Potential therapeutic effects of naringin loaded PLGA nanoparticles for the management of Alzheimer's disease: In vitro, ex vivo and in vivo investigation.

Background: Alzheimer's disease (AD) is the most prevalent type of dementia which has been affected to more the 44 million people globally. It is distinguished by gradually deteriorating memory and other cognitive abilities that precede dementia. Present treatment of AD mainly focuses on symptomatic slowing the evolution of the disease which is associated with numerous side effects such as dizziness, tiredness, nausea, vomiting, heart attack, and stroke etc. Henceforth; there is urgent need to identify the alternative treatment for management of AD. Herbal medicines have been used from long time to treat AD. One of such leading Phyto molecule is Naringin. It showed promising results against AD but suffers from poor bioavailability and require in high dose to cross the blood brain barrier. Objectives: The main objectives of proposed work are to increase the bioavailability of naringin in brain by developing Nano-suspension and preclinical evaluation of neuroprotective effect of Naringin Nano-suspension (NNS) against Scopolamine induced Alzheimer's disease in rats. Methods: The present study deals with the development, characterization of NNSand to evaluate neuroprotective effect of NNS. Nanoparticles of drug were formed by using PLGA polymer and optimized by using 32 factorial design. Optimized batch was further characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD). Further the effectiveness of NNS was preclinically investigated by performing AOTstudy as per OECD guideline 420. AD induced Albino Wistar Rats were treated with NNS orally for 14 days and then evaluated for parameters like Gross examination of brain, Relative brain weight determination, behavioural parameters, neuro-inflammatory parameters and immune-histology. Results: Optimization was carried out to study the effect of polymer concentration and number of HPH cycles on Particle size, Poly dispersity index (PDI) and % entrapment efficiency. Desirability search approach was used to select the optimized formulation. Based on the selection criteria, batch F6 having 357.6 ± 05 nm particle size, 0.168 ± 0.04 PDI and 91 ± 2% EE was selected as optimized batch. SEM analysis showed spherical morphology and XRD confirmed the molecular dispersion. Pre-treatment with NNS showed neuroprotective activity basedon results of behavioural studies, biochemical estimation, neuroinflammatory parameters and immunohistochemistry evaluations. Conclusion: As NNS showed significant neuroprotective and anti-neuro-inflammatory effect, this study opens up new ways to exploit Naringin for various therapeutic and restorative purposes.

Sweetness and positivity together aren't a happy ending: Case controlled study amongst severe COVID-19 for impact of diabetes mellitus on survival.

Background: India is the epicenter of diabetes mellitus (DM). The relationship between COVID and DM in age/gender-matched non-diabetics has not been studied yet. The role of DM in predicting the disease severity and outcome in COVID patients might provide new insight for effective management. Methods: We conducted a prospective comparative study at a COVID care center from 25th April-31st May 2021. Among 357 severe-COVID patients screened, all consecutive diabetes (n-113) and age/gender-matched non-diabetes (n-113) patients were recruited. All diabetics and non-diabetics at admission were subjected to high resolution computed tomography (HRCT) chest and inflammatory markers (C-reactive protein (CRP), D-dimer, ferritin, interleukin-6 (IL-6), lactate dehydrogenase (LDH), Neutrophil-Lymphocyte Ratio (NLR)) before starting anti- COVID therapy. Statistical analysis was done using JMP 15·0 ver·3·0·0. Results: The prevalence of DM among the screened population (n-357) was 38·37%. The mean age of the study population was 61y with male preponderance (57%). There was no statistical difference in the HRCT-score or inflammatory markers in the two groups except for higher NLR (p-0·0283) in diabetics. Diabetics had significantly inferior overall survival (OS) (p-0·0251) with a 15d-OS of diabetics vs. non-diabetics being 58·87%, 72·67%, and 30d-OS of diabetics vs. non-diabetics being 46·76%, 64·61%, respectively. The duration of the hospital stay was not statistically different in the two groups (p-0·2). Conclusion: The mortality is significantly higher in severe-COVID patients with DM when compared to age/gender-matched non-diabetics. There was no significant difference in most inflammatory markers/CT at admission between the two groups.

Correlation of genome methylation of fig tree accessions with natural nematode and rust incidence.

Commercial fig tree cultivation in Brazil involves a single cultivar, 'Roxo-de-Valinhos'. The use of a single cultivar results in serious diseases and related problems. The aim of this study was to characterize fig accessions by analyzing the natural root-knot nematode and leaf rust incidence in relation to the epigenomic profile of the plant, since epigenetic variations affect plant-pathogen interactions. All plants were attacked by nematodes, indicating susceptibility; Meloidogyne incognita was the root-knot nematode species involved. Joint analysis of data showed that methylation and leaf rust incidence were correlated when observed in the same phenological phase, presenting initial evidence of the same factorial pressure loads in genotypes, suggesting similar behavior within these genotypes.

Atomistic and continuum scale modeling of functionalized graphyne membranes for water desalination.

Recent theoretical and experimental studies reported ultra-high water permeability and salt rejection in nanoporous single-layer graphene. However, creating and controlling the size and distribution of nanometer-scale pores pose significant challenges to application of these membranes for water desalination. Graphyne and hydrogenated graphyne have tremendous potential as ultra-permeable membranes for desalination and wastewater reclamation due to their uniform pore-distribution, atomic thickness and mechano-chemical stability. Using molecular dynamics (MD) simulations and upscale continuum analysis, the desalination performance of bare and hydrogenated α-graphyne and γ-{2,3,4}-graphyne membranes is evaluated as a function of pore size, pore geometry, chemical functionalization and applied pressure. MD simulations show that pores ranging from 20 to 50 Å2 reject in excess of 90% of the ions for pressures up to 1 GPa. Water permeability is found to range up to 85 L cm-2 day-1 MPa-1, which is up to three orders of magnitude larger than commercial seawater reverse osmosis (RO) membranes and up to ten times that of nanoporous graphene. Pore chemistry, functionalization and geometry are shown to play a critical role in modulating the water flux, and these observations are explained by water velocity, density, and energy barriers in the pores. The atomistic scale investigations are complemented by upscale continuum analysis to examine the performance of these membranes in application to cross-flow RO systems. This upscale analysis, however, shows that the significant increase in permeability, observed from MD simulations, does not fully translate to current RO systems due to transport limitations. Nevertheless, upscale calculations predict that the higher permeability of graphyne membranes would allow up to six times higher permeate recovery or up to 6% less energy consumption as compared to thin-film composite membranes at currently accessible operating conditions. Significantly higher energy savings and permeate recovery can be achieved if higher feed-flow rates can be realized.

Transcriptomic pathway analysis of urokinase receptor silenced breast cancer cells: a microarray study.

Urokinase plasminogen activator receptor (PLAUR) has been implicated in a variety of physiological and pathological conditions. The multi-functionality of PLAUR is due to its capacity to interact with many co-receptors to regulate extracellular proteolysis and intracellular signaling. Recent reports are identifying novel functions of PLAUR which were not evident in the past; however, the molecular mechanisms of PLAUR signaling are not completely understood. Here, we have compared the transcriptomes of silencing control (sicon) and PLAUR silenced (PLAURsi) MDA-MB-231 breast cancer cells on treatment with radiation. We isolated RNA from the cells, synthesized cDNA and measured the gene expression changes by microarray. We identified 24 downregulated and 53 upregulated genes, which were significantly (P-value < 0.005) affected by PLAUR silencing. Our analysis revealed 415 canonical pathways and 743 causal disease networks affected on silencing PLAUR. Transcriptomic changes and predicted pathways supported and consolidated some of the earlier understanding in the context of PLAUR signaling; including our recent observations in DNA damage and repair process. In addition, we have identified several novel pathways where PLAUR is implicated.

Biochemical studies of amylase, lipase and protease in Callosobruchus maculatus (Coleoptera: Chrysomelidae) populations fed with Vigna unguiculata grain cultivated with diazotrophic bacteria strains.

The objective of this study was to evaluate the enzymatic activity of homogenates of insects fed on grain of cowpea, Vigna unguiculata (L.), cultivars grown with different nitrogen sources. For the experiment we used aliquots of the homogenate of 100 unsexed adult insects, emerged from 10 g of grain obtained from four cowpea cultivars: 'BRS Acauã', 'BRS Carijó', 'BRS Pujante', and 'BRS Tapaihum' grown under different regimes of nitrogen sources: mineral fertilizer, inoculation with strains of diazotrophs (BR 3267, BR 3262, BR 3299; INPA 03-11B, 03-84 UFLA, as well as the control (with soil nitrogen). The parameters evaluated were enzymatic activities of insect protease, amylase and lipase and the starch content of the grains. There were differences in the enzymatic activity of amylase, lipase and protease of insect homogenate according to the food source. A lower activity of the enzyme amylase from C. maculatus homogenate was observed when insects were fed grain of the cultivar BRS Carijó. A lower activity of lipase enzyme from C. maculatus homogenate was observed when the insects fed on grain from the interaction of the cultivar Tapaihum inoculated with BR 3262 diazotrophs. The lowest proteolytic activity was observed in homogenate of insects fed on interaction of 'BRS Carijó' inoculated with BR 3262 diazotrophs. Starch content correlated positively with the amylase activity of C. maculatus homogenate. The cultivar BRS Carijó had a different behavior from the other cultivars, according to the cluster analysis.

CHK1 and RAD51 activation after DNA damage is regulated via urokinase receptor/TLR4 signaling.

Mechanisms of DNA damage and repair signaling are not completely understood that hinder the efficiency of cancer therapy. Urokinase-type plasminogen activator receptor (PLAUR) is highly expressed in most solid cancers and serves as a marker of poor prognosis. We show that PLAUR actively promotes DNA repair in cancer cells. On the contrary, downregulation of PLAUR expression results in delayed DNA repair. We found PLAUR to be essential for activation of Checkpoint kinase 1 (CHK1); maintenance of cell cycle arrest after DNA damage in a TP53-dependent manner; expression, nuclear import and recruitment to DNA-damage foci of RAD51 recombinase, the principal protein involved in the homologous recombination repair pathway. Underlying mechanism implies auto-/paracrine signaling of PLAUR/TLR4 receptor complex leading to activation of CHK1 and DNA repair. The signaling is induced by a danger molecule released by DNA-damaged cells and mediates, at least partially, activation of DNA-damage response. This study describes a new mechanism of DNA repair activation initiated by auto-/paracrine signaling of membrane receptors PLAUR/TLR4. It adds to the understanding of role of PLAUR in cancer and provides a rationale for therapeutic targeting of PLAUR/TLR4 interaction in TP53-positive cancers.

Pulp and Periodontal Regeneration of an Avulsed Permanent Mature Incisor Using Platelet-rich Plasma after Delayed Replantation: A 12-month Clinical Case Study.

Numerous publications have reported revascularization of necrotic immature permanent teeth, but the regenerative potential of pulp in mature teeth has rarely been considered. Platelet-rich plasma (PRP) meets many requirements of a scaffold for regenerative endodontics. To the best of our knowledge, no clinical study has evaluated PRP for endodontic regeneration in a mature avulsed tooth. The present case evaluated PRP for pulpal regeneration in an avulsed mature incisor (>8 hours extraoral dry time) of an 11-year-old boy after delayed replantation. The canal was disinfected after extraoral access cavity preparation and pulp extirpation. The root apex was enlarged, and the tooth was placed in doxycycline solution for 20 minutes. After tooth replantation and splinting, PRP was injected up to the level of the cementoenamel junction and sealed with glass ionomer cement. The 6-month follow-up revealed evidence of internal and external root resorption with periapical radiolucency and an apparent periodontal ligament space. Access was reopened; slurry of 2 antibiotics (minocycline and metronidazole) was inserted into the canal and sealed. Nine- and 12-month radiographs revealed resolution of periapical radiolucency with no further progression of internal resorption. The tooth showed a positive response to thermal and electric pulp tests. The findings observed in this case warrant further research under controlled conditions to evaluate endodontic and periodontal regeneration in a tooth that would otherwise be expected to have an unfavorable prognosis.

Adenosine enhances acetylcholine receptor channel openings and intracellular calcium 'spiking' in mouse skeletal myotubes.

AIMS: The autocrine activity of the embryonic isoform of the nicotinic acetylcholine receptor is crucial for the correct differentiation and trophism of skeletal muscle cells before innervation. The functional activity of extracellular adenosine and adenosine receptor subtypes expressed in differentiating myotubes is still unknown. In this study, we performed a detailed analysis of the role of adenosine receptor-mediated effects on the autocrine-mediated nicotinic acetylcholine receptor channel openings and the associated spontaneous intracellular calcium 'spikes' generated in differentiating mouse myotubes in vitro. METHODS: Cell-attached patch-clamp recordings and intracellular calcium imaging experiments were performed in contracting myotubes derived from mouse satellite cells. RESULTS: The endogenous extracellular adenosine and the adenosine receptor-mediated activity modulated the properties of the embryonic isoform of the nicotinic acetylcholine receptor in myotubes in vitro, by increasing the mean open time and the open probability of the ion channel, and sustaining nicotinic acetylcholine receptor-driven intracellular [Ca(2+) ]i 'spikes'. The pharmacological characterization of the adenosine receptor-mediated effects suggested a prevalent involvement of the A2B adenosine receptor subtype. CONCLUSION: We propose that the interplay between endogenous adenosine and nicotinic acetylcholine receptors represents a potential novel strategy to improve differentiation/regeneration of skeletal muscle.

Loss of urokinase receptor sensitizes cells to DNA damage and delays DNA repair.

DNA damage induced by numerous exogenous or endogenous factors may have irreversible consequences on the cell leading to cell cycle arrest, senescence and cell death. The DNA damage response (DDR) is powerful signaling machinery triggered in response to DNA damage, to provide DNA damage recognition, signaling and repair. Most anticancer drugs induce DNA damage, and DNA repair in turn attenuates therapeutic efficiency of those drugs. Approaches delaying DNA repair are often used to increase efficiency of treatment. Recent data show that ubiquitin-proteasome system is essential for signaling and repair of DNA damage. However, mechanisms providing regulation of proteasome intracellular localization, activity, and recruitment to DNA damage sites are elusive. Even less investigated are the roles of extranuclear signaling proteins in these processes. In this study, we report the involvement of the serine protease urokinase-type plasminogen activator receptor (uPAR) in DDR-associated regulation of proteasome. We show that in vascular smooth muscle cells (VSMC) uPAR activates DNA single strand break repair signaling pathway. We provide evidence that uPAR is essential for functional assembly of the 26S proteasome. We further demonstrate that uPAR mediates DNA damage-induced phosphorylation, nuclear import, and recruitment of the regulatory subunit PSMD6 to proteasome. We found that deficiency of uPAR and PSMD6 delays DNA repair and leads to decreased cell survival. These data may offer new therapeutic approaches for diseases such as cancer, cardiovascular and neurodegenerative disorders.

Critical review on Bhaishajya Kaala (time of drug administration) in Ayurveda.

Bhaishajya Kaala (time of drug administration) is an important principle to be considered while treating a disease. Still hardly a handful of physicians are seen, who account for this. To highlight its imperial role in Chikitsa, there is an immense necessity to analyze this concept, which is the need of the hour. Bhaishajya Kaala is mainly explained in relation with Bala of Roga, Rogi, particular Dosha, Dooshya, and various other factors. The comprehensive understanding of this concept involves so many questions as, why there is a difference in the number of Aushdha Kaala? What is the logic behind their indications as well as contraindications? The present paper focuses on the above points to find out the convincing answers.

Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest.

BACKGROUND: Due to the functional defects in apoptosis signaling molecules or deficient activation of apoptosis pathways, leukemia has become an aggressive disease with poor prognosis. Although the majority of leukemia patients initially respond to chemotherapy, relapse is still the leading cause of death. Hence targeting apoptosis pathway would be a promising strategy for the improved treatment of leukemia. Hydantoin derivatives possess a wide range of important biological and pharmacological properties including anticancer properties. Here we investigated the antileukemic activity and mechanism of action of one of the potent azaspiro hydantoin derivative, (ASHD). MATERIALS AND METHODS: To investigate the antileukemic efficacy of ASHD, we have used MTT assay, cell cycle analysis by FACS, tritiated thymidine incorporation assay, Annexin V staining, JC1 staining and western blot analysis. RESULTS: Results showed that ASHD was approximately 3-fold more potent than the parent compounds in inducing cytotoxicity. Tritiated thymidine assay in conjunction with cell cycle analysis suggests that ASHD inhibited the growth of leukemic cells. The limited effect of ASHD on cell viability of normal cells indicated that it may be specifically directed to cancer cells. Translocation of phosphatidyl serine, activation of caspase 3, caspase 9, PARP, alteration in the ratio of BCL2/BAD protein expression as well as the loss of mitochondrial membrane potential suggests activation of the intrinsic pathway of apoptosis. CONCLUSION: These results could facilitate the future development of novel hydantoin derivatives as chemotherapeutic agents for leukemia.

Evaluation of subchronic genotoxic potential of Swarna Makshika Bhasma.

Extremely diminutive published information is available on the mutagenic activity of Ayurvedic Bhasmas. Genotoxicity of few Bhasmas were reported on single maximum dose, but no reference is available on the sub-chronic level. Hence the present study was carried to generate and evaluate genotoxic potentials of Swarna Makshika Bhasma (mineral preparation) administered at therapeutic dose for 14 days. Chromosomal aberrations and abnormal sperm assay parameters were taken in this study. Cyclophosphamide (CP) was taken as positive group and results were compared. The results revealed a lack of generation of structural deformity in above parameters by tested drugs compared to CP treated group. Observed data indicate that the Bhasmas tested were non-genotoxic under the experimental conditions.

Betamethasone, progesterone and RU-486 (mifepristone) exert similar effects on connexin expression in trophoblast-derived HTR-8/SVneo cells.

Connexins (Cx) are membrane proteins able to influence cell trophoblast responses, such as proliferation, differentiation, migration and invasiveness. Likewise, glucocorticoids are also known to modulate many factors involved in implantation, including trophoblast gap-junction intercellular communication, although their influence on pregnancy is controversial. In order to investigate the effects of betamethasone, a synthetic glucocorticoid, on Cx and glucocorticoid receptor (GR) expression and localisation, as well as on cell proliferation, the extravillous trophoblast-derived HTR-8/SVneo cell line was used as a model. The results, confirmed by means of immunofluorescence, demonstrate that betamethasone selectively modifies GR and Cx expression, enhancing the GRα isoform without affecting GRß, and inhibiting Cx40 expression whilst increasing that of Cx43 and Cx45. Furthermore, betamethasone was shown to exert an inhibitory action on cell proliferation. In this model the abortion drug RU-486 (mifepristone), reported to be a GR antagonist, did not counteract this effect of betamethasone. On the contrary, it induced responses similar to those of the hormone. Knowing that RU-486 is also a potent progesterone-receptor antagonist, the effect of progesterone alone and in combination with the drug on Cx expression and cell proliferation was then tested. Progesterone showed the same effect as betamethasone on Cx expression, but it did not affect proliferation. Based on these results, neither the abortion effects of RU-486 nor the protective action of betamethasone and progesterone are exerted by modulation of Cx. RU-486 did not antagonise the progesterone effect, suggesting that its abortive action does not involve alteration of trophoblast Cx expression.

Use of glucocorticoids in pregnancy.

For many years glucocorticoids have been used world-wide in pregnant women for treatment of a variety of medical disorders, from bronchial asthma to systemic lupus erythematosous, to renal transplant. More recently their administration has been successfully addressed to the prevention of congenital fetal diseases. In some of these, such as for instance the 21-hydroxylase deficiency leading to congenital adrenal hyperplasia, the pathogenic mechanism is well known, while in others, such as the cystic adenomatoid malformation of the lung, it is not yet understood. Besides these types of diseases, there are acquired inflammatory conditions impairing the physiologic evolution of pregnancy that benefit from glucocorticoid administration. This is the case in recurrent miscarriage due to increased concentration of decidual Natural Killer cells, as well as in the Romero's syndrome, leading to premature parturition and related life threatening fetal complications. However, in spite of its prominent efficacy, the therapy is generally viewed with some suspicion because of possible fetal and maternal adverse effects. With the aim to contribute to a better knowledge of the basic mechanisms of glucocorticoid protection, we reviewed the regulation of their trans-placental passage, their biological effects on gestational environment, their possible 'programming' and teratogenic action, and their accepted use for prevention and cure of pregnancy complications. We believe that a more qualified and liberal use of these compounds will lead in many cases to a significant improvement of fetal and maternal prognosis.

cAMP efflux from human trophoblast cell lines: a role for multidrug resistance protein (MRP)1 transporter.

Cyclic adenosine 3'-5'-monophosphate (cAMP) is a second messenger, which exerts an important role in the control of human first-trimester trophoblast functions. In the present study we demonstrate the existence of a mechanism that is able to extrude cAMP from trophoblast-derived cell lines, and show evidence indicating the involvement of multidrug resistance protein (MRP) 1, a transporter belonging to the ATP-binding cassette family, in cAMP egress. MRP1 is expressed in trophoblast cell lines and cAMP efflux is highly reduced by the MRP1 inhibitor, MK-571. In addition, interleukin-1beta and estrone are able to enhance MRP1 gene expression and influence extracellular cAMP concentration. The occurrence of a MRP1-dependent cAMP efflux is also shown in human first-trimester placenta explants. Extracellular cAMP could represent a source for adenosine formation, which in turn could regulate cAMP-dependent responses in placental tissue. Evidence is provided that adenosine receptor subtypes are present and functional in human trophoblast-derived cells. A role for cAMP egress mechanism in the fine modulation of the nucleotide homeostasis is therefore suggested.

Expression and characterization of vitamin C transporter in the human trophoblast cell line HTR-8/SVneo: effect of steroids, flavonoids and NSAIDs.

Vitamin C plays an important role in embryogenesis and fetal growth as well as in the progression of pregnancy and delivery. Therefore, it is important to understand the mechanism that mediates its transport to the fetus as well as the possible influences by endogenous and exogenous substances on its placental uptake. The aim of this study was to investigate placental sodium-dependent vitamin C transporters (SVCT) 1 and 2. By means of RT-PCR, we found that SVCT2, but not SVCT1, mRNA is expressed in human trophoblast cell line HTR-8/SVneo. Our method was able to confirm SVCT2 mRNA expression in human first-trimester chorionic villi but not in term placental tissue. Cell line kinetic studies of [(14)C] ascorbic acid (AA) uptake indicated a one-site model and a saturable process. Fetal bovine serum (FBS) and epidermal growth factor (EGF) do not influence the transport properties, although they significantly increase the expression of SVCT2. Steroid hormones (17beta-estradiol, progesterone and cortisol), flavonoids (genistein and quercetin) and non-steroidal anti-inflammatory drugs (NSAIDs) (indomethacin and diclofenac) inhibit [(14)C]AA uptake in a dose-dependent and non-competitive manner. On the contrary, the process is not influenced by aspirin. Our study suggests the use of HTR-8/SVneo cells as a suitable model for trophoblast vitamin C transport investigation.

Molecular mechanism involved in the transport of a prodrug dopamine glycosyl conjugate.

We have previously demonstrated that dopamine conjugation to glucose allows it to induce therapeutic effects against Parkinson's disease after intravenous administration. In this paper we demonstrate that, unlike dopamine, the prodrug glu-dopamine is a transportable substrate of glucose transporters. Towards this, the effect of glucose-conjugation on the affinity and uptake of dopamine have been assessed in vitro, using human retinal pigment epithelium (HRPE) cells. Glucose transporter-mediated uptake was measured using [(3)H]3-O-methylglucose ([(3)H]3-O-MG) as the tracer. The uptake was found to be rapid and hyperbolically related to its concentrations (K(t)=7.8+/-1.2mM and V(max)=54+/-2 nmol/min mg protein). Inhibition experiments showed that dopamine was able to interact with glucose carriers only when conjugated to glucose (IC(50)=2.6+/-0.6mM). HPLC analysis of HRPE cell extracts showed that both dopamine and the prodrug permeate the cell, but only the uptake of the prodrug is inhibitable by glucose. This confirms that glucose transporters mediate the transport of the prodrug glu-dopamine, but not of dopamine. HRPE cells is therefore proposed as a promising model for in vitro studies involving the glucose transporter-mediated transport of drugs and their conjugates.

Nuclear retinoic acid receptor beta as a tool in chemoprevention trials.

Retinoic acid (RA) and its natural and synthetic derivatives (retinoids) are important dietary factors which regulate cellular differentiation and growth, so that they are thought to be particularly effective at preventing the development of several tumours. They play this role as ligands of the RAR and RXR nuclear retinoic acid receptors, including the RA receptor isoforms alpha, beta, and gamma. These ligand-activated nuclear receptors induce the transcription of target genes by binding to RA-responsive elements in the promoter regions. Among these target genes, the RARbeta gene is of great interest, being able to encode a potential tumour suppressor. It should be emphasized that most breast carcinomas and breast cancer cell lines show loss or down-regulation of RARbeta receptor expression, whereas RARalpha and gamma, as well as retinoid X receptors, appear to be variably expressed in both normal and tumour cells. It is also interesting to note that basal and RA-induced RARbeta mRNA levels tend to increase with senescence of normal cells. This information provides further support for the hypothesis that genetic events involved in cellular senescence may also play a significant role in tumour suppression in humans. The aim of this review is to clarify whether expression of RARbeta could be modulated by chemopreventive intervention and may therefore serve as an intermediate biomarker in chemoprevention trials for some cancers.

Prostaglandin E2 inhibits proliferation and migration of HTR-8/SVneo cells, a human trophoblast-derived cell line.

Normal placentation requires a highly coordinated control of proliferation, migration and invasiveness of extravillous trophoblast cells. Since prostaglandin E2 is a major prostanoid synthesized by intrauterine tissues and highly involved in pregnancy homeostasis, we examined the possibility that it modulates extravillous trophoblast cell functions. Here, we report the presence of mRNAs for prostaglandin E2 EP2 and EP4 receptor isoforms and of proteins in both first-trimester human chorionic villi and in the human trophoblast-derived HTR-8/SVneo cells. Moreover we found that: (i) this cell line releases prostaglandin E2 and the output is enhanced by interleukin-1beta; (ii) the prostanoid consistently inhibits serum- or epidermal growth factor-induced cell proliferation and also migration. An involvement of cAMP in the prostaglandin E2 antiproliferative action is suggested by the observation that the prostanoid greatly enhances cAMP level in HTR-8/SVneo cells and that forskolin inhibits cell proliferation; moreover the administration of prostaglandin E2 plus forskolin, a condition which evokes a synergistic enhancement of cAMP, induces a major impairment of cell growth. Provided that our data are applicable to the trophoblast tissue in vivo, we suggest that prostaglandin E2 exerts an important control on extravillous trophoblast cell functions, preventing an excessive proliferation and migration.