Is PTSD-Phenotype Associated with HPA-Axis Sensitivity? Feedback Inhibition and Other Modulating Factors of Glucocorticoid Signaling Dynamics

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus–pituitary–adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.     

The Endocannabinoid System in the Mediterranean Mussel Mytilus galloprovincialis: Possible Mediators of the Immune Activity?

Anandamide (AEA) is one of the best characterized members of the endocannabinoid family and its involvement in many pathophysiological processes has been well documented in vertebrates and invertebrates. Here, we report the biochemical and functional characterization of key elements of the endocannabinoid system in hemocytes isolated from the Mediterranean mussel Mytilus galloprovincialis. We also show the effects of exogenous AEA, as well as of capsaicin, on the cell ability to migrate and to activate the respiratory burst, upon in vitro stimulation of phagocytosis. Interestingly, our findings show that both AEA and capsaicin suppress the hemocyte response and that the use of selective antagonists of CB₂ and TRPV1 receptors revert their inhibitory effects. Overall, present data support previous evidence on the presence of endocannabinoid signaling in mollusks and advance our knowledge about the evolutionary origins of this endogenous system and its role in the innate response of mollusks.     

The Ascorbate-glutathione-α-tocopherol Triad in Abiotic Stress Response

The life of any living organism can be defined as a hurdle due to different kind of stresses. As with all living organisms, plants are exposed to various abiotic stresses, such as drought, salinity, extreme temperatures and chemical toxicity. These primary stresses are often interconnected, and lead to the overproduction of reactive oxygen species (ROS) in plants, which are highly reactive and toxic and cause damage to proteins, lipids, carbohydrates and DNA, which ultimately results in oxidative stress. Stress-induced ROS accumulation is counteracted by enzymatic antioxidant systems and non-enzymatic low molecular weight metabolites, such as ascorbate, glutathione and α-tocopherol. The above mentioned low molecular weight antioxidants are also capable of chelating metal ions, reducing thus their catalytic activity to form ROS and also scavenge them. Hence, in plant cells, this triad of low molecular weight antioxidants (ascorbate, glutathione and α-tocopherol) form an important part of abiotic stress response. In this work we are presenting a review of abiotic stress responses connected to these antioxidants.     

Is alpha-Pinene a Substrate for Permeability-Glycoprotein in Wood Rats?

alpha-Pinene is the dominant monoterpene in Juniperus monosperma. Wood rat species in the genus Neotoma that consume J. monosperma vary in their inclusion of it in their wild diet and in their tolerance of whole J. monosperma or alpha-pinene in laboratory feeding trials. A proposed mechanism for variable tolerance is a difference in absorption of alpha-pinene from the small intestine that is mediated by the intestinal transporter permeability glycoprotein (Pgp). To determine if alpha-pinene is a Pgp substrate, we tested whether it can competitively inhibit Pgp and thereby increase the accumulation of a known Pgp substrate (digoxin) in (1) everted sleeves of small intestine from Neotoma stephensi, a juniper specialist, N. albigula, a sympatric generalist that consumes juniper, N. cinerea, a more distantly related generalist, and Sprague-Dawley rats, and (2) in Caco-2 cells that over express Pgp. We also measured Pgp ATPase phosphate production in transfected insect membrane vesicles exposed to alpha-pinene. We found no significant increase in digoxin accumulation with competitive inhibition experiments, and no increase in phosphate production with transfected membranes, at any concentration of alpha-pinene up to 100 μM. To test whether other compounds in juniper affect Pgp activity, we acclimated five N. stephensi to a juniper diet for 5 d, but found no significant effect compared to animals on control diet. Our data suggest that alpha-pinene is not a Pgp substrate.     

Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review,Confounders Assessment and Meta-Analysis of Clinical Studies

It has been suggested that molecular pathological mechanisms responsible for periodontitis can be linked with biochemical alterations in neurodegenerative disorders. Hypothetically, chronic systemic inflammation as a response to periodontitis plays a role in the etiology of cognitive impairment. This study aimed to determine whether periodontitis (PDS) is a risk factor for age-related cognitive impairment (ACI) based on evidence of clinical studies. A comprehensive, structured systematic review of existing data adhering to the Preferred Reporting Items for Systematic Review and Meta Analyses (PRISMA) guidelines was carried out. Five electronic databases, PubMed, Embase, Scopus, Web of Science, and Cochrane, were searched for key terms published in peer-reviewed journals until January 2021. The Newcastle–Ottawa scale was used to assess the quality of studies and risk of bias. The primary and residual confounders were explored and evaluated. A meta-analysis synthesizing quantitative data was carried out using a random-effects model. Seventeen clinical studies were identified, including 14 cohort, one cross-sectional, and two case-control studies. Study samples ranged from 85 to 262,349 subjects, with follow-up between 2 and 32 years, and age above 45 years, except for two studies. The findings of studies suggesting the PDS-ACI relationship revealed substantial differences in design and methods. A noticeable variation related to the treatment of confounders was observed. Quality assessment unveiled a moderate quality of evidence and risk of bias. The subgroups meta-analysis and pooled sensitivity analysis of results from seven eligible studies demonstrated overall that the presence of PDS is associated with an increased risk of incidence of cognitive impairment (OR = 1.36, 95% CI 1.03–1.79), particularly dementia (OR = 1.39, 95% CI 1.02–1.88) and Alzheimer’s disease (OR = 1.03 95% CI 0.98–1.07)). However, a considerable heterogeneity of synthesized data (I² = 96%) and potential publication bias might affect obtained results. While there is a moderate statistical association between periodontitis and dementia, as well as Alzheimer’s disease, the risk of bias in the evidence prevents conclusions being drawn about the role of periodontitis as a risk factor for age-related cognitive impairment.     

Peroxisome Proliferator-Activated Receptor γ Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARγ in hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the prognostic value of PPARγ in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARγ staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARγ expression and various parameters. The functional role of PPARγ was determined via PPARγ overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARγ expression were significantly younger (p = 0.006), and exhibited more tumor numbers (p = 0.038), more macroscopic vascular invasion (MVI) (p = 0.008), and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis) stages at diagnosis (p = 0.013) than patients with high HCC tissue PPARγ expression. PPARγ knockdown increased HCC cell growth, migration, and angiogenesis, while PPARγ overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPARγ expression is an independent predictor of more MVI in HCC patients. PPARγ contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPARγ may be a therapeutic target in HCC patients.     

Hyperhomocysteinemia and Cardiovascular Disease: Is the Adenosinergic System the Missing Link?

The influence of hyperhomocysteinemia (HHCy) on cardiovascular disease (CVD) remains unclear. HHCy is associated with inflammation and atherosclerosis, and it is an independent risk factor for CVD, stroke and myocardial infarction. However, homocysteine (HCy)-lowering therapy does not affect the inflammatory state of CVD patients, and it has little influence on cardiovascular risk. The HCy degradation product hydrogen sulfide (H₂S) is a cardioprotector. Previous research proposed a positive role of H₂S in the cardiovascular system, and we discuss some recent data suggesting that HHCy worsens CVD by increasing the production of H₂S, which decreases the expression of adenosine A_2A receptors on the surface of immune and cardiovascular cells to cause inflammation and ischemia, respectively.     

Cell-in-Cell Phenomena in Wall-Less Bacteria: Is It Possible?

This work describes curious structures formed by the mainly phytopathogenic mycoplasma Acholeplasma laidlawii, as well as the human pathogen Ureaplasma parvum cells which resemble cell-in-cell structures of higher eukaryotes and protists. The probable significance of such structures for the mycoplasma cell is discussed. The possibility of their formation in nature and their potential role in the transformation of genetic material, for example, by maintaining (on the one hand) the stability of the genome in the line of generations during asexual reproduction or (on the other hand) the genome plasticity, are substantiated. It should be especially noted that all the arguments presented are based only on morphological data. However, closer attention to unusual structures, the existence of which was shown by electron microscopy images in this case, may prompt researchers to analyze their data more carefully and find something rare and non-trivial among seemingly trivial things. If it is proven by additional methods that cell-in-cell structures can indeed be formed by prokaryotes without a cell wall, this phenomenon may acquire general biological significance.     

Alpha-sheet: The toxic conformer in amyloid diseases?

A novel secondary structure, the alpha-sheet, was identified through molecular dynamics (MD) simulations of various proteins associated with amyloid diseases under amyloidogenic conditions. The structure was first predicted by Pauling and Corey, and it has been directly observed in crystal structures of "nonnatural peptides". There are occurrences of alpha-strands and alpha-sheets in the Protein Data Bank, but they are rare. We propose that alpha-sheet is formed during the conformational changes associated with amyloidosis and that it may represent the toxic conformer. Here, structural properties of the alpha-sheet, background information, and experimental support for this novel structure are presented. Finally we speculate about the possible role of this conformation in disease.     

Vitamin D and Microbiota: Is There a Link with Allergies?

There is increasing recognition of the importance of both the microbiome and vitamin D in states of health and disease. Microbiome studies have already demonstrated unique microbial patterns in systemic autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus. Dysbiosis also seems to be associated with allergies, in particular asthma, atopic dermatitis, and food allergy. Even though the effect of vitamin D supplementation on these pathologies is still unknown, vitamin D deficiency deeply influences the microbiome by altering the microbiome composition and the integrity of the gut epithelial barrier. It also influences the immune system mainly through the vitamin D receptor (VDR). In this review, we summarize the influence of the microbiome and vitamin D on the immune system with a particular focus on allergic diseases and we discuss the necessity of further studies on the use of probiotics and of a correct intake of vitamin D.     

Netrin-1 in Glioblastoma Neovascularization: The New Partner in Crime?

Glioblastoma (GBM) is the most aggressive and common primary tumor of the central nervous system. It is characterized by having an infiltrating growth and by the presence of an excessive and aberrant vasculature. Some of the mechanisms that promote this neovascularization are angiogenesis and the transdifferentiation of tumor cells into endothelial cells or pericytes. In all these processes, the release of extracellular microvesicles by tumor cells plays an important role. Tumor cell-derived extracellular microvesicles contain pro-angiogenic molecules such as VEGF, which promote the formation of blood vessels and the recruitment of pericytes that reinforce these structures. The present study summarizes and discusses recent data from different investigations suggesting that Netrin-1, a highly versatile protein recently postulated as a non-canonical angiogenic ligand, could participate in the promotion of neovascularization processes in GBM. The relevance of determining the angiogenic signaling pathways associated with the interaction of Netrin-1 with its receptors is posed. Furthermore, we speculate that this molecule could form part of the microvesicles that favor abnormal tumor vasculature. Based on the studies presented, this review proposes Netrin-1 as a novel biomarker for GBM progression and vascularization.     

The Impact of Fluid Dynamic Stress in Stirred Bioreactors – The Scale of the Biological Entity: A Personal View

From the start of industrial biotechnology, there has been a perception that biological entities are damaged by stirring, so-called ‘shear damage'. Often, it was the soft option to explain a loss of performance when it was due to other factors, such as bubble ingestion with proteins or on scale-up, where tip speed increased when it was due to decreased homogeneity, especially in pH. For many years, poor control and the range of analytical tools available made a more in-depth explanation difficult; and the concepts of ‘high' and ‘low shear' impellers, now largely disproven, increased it. Here, the size of the biological entity is compared to the Kolmogorov microscale of turbulence leading to a reasonably clear picture emerging. The article starts with the author's introduction to the issue approximately 42 year ago with enzymes, conveniently also the smallest entity; and finishes with the largest, filamentous fungi.     

Is the Jaw Bone Micro-Structure Altered in Response to Osteoporosis and Bisphosphonate Treatment? A Micro-CT Analysis

The aim of the study was to quantify the micro-architectural changes of the jaw bone in response to ovariectomy, exposed or not to bisphosphonate treatment. A total of 47 Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and exposed to osteoporosis preventive treatment for eight weeks either with bisphosphonates (alendronate, ALN; group OVX-ALN) three days/week at a dose of 2 mg/kg or with saline solution (untreated control condition; group OVX). The bone morphometric parameters of the trabecular jaw bone were assessed using ex vivo micro-computed tomography. The regions of interest investigated in the maxilla were the inter-radicular septum of the second molar and the tuber. The regions quantified in the mandible included the three molar regions and the condyle. A one-way analysis of variance followed by pairwise comparison using Tukey’s HSD and the Games–Howell test was conducted to explore significant differences between the groups. In the maxilla, OVX decreased the bone volume in the inter-radicular septum of the second molar. Bisphosphonate treatment was able to prevent this deterioration of the jaw bone. The other investigated maxillary regions were not affected by (un)treated ovariectomy. In the mandible, OVX had a significant negative impact on the jaw bone in the buccal region of the first molar and the inter-radicular region of the third molar. Treatment with ALN was able to prevent this jaw bone loss. At the condyle site, OVX significantly deteriorated the trabecular connectivity and shape, whereas preventive bisphosphonate treatment showed a positive effect on this trabecular bone region. No significant results between the groups were observed for the remaining regions of interest. In summary, our results showed that the effects of ovariectomy-induced osteoporosis are manifested at selected jaw bone regions and that bisphosphonate treatment is capable to prevent these oral bone changes.