Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model.

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-STAT3 pathway in the induction of hepatic steatosis.

NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling.

Berberine (BRB) is commonly used in herbal medicine, but its mechanisms of action are poorly understood. In the present study, we tested BRB in steatohepatitis induced by a methionine- and choline-deficient (MCD) diet, in acute acetaminophen intoxication and in cultured murine macrophages. BRB markedly improved parameters of liver injury and necroinflammation induced by the MCD diet, although increased mortality was observed by mechanisms independent of bacterial infections or plasma levels of BRB.

The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma.

Objective: The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The ERK5 gene may be amplified in hepatocellular carcinoma (HCC), but its biological role has not been clarified. In this study, we explored the role of ERK5 expression and activity in HCC in vitro and in vivo.

Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis.

Expression of CCL2 (CC chemokine ligand 2) (or monocyte chemoattractant protein-1) regulates inflammatory cell infiltration in the liver and adipose tissue, favouring steatosis. However, its role in the pathogenesis of steatohepatitis is still uncertain. In the present study, we investigated the development of non-alcoholic steatohepatitis induced by an MCD diet (methionine/choline-deficient diet) in mice lacking the CCL2 gene on two different genetic backgrounds, namely Balb/C and C57/Bl6J.

Modulation of liver fibrosis by adipokines.

Hepatic fibrosis is an integrated process triggered by chronic liver damage, leading to the accumulation of extracellular matrix. In patients with chronic liver disease, this process is favored by the presence of obesity or overweight, which are also relevant risk factors for the progression of nonalcoholic steatohepatitis. In this paper, we review the available evidence indicating the modulation of the fibrogenic process by adipokines, a group of cytokines secreted primarily by adipose tissue.

Antidepressant-like effect of artemin in mice: a mechanism for acetyl-L-carnitine activity on depression.

Rationale: Depression may be associated with altered plasticity of the nervous system. The importance of neurotrophic factor levels is strongly suggested, and the neuronal-related family is extensively studied with respect to glial-derived one.

Objectives: Aimed to contribute to the study of nervous plasticity modulation as therapeutical target in mood disorders, the role of the glial-derived factor artemin (ARTN) in depression and in the pharmacodynamics of the antidepressant and trophic compound acetyl-L: -carnitine (ALCAR) was evaluated.

Antihyperalgesic activity of verbascoside in two models of neuropathic pain.

Objectives: This study reports on the rapid isolation of verbascoside from Lippia citriodora H.B.K.

Acetyl-L-carnitine increases artemin level and prevents neurotrophic factor alterations during neuropathy.

Damages to the nervous system are the primarily cause of neuropathy and chronic pain. Current pharmacological treatments for neuropathic pain are not able to prevent or revert morphological and molecular consequences of tissue injury. On the other hand, many neurotrophins, like nerve growth factor (NGF), paired off restorative effects with hyperalgesia.

Effects of dietary extra-virgin olive oil on behaviour and brain biochemical parameters in ageing rats.

The aim of the present study was to verify whether extra-virgin olive oil, a dietary component naturally containing phenolic antioxidants, has the potential to protect the brain from the deleterious effects of ageing. To accomplish this goal, we used male rats fed a high-energy diet containing either maize oil, or extra-virgin olive oil with high or low phenol content (720 or 10 mg total phenols/kg oil, corresponding to a daily dose of 4 or 0.05 mg total phenols/kg body weight, respectively) from age 12 months to senescence.

St. John's Wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase Cgamma and epsilon activity.

Current pharmacological treatments for neuropathic pain have limited efficacy and severe side-effect limitations. St. John's Wort (SJW) is a medicinal plant, mainly used as antidepressant, with a favourable side-effect profile.

The central analgesia induced by antimigraine drugs is independent from Gi proteins: superiority of a fixed combination of indomethacin, prochlorperazine and caffeine, compared to sumatriptan, in an in vivo model.

A hypofunctionality of Gi proteins has been found in migraine patients. The fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) is a drug of well-established use in the acute treatment of migraine and tension-type headache. The aim of this study was to investigate if Indoprocaf was able to exert its central antinociceptive action when Gi proteins activity is abolished by pertussis toxin (PTX), compared to its single active ingredients and to sumatriptan.

Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat.

Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of a painful peripheral neuropathy which is reproduced in rodent animal models with features observed in humans. Our focus was to explore the alterations of intracellular second messengers at supraspinal level in oxaliplatin-induced mechanical hyperalgesia. In our experiments, chronic administration of oxaliplatin to rats induced mechanical hyperalgesia which lasted for many days.

Polyphenol metabolites from colonic microbiota exert anti-inflammatory activity on different inflammation models.

The polyphenols in fruits and vegetables may be partly responsible for the health-promoting effects attributed to fruit and vegetable intake. Although their properties have been relatively well studied, the activity of their metabolites, produced after ingestion, has been poorly investigated. Thus, the aim of this work was to study the potential anti-inflammatory effect of 18 polyphenol metabolites, derived from colon microbiota.

Involvement of PLC-beta3 in the effect of morphine on memory retrieval in passive avoidance task.

Phospholipase C (PLC) is one signalling effector enzyme whose activity is directly modulated by opioids. Several physiological studies have implicated PLC-linked pathways in in-vivo pain regulation and opioid tolerance. Co-administration of PLC-beta(2/3) activity blocker M119 with morphine resulted in a dramatic increase in morphine-induced amnesic effect in mice, proving a role for beta subunit of PLC enzyme in these processes.

An antidepressant behaviour in mice carrying a gene-specific InsP3R1, InsP3R2 and InsP3R3 protein knockdown.

Evidence has accumulated for the involvement of Ca(2+) in the pathophysiology of mood disorders. Elevations in both resting and stimulated intracellular Ca(2+) levels in patients with affective disorders have been reported. The role of inositol-1,4,5-trisphosphate receptors (InsP3Rs), which allow mobilization of intracellular Ca(2+) stores, was, then, investigated in the mouse forced swimming test.

A gene-specific cerebral types 1, 2, and 3 RyR protein knockdown induces an antidepressant-like effect in mice.

Elevation of baseline intracellular calcium levels was observed in platelets or lymphoblasts of patients with bipolar affective disorders suggesting an altered intracellular Ca(2+) homeostasis in the pathophysiology of mood disorders. The role of supraspinal endoplasmic ryanodine receptors (RyRs), which allow mobilization of intracellular Ca(2+) stores, in the modulation of depressive states was, then, investigated. Ryanodine and FK506 reduced the immobility time in the mouse forced swimming test showing an antidepressant-like profile comparable with that produced by amitriptyline and clomipramine.

Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes.

The administration of the ryanodine receptor (RyR) agonist 4-Cmc (0.003-9 nmol per mouse intracerebroventricularly [i.c.

Type 1 and type 3 ryanodine receptors are selectively involved in muscarinic antinociception in mice: an antisense study.

The importance of an intracellular calcium content increase to obtain cholinergic antinociception was demonstrated. The physiological and pathological role of ryanodine receptors (RyRs), receptors involved in the mobilization of intracellular calcium stores, at the CNS level is poorly understood. The aim of the present study was, therefore, to investigate the role of supraspinal endoplasmic type 1, 2 and 3 RyR subtypes in muscarinic antinociception in conditions of acute thermal (hotplate test) and inflammatory (abdominal constriction test) pain.

New 1,8-naphthyridine and quinoline derivatives as CB2 selective agonists.

A series of new 1,8-naphthyridine and quinoline derivatives were synthesized and evaluated for their cannabinoid receptor affinity. In particular, compounds 2, 5, 11, and 13 showed a high CB(2) affinity and CB(2) versus CB(1) selectivity, in agreement with molecular modeling studies. Furthermore, compound 2 also exhibited in vivo antinociceptive effects.

Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity.

The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations.

Knockdown of the type 2 and 3 inositol 1,4,5-trisphosphate receptors suppresses muscarinic antinociception in mice.

The involvement of central endoplasmic inositol 1,4,5-trisphosphate receptors (IP3R) in muscarinic antinociception was investigated in the mouse hot plate test. Selective knockdown of type 1, 2 and 3 IP3R was obtained by means of an antisense oligonucleotide (aODN) strategy. A selective IP3R protein level reduction of approximately 30-50% produced by aODN administration for each receptor subtype investigated was demonstrated by Western blotting experiments.

Protective effect of acetyl-L-carnitine on the apoptotic pathway of peripheral neuropathy.

Peripheral neuropathies are widespread disorders induced by autoimmune diseases, drug or toxin exposure, infections, metabolic insults or trauma. Nerve damage may cause muscle weakness, altered functionalities and sensitivity, and a chronic pain syndrome characterized by allodynia and hyperalgesia. Pathophysiological mechanisms related to neuropathic disease are associated with mitochondrial dysfunctions that lead to the activation of the apoptotic cascade.