NA ratio statistically significant differences were discovered between the groups. This study supports the potential protective effects of 10 mg/kg melatonin by modulating critical markers of local immune reaction in a model of LPS-induced sepsis.

Partial changes in apoptotic pathways in hippocampus and hypothalamus of Cc2d1a heterozygous.

Alterations in the apoptosis pathway have been linked to changes in serotonin levels seen in autistic patients. Cc2d1a is a repressor of the HTR1A gene involved in the serotonin pathway. The hippocampus and hypothalamus of Cc2d1a ± mice were analyzed for the expression of apoptosis markers (caspase 3, 8 and 9). Gender differences were observed in the expression levels of the three caspases consistent with some altered activity in the open-field assay. The number of apoptotic cells was significantly increased. We concluded that apoptotic pathways are only partially affected in the pathogenesis of the Cc2d1a heterozygous mouse model. A) Apoptosis is suppressed because the cell does not receive a death signal, or the receptor cannot activate the caspase 8 pathway despite the death signal. B) Since Caspase 8 and Caspase 3 expression is downregulated in our mouse model, the mechanism of apoptosis is not activated.

Inhibition of Ehrlich ascites carcinoma growth by melatonin: Studies with micro-CT.

Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling pathway. Melatonin has many benefits, such as organizing circadian rhythms and acting as a powerful hormone. We aimed to show the antitumor effects of melatonin in both in vivo and in vitro models through the mammalian target of rapamycin (mTOR) signaling pathway and the Argyrophilic Nucleolar Regulatory Region (AgNOR), using the Microcomputed Tomography (Micro CT). Ehrlich ascites carcinoma (EAC) cells were administered into the mice by subcutaneous injection. Animals with solid tumors were injected intraperitoneally with 50 and 100 mg/kg melatonin for 14 days. Volumetric measurements for the taken tumors were made with micro-CT imaging, immunohistochemistry (IHC), real-time polymerase chain reaction (PCR) and AgNOR. Statistically, the tumor tissue volume in the Tumor+100 mg/kg melatonin group was significantly lower than that in the other groups in the data obtained from micro-CT images. In the IHC analysis, the groups treated with Tumor+100 mg/kg melatonin were compared when the mTOR signaling pathway and factor 8 (F8) expression were compared with the control group. It was determined that there was a significant decrease (p < 0.05). Significant differences were found in the total AgNOR area/nuclear area (TAA/NA) ratio in the treatment groups (p < 0.05). Furthermore, there were significant differences between the amount of mTOR mRNA for the phosphatidylinositol 3-kinase (PI3K), AKT Serine/Threonine Kinase (PKB/AKT) genes (p < 0.05). Cell apoptosis was evaluated with Annexin V in an in vitro study with different doses of melatonin; It was observed that 100 µg/mL melatonin dose caused an increase in the apoptotic cell death. In this study, we have reported anti-tumor effects of melatonin in cell culture studies as well as in mice models. Comprehensive characterization of the melatonin-mediated cancer inhibitory effects will be valuable in advancing our fundamental molecular understanding and translatability of pre-clinical findings to earlier phases of clinical trials.