Inorganic stressors of ubiquitin.

Many neurodegenerative proteinopathies are characterized by ubiquitin (Ub)-containing intraneuronal inclusion bodies. Recent reports have shown that Ub is able to bind Cu(II) and Zn(II), the dyshomeostasis of which is a hallmark of neurodegeneration. Here we use complementary techniques like potentiometry, circular dichroism-visible, and electron spin resonance to unveil the Ub/metal species that form, at neutral pH, their binding constants and structural features. Next, we show that both Zn(II) and Cu(II) ions hinder the interactions between Ub and Ub-conjugating E2 enzymes and inhibit significantly both Lys48 and Lys63 self-polyubiquitination reactions in a cell-free medium. The effects of Zn(II) and Cu(II) on Lys63 and Lys48 polyUb chain synthesis are compatible with the hypothesis that metal binding to His68 modifies the Ile44 hydrophobic patch of Ub and makes the protein less available for polyUb. These findings contribute to further arguments for a close relationship between metal dyshomeostasis and abnormal protein degradative pathways in the upstream events, triggering neurodegeneration.

Intermittent self-catheterization training and effects on treatment adherence and infection.

BACKGROUND: Intermittent self-catheterization (CISC) is the preferred treatment for patients with bladder dysfunction due to spinal cord injuries or multiple sclerosis (MS). However, the learning phase plays a crucial role in the still frequent drop-out. AIM: To examine whether the timing of training affects the treatment compliance and the prevalence of urinary tract infections in patients with neurogenic urinary retention. DESIGN: This is a non-randomized observational study. SETTING: The study was carried out from January 2017 to December 2019 in outpatient settings at the Bari Polyclinic Unipolar Spinal Unit (Bari, Italy). POPULATION: The study included adults with a CISC prescription for neurogenic urinary retention and learning the technique for the first time. METHODS: One hundred patients were enrolled, 75 trained immediately after diagnosis and physician prescription, while 25 in the contest of a separate training visit, one or two days after physician prescription. After the training (T0), patient's data and number of prescribed daily catheterizations were recorded and compared with those collected after 6 and 12 months. Accuracy of the procedure and episodes of infections were assessed as well. RESULTS: Adherence to prescribed CISC frequency and complications were not affected by the timing of training. However, patients adherent to the prescribe frequency of catheterization had less risk of infection than those who were not. Further post-hoc analysis confirmed that urodynamic findings and the pathology did not impact the overall occurrence of complications, but infections occurred more frequently in patients with MS (P<0.03). CONCLUSIONS: The timing of CISC education does not affect treatment adherence or the occurrence of complications. However, the adherence to the CISC prescription seems to reduce the risk of infection. CLINICAL REHABILITATION IMPACT: Patient training can be scheduled according to the organization of the centers, as patient compliance and the occurrence of complications are not affected.

Skin-whitening effects of Mediterranean herbal extracts by in vitro and in vivo models.

Several plant extracts are able to protect skin against ultraviolet-light-induced damage and hyperpigmentation in a safe way. The anti-melanogenic effect of herbal extracts seems to be related to their antioxidant activity and their polyphenolic content. In this study, the skin-whitening effect of some Mediterranean species, already known for their strong antioxidant and radical scavenger activity, has been evaluated by in vitro and in vivo models. The results obtained showed that herbal extracts possessed an inhibitory effect on tyrosinase enzyme. Each extract showed a similar inhibiting activity even though it was less intensive than kojic acid and hydroquinone. Otherwise, a significant higher activity than kojic acid and hydroquinone was observed when the herbal extracts were combined. Furthermore, the anti-melanogenic activity and an evaluation of skin tolerance were affected by in vivo methods.

Short-term effects of local microwave hyperthermia on pain and function in patients with mild to moderate carpal tunnel syndrome: a double blind randomized sham-controlled trial.

OBJECTIVE: To determine the short-term effects of local microwave hyperthermia on pain and function in patients with mild to moderate idiopathic carpal tunnel syndrome. DESIGN: Double-blind randomized sham-controlled trial. SETTING: Outpatient clinic of the Department of Physical Medicine and Rehabilitation, University Hospital. PARTICIPANTS: Twenty-two patients with idiopathic carpal tunnel syndrome, 12 of whom had bilateral involvement, for a total of 34 wrists, divided into two groups: a hyperthermia active treatment group (number of wrists = 17) and a sham-controlled group (number of wrists = 17). INTERVENTION: Six sessions, two per week, of either hyperthermia or sham treatment were provided over a period of three weeks. MAIN MEASURES: Visual analogue scale, Levine-Boston Self-Assessment Questionnaire (part I: evaluation of pain intensity; part II: evaluation of functional status) and neurophysiological assessments, were determined at baseline and at the end of the treatment. RESULTS: The hyperthermia group experienced a significant improvement in pain (visual analogue scale: P = 0.002; Levine-Boston part I: P < 0.0001) and functional status (Levine-Boston part II: P = 0.002) relative to baseline. No improvements in pain intensity or functionality were observed in the sham-treated group. Changes in pain severity between baseline and the end of treatment were larger in the hyperthermia group than in the sham-controlled group (Δ visual analogue scale P = 0.004; Δ Levine-Boston part I: P = 0.009). No differences either intra or between groups were observed for median nerve conduction velocity. CONCLUSION: Hyperthermia provides short-term improvements in pain and function in patients with mild to moderate carpal tunnel syndrome.

Changes in gut microbiota in the acute phase after spinal cord injury correlate with severity of the lesion.

After spinal cord injury (SCI), patients face many physical and psychological issues including intestinal dysfunction and comorbidities, strongly affecting quality of life. The gut microbiota has recently been suggested to influence the course of the disease in these patients. However, to date only two studies have profiled the gut microbiota in SCI patients, months after a traumatic injury. Here we characterized the gut microbiota in a large Italian SCI population, within a short time from a not only traumatic injury. Feces were collected within the first week at the rehabilitation center (no later than 60 days after SCI), and profiled by 16S rRNA gene-based next-generation sequencing. Microbial profiles were compared to those publicly available of healthy age- and gender-matched Italians, and correlated to patient metadata, including type of SCI, spinal unit location, nutrition and concomitant antibiotic therapies. The gut microbiota of SCI patients shows distinct dysbiotic signatures, i.e. increase in potentially pathogenic, pro-inflammatory and mucus-degrading bacteria, and depletion of short-chain fatty acid producers. While robust to most host variables, such dysbiosis varies by lesion level and completeness, with the most neurologically impaired patients showing an even more unbalanced microbial profile. The SCI-related gut microbiome dysbiosis is very likely secondary to injury and closely related to the degree of completeness and severity of the lesion, regardless of etiology and time interval. This microbial layout could variously contribute to increased gut permeability and inflammation, potentially predisposing patients to the onset of severe comorbidities.

Dehydroxymethylepoxyquinomicin inhibits expression and production of inflammatory mediators in interleukin-1beta-induced human chondrocytes.

The present research was carried out to determine the effects of a nuclear factor-kappaB (NF-kappaB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), derivative of the antibiotic epoxyquinomicin C, on normal human chondrocytes treated with interleukin-1beta (IL-1beta). This is a cell model particularly useful to reproduce the mechanisms involved in degenerative arthropathies, where oxidative-inflammatory stress determines a progressive destruction of the articular cartilaginous tissue. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inter-cellular adhesion molecule (ICAM)-1 was evaluated through Western blot analysis. The release of chemokines like monocyte chemoattractant protein-1 (MCP-1), regulated upon normal activation T-cell expressed and secreted (RANTES), and interleukin-8 (IL-8) were determined by ELISA assays. DHMEQ acts as a potent inhibitor of iNOS and COX-2 gene expression while also suppressing the production of nitrite in human chondrocytes. In addition, DHMEQ induces a significant dose-dependent decrease in ICAM expression, MCP-1, RANTES, and IL-8 release. DHMEQ helps to decrease the expression and production of pro-inflammatory mediators in IL-1beta-induced chondrocytes. DHMEQ may become a therapeutic agent for treatment of chondro-degenerative diseases.

Dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappaB inhibitor, prevents inflammatory injury induced by interferon-gamma and histamine in NCTC 2544 keratinocytes.

1. The novel nuclear factor (NF)-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) is a derivative of the antibiotic epoxyquinomicin C from Amycolatopsis sp. that has been found to inhibit tumour necrosis factor (TNF)-alpha-induced activation of NF-kappaB by suppressing nuclear translocation of NF-kappaB. The aim of the present study was to determine the effects of DHMEQ on interferon (IFN)-gamma- and histamine-activated NCTC 2544 keratinocytes. 2. Keratinocytes were stimulated or not with 200 U/mL IFN-gamma and 10(-4) mol/L histamine in the absence or presence of different concentrations of DHMEQ (1, 5 and 10 microg/mL) or hydrocortisone (10(-5) mol/L), which was used as a reference anti-inflammatory drug. After 48 h, each sample was tested for the presence of intercellular adhesion molecule (ICAM)-1 by western blot analysis, as well as for the release of monocyte chemoattractant protein (MCP)-1, RANTES and interleukin (IL)-8 using specific sandwich ELISAs. To verify the effect of DHMEQ on cell viability of non-stimulated NCTC 2544 keratinocytes, the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used. 3. The results showed that 10 microg/mL DHMEQ potently inhibited ICAM-1 production (by 50%), as well as the release of MCP-1 (to 25% of control), RANTES (to 5% of control) and IL-8 (to 2% of control). The results of the MTT assay indicated that DHMEQ has no effect on cell viability. 4. In conclusion, DHMEQ inhibits the IFN-gamma- and histamine-induced activation of the keratinocyte cell line NCTC 2544. The anti-inflammatory effects of DHMEQ could be exploited by applying the drug topically alone or in combination with sub-toxic concentrations of anti-inflammatory drugs to producer a synergistic effect.

Antiinflammatory effects of a red orange extract in human keratinocytes treated with interferon-gamma and histamine.

Red oranges are an important component of the so-called Mediterranean diet and they have been used by traditional medicine for their health protective properties, particularly to heal sore throat and cough, suggesting an interesting antiinflammatory activity. The purpose of this study was to evaluate the antiinflammatory activity of a red orange (Citrus sinensis varieties: Moro, Tarocco, Sanguinello) complex (ROC), characterized by high levels of anthocyanins, flavanones, hydroxycinnamic acids and ascorbic acid, on the human keratinocyte line NCTC 2544 exposed to interferon-gamma (IFN-gamma) and histamine. The expression of immunomodulatory membrane molecules such as inter-cellular adhesion molecule-1 (ICAM-1) by Western blot analysis, and the release of chemokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) through ELISA kits, were determined. ICAM-1 modulates the permanence and activation of T lymphocytes in the epidermis. MCP-1 is a specific chemoattractant for monocytes and dendritic cells. IL-8 is important for the recruitment of both neutrophils and T lymphocytes. Addition of ROC at different concentrations together with IFN-gamma and histamine induced a dose-dependent inhibition of ICAM-1 expression and MCP-1 and IL-8 release. ROC shows interesting antiinflammatory properties in human keratinocyte cells NCTC 2544. This natural complex could have a topical employment and mitigate the consequences of some skin pathologies.

Comparative in vivo study of the efficacy and tolerance of exfoliating agents using reflectance spectrophotometric methods.

The aim of the present study was to compare the effectiveness and the safety of different topical agents (glycolic acid, mandelic acid, and grape juice acid mixture) in skin exfoliation by objective instrumental methods. To evaluate the exfoliating effects of these substances, a new experimental in vivo protocol based on DHA (dihydroxyacetone)-induced skin pigmentation was used. Skin acceptability towards acid application was investigated by the evaluation of skin erythema induced by topical application of these substances at increased concentrations. Furthermore, their photosensitizing effects were evaluated by determining the increase in sensitivity to UV-light exposure in cutaneous sites previously treated with acids. These in vivo evaluations were monitored by reflectance spectophotometry. From the results obtained, we observed the differing capacities of the tested acids to increase the rate of skin regeneration, with a significant reduction in the time required to obtain skin renewal. The study pointed out that glycolic acid (10% w/w) induced a faster skin exfoliation, a more intense erythema, and a higher photosensitizing effect in comparison with the mandelic acid and grape juice acid mixtures. Further evidence showed that the mandelic acid and grape juice acid mixtures were able to induce a slower and safer peeling action in comparison with glycolic acid. Finally, our results suggest that the methodologies and protocols used in this study may help in choosing the most appropriate topical agents for skin exfoliating treatments.

Integrins mediate beta-amyloid-induced cell-cycle activation and neuronal death.

Early intracellular events responsible for cell-cycle induction by beta-amyloid (A beta) in neurons have not been identified yet. Extracellular signal-regulated kinases 1/2 (ERK1/2) have been identified in this pathway, and inhibition of ERK activity prevents cell-cycle activation and reduces neuronal death induced by A beta. To identify upstream events responsible for ERK activation, attention has been focused on integrins. Treatment of SH-SY5Y cells, differentiated by long-term exposure to 10 microM retinoic acid with a neutralizing anti-alpha1-integrin antibody significantly reduced A beta-induced neuronal death. However, cell-cycle analysis showed that treatment with anti-alpha1-integrin per se produced changes in the distribution of cell populations, thus hampering any effect on A beta-induced cell-cycle activation. 4-Amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-D)pyramide, an inhibitor of src protein kinases that colocalizes with focal adhesion kinase (FAK) and is involved in integrin signaling, was effective in reducing activation of the cell cycle and preventing induction of neuronal death by A beta while inhibiting ERK1/2 phosphorylation. Similar results were obtained when FAK expression was down-regulated by siRNA silencing. The present study identifies a sequence of early events in the toxic effect of A beta in neuronal cultures that involves interaction with integrins, activation of FAK/src, enhanced phosphorylation of ERK1/2, and induction of the cell cycle, all leading to neuronal death.

Inhibition or knock out of inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury.

BACKGROUND: In the present study, by comparing the responses in wild-type mice (WT) and mice lacking (KO) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the role played by iNOS in the development of on the lung injury caused by bleomycin administration. When compared to bleomycin-treated iNOSWT mice, iNOSKO mice, which had received bleomycin, exhibited a reduced degree of the (i) lost of body weight, (ii) mortality rate, (iii) infiltration of the lung with polymorphonuclear neutrophils (MPO activity), (iv) edema formation, (v) histological evidence of lung injury, (vi) lung collagen deposition and (vii) lung Transforming Growth Factor beta1 (TGF-beta1) expression. METHODS: Mice subjected to intratracheal administration of bleomycin developed a significant lung injury. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in lungs from bleomycin-treated iNOSWT mice. RESULTS: The intensity and degree of nitrotyrosine staining was markedly reduced in tissue section from bleomycin-iNOSKO mice. Treatment of iNOSWT mice with of GW274150, a novel, potent and selective inhibitor of iNOS activity (5 mg/kg i.p.) also significantly attenuated all of the above indicators of lung damage and inflammation. CONCLUSION: Taken together, our results clearly demonstrate that iNOS plays an important role in the lung injury induced by bleomycin in the mice.

Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against beta-amyloid toxicity.

Nicergoline, a drug used for the treatment of Alzheimer's disease and other types of dementia, was tested for its ability to protect neurons against beta-amyloid toxicity. Pure cultures of rat cortical neurons were challenged with a toxic fragment of beta-amyloid peptide (betaAP(25-35)) and toxicity was assessed after 24 h. Micromolar concentrations of nicergoline or its metabolite, MDL, attenuated betaAP(25-35)-induced neuronal death, whereas MMDL (another metabolite of nicergoline), the alpha1-adrenergic receptor antagonist, prazosin, or the serotonin 5HT-2 receptor antagonist, methysergide, were inactive. Nicergoline increased the basal levels of Bcl-2 and reduced the increase in Bax levels induced by beta-amyloid, indicating that the drug inhibits the execution of an apoptotic program in cortical neurons. In mixed cultures of rat cortical cells containing both neurons and astrocytes, nicergoline and MDL were more efficacious than in pure neuronal cultures in reducing beta-amyloid neurotoxicity. Experiments carried out in pure cultures of astrocytes showed that a component of neuroprotection was mediated by a mechanism of glial-neuronal interaction. The conditioned medium of cultured astrocytes treated with nicergoline or MDL for 72-96 h (collected 24 h after drug withdrawal) was neuroprotective when transferred to pure neuronal cultures challenged with beta-amyloid. In cultured astrocytes, nicergoline increased the intracellular levels of transforming-growth factor-beta and glial-derived neurotrophic factor, two trophic factors that are known to protect neurons against beta-amyloid toxicity. These results raise the possibility that nicergoline reduces neurodegeneration in the Alzheimer's brain.

Role of F3/contactin expression profile in synaptic plasticity and memory in aged mice.

We have recently shown that overexpression of the F3/contactin adhesive glycoprotein (also known as Contactin-1) promotes neurogenesis in adult hippocampus, which correlates with improved synaptic plasticity and memory. Because F3/contactin levels physiologically decrease with age, here, we aim at investigating whether its overexpression might counteract the cognitive decline in aged animals. For this we use 20- to 24-month-old TAG/F3 transgenic mice in which F3/contactin overexpression is driven by regulatory sequences from the gene encoding the transient axonal glycoprotein TAG-1 throughout development. We show that aged TAG/F3 mice display improved hippocampal long-term potentiation and memory compared with wild-type littermates. The same mice undergo a decrease of neuronal apoptosis at the hippocampal level, which correlated to a decrease of active caspase-3; by contrast, procaspase-3 and Bax as well as the anti-apoptotic and plasticity-related pathway BDNF/CREB/Bcl-2 were rather increased. Interestingly, amyloid-precursor protein processing was shifted toward sAPPα generation, with a decrease of sAPPß and amyloid-beta levels. Our data confirm that F3/contactin plays a role in hippocampal synaptic plasticity and memory also in aged mice, suggesting that it acts on molecular pathways related to apoptosis and amyloid-beta production.

Beta-amyloid-activated cell cycle in SH-SY5Y neuroblastoma cells: correlation with the MAP kinase pathway.

Primary cultures of rat cortical neurons exposed to toxic concentrations of beta-amyloid peptide (betaAP) begin an unscheduled mitotic cell cycle that does not progress beyond the S phase. To analyze possible signal transduction pathways involved in this effect, the action of betaAP has been studied in SH-SY5Y neuroblastoma cells differentiated by a 7-d exposure to 10 microM retinoic acid. Treatment with the betaAP fragment, betaAP(25-35), (25 microM) for 24, 48, or 72 h caused apoptotic cell death, detected by flow cytometry as a prediploid cell population. Cell cycle analysis showed that betaAP(25-35) modified cell cycle profiles by markedly increasing the number of cells in the S phase and reducing the population of the G2/M area. These effects seem to involve activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2). Inhibition of this pathway by the specific inhibitor PD98059 (2 microM) completely prevented changes of cell cycle distribution induced by betaAP and significantly reduced neuronal death. The data suggest that MAPK cascade can mediate the induction of cell cycle induced by betaAP, thus contributing to the toxicity of the peptide.

Effects of phenformin on the proliferation of human tumor cell lines.

Phenformin is a biguanide that has been largely used in the past for its anti-diabetic activity. A large body of evidence suggests additional effects of phenformin including antitumoral activity in different animal models in vivo. Thus, the present study has been conducted in order to elucidate possible mechanisms involved in the antitumoral effects of phenformin. In various tumoral cell lines (SH-SY5Y neuroblastoma and LNCaP prostate adenocarcinoma cells), increasing concentrations of phenformin (50-500 microM) induced a concentration-dependent inhibition of cell proliferation. This effect was not dependent on the ability of the drug to reduce glucose levels and was accompanied by induction of apoptotic cell death as measured by cytofluorometric analysis. In addition, a short-time incubation of SH-SY5Y cells with phenformin induced enhanced and transient expression of the cell cycle inhibitor p21 suggesting that phenformin causes inhibition of cell cycle progression prior to induction of apoptosis. These results demonstrate an activity at the cellular level of phenformin that supports its antitumoral effect observed in vivo.

Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice.

Age-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aß) peptide. Because it has been previously demonstrated that phosphodiesterase-5 inhibitors (PDE5-Is) protect against hippocampal synaptic dysfunction and memory deficits in mouse models of Alzheimer's disease and physiological aging, we investigated the effect of a treatment with the PDE5-I, sildenafil, on cell death, pro- and antiapoptotic molecules, and Aß production. We demonstrated that chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) decreased terminal deoxyuridine triphosphate nick end labeling-positive cells in the CA1 hippocampal area of 26-30-month-old mice, downregulating the proapoptotic proteins, caspase-3 and B-cell lymphoma 2-associated X, and increasing antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor. Also, sildenafil reverted the shifting of amyloid precursor protein processing toward Aß42 production and the increase of the Aß42:Aß40 ratio in aged mice. Our data suggest that PDE5-I might be beneficial to treat age-related detrimental features in a physiological mouse model of aging.

Nocellaralactone, a new monoterpenoid with anti-inflammatory activity, from Olea europaea L., cultivar Nocellara del Belice.

Nocellara del Belice, a cultivated variety (cultivar) of olive tree (Olea europæa L.), was examined with respect to the medium-polar compounds present in the wastewaters of olive oil extraction at the end of 2007. Charcoal-polyamide chromatography of obtained wastewaters showed the presence of the chemotaxonomical markers of Olea europaea. In addition a new compound was isolated which resulted to be a lactone related to oleuropein aglycone. We propose the name of nocellaralactone (NOC). This compound is also present in the leaves and it appears to be structurally, probably biogenetically, related to jasminanhydride, a monoterpenoid previously isolated from Jasminum grandiflorum. NOC showed a significant in vitro anti-inflammatory activity.

Aromadendrine, a new component of the flavonoid pattern of Olea europaea L. and its anti-inflammatory activity.

Leaves of Olea europaea, cultivar Nocellara del Belice, were examined with respect to the medium-polar fraction, obtained by an ethyl acetate extraction of the whole extract. In the medium polar fraction, we isolated the two hydroxy-phenyl-ethyl alcohols (hydroxyl-tyrosol and tyrosol) that are the main component of olives. In addition, we isolated a flavonoidic compound, aromadendrine, a dihydroflavonol yet known but quite rare in nature. It is the first time that aromadendrine is isolated in O. europaea and we studied the aromadendrine biological activity. In particular, the ability of aromadendrine to reduce the inflammation induced in normal keratinocytes using an in vitro cell model was evaluated. The results of the present research indicate aromadendrine as a novel component in O. europaea with effective activity against skin inflammation.

Gelatin tannate reduces the proinflammatory effects of lipopolysaccharide in human intestinal epithelial cells.

BACKGROUND: Gelatin tannate is a mixture of tannic acid and gelatin. Tannic acid has astringent properties, due to its capacity to form protein-macromolecular complexes, as well as antibacterial and antioxidant properties. However, little is known about its anti-inflammatory properties. PURPOSE: To evaluate the anti-inflammatory activity of gelatin tannate by quantifying the suppression of key molecules produced during inflammatory events in lipopolysaccharide (LPS)-stimulated human intestinal cells. METHODS: Intercellular adhesion molecule-1 (ICAM-1) expression was determined by Western blot analysis; interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) concentrations were measured by enzyme-linked immunosorbent assays in Caco-2 cells 24 hours after treatment with LPS (1 µg/mL) in presence of different concentrations of gelatin tannate. RESULTS: ICAM-1 is induced on a wide variety of cells by inflammatory stimuli such as LPS. Our results have shown gelatin tannate as a potent inhibitor of ICAM-1 expression in LPS-stimulated Caco-2 cells. IL-8 and TNF-α are important inflammatory mediators, recruiting neutrophils and T-lymphocytes. Together with LPS, adding gelatin tannate at different concentrations induced a dose-dependent inhibition of IL-8 and TNF-α released by Caco-2 cells. CONCLUSION: These results suggest that gelatin tannate exerts anti-inflammatory effects by inhibiting the specific cytokines and adhesion molecules involved in several inflammatory disorders.

Curcumin loaded NLC induces histone hypoacetylation in the CNS after intraperitoneal administration in mice.

The natural p300-specific histone acetyltransferase (HAT) inhibitor, curcumin (CUR), has been widely investigated for its potential therapeutic effect as an anticancer and anti-inflammatory agent. Notwithstanding this interesting pharmacological profile, CUR shows some drawbacks, such as poor absorption and a very fast metabolism and elimination, that limit its clinical use. Aim of the present study was to formulate CUR loaded nanostructured lipid carriers (NLC-CUR) in order to improve the bioavailability and stability of this compound after systemic administration with increased effects in the central nervous system (CNS). NLC-CUR were prepared and characterized on their physicochemical properties by PCS and DSC analyses. Thus, NLC-CUR were systemically injected and the effects in the CNS were compared with a CUR control formulation containing 0.05% DMSO (DMSO-CUR). Our results demonstrate that CUR is able to decrease histone acetylation in the CNS when included in NLCs. Western blot analysis shows that intraperitoneal injection of NLC-CUR (100mg/kg) in mice induces a marked hypoacetylation of histone 4 (H4) at lysine 12 (K12) in the spinal cord compared with control group. Notably, DMSO-CUR (100mg/kg) did not change the H4K12 acetylation level in the CNS. Our study suggests a novel approach to ameliorate the pharmacokinetics of CUR that allows a better permeation in the CNS.