Oxaliplatin, a platinum-based chemotherapeutic agent, has become a standard treatment for advanced colorectal cancer. The dose-limiting toxicity of this compound is the development of peripheral ...neuropathy. A tangled panel of symptoms, sensory loss, paresthesia, dysesthesia and pain, may be disabling for patients and adversely affect their quality of life.
Recently, we described a characteristic glial activation profile in a rat model of oxaliplatin-induced neuropathy. Glial cells are considered a new pharmacological target for neuropathic pain relief but its relevance in chemotherapy-dependent neuropathies is debated. Aimed to evaluate the significance of glial activation in pain generated by oxaliplatin, the microglial inhibitor minocycline or the astrocyte inhibitor fluorocitrate were continuously infused by intrathecal route in oxaliplatin-treated rats. Both compounds significantly reduced oxaliplatin-evoked pain though the efficacy of fluorocitrate was higher revealing a prominent role of astrocytes.
Immunohistochemical analysis of the dorsal horn confirmed the specific Iba1-positive cell inhibition caused by minocycline as well as the selectivity of fluorocitrate on GFAP-positive cells. The activation of astrocytes in minocycline-treated rats suggests a microglia-independent modulation of astrocytes by oxaliplatin neurotoxicity. Neither the selective activation of astrocyte after minocycline treatment nor the exclusive microglial response after fluorocitrate is able to evoke pain.
Morphometric and morphological determinations performed on dorsal root ganglia evidenced that the glial inhibitors did not prevent the oxaliplatin-dependent increase of eccentric nucleoli and multinucleolated neurons. The decrease of soma area was also unaltered.
In summary, these data highlight the role of central glial cells in oxaliplatin-dependent neuropathic pain. On the other hand, glial inhibition is not associated with neuroprotective effects suggesting the need for careful modulation of glial signaling to prevent the pathophysiology that leads to persistent neuropathic pain.
•Prevention of microglia or astrocyte activation reduces oxaliplatin-dependent pain.•Astrocytes have a preponderant role.•Astrocyte number increase is not consequential to microglial activation.•Oxaliplatin induces pain by the synergistic signal of microglia and astrocytes.•Glial cell inhibition is not associated with neuroprotection.
We report the synthesis of a series of hybrid compounds incorporating 6- and 7-substituted coumarins (carbonic anhydrase, CA inhibitors) derivatized with clinically used NSAIDs (indomethacin, ...sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) as agents for the management of rheumatoid arthritis (RA). Most compounds were effective in inhibiting the RA overexpressed hCA IX and XII, with K I values in the low nanomolar–subnanomolar ranges. The antihyperalgesic activity of such compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model. Among all tested compounds, the 7-coumarine hybrid with ibuprofen showed potent and persistent antihyperalgesic effect up to 60 min after administration.
Plants of the Brassicaceae family are well‐known for containing the glucosinolate myrosinase system, which is able to release isothiocyanates after plant biotic and abiotic lesions. Erucin (ERU; ...1‐isothiocyanato‐4‐(methylthio)‐butane), an isothiocyanate particularly abundant in arugula (Eruca sativa Mill., Eruca vesicaria L., etc.), derives from the hydrolysis of the glucosinolate glucoerucin by the enzyme myrosinase. Many other natural isothiocyanates influence cancer cells and, in particular, induce antiproliferative effects at relatively high concentrations. Similar antiproliferative effects have also been shown by the newly emerging gasotransmitter hydrogen sulfide (H2S) and by H2S‐releasing compounds. In a previous study, our group demonstrated that isothiocyanates release H2S in biological environments. In this work, we demonstrated the H2S‐donor properties of ERU in pancreatic adenocarcinoma cells (AsPC‐1) and delineated its profile as a chemopreventive or anticancer agent. Indeed, ERU showed significant antiproliferative effects: ERU inhibited AsPC‐1 cell viability at relatively high concentrations (30–100 μM). Moreover, ERU inhibited cell migration, altered the AsPC‐1 cell cycle, and exhibited proapoptotic effects. Finally, ERU inhibited ERK1/2 phosphorylation. This mechanism is particularly important in AsPC‐1 cells because they are characterized by a mutation in KRAS that determines KRAS hyperactivation followed by MAP‐kinase hyperphosphorylation, which plays a pivotal role in pancreatic cancer proliferation, growth, and survival.
Magnetic nanoparticles, MNPs, mineralized within a human ferritin protein cage, HFt, can represent an appealing platform to realize smart therapeutic agents for cancer treatment by drug delivery and ...magnetic fluid hyperthermia, MFH. However, the constraint imposed by the inner diameter of the protein shell (ca. 8 nm) prevents its use as heat mediator in MFH when the MNPs comprise pure iron oxide. In this contribution, we demonstrate how this limitation can be overcome through the controlled doping of the core with small amount of Co(II). Highly monodisperse doped iron oxide NPs with average size of 7 nm are mineralized inside a genetically modified variant of HFt, carrying several copies of α-melanocyte-stimulating hormone peptide, which has already been demonstrated to have excellent targeting properties toward melanoma cells. HFt is also conjugated to poly(ethylene glycol) molecules to increase its in vivo stability. The investigation of hyperthermic properties of HFt-NPs shows that a Co doping of 5% is enough to strongly enhance the magnetic anisotropy and thus the hyperthermic efficiency with respect to the undoped sample. In vitro tests performed on B16 melanoma cell line demonstrate a strong reduction of the cell viability after treatment with Co doped HFt-NPs and exposure to the alternating magnetic field. Clear indications of an advanced stage of apoptotic process is also observed from immunocytochemistry analysis. The obtained data suggest this system represents a promising candidate for the development of a protein-based theranostic nanoplatform.
Imaging in COVID-19-related myocardial injury Cau, Riccardo; Bassareo, Pier Paolo; Mannelli, Lorenzo ...
The International Journal of Cardiovascular Imaging,
04/2021, Letnik:
37, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), previously named “2019 novel coronavirus” (2019-nCoV) is an emerging disease and a major public health issue. At the moment, little is ...known, except that its spread is on a steady upward trend. That is the reason why it was declared pandemic since March 11th, 2020. Respiratory symptoms dominate the clinical manifestations of the virus, but in a few patients also other organs are involved, such as their heart. This review article provides an overview of the existing literature regarding imaging of heart injury during COVID-19 acute infection and follow-up.
We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a ...link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy.
Neurotoxicity is the limiting side effect of the anticancer agent oxaliplatin. A tangled panel of symptoms, sensory loss, paresthesia, dysesthesia, and pain may be disabling for patients and ...adversely affect their quality of life. To elucidate the morphologic and molecular alterations that occur in the nervous system during neuropathy, rats were daily injected with 2.4 mg kg(-1) oxaliplatin intraperitoneally. A progressive decrease in the pain threshold and hypersensitivity to noxious and nonnoxious stimuli were evidenced during the treatment (7, 14, 21 days). On day 21, morphometric alterations were detectable exclusively in the dorsal root ganglia, whereas the activating transcription factor 3 and neurofilament (heavy-chain) expression changed dramatically in both the nerves and ganglia. Inflammatory features were not highlighted. Interestingly, satellite cells exhibited signs of activation. Glial modulation was characterized in the spinal cord and brain areas involved in pain signaling. On the 21st day, spinal astrocytes increased numerically whereas the microglial population was unaltered. The number of glial cells in the brain differed according to the zone and treatment time points. In particular, on day 21, a significant astrocyte increase was measured in the anterior cingulate cortex, somatosensory area 1, neostriatum, ventrolateral periaqueductal gray, and nucleus raphe magnus.
These data highlight the relevance of glial cells in chemotherapy-induced neurotoxicity as part of the investigation of the role that specific brain areas play in neuropathy.
Current epidemiological data estimate that one in five people suffers from chronic pain with considerable impairment of health-related quality of life. The pharmacological treatment is based on ...first- and second-line analgesic drugs, including COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs, paracetamol, antidepressants, anti-seizure drugs and opioids, that are characterized by important side effects.
N-palmitoylethanolamine (PEA) is a body's own fatty-acid ethanolamide belonging to the family of autacoid local injury antagonist amides. The anti-inflammatory and pain-relieving properties of PEA have been recognized for decades and prompted to depict its role in the endogenous mechanisms of pain control. Together with its relative abundance in food sources, this opened the way to the use of PEA as a pain-relieving nutritional intervention.
Naïve PEA is a large particle size lipid molecule with low solubility and bioavailability. Reducing particle size is a useful method to increase surface area, thereby improving dissolution rate and bioavailability accordingly. Micron-size formulations of PEA (e.g., ultramicronized and co-(ultra)micronized) have shown higher oral efficacy compared to naïve PEA. In particular, ultramicronized PEA has been shown to efficiently cross the intestinal wall and, more importantly, the blood-brain and blood-spinal cord barrier. Several preclinical and clinical studies have shown the efficacy, safety and tolerability of ultramicronized PEA.
This narrative review summarizes the available pharmacokinetic/pharmacodynamic data on ultramicronized PEA and focuses to its contribution to pain control, in particular as ‘add-on’ nutritional intervention. Data showing the ability of ultramicronized PEA to limit opioid side effects, including the development of tolerance, have also been reviewed.
Cadmium (Cd), a worldwide occupational pollutant, is an extremely toxic heavy metal, capable of damaging several organs, including the brain. Its toxicity has been related to neurodegenerative ...diseases such as Alzheimer's and Parkinson's diseases. The neurotoxic potential of Cd has been attributed to the changes induced in the brain enzyme network involved in counteracting oxidative stress. On the other hand, it is also known that trace elements, such as zinc (Zn) and selenium (Se), required for optimal brain functions, appears to have beneficial effects on the prevention of Cd intoxication.
Based on this protective effect of Zn and Se, we aimed to investigate whether these elements could protect neuronal cells from Cd-induced excitotoxicity. The experiments, firstly carried out on SH-SY5Y catecholaminergic neuroblastoma cell line, demonstrated that the treatment with 10 μM cadmium chloride (CdCl2) for 24 h caused significant modifications both in terms of oxidative stress and neuronal sprouting, triggered by endoplasmic reticulum (ER) stress. The evaluation of the effectiveness of 50 μM of zinc chloride (ZnCl2) and 100 nM sodium selenite (Na2SeO3) treatments showed that both elements were able to attenuate the Cd-dependent neurotoxicity. However, considering that following induction with retinoic acid (RA), the neuroblastoma cell line undergoes differentiation into a cholinergic neurons, our second aim was to verify the zinc and selenium efficacy also in this neuronal phenotype.
Our data clearly demonstrated that, while zinc played a crucial role on neuroprotection against Cd-induced neurotoxicity independently from the cellular phenotype, selenium is ineffective in differentiated cholinergic cells, supporting the notion that the molecular events occurring in differentiated SH-SY5Y cells are critical for the response to specific stimuli.
•Cd inhibits neurite outgrowth, induces oxidative stress, leads to neuronal apoptosis.•Zn protects undifferentiated and RA differentiated SH-SY5Y neurons from Cd toxicity.•Se is effective against Cd-neurotoxicity only in undifferentiated SH-SY5Y cells.
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