Chronic hyperglycemia has been associated with an increased prevalence of pathological conditions including cardiovascular disease, cancer, or various disorders of the immune system. In some cases, these associations may be traced back to a common underlying cause, but more often, hyperglycemia and the disturbance in metabolic balance directly facilitate pathological changes in the regular cellular functions. One such cellular function crucial for every living organism is cell cycle regulation/mitotic activity. Although metabolic challenges have long been recognized to influence cell proliferation, the direct impact of diabetes on cell cycle regulatory elements is a relatively uncharted territory. Among other “nutrient sensing” mechanisms, protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification emerged in recent years as a major contributor to the deleterious effects of hyperglycemia. An increasing amount of evidence suggest that O-GlcNAc may significantly influence the cell cycle and cellular proliferation. In our present review, we summarize the current data available on the direct impact of metabolic changes caused by hyperglycemia in pathological conditions associated with cell cycle disorders. We also review published experimental evidence supporting the hypothesis that O-GlcNAc modification may be one of the missing links between metabolic regulation and cellular proliferation.

Immunomodulatory effects of oenothein B (1), a macrocyclic ellagitannin from various Onagraceae species, have been described previously. However, the mechanisms underlying the anti-inflammatory activity of 1 have not been fully clarified. The effects of 1 were investigated on inducible nitric oxide synthase, TLR-dependent and TLR-independent signal transduction cascades, and cytokine expression using murine macrophages (RAW 264.7). Compound 1 (10-60 μg/mL) reduced NO production, iNOS mRNA, and iNOS protein levels in a dose-dependent manner, without inhibition of iNOS enzymatic activity. It reduced the binding of the NF-κB p50 subunit to the biotinylated-consensus sequence and decreased nuclear p65 translocation. Gallic acid as a subunit of the macrocyclic ellagitannin 1 showed a far lower inhibitory activity. Nitric oxide production was reduced by 1 after stimulation using TLR2 (Pam2CSK4) and TLR4 (Kdo2) agonists, but this compound did not inhibit inducible nitric oxide synthesis after stimulation using interferon-gamma. IL-1beta, IL-6, and TNF-alpha mRNA synthesis was clearly reduced by the addition of 1. Oenothein B (1) inhibits iNOS after stimulation with LPS, TLR2, and TLR4 agonists via inhibition of TLR/NF-κB-dependent inducible nitric oxide and cytokine synthesis independent from IFN-gamma/JAK/STAT pathways. The full molecular structure of this macrocyclic ellagitannin seems to be required for its immunomodulatory actions.

During the mitotic cycle, the rod‐shaped fission yeast cells grow only at their tips. The newly born cells grow first unipolarly at their old end, but later in the cycle, the ‘new end take‐off’ event occurs, resulting in bipolar growth. Photographs were taken of several steady‐state and induction synchronous cultures of different cell cycle mutants of fission yeast, generally larger than wild type. Length measurements of many individual cells were performed from birth to division. For all the measured growth patterns, three different functions (linear, bilinear and exponential) were fitted, and the most adequate one was chosen by using specific statistical criteria, considering the altering parameter numbers. Although the growth patterns were heterogeneous in all the cultures studied, we could find some tendencies. In cultures with sufficiently wide size distribution, cells large enough at birth tend to grow linearly, whereas the other cells generally tend to grow bilinearly. We have found that among bilinearly growing cells, the larger they are at birth, the rate change point during their bilinear pattern occurs earlier in the cycle. This shifting near to the beginning of the cycle might finally cause a linear pattern, if the cells are even larger. In all of the steady‐state cultures studied, a size control mechanism operates to maintain homeostasis. By contrast, strongly oversized cells of induction synchronous cultures lack any sizer, and their cycle rather behaves like an adder. We could determine the critical cell size for both the G1 and G2 size controls, where these mechanisms become cryptic. TAKE AWAY Most individual fission yeast cells in steady‐state cultures grow bilinearly. In strongly oversized fission yeast cells, linear growth dominates over bilinear. Above birth length thresholds, both the G1 and G2 size controls become cryptic.

The aim of this study was to reveal whether increased reward dependence (RD) plays a role in the catecholamine neurotransmitter release and testosterone hormone regulation during physical activities among healthy trained participants. Twenty-two male participants (mean age: 40.27 ± 5.4 years) participated in this study. Two conditions were constructed, namely, a noncompetitive and a competitive running task (RT), which were separated by a 2-week interval. Urine and blood samples were collected prior to and following the running tasks. Noradrenaline (NA), adrenaline (A), dopamine (D), and their metabolites, vanillylmandelic acid (VMA) and homovanillic acid (HVA), were measured from urine, while testosterone levels were analyzed from blood samples. RD was assessed using the Cloninger’s Personality Inventory (PI). Mental health was evaluated using the WHO Well-Being, Beck Depression, and Perceived Life Stress Questionnaires. According to our findings, levels of NA, A, D, VMA, and testosterone released underwent an increase following physical exertion, independently from the competitive condition of the RT, while HVA levels experienced a decrease. However, we found that testosterone levels showed a significantly lower tendency to elevate in the competitive RT, compared with the noncompetitive condition (p = 0.02). In contrast, HVA values were higher in the competitive compared with the noncompetitive condition (p = 0.031), both before and after the exercise. Considering the factor RD, in noncompetitive RT, its higher values were associated with elevated NA levels (p = 0.007); however, this correlation could not be detected during the competitive condition (p = 0.233). Among male runners, the NA and testosterone levels could be predicted to the degree of RD by analyzing competitive and noncompetitive physical exercises.

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Among the 300 peripheral T-cell lymphomas (PTCL) searched for EBV positive non-resting B-cells by EBER in situ hybridization 12 have been identified with various forms of EBV-driven B-cell proliferation. This could be categorized into three major forms. i. In the first form scattered immature, mononuclear B-cells of immuno-, centroblastic type with CD20+. CD30+ CD45+, LMP1+ phenotype, reactive appearance and polyclonal immunoglobulin heavy chains gene rearrangement (IgH-R) were admixed to the PTCL cells. ii. The second form mimicked diffuse large B-cell lymphoma as homogenous sheets, largely demarcated from the PTCL, of mononuclear, immature B-cell of CD20+, CD30+, CD45+, LMP1+, EBNA-2+ phenotype but with lack of monoclonal IgH-R were present. iii. In the third form scattered Hodgkin-Reed-Sternberg (HRS) type of cells were noticed which exhibited the CD15+/-, CD20-/+, CD30+, CD45-, LMP1+, EBNA-2- phenotype and in 50% showed clonal IgH gene rearrangement in whole tissue DNA extract. The IgH associated transcription factors' (OCT2, BOB.1/OBF.1, PU.1) expression patterns in these cells corresponded to those of HRS cells in cHL. Based on analysis of 65 PTCLs, we have identified in the positive cases a highly significant increase of EBV+ small, reactive, resting B-cell compartment (75.9 / 100 HPF in PTCL vs. 1.5 / 100 HPF in control lymph nodes) likely to be due to the decreased immune surveillance. This progressive accumulation of EBV+ by-stander B-cell population in PTCLs might be the source of various B-cell proliferations, which in any form represent major diagnostic pitfalls and require a careful differential diagnostic procedure.

Regulation of G2 phase is based on inhibition of MPF (M-phase Promoting Factor) through phosphorylation by Wee1-like kinases. Removal of the inhibiting phosphate group requires Cdc25-like phosphatases. In fission yeast, size control is achieved by monitoring cell length via interactions of Pom1, Nif1, Cdr1 and Cdr2 proteins, regulating MPF via the Wee1 kinase. Here, a search for homologues of these key proteins was performed in the genomes of several model organisms to analyze the evolution of G2 size control. Both the known upstream pathways regulating Wee1 protein (Pom1 → Cdr2, and Nif1 → Cdr1) have been found to be characteristic only in fission yeasts. Mik1, a backup copy of Wee1 kinase probably appeared in the common ancestor of the fission yeasts. The duplication resulting in Wee1A and Wee1B isoforms probably happened in a common ancestor of higher animals, while the Myt1 protein (found only in animals) could be a variant between an ancient serine / threonine kinase and the Wee1 tyrosine kinase. Probably both the ancestors of plants and that of fungi may have lost the myt1 gene. In fission yeasts, Pyp3 is a backup phosphatase of Cdc25, also activating MPF in late G2. Interestingly, we found that the small Ibp1 phosphatase appeared to be a closer homologue of Cdc25, although its function is different. Moreover, Cdc25 homologues identified in plants were found to be more closely related to Ibp1 rather than to Cdc25 of fission yeast. In the Cdc25-like proteins, a novel conserved region was found with the consensus sequence LxxG(Y/F).

Fission yeast is commonly used as a model organism in eukaryotic cell growth studies. To describe the cells’ length growth patterns during the mitotic cycle, different models have been proposed previously as linear, exponential, bilinear and biexponential ones. The task of discriminating among these patterns is still challenging. Here, we have analyzed 298 individual cells altogether, namely from three different steady-state cultures (wild-type, wee1-50 mutant and pom1Δ mutant). We have concluded that in 190 cases (63.8%) the bilinear model was more adequate than either the linear or the exponential ones. These 190 cells were further examined by separately analyzing the linear segments of the best fitted bilinear models. Linear and exponential functions have been fitted to these growth segments to determine whether the previously fitted bilinear functions were really correct. The majority of these growth segments were found to be linear; nonetheless, a significant number of exponential ones were also detected. However, exponential ones occurred mainly in cases of rather short segments (<40 min), where there were not enough data for an accurate model fitting. By contrast, in long enough growth segments (≥40 min), linear patterns highly dominated over exponential ones, verifying that overall growth is probably bilinear.