Role Of PG Research Articles

Prodigiosin inhibits cholangiocarcinoma cell proliferation and induces apoptosis via suppressing SNAREs-dependent autophagy

BackgroundProdigiosin (PG), a natural red pigment produced by numerous bacterial species, has been a eye-catching research point in recent years for its anticancer activity. However, the role of PG in the cancer biology of cholangiocarcinoma (CCA) remains vague.MethodsThe proliferation of CCA cells was detected by Cell Counting Kit-8(CCK-8), Colony formation assay and 5-ethynyl-2′-deoxyuridine (EdU) assay. Cell apoptosis was evaluated by flow cytometry assay and western blot assay. The effects of PG or SNAREs on cell autophagy were measured by autophagy flux assay and western blot assay. Xenograft mouse models were used to assess the role of PG in CCA cells in vivo.ResultsPG could inhibit the proliferation and viability of CCA cells in a concentration- and time-dependent manner via suppressing the late stage of autophagy. Mechanistically, PG inhibits the fusion of autophagosomes and lysosomes by blocking STX17 and SNAP29, components of soluble N-ethyl-maleimide-sensitive factor attachment protein receptors (SNAREs)complex. When STX17 and SNAP29 were overexpressed, the inhibitory effect of PG on CCA cells autophagy was relieved. In addition, PG showed obvious inhibitory effects on cancer cell viability but no toxic effects on organs in xenotransplantation models.ConclusionTaken together, our results demonstrated that PG inhibits CCA cell proliferation via suppressing SNAREs-dependent autophagy, implying that PG could be a potential chemotherapy drug for advanced CCA.

Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer's Disease.

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

Plakoglobin Reduces the in vitro Growth, Migration and Invasion of Ovarian Cancer Cells Expressing N-Cadherin and Mutant p53.

Aberrant expression of cadherins and catenins plays pivotal roles in ovarian cancer development and progression. Plakoglobin (PG, γ-catenin) is a paralog of β-catenin with dual adhesive and signaling functions. While β-catenin has known oncogenic function, PG generally acts as a tumor/metastasis suppressor. We recently showed that PG interacted with p53 and that its growth/metastasis inhibitory function may be mediated by this interaction. Very little is known about the role of PG in ovarian cancer. Here, we investigated the in vitro tumor/metastasis suppressor effects of PG in ovarian cancer cell lines with mutant p53 expression and different cadherin profiles. We showed that the N-cadherin expressing and E-cadherin and PG deficient ES-2 cells were highly migratory and invasive, whereas OV-90 cells that express E-cadherin, PG and very little/no N-cadherin were not. Exogenous expression of PG or E-cadherin or N-cadherin knockdown in ES-2 cells (ES-2-E-cad, ES-2-PG and ES-2-shN-cad) significantly reduced their migration and invasion. Also, PG expression or N-cadherin knockdown significantly decreased ES-2 cells growth. Furthermore, PG interacted with both cadherins and with wild type and mutant p53 in normal ovarian and ES-2-PG cell lines, respectively.

Periodontitis and Rheumatoid Arthritis: What Do We Know?

Currently, in the field of rheumatology, there is much attention given towards the possible causality between periodontitis and rheumatoid arthritis (RA), specifically regarding the role of Porphyromonas gingivalis (Pg). This bacterium is unique, having a citrullinating enzyme. Antibodies against citrullinated proteins are rather specific for RA. Because causality is ultimately tested in longitudinal cohort studies which currently do not exist for periodontitis and RA, this commentary applied Bradford Hill criteria on the existing literature to assess causality as the most likely interpretation of this association. From an epidemiologic point of view, patients with RA have a higher incidence of periodontal disease than individuals without RA. In addition, there is a dose-response pattern in the association between the severity of periodontitis and RA disease activity. There are indications that periodontitis precedes RA, but there is no evidence yet available to show that Pg plays a direct role in this temporal relationship. The role of the unique characteristic of citrullination by Pg remains unexplained. However, in animal models, citrullination by Pg plays a distinct role in the development and aggravation of experimental arthritis. Although the role of Pg in RA remains speculative, a causative role for periodontitis as a chronic inflammatory disease caused by infectious agents in RA seems biologically plausible.

Sexual behavior in ewes and other domestic ruminants

Similarities as well as differences across species in the control of sexual behavior are helping to fully understand the subtle relations between physiology and eco-ethological constraints and how the brain integrates such information. We will illustrate this with sexual behavior in domestic ruminants and especially ewes. Females of these species like humans, but unlike rodents, have a long luteal phase. A prolonged exposure to progesterone (Pg) before the preovulatory estradiol rise is necessary for estrous behavior to be displayed. Estradiol action and receptor localization is very similar to that observed in other species. But not too surprisingly, the role of Pg is rather different with a priming effect not observed in rodents. However, as in rodents, Pg also has an inhibitory effect, is necessary for the display of proceptivity and is responsible for the timing of the different periovulatory events. These steroids act on the central nervous system in similar areas across mammalian species to regulate estrous behavior. Steroid fluctuations during the estrous cycle cause changes in catecholaminergic activity in the hypothalamus. Interestingly, these neurotransmitters seem to have very similar effects in ewes and rats as illustrated by the norepinephrine rise after male–female interactions observed in both species. Similar comparisons can be made regarding the action of some neuropeptides, including oxytocin and GnRH, and more integrative processes like sexual differentiation and modulation of reproduction by social interactions. Data on sheep, goats and cows will be compared with those of rodents.

Plakoglobin Deficiency Protects Keratinocytes from Apoptosis

The armadillo family protein plakoglobin (Pg) is a well-characterized component of anchoring junctions, where it functions to mediate cell-cell adhesion and maintain epithelial tissue integrity. Although its closest homolog beta-catenin acts in the Wnt signaling pathway to dictate cell fate and promote proliferation and survival, the role of Pg in these processes is not well understood. Here, we investigate how Pg affects the survival of mouse keratinocytes by challenging both Pg-null cells and their heterozygote counterparts with apoptotic stimuli. Our results indicate that Pg deletion protects keratinocytes from apoptosis, with null cells exhibiting delayed mitochondrial cytochrome c release and activation of caspase-3. Pg-null keratinocytes also exhibit increased messenger RNA and protein levels of the anti-apoptotic molecule Bcl-X(L) compared to heterozygote controls. Importantly, reintroduction of Pg into the null cells shifts their phenotype towards that of the Pg+/- keratinocytes, providing further evidence that Pg plays a direct role in regulating cell survival. Taken together, our results suggest that in addition to its adhesive role in epithelia, Pg may also function in contrast to the pro-survival tendencies of beta-catenin, to potentiate death in cells damaged by apoptotic stimuli, perhaps limiting the potential for the propagation of mutations and cellular transformation.

Differential Expression and Regulation of Cyclooxygenase Isozymes in Thymic Stromal Cells

Prostaglandins (PGs) are lipid-derived mediators of rapid and localized cellular responses. Given the role of PG in supporting thymic T cell development, we investigated the expression of the PG synthases, also known as cyclooxygenases (COX)-1 and -2, in the biosynthesis of PGs in thymic stromal cell lines. The predominant isozyme expressed in cortical thymic epithelial cells was COX-1, while COX-2 predominated in the medulla. IFN-gamma up-regulated expression and activity of COX-2 in medullary cells, in which COX-2 was expressed constitutively. In contrast, IFN-gamma down-regulated COX-1 activity, but not expression, in cortical cells. Stromal cells support T cell development in the thymus, although the mediators of this effect are unknown. Selective inhibition of COX-2, but not COX-1, blocked the adhesion of CD4+CD8+ and CD4+CD8- thymocytes to medullary cell lines. No effect of the inhibitors was observed on the interactions of thymocytes with cortical epithelial lines. These data further support the differential regulation of COX-1 and COX-2 expression and function in thymic stromal cells. PGs produced by COX-2 in the medullary thymic stroma may regulate the development of thymocytes by modulating their interaction with stromal cells.

To PG or Not to PG?

The absence of endo-α-1,4-d-galacturonanase (PG, EC 3.2.1.15) in some fruits and the molecular suppression of PG in tomato fruit have collectively provided evidence that this protein is neither required nor sufficient to achieve normal softening in fleshy fruits. On the other hand, initial claims that down-regulation of PG was without effect on tomato softening were overstated. The influence of PG on softening does appear to be minimal during the initial stages of ripening, during which time changes in the locule tissues can significantly alter texture as monitored in whole fruit. Enzymes, including pectinmethylesterases, cellulases, rhamnogalacturonanase, and glycosidases may also play pivotal roles in softening. β-galactosidases have attracted much attention as potential determinants of fruit texture; however, conclusive evidence for this role is lacking, and increased levels of β-galatosidase (and net cell wall galactosyl residue loss) have been noted in senescing vegetative and floral organs as well as in fruit. Apoplastic pH, ionic activity, and composition are likely to contribute to tissue and wholeorgan texture through weakening of polymer aggregates and/or through modulation of cell wall enzyme activity. During the latter stages of ripening and overripening, the role of PG is apparent from the persistent structural integrity of fruit transformed with PG antisense constructs. Patterns of softening and deterioration in normal tomato fruit suggest that the catalytic activity of PG in vivo is initially queued and does not parallel the accumulation of PG protein. Developmental changes in membrane permeability, physical injury, and other stress conditions can alter the apoplastic environment, releasing constraints on PG action.

Mesangial cell DNA synthesis induced by hydrogen peroxide, interleukin-6, and platelet-derived growth factor: effects of indomethacin and dazmegrel.

This study indirectly examined the role of prostanoids (PG) in mediating rat mesangial cell (MC) DNA synthesis induced by hydrogen peroxide (H2O2), interleukin 6 (IL-6), and platelet-derived growth factor (PDGF). MC were exposed to three daily pulses of 10(-6) mol/l H2O2 alone or in combination with IL-6 (5 ng/ml) or PDGF (10 ng/ml). In order to examine (indirectly) the role of PG in mediating changes in MC DNA synthesis, indomethacin (1.5 x 10(-5) mol/l) or the thromboxane A2 synthetase inhibitor Dazmegrel (10(-5) mol/l) was added to the medium and DNA synthesis assessed after 72 h using 3H-thymidine incorporation (3H-TdR). Stimulation of MC by H2O2 alone resulted in an increase in 3H-TdR of 34.7 +/- 5.5% (p < 0.01). H2O2 enhanced the mitogenic effects of IL-6 and PDGF, 3H-TdR increasing by 52 +/- 12.1% (p < 0.01) and 100 +/- 21% (p < 0.001), respectively. Indomethacin suppressed the DNA synthesis induced by H2O2 alone, 3H-TdR decreasing by 33 +/- 12% (p < 0.05). Indomethacin also reduced the mitogenic response to H2O2 plus IL-6 and H2O2 plus PDGF by 91 +/- 17 and 97 +/- 12%, respectively (p < 0.05). Dazmegrel reduced 3H-TdR when MC were exposed to H2O2 alone by 31.8 +/- 16% (p < 0.05) and when combined with IL-6 or PDGF by 80 +/- 26 and 120 +/- 13%, respectively (p < 0.05). These data suggest that the pathways through which H2O2-induced growth of MC is mediated appear, at least in part, to involve PG, particularly thromboxane A2.

The Role of PG(6-keto-PGF1, PGE2 and TxB2) as the Metastasis Factor in Gestational Trophoblastic Tumor

The Role of PG(6-keto-PGF1, PGE2 and TxB2) as the Metastasis Factor in Gestational Trophoblastic Tumor

A local pathophysiologic mechanism of the resorption of residual ridges: Prostaglandin as a mediator of bone resorption

The role of PG as a bone resorption mediator in RRR was investigated in the rat model and the following may be concluded from the data. 1. PG is suggested to be a mediator of the RRR. 2. The continuous and localized bone resorption in RRR may be caused by continuous synthesis of local PG. 3. PG producing cells and specific stimuli responsible for RRR are still unknown.

Prostaglandins and other arachidonic acid metabolites in the kidney

This very brief summary of the various possible contributions of PG to normal and abnormal renal function should highlight the problem of assigning a specific role to PG in overall renal physiology and pathophysiology. PG produced in specific segments of the nephron will affect specific functions occurring in this segment. These effects need not necessarily be reflected in the overall renal function. Also in some cases, the determinant may not be prostaglandins, that is, cyclooxygenase derivatives of AA, but perhaps lipoxygenase or epoxygenase products that influence the functional parameters of the specific segment. Despite the multitude of renal functions that may be influenced by PG, we would like to propose a teleological hypothesis for an overall role of PG in the kidney, that is, that of cytoprotective agents. Renal vasodilatatory prostaglandins will maintain renal blood flow when the latter is challenged, thus, preventing hypoxic injury to the tissue. Endogenous prostaglandins may also protect tubular cells from extreme environmental changes as may occur on both the luminal and contraluminal sides. For example, tubular cells may be exposed to luminal fluid that may vary from hypotonic to hypertonic, from alkaline to acid, and so forth. Similarly, the interstitial fluid osmolality and solute composition is subject to considerable variations which may be opposite to those existing on the urinary side. The role of PG might be to maintain the internal milieu of the cells exposed to such extreme changes in environment. This could be accomplished by changing the permeability characteristics of the membranes and the function of pumps. Thus, specific PGs could dampen the hormonal response to protect the specific nephron segment, which might otherwise suffer injury. This hypothesis might also help to explain why the effect of PG administration or inhibition of PG synthesis may vary considerably depending on the overall physiological state of the subject: Maintenance of a local internal milieu may require different responses from those required for total body homeostasis.

PROSTAGLANDINS (PG) AND MYOCARDIAL CONTRACTILE FUNCTION IN GROUP B STREPTOCOCCAL (STREP) SHOCK

The role of PG and myocarial contractile function in STREP shock has not been reported. To evaluate this phenomenon, rabbits were instrumented to measure mean arterial pressure (MAP), pulmonary artery pressure (PAP), cardiac output (CO), heart rate (HR), left ventricular end diastolic pressure (LVEDP) and dP/dt and to calculate total peripheral (TPR) and pulmonary vascular resistance (PVR) before and after STREP (1012 cells/Kg) infusion. The table shows the effect on the various parameters of indomethacin (IND) pretreatment (4 mg/Kg; GpII) on STREP induced changes from the basal (BASE) values (GpI). *=P<0.05 vs BASE. Values are X̄ ±SEM.LVEDP and TPR remained unchanged and afterload did not increase in either group after STREP infusion. The table shows that IND (GpII) prevented STREP-induced decreases in dP/dt and HR, and increase in PVR (GpI). Thus, we conclude that: 1) STREP infusion illicits a dramatic fall in myocardial contractility that appears to be an important component of the shock process, and 2) STREP-induced changes in contractility and PVR appear to be PG dependent.

Vasopressin-prostaglandin interactions in the regulation of epithelial cell permeability to water

Prostaglandins (PG's) have effects at several sites involved in the regulation of water balance. Many of these are discussed elsewhere in this symposium. This review will consider vasopressin-PG interactions that are involved in the regulation of water permeability of epithelia, particularly the renal collecting duct and toad urinary bladder. It is well established that the increase in permeability to water that vasopressin elicits in epithelia involves stimulation of the formation of cyclic AMP [1] and that PGE inhibits the water permeability response by inhibiting the stimulation of cyclic AMP formation [2, 3]. After summarizing the current understanding of the cellular action of vasopressin and the development of ideas and information regarding the role of PG's in regulating the response to vasopressin, the mechanisms of the effects of PG's will be considered, as well as the effect of vasopressin on the metabolism of PG's and related compounds. Finally, the foregoing will be considered in terms of normal and abnormal regulation of water permeability.