Effect of late gadolinium enhancement on left atrial impairment in myocarditis patients.

OBJECTIVE: The aims of our study were to investigate the effect of the extent and location of late gadolinium enhancement (LGE) on the left atrium (LA) function in patients with acute myocarditis (AM) using cardiovascular magnetic resonance (CMR). METHOD: This retrospective study performed CMR scans in 113 consecutive patients (89 males, 24 females; mean age 45.8 ± 17.3 years) with AM that met the updated Lake Louise criteria. Reservoir, conduit, and booster LA functions were analyzed by CMR feature tracking using dedicated software. Besides LA strain measurements, myocardial scar location and extent were assigned and quantified by LGE imaging. RESULTS: AM patients with septal LGE had impaired reservoir, conduit, and conduit strain rate function in comparison with AM patients with non-septal LGE (p = 0.001, for all). In fully adjusted multivariable linear regression, reservoir and conduit were significantly associated with left ventricle (LV) LGE location (ß coefficient = 8.205, p = 0.007; ß coefficient = 5.185, p = 0.026; respectively). In addition, LA parameters decreased according to the increase in the extent of LV fibrosis (LGE ≤ 10%; LGE 11-19%; LGE ≥ 20%). After adjustment in multivariable linear regression, the association with LV LGE extent was no longer statistically significant. CONCLUSION: In patients with acute myocarditis, LA function abnormalities are significantly associated with LV LGE location, but not with LGE extent. Septal LGE is paralleled by a deterioration of LA reservoir and conduit function. CLINICAL RELEVANCE STATEMENT: Left atrium dysfunction is associated with the presence of late gadolinium enhancement in the left ventricle septum and can be useful in the clinical prognostication of patients with acute myocarditis, allowing individually tailored treatment. KEY POINTS: • Myocardial fibrosis is related to atrial impairment. • The location of myocardial fibrosis is the main determinant of atrial dysfunction in myocarditis patients. • The quantification of atrial mechanisms may provide more in-depth insight into myocarditis pathophysiology.

Correlation of Cognitive Reappraisal and the Microstructural Properties of the Forceps Minor: A Deductive Exploratory Diffusion Tensor Imaging Study.

Cognitive reappraisal (CR) is a mechanism for emotion regulation, and the prefrontal cortex (PFC) plays a central role in the regulation of emotions. We tested the hypothesis of an association between CR function and microstructural properties of forceps minor (a commissural bundle within the PFC) in healthy subjects (HS). We analyzed a population of 65 young HS of a public dataset. The diffusion tensor imaging (DTI) sequence of every subject was analyzed to extract the derived shape (diameter and volume) and DTI metrics in terms of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) of the forceps minor. The CR subscale of the German version of the Emotion Regulation Questionnaire (ERQ) was used for CR assessment. The Shapiro-Wilk test was applied to test the assumption of normality in all these parameters, adopting a statistical threshold at p < 0.05. Whenever appropriate a non-parametric two-tailed partial correlation analysis was applied to test for correlations between the CR ERQ score and the derived shape and DTI metrics, including age and sex as confounders, adopting a statistical threshold at p < 0.05. The non-parametric two-tailed partial correlation analysis revealed a mildly significant correlation with FA (ρ = 0.303; p = 0.016), a weakly significant negative correlation with MD (ρ = - 0.269; p = 0.033), and a mildly significant negative correlation with RD (ρ = - 0.305; p = 0.015). These findings suggest a correlation between DTI microstructural properties of forceps minor and CR.

Anti-inflammatory and anti-hyperalgesic effects induced by an aqueous aged black garlic extract in rodent models of ulcerative colitis and colitis-associated visceral pain.

Inflammatory bowel disease (IBD) is a morbid condition characterized by relapsing-remitting inflammation of the colon, accompanied by persistent gut dysmotility and abdominal pain. Different reports demonstrated biological activities of aged black garlic (ABG), including anti-inflammatory and antioxidant effects. We aimed to investigate beneficial effects exerted by ABGE on colon inflammation by using ex vivo and in vivo experimental models. We investigated the anti-inflammatory effects of an ABG water extract (ABGE) on rat colon specimens exposed to E. coli lipopolysaccharide (LPS), a known ex vivo experimental model of ulcerative colitis. We determined gene expression of various biomarkers involved in inflammation, including interleukin (IL)-1ß, IL-6, nuclear factor-kB (NF-kB), tumor necrosis factor (TNF)-α. Moreover, we studied the acute effects of ABGE on visceral pain associated with colitis induced by 2,4-di-nitrobenzene sulfonic acid (DNBS) injection in rats. ABGE suppressed LPS-induced gene expression of IL-1ß, IL-6, NF-kB, and TNF-α. In addition, the acute administration of ABGE (0.03-1 g kg-1) dose-dependently relieved post-inflammatory visceral pain, with the higher dose (1 g kg-1) able to significantly reduce both the behavioral nociceptive response and the entity of abdominal contraction (assessed by electromyography) in response to colorectal distension after the acute administration in DNBS-treated rats. Present findings showed that ABGE could represent a potential strategy for treatment of colitis-associated inflammatory process and visceral pain. The beneficial effects induced by the extract could be related to the pattern of polyphenolic composition, with particular regard to gallic acid and catechin.

DDD-028: A potent, neuroprotective, non-opioid compound for the treatment of diabetic neuropathy.

Diabetic neuropathy (DN) is a painful, chronic ailment that affects a large segment of diabetic population worldwide. Current medications such as pregabalin or duloxetine treat only the pain symptom associated with DN, but not the underlying nerve damage. DDD-028 (1) is a small molecule that displays potent pain-relieving activity in streptozotocin (STZ)-induced rodent model of DN. Combined with other studies indicating that DDD-028 suppresses astrogliosis and nerve damage induced by the anti-cancer drug, paclitaxel, the present study suggests that DDD-028 would be useful as a disease modifying therapeutic in the treatment of DN. The 3-dimensional structure of DDD-028 was confirmed by single crystal X-ray crystallography.

The Antinociceptive Activity of (E)-3-(thiophen-2-yl)- N -(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)- N -methyl- N -(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor.

BACKGROUND: The primary objective of this study was to characterize the pharmacological and behavioral activity of 2 novel compounds, DM497 [(E)-3-(thiophen-2-yl)- N -(p-tolyl)acrylamide] and DM490 [(E)-3-(furan-2-yl)- N -methyl- N -(p-tolyl)acrylamide], structural derivatives of PAM-2, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). METHODS: A mouse model of oxaliplatin-induced neuropathic pain (2.4 mg/kg, 10 injections) was used to test the pain-relieving properties of DM497 and DM490. To assess possible mechanisms of action, the activity of these compounds was determined at heterologously expressed α7 and α9α10 nAChRs, and voltage-gated N-type calcium channel (Ca V 2.2) using electrophysiological techniques. RESULTS: Cold plate tests indicated that 10 mg/kg DM497 was able to decrease neuropathic pain in mice induced by the chemotherapeutic agent oxaliplatin. In contrast, DM490 induced neither pro- nor antinociceptive activity but inhibited DM497's effect at equivalent dose (30 mg/kg). These effects are not a product of changes in motor coordination or locomotor activity. At α7 nAChRs, DM497 potentiated whereas DM490 inhibited its activity. In addition, DM490 antagonized the α9α10 nAChR with >8-fold higher potency than that for DM497. In contrast, DM497 and DM490 had minimal inhibitory activity at the Ca V 2.2 channel. Considering that DM497 did not increase the mouse exploratory activity, an indirect anxiolytic mechanism was not responsible for the observed antineuropathic effect. CONCLUSIONS: The antinociceptive activity of DM497 and the concomitant inhibitory effect of DM490 are mediated by opposing modulatory mechanisms on the α7 nAChR, whereas the involvement of other possible nociception targets such as the α9α10 nAChR and Ca V 2.2 channel can be ruled out.

Application of multi-spectral CT imaging in Crohn's disease: a systematic review.

BACKGROUND: No quantitative computed tomography (CT) biomarker is actually sufficiently accurate to assess Crohn's disease (CD) lesion activity, with adequate precision to guide clinical decisions. PURPOSE: To assess the available literature on the use of iodine concentration (IC), from multi-spectral CT acquisition, as a quantitative parameter able to distinguish healthy from affected bowel and assess CD bowel activity and heterogeneity of activity along the involved segments. MATERIAL AND METHODS: A literature search was conducted to identify original research studies published up to February 2022. The inclusion criteria were original research papers (>10 human participants), English language publications, focus on dual-energy CT (DECT) of CD with iodine quantification (IQ) as an outcome measure. The exclusion criteria were animal-only studies, languages other than English, review articles, case reports, correspondence, and study populations <10 patients. RESULTS: Nine studies were included in this review; all of which showed a strong correlation between IC measurements and CD activity markers, such as CD activity index (CDAI), endoscopy findings and simple endoscopic score for Crohn's disease (SES-CD), and routine CT enterography (CTE) signs and histopathologic score. Statistically significant differences in IC were reported between affected bowel segments and healthy ones (higher P value was P < 0.001), normal segments and those with active inflammation (P < 0.0001) as well as between patients with active disease and those in remission (P < 0.001). CONCLUSION: The mean normalized IC at DECTE could be a reliable tool in assisting radiologists in the diagnosis, classification and grading of CD activity.

Searching for Novel Sources of Hydrogen Sulfide Donors: Chemical Profiling of Polycarpa aurata Extract and Evaluation of the Anti-Inflammatory Effects.

Hydrogen sulfide (H2S) is a signaling molecule endogenously produced within mammals' cells that plays an important role in inflammation, exerting anti-inflammatory effects. In this view, the research has shown a growing interest in identifying natural H2S donors. Herein, for the first time, the potential of marine extract as a source of H2S-releasing agents has been explored. Different fractions obtained by the Indonesian ascidian Polycarpa aurata were evaluated for their ability to release H2S in solution. The main components of the most active fraction were then characterized by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and NMR spectroscopy. The ability of this fraction to release H2S was evaluated in a cell-free assay and J774 macrophages by a fluorimetric method, and its anti-inflammatory activity was evaluated in vitro and in vivo by using carrageenan-induced mouse paw edema. The anti-inflammatory effects were assessed by inhibiting the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), and interleukin-6 (IL-6), coupled with a reduction in nitric oxide (NO) and IL-6 levels. Thus, this study defines the first example of a marine source able to inhibit inflammatory responses in vivo through the release of H2S.

Ellagitannins and triterpenoids extracts of Anogeissus leiocarpus stem bark extracts: Protective effects against osteoarthritis.

Osteoarthritis (OA) is a complex joint disease characterized by persistent pain. Unfortunately, current pharmacological therapies are unsatisfactory and characterized by side effects, reason why new strategies are needed. We tested the efficacy of different classes of compounds, ellagitannins and olean-type triterpenoids, contained in Anogeissus leiocarpus extract (Combretaceae family) in comparison to ellagitannins of Castanea sativa extract in a rat model of osteoarthritis induced by the intra-articular injection of sodium monoiodoacetate (MIA). The decoction of stem bark of A. leiocarpus AL-DEC-TOT (300 mg/kg; 4.8% triterpenoids; 11.0% tannins), the butanol extract AL-BuOH-EXT (120 mg/kg; triterpenoids 20.9%; tannins 6.4%) and its correlated aqueous residue AL-Res-H2 O (300 mg/kg; triterpenoids 0.7%; tannins 8.7%) and the decoction of C. sativa, CS-DEC-TOT, (240 mg/kg; triterpenoids 0.65%; tannins 10.8%) were orally administered for two weeks starting from the day of the damage. Behavioural tests highlighted that all stem bark extracts of A. leiocarpus counteracted hypersensitivity development, reduced spontaneous pain, and improved motor skills. Histologically, AL-DEC-TOT, AL-BuOH-EXT and AL-Res-H2 O were effective in preventing joint alterations. In conclusion, all the extracts were effective demonstrating that both olean-type triterpenoid and ellagitannin fractions have anti-hypersensitivity and restorative properties running the stem bark extracts of A. leiocarpus as a candidate in the treatment of OA.

Echinacea purpurea against neuropathic pain: Alkamides versus polyphenols efficacy.

Chemotherapy-induced neuropathy represents the main dose-limiting toxicity of several anticancer drugs, such as oxaliplatin, leading to chronic pain and an impairment of the quality of life. Echinacea purpurea n-hexane extract (EP4 -RE ; rich in alkamides) and butanolic extract (EP4 -RBU ; rich in polyphenols) have been characterized and tested in an in vivo model of oxaliplatin-induced neuropathic pain, addressing the endocannabinoid system with alkamides and counteracting the redox imbalance with polyphenols. Thermal hypersensitivity was evaluated by the Cold Plate test. EP4 -RE showed a dose-dependent anti-hyperalgesic profile. The extract was more effective than its main constituent, dodeca-2 E,4 E,8Z,10 E/Z-tetraenoic acid isobutylamide (18 mg kg-1 , twofold to equimolar EP4 -RE 30 mg kg-1 ), suggesting a synergy with other extract constituents. Administration of cannabinoid type 2 (CB2) receptor-selective antagonist completely blocked the anti-allodynic effect of EP4 -RE , differently from the antagonism of CB1 receptors. EP4 -RBU (30 mg kg-1 ) exhibited anti-neuropathic properties too. The effect was mainly exerted by chicoric acid, which administered alone (123 µg kg-1 , equimolar to EP4 -RBU 30 mg kg-1 ) completely reverted oxaliplatin-induced allodynia. A synergy between different polyphenols in the extract had not been highlighted. Echinacea extracts have therapeutic potential in the treatment of neuropathic pain, through both alkamides CB2-selective activity and polyphenols protective properties.

Anti-Hyperalgesic Efficacy of Acetyl L-Carnitine (ALCAR) Against Visceral Pain Induced by Colitis: Involvement of Glia in the Enteric and Central Nervous System.

The management of abdominal pain in patients affected by inflammatory bowel diseases (IBDs) still represents a problem because of the lack of effective treatments. Acetyl L-carnitine (ALCAR) has proved useful in the treatment of different types of chronic pain with excellent tolerability. The present work aimed at evaluating the anti-hyperalgesic efficacy of ALCAR in a model of persistent visceral pain associated with colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) injection. Two different protocols were applied. In the preventive protocol, ALCAR was administered daily starting 14 days to 24 h before the delivery of DNBS. In the interventive protocol, ALCAR was daily administered starting the same day of DNBS injection, and the treatment was continued for 14 days. In both cases, ALCAR significantly reduced the establishment of visceral hyperalgesia in DNBS-treated animals, though the interventive protocol showed a greater efficacy than the preventive one. The interventive protocol partially reduced colon damage in rats, counteracting enteric glia and spinal astrocyte activation resulting from colitis, as analyzed by immunofluorescence. On the other hand, the preventive protocol effectively protected enteric neurons from the inflammatory insult. These findings suggest the putative usefulness of ALCAR as a food supplement for patients suffering from IBDs.

Carotid Artery Plaque Calcifications: Lessons From Histopathology to Diagnostic Imaging.

The role of calcium in atherosclerosis is controversial and the relationship between vascular calcification and plaque vulnerability is not fully understood. Although calcifications are present in ≈50% to 60% of carotid plaques, their association with cerebrovascular ischemic events remains unclear. In this review, we summarize current understanding of carotid plaque calcification. We outline the role of calcium in atherosclerotic carotid disease by analyzing laboratory studies and histopathologic studies, as well as imaging findings to understand clinical implications of carotid artery calcifications. Differences in mechanism of calcium deposition express themselves into a wide range of calcification phenotypes in carotid plaques. Some patterns, such as rim calcification, are suggestive of plaques with inflammatory activity with leakage of the vasa vasourm and intraplaque hemorrhage. Other patterns such as dense, nodular calcifications may confer greater mechanical stability to the plaque and reduce the risk of embolization for a given degree of plaque size and luminal stenosis. Various distributions and patterns of carotid plaque calcification, often influenced by the underlying systemic pathological condition, have a different role in affecting plaque stability. Modern imaging techniques afford multiple approaches to assess geometry, pattern of distribution, size, and composition of carotid artery calcifications. Future investigations with these novel technologies will further improve our understanding of carotid artery calcification and will play an important role in understanding and minimizing stroke risk in patients with carotid plaques.

Neuronal alarmin IL-1α evokes astrocyte-mediated protective signals: Effectiveness in chemotherapy-induced neuropathic pain.

The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies, we studied the role of interleukin 1α (IL-1α), an alarmin belonging to the larger family of damage-associated molecular patterns endogenously secreted to restore homeostasis. The treatment of rat primary neurons with increasing doses of the neurotoxic anticancer drug oxaliplatin (0.3-100µM, 48 h) induced the release of IL-1α. The knockdown of the alarmin in neurons leads to their higher mortality when co-cultured with astrocytes. This toxicity was related to increased extracellular ATP and decreased release of transforming growth factor ß1, mostly produced by astrocytes. In a rat model of neuropathy induced by oxaliplatin, the intrathecal treatment with IL-1α was able to reduce mechanical and thermal hypersensitivity both after acute injection (100 ng and 300 ng) and continuous infusion (100 and 300 ng/die-1). Ex vivo analysis on spinal purified astrocyte processes (gliosomes) and nerve terminals (synaptosomes) revealed the property of IL-1α to reduce the endogenous glutamate release induced by oxaliplatin. This protective effect paralleled with an increased number of GFAP-positive cells in the spinal cord, suggesting the ability of IL-1α to evoke a positive, conservative astrocyte phenotype. Endogenous IL-1α induced protective signals in the cross-talk between neurons and astrocytes. Exogenously administered in rats, IL-1α prevented neuropathic pain in the presence of spinal glutamate decrease and astrocyte activation.

The mid-term effects of carotid endarterectomy on cognition and regional neural activity analyzed with the amplitude of low frequency fluctuations technique.

PURPOSE: The study aims to evaluate the mid-term effects of carotid endarterectomy (CEA) on cognition and resting-state functional magnetic resonance imaging (rs-fMRI) using the Amplitude of Low Frequency Fluctuations (ALFF) technique. METHODS: In this observational study, patients eligible for CEA were prospectively included. On the same day, within 1 week of the CEA procedure performed and 12 months after the CEA procedure, all patients underwent (i) an MRI examination for rs-fMRI analysis and (ii) a cognitive evaluation using the Italian version of the Mini-Mental State Examination (MMSE) corrected for age and schooling. Pre-CEA and post-CEA MMSE scores were evaluated using paired sample t-tests, adopting a p-value < 0.05 as statistical threshold. The ALFF technique was used for analyzing the differences between pre-CEA and post-CEA rs-fMRI scans in terms of regional neural activation. This was accomplished by applying non-parametric statistics based on randomization/permutation for cluster-level inferences, adopting a cluster-mass p-value corrected for false discovery < 0.05 for cluster threshold, and a p-uncorrected < 0.01 for the voxel threshold. RESULTS: Twenty asymptomatic patients were enrolled. The mean MMSE score resulted improved following CEA procedure (p-value = 0.001). The ALFF analysis identified a single cluster of 6260 voxels of increased regional neural activity following CEA, and no cluster of reduced activity. The majority of voxels covered the right precentral gyrus, the right middle frontal gyrus, and the anterior division of the cingulate gyrus. CONCLUSION: Mid-term cognitive improvements observed after CEA are associated to increased regional neural activity of several cerebral regions.

The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII.

Human (h) carbonic anhydrase (CAs, EC 4.2.1.1) isoforms IX and XII were recently confirmed as anticancer targets against solid hypoxic tumours. The "three-tails approach" has been proposed as an extension of the forerunner "tail" and "dual-tail approach" to fully exploit the amino acid differences at the medium/outer active site rims among different hCAs and to obtain more isoform-selective inhibitors. Many three-tailed inhibitors (TTIs) showed higher selectivity against the tumour-associated isoforms hCA IX and XII with respect to the off-targets hCA I and II. X-ray crystallography studies were performed to investigate the binding mode of four TTIs in complex with a hCA IX mimic. The ability of the most potent and selective TTIs to reduce in vitro the viability of colon cancer (HT29), prostate adenocarcinoma (PC3), and breast cancer (ZR75-1) cell lines was evaluated in normoxic (21% O2) and hypoxic (3% O2) conditions demonstrating relevant anti-proliferative effects.

Conus regius-Derived Conotoxins: Novel Therapeutic Opportunities from a Marine Organism.

Conus regius is a marine venomous mollusk of the Conus genus that captures its prey by injecting a rich cocktail of bioactive disulfide bond rich peptides called conotoxins. These peptides selectively target a broad range of ion channels, membrane receptors, transporters, and enzymes, making them valuable pharmacological tools and potential drug leads. C. regius-derived conotoxins are particularly attractive due to their marked potency and selectivity against specific nicotinic acetylcholine receptor subtypes, whose signalling is involved in pain, cognitive disorders, drug addiction, and cancer. However, the species-specific differences in sensitivity and the low stability and bioavailability of these conotoxins limit their clinical development as novel therapeutic agents for these disorders. Here, we give an overview of the main pharmacological features of the C. regius-derived conotoxins described so far, focusing on the molecular mechanisms underlying their potential therapeutic effects. Additionally, we describe adoptable chemical engineering solutions to improve their pharmacological properties for future potential clinical translation.

Cardiovascular benefits of Eruca sativa mill. Defatted seed meal extract: Potential role of hydrogen sulfide.

Eruca sativa Mill. is an edible plant belonging to the Brassicaceae botanical family with a long story as a medicinal material, mainly linked to the presence of glucoerucin. One of the main products of this glucosinolate is erucin, a biologicallly active isothiocyanate recently recognized as a hydrogen sulfide (H2 S) donor. In this work, an Eruca sativa extract has been obtained from a defatted seed meal (DSM), achieving a powder rich in thiofunctionalized glucosinolates, glucoerucin, and glucoraphanin, accounting for 95% and 5% of the total glucosinolate content (17% on a dry weight basis), associated with 13 identified phenolic acids and flavonoids accounting for 2.5%. In a cell-free model, Eruca sativa DSM extract slowly released H2 S. Moreover, this extract promoted significant hypotensive effects in hypertensive rats, and evoked dose-dependent cardioprotection in in vivo model of acute myocardial infarct, obtained through a reversible coronary occlusion. This latter effect was sensitive to blockers of mitochondrial KATP and Kv7.4 potassium channels, suggesting a potential role of these mitochondrial channels in the protective effects of Eruca sativa DSM extract. Accordingly, Eruca sativa DSM extract reduced calcium uptake and apoptotic cell death in isolated cardiac mitochondria. Taken together, these results demonstrate that Eruca sativa DSM extract is endowed with an interesting nutraceutical profile on the cardiovascular system due to, at least in part, its H2 S releasing properties. These results pave the way for future investigations on active metabolites.

Inhibition of Monoacylglycerol Lipase by NSD1819 as an Effective Strategy for the Endocannabinoid System Modulation against Neuroinflammation-Related Disorders.

Neuroinflammation is a key pathological event shared by different diseases affecting the nervous system. Since the underlying mechanism of neuroinflammation is a complex and multifaceted process, current pharmacological treatments are unsatisfactory-a reason why new therapeutic approaches are mandatory. In this context, the endocannabinoid system has proven to possess neuroprotective and immunomodulatory actions under neuroinflammatory status, and its modulation could represent a valuable approach to address different inflammatory processes. To this aim, we evaluated the efficacy of a repeated treatment with NSD1819, a potent ß-lactam-based monoacylglycerol lipase inhibitor in a mouse model of neuroinflammation induced by lipopolysaccharide (LPS) injection. Mice were intraperitoneally injected with LPS 1 mg/kg for five consecutive days to induce systemic inflammation. Concurrently, NSD1819 (3 mg/kg) was daily per os administered from day 1 until the end of the experiment (day 11). Starting from day 8, behavioral measurements were performed to evaluate the effect of the treatment on cognitive impairments, allodynia, motor alterations, anhedonia, and depressive-like behaviors evoked by LPS. Histologically, glial analysis of the spinal cord was also performed. The administration of NSD1819 was able to completely counteract thermal and mechanical allodynia as highlighted by the Cold plate and von Frey tests, respectively, and to reduce motor impairments as demonstrated by the Rota rod test. Moreover, the compound was capable of neutralizing the memory loss in the Passive avoidance test, and reducing depressive-like behavior in the Porsolt test. Finally, LPS stimulation caused a significant glial cells activation in the dorsal horn of the lumbar spinal cord that was significantly recovered by NSD1819 repeated treatment. In conclusion, NSD1819 was able to thwart the plethora of symptoms evoked by LPS, thus representing a promising candidate for future applications in the context of neuroinflammation and related diseases.

New Panx-1 Blockers: Synthesis, Biological Evaluation and Molecular Dynamic Studies.

The channel protein Panx-1 is involved in some pathologies, such as epilepsy, ischemic stroke, cancer and Parkinson's disease, as well as in neuropathic pain. These observations make Panx-1 an interesting biological target. We previously published some potent indole derivatives as Panx-1 blockers, and as continuation of the research in this field we report here the studies on additional chemical scaffolds, naphthalene and pyrazole, appropriately substituted with those functions that gave the best results as in our indole series (sulphonamide functions and one/two carboxylic groups) and in Panx-1 blockers reported in the literature (sulphonic acid). Compounds 4 and 13, the latter being an analogue of the drug Probenecid, are the most potent Panx-1 blockers obtained in this study, with I = 97% and I = 93.7% at 50 µM, respectively. Both compounds, tested in a mouse model of oxaliplatin-induced neuropathic pain, showed a similar anti-hypersensitivity profile and are able to significantly increase the mouse pain threshold 45 min after the injection of the doses of 1 nmol and 3 nmol. Finally, the molecular dynamic studies and the PCA analysis have made it possible to identify a discriminating factor able to separate active compounds from inactive ones.

Beneficial Effect of H2S-Releasing Molecules in an In Vitro Model of Sarcopenia: Relevance of Glucoraphanin.

Sarcopenia is a gradual and generalized skeletal muscle (SKM) syndrome, characterized by the impairment of muscle components and functionality. Hydrogen sulfide (H2S), endogenously formed within the body from the activity of cystathionine-γ-lyase (CSE), cystathionine- ß-synthase (CBS), and mercaptopyruvate sulfurtransferase, is involved in SKM function. Here, in an in vitro model of sarcopenia based on damage induced by dexamethasone (DEX, 1 µM, 48 h treatment) in C2C12-derived myotubes, we investigated the protective potential of exogenous and endogenous sources of H2S, i.e., glucoraphanin (30 µM), L-cysteine (150 µM), and 3-mercaptopyruvate (150 µM). DEX impaired the H2S signalling in terms of a reduction in CBS and CSE expression and H2S biosynthesis. Glucoraphanin and 3-mercaptopyruvate but not L-cysteine prevented the apoptotic process induced by DEX. In parallel, the H2S-releasing molecules reduced the oxidative unbalance evoked by DEX, reducing catalase activity, O2- levels, and protein carbonylation. Glucoraphanin, 3-mercaptopyruvate, and L-cysteine avoided the changes in myotubes morphology and morphometrics after DEX treatment. In conclusion, in an in vitro model of sarcopenia, an impairment in CBS/CSE/H2S signalling occurs, whereas glucoraphanin, a natural H2S-releasing molecule, appears more effective for preventing the SKM damage. Therefore, glucoraphanin supplementation could be an innovative therapeutic approach in the management of sarcopenia.

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice.

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient's quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca2+ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30-100 mg/kg, per os - p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.