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Our review of Liouville theorems includes a special focus on nonlinear partial differential equations and inequalities.

We study distributional solutions of semilinear biharmonic equations of the type Δ2u+f(u)=0 onℝN,{\Delta ^2}u + f(u) = 0\quad on\;{{\mathbb R} ^N}, where f is a continuous function satisfying f (t)t ≥ c |t|q+1 for all t ∈ ℝ with c > 0 and q > 1. By using a new approach mainly based on careful choice of suitable weighted test functions and a new version of Hardy- Rellich inequalities, we prove several Liouville theorems independently of the dimension N and on the sign of the solutions.

While the urotensinergic system plays a role in influencing various pathologies, its potential remains untapped because of the absence of therapeutically effective urotensin II receptor (UTR) modulators. Herein, we developed analogues of human urotensin II ( h U-II ) peptide in which, along with well-known antagonist-oriented modifications, the Glu 1 residue was subjected to single-point mutations. The generated library was tested by a calcium mobilization assay and ex vivo experiments, also in competition with selected ligands. Interestingly, many derivatives showed noncompetitive modulation that was rationalized by the lateral allostery concept applied to a G protein-coupled receptor (GPCR) multimeric model. UPG-108 showed an unprecedented ability to double the efficacy of h U-II , while UPG-109 and UPG-111 turned out to be negative allosteric modulators of UTR. Overall, our investigation will serve to explore and highlight the expanding possibilities of modulating the UTR system through N-terminally modified h U-II analogues and, furthermore, will aim to elucidate the intricate nature of such a GPCR system.

Vinclozolin (VCZ) is a common dicarboximide fungicide used to protect crops from diseases. It is also an endocrine disruptor, and its effects on various organs have been described but its influence on vasculature has not yet been addressed. This study focuses on the potential mechanism of VCZ-induced vascular injury. The effect of VCZ on vascular function in terms of relaxing and contracting response was evaluated in mice aorta. A short exposure to VCZ affected the endothelial but not the smooth muscle component. Specifically, it caused a disruption of the eNOS/NO signaling. In line, a short exposure to VCZ in bovine aortic endothelial cells promoted eNOS uncoupling resulting in a reduction of NO bioavailability and eNOS dimer/monomer ratio, and in turn an increase of nitro-tyrosine levels and ROS formation. Prolonging the exposure to VCZ (3 and 6h) an up-regulation of Nox4, enzyme-generating ROS constitutively expressed in endothelial cells, and an increase in ROS and malondialdehyde content coupled with a reduction in NO levels were found. These events were strictly linked to endoplasmic reticulum stress as demonstrated by the phosphorylation of inositol-requiring transmembrane kinase endoribonuclease 1α (IRE1α), a stress sensor and its reversion by using a selective inhibitor. Collectively, these results demonstrated that VCZ provokes endothelial dysfunction by oxidative stress involving eNOS/Nox4/IRE1α axis. The rapid exposure affected the endothelial function promoting eNOS uncoupling while a post-transcriptional modification, involving Nox4/IRE1α signaling, occurred following prolonged exposure. Thus, exposure to VCZ could contribute to the onset and/or progression of cardiovascular diseases associated with endothelial dysfunction., Competing Interests: Declaration of competing interest The authors declare to have no conflicting interests regarding this research topic., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inflammatory bowel diseases (IBDs) are chronic intestinal disorders often characterized by a dysregulation of T cells, specifically T helper (Th) 1, 17 and T regulatory (Treg) repertoire. Increasing evidence demonstrates that dietary polyphenols from Mangifera indica L. extract (MIE, commonly known as mango) mitigate intestinal inflammation and splenic Th17/Treg ratio. In this study, we aimed to dissect the immunomodulatory and anti-inflammatory properties of MIE using a reverse translational approach, by initially using blood from an adult IBD inception cohort and then investigating the mechanism of action in a preclinical model of T cell-driven colitis. Of clinical relevance, MIE modulates TNF-α and IL-17 levels in LPS spiked sera from IBD patients as an ex vivo model of intestinal barrier breakdown. Preclinically, therapeutic administration of MIE significantly reduced colitis severity, pathogenic T-cell intestinal infiltrate and intestinal pro-inflammatory mediators (IL-6, IL-17A, TNF-α, IL-2, IL-22). Moreover, MIE reversed colitis-induced gut permeability and restored tight junction functionality and intestinal metabolites. Mechanistic insights revealed MIE had direct effects on blood vascular endothelial cells, blocking TNF-α/IFN-γ-induced up-regulation of COX-2 and the DP2 receptors. Collectively, we demonstrate the therapeutic potential of MIE to reverse the immunological perturbance during the onset of colitis and dampen the systemic inflammatory response, paving the way for its clinical use as nutraceutical and/or functional food., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hydrogen sulfide (H 2 S) 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 H 2 S donors. Herein, for the first time, the potential of marine extract as a source of H 2 S-releasing agents has been explored. Different fractions obtained by the Indonesian ascidian Polycarpa aurata were evaluated for their ability to release H 2 S 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 H 2 S 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 H 2 S.

This study investigates the inflammatory response to intra-plantar injection of L-cysteine in a murine model. L-cysteine induces a two-phase response: an early phase lasting 6 h and a late phase peaking at 24 h and declining by 192 h. The early phase shows increased neutrophil accumulation at 2 h up to 24 h, followed by a reduction at 48 h. On the other hand, the late phase exhibits increased macrophage infiltration peaking at 96 h. Inhibition of cystathionine β-synthase (CBS), the first enzyme in the transsulfuration pathway, significantly reduces L-cysteine-induced edema, suggesting its dependence on CBS-derived hydrogen sulfide (H 2 S). Sequential formation of sphingosine-1-phosphate (S1P) preceding nitric oxide (NO) generation suggests the involvement of a CBS/S1P/NO axis in the inflammatory response. Inhibition of de novo sphingolipid biosynthesis, S1P1 receptor, and endothelial NO synthase (eNOS) attenuates L-cysteine-induced paw edema. These findings indicate a critical role of the CBS/H 2 S/S1P/NO signaling pathway in the development and maintenance of L-cysteine-induced inflammation. The co-presence of H 2 S and NO is necessary for inducing and sustaining the inflammatory response, as NaHS or L-arginine alone do not replicate the marked and prolonged inflammatory effect observed with L-cysteine. This study enhances our understanding of the complex molecular mechanisms of the interplay between NO and H 2 S pathways in inflammation and identifies potential therapeutic targets for inflammatory disorders., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The corpus cavernosum (CC) is a highly vascularized tissue and represents an excellent example of microcirculation. Indeed, erectile dysfunction is considered an early index of cardiovascular disease. Hydrogen sulfide (H 2 S) at the vascular level is endogenously produced from L-cysteine mainly by the action of cystathionine-γ-lyase (CSE) and plays a role in CC vascular homeostasis. Here we have evaluated the involvement of the endogenous H 2 S in the regulation of the soluble guanylate cyclase (sCG) redox state. The lack of CSE-derived endogenous H 2 S, in CSE -/- mice, disrupted the eNOS/NO/sGC/PDE pathway. Indeed, the absence of CSE-derived endogenous H 2 S caused a significant reduction of the relaxant response to riociguat, an sGC redox-dependent stimulator. Conversely, the response to cinaciguat, an sGC redox-independent activator, was not modified. The relevance of the role played at the redox level of the endogenous H 2 S was confirmed by the findings that in CC harvested from CSE -/- mice there was a significant reduction of GC β1 expression coupled with a decrease in CYP5R3, a reductase involved in the regulation of the redox state of sGC. These molecular changes driven by the lack of endogenous H 2 S translate into a significant reduction in cGMP levels. The replenishment of the lack of H 2 S with an H 2 S donor rescued the relaxant response to riociguat in CC of CSE -/- mice. In conclusion, the endogenous CSE-derived H 2 S plays a physiological key role in the regulation of the redox state of sGC in CC microcirculation., Competing Interests: Declaration of Competing Interest The authors declare no competing interests related to the present study., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diabetes is associated with severe vascular complications involving the impairment of endothelial nitric oxide synthase (eNOS) as well as cystathionine γ-lyase (CSE) activity. eNOS function is suppressed in hyperglycaemic conditions, resulting in reduced NO bioavailability, which is paralleled by reduced levels of hydrogen sulfide (H 2 S). Here we have addressed the molecular basis of the interplay between the eNOS and CSE pathways. We tested the impact of H 2 S replacement by using the mitochondrial-targeted H 2 S donor AP123 in isolated vessels and cultured endothelial cells in high glucose (HG) environment, at concentrations not causing any vasoactive effect per se. Aorta exposed to HG displayed a marked reduction of acetylcholine (Ach)-induced vasorelaxation that was restored by the addition of AP123 (10 nM). In HG condition, bovine aortic endothelial cells (BAEC) showed reduced NO levels, downregulation of eNOS expression, and suppression of CREB activation (p-CREB). Similar results were obtained by treating BAEC with propargylglycine (PAG), an inhibitor of CSE. AP123 treatment rescued eNOS expression, as well as NO levels, and restored p-CREB expression in both the HG environment and the presence of PAG. This effect was mediated by a PI3K-dependent activity since wortmannin (PI3K inhibitor) blunted the rescuing effects operated by the H 2 S donor. Experiments performed in the aorta of CSE -/- mice confirmed that reduced levels of H 2 S not only negatively affect the CREB pathway but also impair Ach-induced vasodilation, significantly ameliorated by AP123. We have demonstrated that the endothelial dysfunction due to HG involves H 2 S/PI3K/CREB/eNOS route, thus highlighting a novel aspect of the H 2 S/NO interplay in the vasoactive response., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is one of the most prevalent forms of neurodegenerative disorders. Previously, we have shown that in vivo administration of an IL-17 neutralizing antibody (IL-17Ab) rescues amyloid-β-induced neuro-inflammation and memory impairment, demonstrating the pivotal role of IL-17 in AD-derived cognitive deficit. Recently, AD has been recognized as a more intriguing pathology affecting vascular networks and platelet function. However, not much is known about peripheral vascular inflammation and how pro-inflammatory circulating cells/mediators could affect peripheral vessels' function. This study aimed to evaluate whether IL-17Ab treatment could also impact peripheral AD features, such as systemic inflammation, peripheral vascular dysfunction, and related pro-thrombotic state in a non-genetic mouse model of AD. Mice were injected intracerebroventricularly with Aβ 1-42 peptide (3 μg/3 μl). To evaluate the systemic/peripheral protective profile of IL-17Ab, we used an intranasal administration of IL-17Ab (1 μg/10 μl) at 5, 12, and 19 days after Aβ 1-42 injection. Circulating Th17/Treg cells and related cyto-chemokines, haematological parameters, vascular/endothelial reactivity, platelets and coagulation function in mice were evaluated. IL-17Ab treatment ameliorates the systemic/peripheral inflammation, immunological perturbance, vascular/endothelial impairment and pro-thrombotic state, suggesting a key role for this cytokine in fostering inflammatory processes that characterize the multifaced aspects of AD., Competing Interests: Conflict of interest This article has been conducted and written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The potential of intra-venous gallium nitrate (GaN) administration against Pseudomonas aeruginosa pneumonia was recently demonstrated in mice and in cystic fibrosis (CF) patients. Likewise, the added value of direct lung delivery of Ga(III) has been shown in rats. Therefore, the design of a drug delivery system specifically engineered for Ga(III) inhalation is imperative to improve its accumulation in lungs. To this purpose, Ga(III) was efficiently encapsulated into hyaluronic acid/chitosan nanoparticles (Ga_HA/CS NPs), whose features were tuned to facilitate access to the target by overcoming mucus and biofilm surrounding bacteria. Then, to improve in vivo lung deposition, Ga_HA/CS NPs were engineered into mannitol-based NEM (Ga_Man NEM). The powders showed optimal in vitro aerosol performance, and sustained release kinetics in lung lining fluids. Moreover, good tolerability and antimicrobial properties were shown in vitro. Intratracheal insufflation of Ga_Man NEM in rats resulted in a significant improvement of Ga(III) persistence in the lungs coupled to a lower Ga(III) concentration in plasma and urine, compared to GaN solution. Noteworthy, the developed formulation significantly modifies the unfavorable Ga(III) kinetic increasing the Ga(III) to the lung and preventing Ga(III) accumulation in the kidney, key responsible for adverse effects, conclusively demonstrating the benefit of Ga_Man NEM to exploit the therapeutic effect of Ga(III) via inhalation route., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Endocrine-disrupting chemicals (EDCs) are different natural and synthetic chemicals that may interfere with several mechanisms of the endocrine system producing adverse developmental, metabolic, reproductive, and neurological effects in both human beings and wildlife. Among pesticides, numerous chemicals have been identified as EDCs. MicroRNAs (miRNAs) can regulate gene expression, making fine adjustments in mRNA abundance and regulating proteostasis. We hypothesized that exposure to low doses of atrazine, cypermethrin, and vinclozolin may lead to effects on miRNA expression in SH-SY5Y cells. In particular, the exposure of SH-SY5Y cells to subtoxic concentrations of vinclozolin is able to downregulate miR-29b-3p expression leading to the increase in the related gene expression of ADAM12 and CDK6, which may promote a pro-oncogenic response through the activation of the PI3K/Akt/mTOR pathway and counteracting p53 activity. A better understanding of the molecular mechanisms of EDCs could provide important insight into their role in human disease.

It is now well established that the urothelium does not act as a passive barrier but contributes to bladder homeostasis by releasing several signaling molecules in response to physiological and chemical stimuli. Here, we investigated the potential contribution of the hydrogen sulfide (H 2 S) pathway in regulating human urothelium function in β 3 adrenoceptor-mediated relaxation. The relaxant effect of BRL 37344 (0.1-300 µM), a selective β 3 adrenoceptor agonist, was evaluated in isolated human bladder strips in the presence or absence of the urothelium. The relaxant effect of BRL 37344 was significantly reduced by urothelium removal. The inhibition of cystathionine-γ-lyase (CSE), but not cystathionine-β-synthase (CBS), significantly reduced the BRL 37344 relaxing effect to the same extent as that given by urothelium removal, suggesting a role for CSE-derived H 2 S. β 3 adrenoceptor stimulation in the human urothelium or in T24 urothelial cells markedly increased H 2 S and cAMP levels that were reverted by a blockade of CSE and β 3 adrenoceptor antagonism. These findings demonstrate a key role for urothelium CSE-derived H 2 S in the β 3 effect on the human bladder through the modulation of cAMP levels. Therefore, the study establishes the relevance of urothelial β 3 adrenoceptors in the regulation of bladder tone, supporting the use of β 3 agonists in patients affected by an overactive bladder.

The role of H 2 S in urothelial carcinoma (UC) is still unclear. Here we have evaluated the expression of H 2 S producing enzymes as well as the effect of endogenous and exogenous H 2 S on human bladder UC cells. In human UC cells the expression of cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST); is significantly lower as compared to healthy cells. A modulatory role for the H 2 S pathway is supported by the finding that, the overexpression of CSE or CBS, but not 3-MST, inhibits cell proliferation and promotes apoptosis. A similar effect is obtained by using exogenous H 2 S. Diallyl trisulfide (DATS), which is a fully characterized H 2 S donor, inhibits the proliferation of UC cells in a time and concentration-dependent manner as well as promotes apoptosis. Moreover, DATS also induces autophagy, as determined by transcriptomic and western blot analysis. Finally, DATS inhibits mRNA expression levels of canonical markers of epithelial-mesenchymal transition by limiting migration and clonogenic ability of human UC cells in vitro. In conclusion, in urothelial carcinoma, there is an impairment of H 2 S pathway that involves CSE and CBS- derived hydrogen sulfide. Thus, targeting H 2 S signaling pathway in urothelial carcinoma could represent a novel therapeutic strategy., (Copyright © 2022. Published by Elsevier Masson SAS.)

Significance: Emerging evidence suggests that perivascular adipose tissue (PVAT) has a relevant role in the control of vascular tone in physiology and pathology. Healthy PVAT has anticontractile, anti-inflammatory, and antioxidative actions. Accumulating data from both human and experimental animal models indicate that PVAT dysfunction is conceivably coupled to cardiovascular diseases, and it is associated with vascular inflammation, oxidative stress, and arterial remodeling. Therefore, "healthy" PVAT may constitute a novel therapeutic target for the prevention and treatment of cardiovascular diseases. Recent Advances: Hydrogen sulfide (H 2 S) has been recognized as a vascular anti-contractile factor released from PVAT. The enzymes deputed to H 2 S biosynthesis are variously expressed in PVAT and strictly dependent on the vascular bed and species. Metabolic and cardiovascular diseases can alter the morphological and secretory characteristics of PVAT, influencing also the H 2 S signaling. Here, we discuss the role of PVAT-derived H 2 S in healthy conditions and its relevance in alterations occurring in vascular disorders. Critical Issues: We discuss how a better understanding may help in the prevention of vascular dysfunction related to alteration in PVAT-released H 2 S as well as the importance of the interplay between PVAT and H 2 S. Future Directions: We propose future directions to evaluate the contribution of each enzyme involved in H 2 S biosynthesis and their alteration/switch occurring in vascular disorders and the remaining challenges in investigating the role of H 2 S. Antioxid. Redox Signal . 37, 84-97.

Sarcopenia is a gradual and generalized skeletal muscle (SKM) syndrome, characterized by the impairment of muscle components and functionality. Hydrogen sulfide (H 2 S), endogenously formed within the body from the activity of cystathionine-γ-lyase (CSE), cystathionine- β-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 H 2 S, i.e., glucoraphanin (30 μM), L-cysteine (150 μM), and 3-mercaptopyruvate (150 μM). DEX impaired the H 2 S signalling in terms of a reduction in CBS and CSE expression and H 2 S biosynthesis. Glucoraphanin and 3-mercaptopyruvate but not L-cysteine prevented the apoptotic process induced by DEX. In parallel, the H 2 S-releasing molecules reduced the oxidative unbalance evoked by DEX, reducing catalase activity, O 2 - 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/H 2 S signalling occurs, whereas glucoraphanin, a natural H 2 S-releasing molecule, appears more effective for preventing the SKM damage. Therefore, glucoraphanin supplementation could be an innovative therapeutic approach in the management of sarcopenia.