High-fat diet and aging-associated memory impairments persist in the absence of microglia in female rats.

Aging is associated with a priming of microglia such that they are hypersensitive to further immune challenges. As such high-fat diet during aging can have detrimental effects on cognition that is not seen in the young. However, conflicting findings also suggest that obesity may protect against cognitive decline during aging. Given this uncertainty we aimed here to examine the role of microglia in high-fat, high-sucrose diet (HFSD)-induced changes in cognitive performance in the aging brain. We hypothesised that 8 weeks of HFSD-feeding would alter microglia and the inflammatory milieu in aging and worsen aging-related cognitive deficits in a microglia-dependent manner. We found that both aging and HFSD reduced hippocampal neuron numbers and open field exploration; they also impaired recognition memory. However, the aging-related deficits occurred in the absence of a pro-inflammatory response and the deficits in memory performance persisted after depletion of microglia in the Cx3cr1-Dtr knock-in rat. Our data suggest that mechanisms additional to the acute microglial contribution play a role in aging- and HFSD-associated memory dysfunction.

Inhibiting microglia exacerbates the early effects of cuprizone in males in a rat model of multiple sclerosis, with no effect in females.

Hyper-activity of the brain's innate immune cells, microglia, is a hallmark of multiple sclerosis (MS). However, it is not clear whether this involvement of microglia is beneficial or detrimental or whether manipulating microglial activity may be therapeutic. We investigated if inhibiting microglial activity with minocycline prevents the early changes in oligodendrocyte and myelin-related markers associated with a demyelinating challenge in adult female and male rats. Cuprizone reduced the expression of myelin and oligodendrocyte genes in both females and males, reflective of cuprizone intoxication and the early phases demyelination, and reduced the number of oligodendrocytes in the corpus callosum. However, we see notable differences in the role for microglia in this response between females and males. In males, myelin and oligodendrocyte genes, as well as oligodendrocytes were also reduced by minocycline treatment; an effect that was not seen in females. In males, but not females, early changes in oligodendrocyte and myelin-related genes were associated with microglial proliferation in corpus callosum, and this increase was reversed by minocycline. These data indicate sex-specific effects of inhibiting microglia on the early changes leading to demyelination in an MS model and suggest microglia may play a key role in myelin stability in males but not in females. This highlights a strong need for sex-specific understanding of disease development in MS and suggest that treatments targeting microglia may be more effective in males than in females due to differing mechanisms of disease progression.

Vitamin D in respiratory viral infections: a key immune modulator?

Respiratory viral infections are common respiratory diseases. Influenza viruses, RSV and SARS-COV2 have the potential to cause severe respiratory infections. Numerous studies have shown that unregulated immune response to these viruses can cause excessive inflammation and tissue damage. Therefore, regulating the antiviral immune response in the respiratory tract is of importance. In this regard, recent years studies have emphasized the importance of vitamin D in respiratory viral infections. Although, the most well-known role of vitamin D is to regulate the metabolism of phosphorus and calcium, it has been shown that this vitamin has other important functions. One of these functions is immune regulation. Vitamin D can regulate the antiviral immune response in the respiratory tract in order to provide an effective defense against respiratory viral infections and prevention from excessive inflammatory response and tissue damage. In addition, this vitamin has preventive effects against respiratory viral infections. Some studies during the COVID-19 pandemic have shown that vitamin D deficiency may be associated with a higher risk of mortality and sever disease in patients with COVID-19. Since, more attention has recently been focused on vitamin D. In this article, after a brief overview of the antiviral immune response in the respiratory system, we will review the role of vitamin D in regulating the antiviral immune response comprehensively. Then we will discuss the importance of this vitamin in influenza, RSV, and COVID-19.

Long-term role of neonatal microglia and monocytes in ovarian health.

Early life microglia are essential for brain development, and developmental disruption in microglial activity may have long-term implications for the neuroendocrine control of reproduction. We and others have previously shown that early life immune activation compromises the long-term potential for reproductive function in females. However, the supportive role of microglia in female reproductive development is still unknown. Here, we examined the long-term programming effects of transient neonatal microglial and monocyte ablation on hypothalamic-pituitary-gonadal (HPG) axis function in female rats. We employed a Cx3cr1-Dtr transgenic Wistar rat model to acutely ablate microglia and monocytes, commencing on either postnatal day (P) 7 or 14, since the development of the HPG axis in female rodents primarily occurs during the first two to three postnatal weeks. After an acutely diminished expression of microglia and monocyte genes in the brain and ovaries, respectively, microglia had repopulated the brain by P21, albeit that cellular complexity was still reduced in both groups at this time. Removal of microglia and monocytes on P7, but not P14 reduced circulating luteinising hormone levels in adulthood and ovarian gonadotropin receptors mRNA. These changes were notably associated with fewer primary and antral follicles in these rats. These data suggest that transient ablation of microglia and monocytes at the start of the second but not the third postnatal week has long-term effects on ovarian health. The findings highlight the important developmental role of a healthy immune system for female potential reproductive capacity and the importance of critical developmental periods to adult ovarian health.

DNA repair and damage pathways in mesothelioma development and therapy.

Malignant mesothelioma (MMe) is an aggressive neoplasm that occurs through the transformation of mesothelial cells. Asbestos exposure is the main risk factor for MMe carcinogenesis. Other important etiologies for MMe development include DNA damage, over-activation of survival signaling pathways, and failure of DNA damage response (DDR). In this review article, first, we will describe the most important signaling pathways that contribute to MMe development and their interaction with DDR. Then, the contribution of DDR failure in MMe progression will be discussed. Finally, we will review the latest MMe therapeutic strategies that target the DDR pathway.

From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs?

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.

Targeting Wnt/ß-catenin signaling by microRNAs as a therapeutic approach in chemoresistant osteosarcoma.

Osteosarcoma (OS) is an adolescent and young adult malignancy that mostly occurs in long bones. The treatment of OS is still a big challenge for clinicians due to increasing chemoresistance, and many efforts are being made today to find more beneficial treatments. In this regard, the use of microRNAs has shown a high capacity to develop promising therapies. By targeting cancer-involved signaling pathways, microRNAs reduce the cellular level of these protein pathways; thereby reducing the growth and invasion of tumors, and even leading cancer cells to apoptosis. One of these oncogenic pathways that play an important role in OS development and can be targeted by microRNAs is the Wnt/ß-catenin signaling pathway. Hence, the first goal of this review article is to explain the cross-talk of microRNAs and the Wnt/ß-catenin signaling in OS and then discussing recent findings of the use of microRNAs as a therapeutic approach in OS.

Monocyte perturbation modulates the ovarian response to an immune challenge.

Our recent findings indicate that an acute depletion of monocytes has no sustained effects on ovarian follicle health. Here, we utilised a Cx3cr1-Dtr transgenic Wistar rat model to transiently deplete monocytes and investigated the impact of an acute immune challenge by lipopolysaccharide (LPS) on ovarian follicle health and ovulatory capacity relative to wt once the monocytes had repopulated. Monocyte depletion and repopulation exacerbated the effects of LPS in several domains. As such, monocyte perturbation decreased the numbers of secondary follicles in those challenged with LPS. Monocyte perturbation was also associated with reduced antral follicle numbers and circulating luteinising hormone (LH) levels, as well as potential changes in ovarian sensitivity to LH, exacerbated by LPS. These data suggest that monocyte depletion and repopulation induce a transient suppression of ovulatory capacity in response to a subsequent immune challenge, but this is likely to be restored once the pro-inflammatory environment is resolved.

Maternal diet before and during pregnancy modulates microglial activation and neurogenesis in the postpartum rat brain.

The implications of poor maternal diet on offspring metabolic and neuroimmune development are well established. Increasing evidence now suggests that maternal obesity and poor diet can also increase the risk of postpartum mood disorders, but the mechanisms are unknown. Here we investigated the effects of a poor, high-fat-high-sugar diet (HFSD) on peripheral and central inflammation, neurogenesis and postpartum anxiety-like behaviours. We hypothesised that long-term consumption of a HFSD pre- and post-conception would increase the levels of circulating cytokines and induce microglial activation, particularly in the arcuate nucleus of the hypothalamus (ARC), as the primary brain region involved in the integration of satiety signalling; and this would lead to increased anxiety, stress responsivity and disrupted neurogenesis. We further hypothesised that these effects would be ameliorated by consumption of a healthier diet during pregnancy - specifically a diet high in omega-3 polyunsaturated fatty acids (PUFAs). As expected, the HFSD significantly increased pre-conception body weight, elevated circulating cytokines and activated microglia in the ARC, as well as in the basolateral amygdala. The HFSD also significantly increased the numbers of immature (doublecortin (DCX)-positive) neurons in the subgranular/granular region of the hippocampus, a neurogenic response that was, surprisingly, mimicked by consumption of a diet high in omega-3 PUFAs. Despite these effects of peri-pregnancy dietary imbalance, we detected no differences in anxiety-like behaviours or hypothalamic-pituitary-adrenal (HPA) axis reactivity between the groups. A shift to a healthier diet post-conception reversed the peripheral inflammation and alleviated the microglial activation. These novel data indicate the importance of a balanced peri-pregnancy diet and highlight the need for future research into key triggers that alter the neuroimmune balance in the maternal brain.

Erratum: Xavier et al. High Maternal Omega-3 Supplementation Dysregulates Body Weight and Leptin in Newborn Male and Female Rats: Implications for Hypothalamic Developmental Programming. Nutrients 2021, 13, 89.

The authors would like to correct a typographical error in their recently published paper [...].

Cytotoxicity and apoptosis of nanoparticles on osteosarcoma cells using doxorubicin and methotrexate: A systematic review.

The safe development of nanotechnology and usage of nanoparticles (NPs) require the cellular toxicity examination of these NPs. Systematic studies are necessary to collect related data and comparison of the physicochemical features of NPs and their effects on cellular viability on model systems. In the present study, we systematically reviewed original studies, which investigated the cytotoxic effects and apoptosis of free NPs (loaded with doxorubicin (Dox)/or methotrexate (MTX)) via in vitro models. Articles were systematically collected by screening the literature published online in the following databases; PUBMED and SCOPUS and Web of Science and EMBASE. 23 in vitro cytotoxicity studies with 8 apoptosis examinations were found on osteosarcoma (OS) cell lines (mostly on MG-63). 43.47% of the synthesized NPs (10 studies) showed no cytotoxicity to OS cells. 39.13% of the synthesized NPs (9 studies) showed time and/or concentration related-cytotoxicity. Potent cytotoxic synthesized NP did not state. Significance difference between the half-maximal inhibitory concentration (IC50) of drug and drug/NP reported in all studies. Involved NPs in this systematic review for delivery of Dox/or MTX to OS cells have higher safety index and biocompatibility, although small and positively charged NPs acted more toxic in comparison to larger and negative ones, apoptosis rate like cytotoxicity index was notable in drug/NP group, to apply them in clinical works. Future studies are required to address the mechanisms involved in cytotoxicity and apoptosis with a special focus on in vivo investigations.

The molecular mechanism of nuclear signaling for degradation of cytoplasmic DNA: Importance in DNA damage response and cancer.

This review summarizes and addresses non-coding RNAs (rRNA, tRNA, Vault and Y RNA, snRNA, and miRNA) cytoplasmic decay pathways, the molecules, enzymes, and modifications such as uridylation, which play vital roles in the degradation processes in various eukaryotic organisms. Plus, SIRT1's role in fundamental cellular processes, including autophagy, DNA repair, DNA damage response (DDR), and the molecular mechanisms, is explored. Further, the HuR (an RNA-binding protein) impact on the expression of genes following DNA damage, and the pathways that regulate HuR function, which is through phosphorylation by Chk1/Cdk1 and Chk2, are specified. Finally, the role of DIF1/ Rnr2-Rnr4 in DDR has been discussed.

Multiple interactions between melatonin and non-coding RNAs in cancer biology.

The melatonin hormone secreted by the pineal gland is involved in physiological functions such as growth and maturation, circadian cycles, and biological activities including antioxidants, anti-tumor, and anti-ischemia. Melatonin not only interacts with proteins but also has functional effects on regulatory RNAs such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). In this study, we overview various physiological and pathological conditions affecting melatonin through lncRNA and miRNA. The information compiled herein will serve as a solid foundation to formulate ideas for future mechanistic studies on melatonin. It will also provide a chance to more clarify the emerging functions of the non-coding transcriptome.

Cyclin-dependent kinase inhibitors (CDKIs) and the DNA damage response: The link between signaling pathways and cancer.

At the cellular level, DNA repair mechanisms are crucial in maintaining both genomic integrity and stability. DNA damage appears to be a central culprit in tumor onset and progression. Cyclin-dependent kinases (CDKs) and their regulatory partners coordinate the cell cycle progression. Aberrant CDK activity has been linked to a variety of cancers through deregulation of cell-cycle control. Besides DNA damaging agents and chromosome instability (CIN), disruptions in the levels of cell cycle regulators including cyclin-dependent kinase inhibitors (CDKIs) would result in unscheduled proliferation and cell division. The INK4 and Cip/Kip (CDK interacting protein/kinase inhibitor protein) family of CDKI proteins are involved in cell cycle regulation, transcription regulation, apoptosis, and cell migration. A thorough understanding of how these CDKIs regulate the DNA damage response through multiple signaling pathways may provide an opportunity to design efficient treatment strategies to inhibit carcinogenesis.

Ovarian follicles are resistant to monocyte perturbations-implications for ovarian health with immune disruption†.

Monocytes and macrophages are the most abundant immune cell populations in the adult ovary, with well-known roles in ovulation and corpus luteum formation and regression. They are activated and proliferate in response to immune challenge and are suppressed by anti-inflammatory treatments. It is also likely they have a functional role in the healthy ovary in supporting the maturing follicle from the primordial through to the later stages; however, this role has been unexplored until now. Here, we utilized a Cx3cr1-Dtr transgenic Wistar rat model that allows a conditional depletion of circulating monocytes, to investigate their role in ovarian follicle health. Our findings show that circulating monocyte depletion leads to a significant depletion of ovarian monocytes and monocyte-derived macrophages. Depletion of monocytes was associated with a transient reduction in circulating anti-Müllerian hormone (AMH) at 5 days postdepletion. However, the 50-60% ovarian monocyte/macrophage depletion had no effect on ovarian follicle numbers, follicle atresia, or apoptosis, within 5-21 days postdepletion. These data reveal that the healthy adult ovary is remarkably resistant to perturbations of circulating and ovarian monocytes despite acute changes in AMH. These data suggest that short-term anti-inflammatory therapies that transiently impact on circulating monocytes are unlikely to disrupt ovarian follicle health, findings that have significant implications for fertility planning relative to the experience of an immune challenge or immunosuppression.

The cross-talk between signaling pathways, noncoding RNAs and DNA damage response: Emerging players in cancer progression.

The DNA damage response (DDR) pathway's primary purpose is to maintain the genome structure's integrity and stability. A great deal of effort has done to understand the exact molecular mechanisms of non-coding RNAs, such as lncRNA, miRNAs, and circRNAs, in distinct cellular and genomic processes and cancer progression. In this regard, the ncRNAs possible regulatory role in DDR via modulation of key components expression and controlling repair signaling pathway activation is validated. Therefore, in this article, we will discuss the latest developments of ncRNAs contribution in different aspects of DNA repair through regulation of ATM-ATR, P53, and other regulatory signaling pathways.

Competing Endogenous RNAs (CeRNAs): Novel Network in Neurological Disorders.

Neurological disorders (NDs) comprise a broad range of diseases affecting both central and peripheral nervous systems. These complex multifactorial diseases have a high rate of mortality all over the world, particularly in aged people. Today, new evidence drove our attention to the notable role of noncoding RNAs (ncRNAs) in the progression of NDs. Remarkably, recent studies showed that there are close communication networks among RNA transcripts such as mRNAs, long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and pseudogenes for regulating each other's expression through competing for shared sequences in microRNAs (miRs). This concept is a new area of ongoing research recognized as competing endogenous RNA (ceRNA) hypothesis. CeRNAs are novel regulatory molecules in a wide range of biological stages and pathological contexts. Indeed, the disruption of ceRNA networks (ceRNETs) may affect neural development genes and induce neuropathological changes leading to the development of NDs. Because of this, identifying the correlation of ceRNETs with NDs will open a new window for expanding our knowledge about this field of science, as well as creating novel roads for developing specific diagnostic biomarkers for NDs management. Owing to these unique features, exploring the exact role of ceRNAs is a hot topic in NDs investigations. Hence, in this review, we will summarize the evidence supporting ceRNETs in the regulation of NDs-related gene expression.

The role of microglia in the second and third postnatal weeks of life in rat hippocampal development and memory.

Microglia are resident immune cells of the central nervous system (CNS). In adulthood they are involved in surveillance and responses to pathogens and injury and prenatally they play a role in brain development. However, the role of microglia during the early postnatal period and how they impact development long-term remains poorly understood. Here, to investigate the specific role of microglia in postnatal development, we used a Cx3cr1-Dtr transgenic Wistar rat model to acutely ablate microglia from either postnatal day (P) 7 or 14. We specifically assessed how transient microglial ablation affected astrocytes and neurons acutely, during the juvenile period, and in adulthood. Hippocampal microglial numbers remained low at P21 in the P7-ablated animals and complexity remained reduced after P14-ablation. This protracted effect on these key immune cells led to a small but significant increase in CA1 mature neuron numbers and a significant increase in astrocyte density in the subgranular dentate gyrus in adults that had their microglia ablated at P14. However, these histological differences were small, and spatial and recognition memory in novel objection and place recognition tests were not affected. Overall, our data reveal for the first time that the transient depletion of microglia during the neonatal period impacts briefly on the brain but that the long-lasting effects are minimal. Neonatal microglia may be dispensable in the establishment of hippocampal brain function. These data also imply that novel therapeutic anti-inflammatories that cross the blood-brain barrier to inhibit microglia are unlikely to have long-term negative consequences if administered in the neonatal period.

High Maternal Omega-3 Supplementation Dysregulates Body Weight and Leptin in Newborn Male and Female Rats: Implications for Hypothalamic Developmental Programming.

Maternal diet is critical for offspring development and long-term health. Here we investigated the effects of a poor maternal diet pre-conception and during pregnancy on metabolic outcomes and the developing hypothalamus in male and female offspring at birth. We hypothesised that offspring born to dams fed a diet high in fat and sugar (HFSD) peri-pregnancy will have disrupted metabolic outcomes. We also determined if these HFSD-related effects could be reversed by a shift to a healthier diet post-conception, in particular to a diet high in omega-3 polyunsaturated fatty acids (ω3 PUFAs), since ω3 PUFAs are considered essential for normal neurodevelopment. Unexpectedly, our data show that there are minimal negative effects of maternal HFSD on newborn pups. On the other hand, consumption of an ω3-replete diet during pregnancy altered several developmental parameters. As such, pups born to high-ω3-fed dams weighed less for their length, had reduced circulating leptin, and also displayed sex-specific disruption in the expression of hypothalamic neuropeptides. Collectively, our study shows that maternal intake of a diet rich in ω3 PUFAs during pregnancy may be detrimental for some metabolic developmental outcomes in the offspring. These data indicate the importance of a balanced dietary intake in pregnancy and highlight the need for further research into the impact of maternal ω3 intake on offspring development and long-term health.

Dyshomeostasis of Serum Oxidant/Antioxidant Status and Copper, Zinc, and Selenium Levels in Elderly Physically Disabled Persons: an AHAP-Based Study.

The percentage of elderly persons is rapidly growing. Physical disability is one of the main age-related diseases which affect life quality. There are some studies that suggest the oxidative stress and trace elements are involved in physical disability in elderly persons, but the results are inconclusive. Therefore, the aim of this study was to investigate the status of aforementioned parameters in elderly physically disabled patients vs. healthy ones. According to the Katz questionnaire form, 44 subjects with physical disability and 66 age-gender-matched healthy subjects were selected from Amirkola Health and Aging Project (AHAP). The results indicated that patient group had lower serum Zn, Se, and total antioxidant levels than the control group (p < 0.001), whereas serum total oxidant level and Cu to Zn ratio (CZr) were higher in control group than in healthy one (p < 0.001). A positive correlation was found between Zn, Se, total antioxidant, and bone mineral density of femur (BMD.F) with activities of daily living (ADL) score (p < 0.01); meanwhile, a negative correlation between CZr and total oxidant with ADL score was observed (p < 0.01). Serum total oxidant level and CZr index had the highest area under the curve in receiver operating characteristic (ROC) analysis among the included parameters for discrimination of physically disabled patients than the normal ones. Decrease in serum Zn and Se levels, low BMD, and increase in CZr and oxidative stress were observed in physically disabled patients. It seems that CZr is more reliable parameter than the others to discriminate the physically disabled patients than the healthy persons.