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Phenylpropanoid glycosides are a class of natural substances of plant origin with interesting biological activities and pharmacological properties. This study reports the antinociceptive and anti-inflammatory effects of calceolarioside A, a phenylpropanoid glycoside previously isolated from various Calceolaria species. In models of acute nociception induced by thermal stimuli, such as the hot plate and tail flick test, calceolarioside administered at doses of 1, 5, and 10 μg in the left cerebral ventricles did not modify the behavioral response of mice. In an inflammatory based persistent pain model as the formalin test, calceolarioside A at the high dose tested (100 μg/paw) reduced the licking activity induced by formalin by 35% in the first phase and by 75% in the second phase of the test. In carrageenan-induced thermal hyperalgesia, calceolarioside A (50 and 100 μg/paw) was able to significantly reverse thermal hyperalgesia induced by carrageenan. The anti-inflammatory activity of calceolarioside A was then assessed using the zymosan-induced paw edema model. Calceolarioside A (50 and 100 μg/paw) induced a significant reduction in the edema from 1 to 4 h after zymosan administration. Measuring IL-6, TNFα, and IL-1β pro-inflammatory cytokines released from LPS-stimulated THP-1 cells, calceolarioside A in a concentration-dependent manner reduced the release of these cytokines from THP-1 cells. Taken together, our results highlight, for the first time, the potential and selective anti-inflammatory properties of this natural-derived compound, prompting its rationale use for further investigations.

Background: Piperine, an alkaloid from Piper nigrum, modulates oxidative stress, proliferation, and survival pathways in several cancer models; however, its mechanistic effects in colorectal epithelial Caco-2 cells remain insufficiently defined. Objective: This study aimed to investigate the cytotoxic, antiproliferative, oxidative, autophagic, and anti-migratory effects of piperine in Caco-2 cells. Methods: Caco-2 cells were treated with piperine (0.001–0.1 mg/mL) for up to 72 h. Cell viability, proliferation, and migration were assessed using SRB and scratch assays. Oxidative stress, apoptosis, autophagy, and tight junction integrity were evaluated through ROS quantification, Western blotting, gene expression analysis, confocal microscopy, and transmission electron microscopy (TEM). NACET was used to determine the contribution of oxidative stress to piperine-induced cytotoxicity and autophagy. Results: Piperine induced a time- and dose-dependent reduction in viability, with viability decreasing to 53.0 ± 2.88% at 0.1 mg/mL after 72 h. Proliferation decreased to 51% of control levels (p < 0.001), accompanied by p21 upregulation (p < 0.05), indicating G2/M cell cycle arrest. Piperine markedly increased intracellular ROS (p < 0.001), downregulated NRF2 (p < 0.05), and suppressed GSTA1 expression (p < 0.001), while NACET co-treatment restored viability (p < 0.001). No activation of caspase-dependent apoptosis was observed. Piperine significantly enhanced autophagic flux, as shown by the increased LC3B-II/LC3B-I ratio (p < 0.01), elevated LC3B-II/LAMP-1 co-localization (p < 0.01), and chloroquine-induced accumulation of LC3B-II and p62 (p < 0.01), with preserved lysosomal function. TEM analysis confirmed a marked increase in double-membrane autophagosomes in piperine-treated cells compared with controls. NACET reduced LC3B-II/LC3B-I levels, increased p21 expression, and significantly improved cell viability, indicating that piperine-induced autophagy is cytotoxic and driven by oxidative stress. Additionally, piperine upregulated occludin (p < 0.01) and reduced cell migration independently of proliferation (p < 0.01). Conclusions: Piperine exerts antiproliferative effects in Caco-2 cells through ROS-mediated stress, p21-dependent G2/M arrest, and activation of cytotoxic autophagy. Its ability to impair migration and enhance tight junction integrity further supports its potential as a complementary therapeutic agent in colon cancer.

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats’ eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.

Cannabinoids help in pain treatment through their action on CB1 and CB2 receptors. β-caryophyllene (BCP), an ancient remedy to treat pain, is a sesquiterpene found in large amounts in the essential oils of various spice and food plants such as oregano, cinnamon and black pepper. It binds to the CB2 receptor, acting as a full agonist. Sex differences in the BCP-induced analgesic effect were studied by exposing male and female rats to a persistent/repeated painful stimulation. To simulate treatment of a repeated inflammatory condition, after the first formalin-injection (FT1) (50 l, 2.5%), rats received BCP per os for 7 days at two dosages: 5 mg/kg and 10 mg/kg dissolved in olive oil (OIL). The control group was treated with OIL for 7 days. On day 8 the formalin test was repeated (FT2) with a lower formalin concentration (50 l, 1%). During the first and second formalin test, pain induced responses (licking, flexing, paw-jerk) and spontaneous behaviors were recorded and analyzed. In the FT1 (before the beginning of treatment with BCP), females displayed higher pain responses than males during the first part of the test (I phase and interphase), while during the second part (II phase late and early) the values were more similar between the two sexes. In the FT2, pain responses generally decreased in the BCP groups in a dose-dependent manner (i.e. greater effect of BCP 10), with a more pronounced reduction in males than females; moreover, pain responses remained high in the OIL groups and in the female BCP 5 group. In conclusion, long-term intake of BCP appears to be able to decrease pain behaviors in a model of repeated inflammatory pain in both sexes, but to a greater degree in males.

Formyl peptide receptor type 2 (FPR2/ALX) belongs to the formyl peptide receptors (FPRs) family clustered on chromosome 19 and encodes a family of three Class A of G protein-coupled receptors (GPCRs). A short N-terminal region, an NPXXY motif in transmembrane (TM) region 7 and an E/DRY motif that bridges TM3 and TM6 stabilizing inactive receptor conformations characterize this class of receptors. In recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), FPRs play a crucial role in innate immune responses. FPR2/ALX is highly expressed in myeloid cells, as well as in chondrocytes, fibroblasts, endothelial, epithelial and smooth muscle cells. FPR2/ALX mRNA expression was recently reported in the rat brainstem, spinal cord, thalamus/hypothalamus, cerebral neocortex, hippocampus, cerebellum and striatum. The central nervous system (CNS) distribution of FPR2/ALX suggests important functions in nociception. Thus, the present study was carried out to investigate the possible role of FPR2/ALX in nociception in mice. Intrathecal administration of the formyl peptide receptor type 1 (FPR1) agonist fMLF and the FPR2/ALX agonist BML-111 relieved nociception and these effects were reduced by contemporary administration of the FPR2/ALX antagonist WRW4. Furthermore, measurement of cytokines and brain-derived neurotrophic factor (BDNF) in the spinal cord of neuropathic mice demonstrated that the antinociceptive effects of BML-111 might depend on the reduction in cytokine release and BDNF in the spinal cord. These results suggest a possible role of FPR2/ALX for pain control in the spinal cord.

Previous studies have shown that music preferences are influenced by cultural \"rules\", and some others have suggested a universal preference for some features over others. We investigated cultural differences on the \"consonance effect\", consisting in higher pleasantness judgments for consonant compared to dissonant chords-according to the Western definition of music: Italian and Himalayan participants were asked to express pleasantness judgments for consonant and dissonant chords. An Italian and a Nepalese sample were tested both at 1,450 m and at 4,750 m of altitude, with the further aim to evaluate the effect of hypoxia on this task. A third sample consisted of two subgroups of Sherpas: lowlanders (1,450 m of altitude), often exposed to Western music, and highlanders (3,427 m of altitude), less exposed to Western music. All Sherpas were tested where they lived. Independently from the altitude, results confirmed the consonance effect in the Italian sample, and the absence of such effect in the Nepalese sample. Lowlander Sherpas revealed the consonance effect, but highlander Sherpas did not show this effect. Results of this pilot study show that neither hypoxia (altitude), nor demographic features (age, schooling, or playing music), nor ethnicity per se influence the consonance effect. We conclude that music preferences are attributable to music exposure.

Chronic pain is a medical condition that affects a considerable number of people of all ages [...]

Fibromyalgia (FM) is a common chronic disorder with chronic pain. FM generally affects all ages and occurs more commonly in women. The cause of FM remains undefined, but a number of factors suggest the cardiovascular system and the blood in particular as contributors to its occurrence and maintenance. Hemograms and other blood indexes often show high percentages of values at the ‘normal’, low, or high limits and several values outside of the ‘normal’ ranges. On the other hand, vessels regulate blood arrival to tissues depending on many internal and external factors. Both aspects can interfere with tissue oxygenation and then with the numerous consequences induced by hypoxia. In this narrative review, efforts were made to highlight factors that are potentially able to affect oxygen arrival in cells, as well as other factors related to blood elements that can play a role in the chronic pain experienced by FM patients. Data strongly indicate that most of the symptoms commonly present in FM patients can find their physio-pathological basis in the blood, suggesting blood-related interventions in these patients.

ObjectiveDiscussion about the potential addictive role of certain types of food and their link with obesity has recently increased. Researchers have developed instruments to specifically assess food addiction (FA). The aim of this pilot study was to investigate the prevalence of food addiction in a nonclinical sample of the Italian population.MethodsAll participants (n = 148: 46 males, 102 females) completed the Yale Food Addiction Scale 2.0 (YFAS 2.0) and provided self-reported measures and demographic information. They were divided into three age groups.ResultsThe prevalence of FA was 15.5% of our sample (82.6% of the subjects diagnosed with FA were female). The FA symptoms mean was 1.90 (SD = 2.87). In both sexes, participants aged 18–30 had the highest diagnosis of FA, with 52.1% of all FA subjects being females aged 18–30. According to the Body Mass Index (BMI), all the males diagnosed with FA were overweight or obese, as were most (63.2%) of the FA females.ConclusionsFuture food education policies could consider FA assessment together with that of other eating disorders, even among nonclinical subjects in order to anticipate diagnosis and improve treatment.