Anticonvulsant effect of glycitin in pentylenetetrazol induced male Wistar rat model by targeting oxidative stress and Nrf2/HO-1 signaling.

Epilepsy, characterized by recurrent seizures, poses a significant health challenge globally. Despite the availability of anti-seizure medications, their adverse effects and inadequate efficacy in controlling seizures propel the exploration of alternative therapeutic measures. In hypothesis, glycitin is a phytoestrogenic compound found in soybeans and due to its estrogenic properties may have anti-epileptic and neuroprotective effects. This study investigates the potential anti-epileptic properties of glycitin in the context of pentylenetetrazol (PTZ) induced seizures in male Wistar rats. The rats were pretreated with varying doses of glycitin (5, 10, and 20 mg/kg) before PTZ (35 mg/kg) administration, and assessments included behavioral observations and histological evaluation via hematoxylin and eosin (H&E) staining. Additionally, oxidative stress markers, such as malondialdehyde (MDA), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels, were quantified to examine glycitin's impact on oxidative stress. Molecular analysis was conducted to assess the activation of the Nuclear factor erythroid 2-related factor (Nrf2)/Heme oxygenase 1 (HO-1) signaling pathway. Results indicated that glycitin pretreatment effectively mitigated PTZ-induced convulsive behaviors, supported by histological findings from H&E staining. Furthermore, glycitin administration led to significant alterations in MDA, GPx, and SOD levels, suggestive of its ability to modulate oxidative stress. Notably, glycitin treatment induced activation of the Nrf2/HO-1 signaling pathway. These findings underscore the potential of glycitin as an anticonvulsant agent, elucidating its mechanism of action through histological protection, modulation of oxidative stress markers, and activation of the Nrf2/HO-1 signaling pathway.

Neuroprotective impact of glycitin on memory impairment in a pentylenetetrazol-induced chronic epileptic rat model: insights into hippocampal histology, oxidative stress, and inflammation.

Epilepsy, characterized by recurrent seizures, often accompanies neurocognitive impairments and is associated with increased oxidative stress and inflammation. This study investigates the possible neuroprotective properties of glycitin, a soy isoflavone, on memory impairment, its impact on oxidative stress responses, and inflammatory gene expression in a chronic epileptic rat model induced by pentylenetetrazol (PTZ). Glycitin was administered at varying doses to evaluate its potential neuroprotective impact on memory, oxidative stress, and inflammation in this model. Behavioural assessments, memory retention and recall capabilities, histopathological examinations, measurements of oxidative stress biomarkers, and molecular assessments were employed for comprehensive evaluation. The results demonstrated that glycitin significantly improved memory impairment and reduced oxidative stress in epileptic rats. Additionally, glycitin treatment decreased the expression of tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB), indicating its potential to modulate the inflammatory response associated with epilepsy. These observations underscore the potential of glycitin as a therapeutic candidate for mitigating memory impairments linked to chronic epilepsy due to its antioxidant and anti-inflammatory properties, offering insights into novel avenues for the development of targeted interventions aimed at preserving cognitive function and ameliorating oxidative damage and inflammation in epileptic conditions.

Therapeutic Effects of Exosome Therapy and Photobiomodulation Therapy on the Spermatogenesis Arrest in Male Mice After Scrotum Hyperthermia.

Introduction: In men, several factors cause infertility, among which we can mention damage to sperm due to high temperature. So far, various treatments have been proposed for it, but they have not been highly effective. The current study aimed to evaluate the effect of exosome therapy (EXO) and photobiomodulation therapy (PBMT) on spermatogenesis arrest in male mice after scrotum hyperthermia. Methods: In this experimental study, the animals were divided into four groups: control, scrotal hyperthermia, scrotal hyperthermia+EXO (100 µL/d) (mice were treated for 30 days), scrotal hyperthermia+PBMT (laser of 0.03 J/cm2 for 30 seconds/for 30 days). Hyperthermia was induced by exposure to the temperature of 43 °C for 20 minute every day for 5 times. After 6 weeks, the animals were sacrificed. Results: The treated groups showed a significant increase in sperm parameters, as compared to the hyperthermic groups. Moreover, these favorable effects were observed in relation to the volume of testicular tissue, the number of germ cells, Leydig cells and Sertoli cells, and the level of testosterone. Research on antioxidants showed a significant reduction in oxidized glutathione (GSSG) and reactive oxygen species (ROS) in the treatment groups in comparison to the hyperthermia group (P<0.001). Also, there has been a significant increase in the amount of hydrogen peroxide enzyme observed in the hyperthermia group as opposed to the treatment group (P<0.001). Conclusion: These findings show that EXO and PBMT can improve spermatogenesis caused by hyperthermia, reduce ROS and GSSG, and increase glutathione (GSH) and sperm quality.

Orexin antagonism and substance-P: Effects and interactions on polycystic ovary syndrome in the wistar rats.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder without definitive treatments. Orexin and Substance-P (SP) neuropeptides can affect the ovarian steroidogenesis. Moreover, there are limited studies about the role of these neuropeptides in PCOS. We aimed here to clarify the effects of orexins and SP in PCOS as well as any possible interactions between them. METHODS: For this purpose, the animals (n = five rats per group) received intraperitoneally a single dose of SB-334,867-A (orexin-1 receptor antagonist; OX1Ra), JNJ-10,397,049 (orexin-2 receptor antagonist; OX2Ra), and CP-96,345 (neurokinin-1 receptor antagonist; NK1Ra), alone or in combination with each other after two months of PCOS induction. The blocking of orexin and SP receptors was studied in terms of ovarian histology, hormonal changes, and gene expression of ovarian steroidogenic enzymes. RESULTS: The antagonists' treatment did not significantly affect the formation of ovarian cysts. In the PCOS groups, the co-administration of OX1Ra and OX2Ra as well as their simultaneous injections with NK1Ra significantly reversed testosterone levels and Cyp19a1 gene expression when compared to the PCOS control group. There were no significant interactions between the PCOS groups that received NK1Ra together with one or both OX1R- and OX2R-antagonists. CONCLUSION: The blocking of the orexin receptors modulates abnormal ovarian steroidogenesis in the PCOS model of rats. This suggests that the binding of orexin-A and -B to their receptors reduces Cyp19a1 gene expression while increasing testosterone levels.

Mesenchymal stem cells and prostate cancer: A concise review of therapeutic potentials and biological aspects.

Prostate cancer (PCa) arises from a cancer stem or progenitor cell with homogenous characteristics, especially among the aging men population. Over the past decade, the increasing PCa incidence has led to significant changes in both disease diagnosis and treatment. Recently, the therapeutic aspects of stem cells in many cancers, including PCa, have been debatable. The new generation of PCa studies seek to present definitive treatments with reduced therapeutic side effects. Since discovering unique properties of stem cells in modulating immunity, selective migration to inflammatory regions, and secretion of various growth factors, they have been a promising therapeutic target. The existing properties of stem cell therapy bring new opportunities for cancer inhibition: transferring chemotherapeutics, activating prodrugs, affecting the expression of genes involved in cancer, genetically modifying the production of anti-cancer compounds, proteins, and/or deriving extracellular vesicles (EVs) containing therapeutic agents from stem cells. However, their dual properties in carcinogenicity as well as their ability to inhibit cancer result in particular limitations studying them after administration. A clear understanding of the interaction between MSCs and the prostate cancer microenvironment will provide crucial information in revealing the precise applications and new practical protocols for clinical use of these cells..

Cancer regulator EGFR-ErbB4 heterodimer is stabilized through glycans at the dimeric interface.

EGFR and ErbB4 are the only two members of cancer-regulating ErbB RTKs that maintain the activation of their extracellular ligand-binding domain and intracellular tyrosine kinase domain. EGFR and ErbB4 could form homo and heterodimers upon their activation. Heterodimerization triggers more diverse intracellular pathways compared to homodimerization. Moreover, it is known that N-glycosylation is crucial for the stabilization and activation of EGFR and ErbB4 receptors. Herein, atomistic molecular dynamics were simulated to study the EGFR-ErbB4 heterodimer in the glycosylated and unglycosylated states. It was shown that the EGFR-ErbB4 heterodimer is highly stabilized by glycosylation. The increased stability is most significant at the dimeric interfaces, regulated by packing of three glycans attached to EGFR (Asn337) and ErbB4 (Asn333, Asn523) at the dimeric interface. Finally, it is proposed that heterodimerization is the persistent key player in the EGFR and ErbB4 activation. Thus, targeting the heterodimers in future therapeutic designs could be a promising approach against drug resistance to ErbB-positive cancers.

Decrease in RNase HII and Accumulation of lncRNAs/DNA Hybrids: A Causal Implication in Psoriasis?

Functional long non-coding RNAs (lncRNAs) have been in the limelight in aging research because short telomeres are associated with higher levels of TERRA (Telomeric Repeat containing RNA). The genomic instability, which leads to short telomeres, is a mechanism observed in cell aging and in a class of cancer cells. Psoriasis, a skin disease, is a disorder of epidermal keratinocytes, with altered telomerase activity. Research on the fraction of nascent RNAs in hybrid with DNA offers avenues for new strategies. Skin and blood samples from patients were fractionated to obtain the RNA associated with DNA as a R-loop structure. The higher amount of TERRA levels attached with each chromosome end was found with psoriasis patients in blood and skin. In addition to telomeric TERRA, we evidenced accumulation of others non-coding RNA, such as non-telomeric TERRA and centromeric transcripts. Increased levels of non-coding RNAs attached to DNA correlates with a decreased in Ribonuclease HII (RNase-HII) transcript which means that overall unresolved DNA-RNA hybrids can ultimately weaken DNA and cause skin lesions. Since the genome is actively transcribed, cellular RNase-HII is essential for removing RNA from the DNA-RNA hybrid in controls of genome stability and epigenome shaping and can be used as a causal prognostic marker in patients with psoriasis.

Genetic differentiation of the house mouse around the Mediterranean basin: matrilineal footprints of early and late colonization.

The molecular signatures of the recent expansion of the western house mouse, Mus musculus domesticus, around the Mediterranean basin are investigated through the study of mitochondrial D-loop polymorphism on a 1313 individual dataset. When reducing the complexity of the matrilineal network to a series of haplogroups (HGs), our main results indicate that: (i) several HGs are recognized which seem to have almost simultaneously diverged from each other, confirming a recent expansion for the whole subspecies; (ii) some HGs are geographically delimited while others are widespread, indicative of multiple introductions or secondary exchanges; (iii) mice from the western and the eastern coasts of Africa harbour largely different sets of HGs; and (iv) HGs from the two shores of the Mediterranean are more similar in the west than in the east. This pattern is in keeping with the two-step westward expansion proposed by zooarchaeological data, an early one coincident with the Neolithic progression and limited to the eastern Mediterranean and a later one, particularly evident in the western Mediterranean, related to the generalization of maritime trade during the first millennium BC and onwards. The dispersal of mice along with humans, which continues until today, has for instance left complex footprints on the long ago colonized Cyprus or more simple ones on the much more recently populated Canary Islands.

Glycosylation promotes the cancer regulator EGFR-ErbB2 heterodimer formation - molecular dynamics study.

ErbB family of receptor tyrosine kinases play significant roles in cellular differentiation and proliferation. Mutation or overexpression of these receptors leads to several cancers in humans. The family has four homologous members including EGFR, ErbB2, ErbB3, and ErbB4. From which all except the ErbB2 bind to growth factors via the extracellular domain to send signals to the cell. However, dimerization of the ErbB receptor occurs in extracellular, transmembrane, and intracellular domains. The ErbB receptors are known to form homodimers and heterodimers in the active form. Heterodimerization increases the variety of identified ligands and signaling pathways that can be activated by these receptors. Furthermore, glycosylation of the ErbB receptors has shown to be critical for their stability, ligand binding, and dimerization. Here, atomistic molecular dynamics simulations on the glycosylated and unglycosylated heterodimer showed that the EGFR-ErbB2 heterodimer is more stable in its dynamical pattern compared to the EGFR-EGFR homodimer. This increased stability is regulated by maintaining the dimeric interface by the attached glycans. It was also shown that the presence of various glycosylation sites within the ErbB2 growth factor binding site leads to occlusion of this site by the glycans that inhibit ligand binding to ErbB2 and participate in further stabilization of the heterodimer construct. Putting together, glycosylation seems to promote the heterodimer formation within the ErbB family members as the dominant molecular mechanism of activation for these receptors.

Pleistocene climate fluctuations as the major driver of genetic diversity and distribution patterns of the Caspian green lizard, Lacerta strigata Eichwald, 1831.

Green lizards of the genus Lacerta have served as excellent models for studying the impact of Pleistocene climatic oscillations on genetic structures. The Caspian green lizard, Lacerta strigata, occupies various habitats across the Caucasus and the South Caspian Sea, with the Hyrcanian Forests and north of the Alborz Mountains forming the core of the range. This study aimed to re-examine the phylogenetic relationships of L. strigata with other congeneric members and to assess the genetic structure and historical demography of the species. Furthermore, Species Distribution Models (SDMs) were performed to infer the species' potential habitat suitability and were then projected on climate scenarios reflecting current and past (6 ky and 21 ky before present) conditions. A total of 39 individuals collected from most of the distribution range, together with additional lacertid species sequences from the GenBank database, were examined using mtDNA (Cyt b and 12S ribosomal RNA) and nuclear (C-mos and ß-fibrinogen) sequence data. Based on the phylogenetic analyses, L. strigata was found to be a sister taxon to all other members of the genus. The species included two main clades (regional western and eastern) that diverged in a period between the Early and Middle Pleistocene. Based on the BBM and S-Diva analyses, both dispersal and vicariance events explained the phylogeographic structure of the species in the Hyrcanian Forests. The historical demographic analyses using Bayesian skyline plots showed a mild increase in the effective population size from about 120 Kya for the western regional clade. According to phylogeographic structures and SDMs evidence, as in other species within the region, it appears that the south of the Caspian Sea (Hyrcanian Forests), and the Alborz Mountains acted as multiple refugia during cold periods and promoted expansion outwards amid the warm periods. Overall, the results provided evidence that the genetic structure of the species has been influenced by the Pleistocene climatic fluctuations.

Genome-Wide Distribution of Nascent Transcripts in Sperm DNA, Products of a Late Wave of General Transcription.

Mature spermatozoa contain a whole repertoire of the various classes of cellular RNAs, both coding and non-coding. It was hypothesized that after fertilization they might impact development, a claim supported by experimental evidence in various systems. Despite the current increasing interest in the transgenerational maintenance of epigenetic traits and their possible determination by RNAs, little remains known about conservation in sperm and across generations and the specificities and mechanisms involved in transgenerational maintenance. We identified two distinct fractions of RNAs in mature mouse sperm, one readily extracted in the aqueous phase of the classical TRIzol procedure and a distinct fraction hybridized with homologous DNA in DNA-RNA complexes recovered from the interface, purified after DNase hydrolysis and analyzed by RNA-seq methodology. This DNA-associated RNA (D RNA) was found to represent as much as half of the cell contents in differentiated sperm, in which a major part of the cytoplasmic material has been discarded. Stable complexes were purified free of proteins and identified as hybrids (R-loops) on the basis of their sensitivity to RNase H hydrolysis. Further analysis by RNA-seq identified transcripts from all the coding and non-coding regions of the genome, thus revealing an extensive wave of transcription, prior to or concomitant with the terminal compaction of the chromatin.

Genetic vs environment influences on house mouse hybrid zone in Iran.

Genetic divergence and environment influence on speciation process are the great deal studies over recent decades. One of the best ways for exploring the interaction of geography and genetics is the evaluation of hybrids in a contact zone. To understand if there is one or more hybrid zone between house mouse subspecies in Iran and what are the differences comparing these zones with European well-known hybrid zone, we performed this approach. Samples were live-trapped from Ilam city in west for sensu lato M. m. domesticus subspecies, and Neishabur city in north-east of Iran for sensu lato M. m. musculus subspecies. In five experimental groups, male and female mice of the two subspecies were crossed reciprocally to generate F1 hybrids, and then F1 offspring males and females were crossed also reciprocally between siblings to generate F2 hybrids. In the same manner as seen in European hybrid zone, hybridization between female M. m. musculus and male M. m. domesticus of all five groups showed male sterility in F1 generation, but intact female offspring. These sterile males comparing with a parent or healthy males showed low count and more abnormal sperm percentage in morphological and testis histological section studies. Comparing the results from this study with numerous studies carried out during several years on the European hybrid zone showed an equal condition of contact between two subspecies. Genetical elements have kept their same influence on postzygotic reproductive isolation more than environmental effects far from the Europe, here in Iran.

Phylogeography, genetic diversity and demographic history of the Iranian Kurdish groups based on mtDNA sequences.

Throughout the history of modern humans, the current Kurdish-inhabited area has served as part of a tricontinental crossroad for major human migrations. Also, a significant body of archaeological evidence points to this area as the site of Neolithic transition. To investigate the phylogeography, origins and demographic history, mtDNA D-loop region of individuals representing four Kurdish groups from Iran were analysed. Our data indicated that most of the Kurds mtDNA lineages belong to branches of the haplogroups with the Western Eurasian origin; with small fractions of the Eastern Eurasian and sub-Saharan African lineages. The low level of mtDNA diversity observed in the Havrami group presented a bias towards isolation or increased drift due to small population size; while in the Kurmanji group it indicated a bias towards drift or mass migration events during the 5-18th century AD. The Mantel test showed strong isolation by distance, and AMOVA results for global and regional scales confirmed that the geography had acted as the main driving force in shaping the current pattern of mtDNA diversity, rather than linguistic similarity. The results of demographic analyses, in agreement with archaeological data, revealed a recent expansion of the Kurds (~9,500 years before present) related to the Neolithic transition from hunting and gathering, to farming and cattle breeding in the Near East. Further, the high frequencies of typical haplogroups for early farmers (H; 37.1%) and hunter-gatherers (U; 13.8%) in the Kurds may testify the earlier hunter-gatherers in the Kurdish-inhabited area that adopted and admixed the Kurds ancestors following the Neolithic transition.

Phylogeography and postglacial expansion of Mus musculus domesticus inferred from mitochondrial DNA coalescent, from Iran to Europe.

Few genetic data document the postglacial history of the western house mouse, Mus musculus domesticus. We address this by studying a sample from the southeastern tip of the Fertile Crescent in the Iranian province of Ahvaz. Including other published and unpublished data from France, Germany, Italy, Bulgaria, Turkey and other places in Iran, altogether 321 mitochondrial D-loop sequences are simultaneously analysed. The patterns of coalescence obtained corroborate the classical proposal according to which the Fertile Crescent is where commensalism with humans has started in the Western Hemisphere, and from where the subspecies has expanded further west. Our data also clearly show that despite multiple colonisations and long-range transportation, there is still a rather high PhiST of 0.39. The original expansion signal is still recognisable, with two well-separated derived clades, allowing us to propose a hypothetical scenario in which expansion toward Europe and Asia Minor took at least two routes, tentatively termed the Mediterranean and the Bosphorus/Black Sea routes. This scenario resembles that of another domesticated species, the goat, and fits with the known progression of Neolithic culture. Given the concomitance of both phenomena around 12,000 years ago, we propose a recalibration of the D-loop mutation rate to a much faster tick of approximately 40% per site per million years (Myr). This value should be used for intrasubspecific polymorphism, while the interspecific rate in Mus is presently estimated at 6-10%/site/Myr. This is in keeping with the now well recognised fact that only a subfraction of segregating mutations go to fixation.