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Reperfusion injury after oxygen starvation is a key pathogenic step in ischemic diseases. It mainly consists in oxidative stress, related to mitochondrial derangement and enhanced generation of reactive oxygen species (ROS), mainly superoxide anion (O2•2), and peroxynitrite by cells exposed to hypoxia. This in vitro study evaluates whether MnII(4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate).2H2O, or MnII(Me2DO2A), a new low molecular weight, MnII-containing O2• scavenger, has a direct protective action on H9c2 rat cardiac muscle cells subjected to hypoxia and reoxygenation. MnII(Me2DO2A) (1 and 10 μmol/l) was added to the culture medium at reoxygenation and maintained for 2 h. In parallel experiments, the inactive congener ZnII(Me2DO2A), in which ZnII replaced the functional MnII center in the same organic scaffold, was used as negative control. MnII(Me2DO2A) (10 μmol/l) significantly increased cardiac muscle cell viability (trypan blue assay), improved mitochondrial activity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test, membrane potential Δψ), reduced apoptosis (mitochondrial permeability transition pore opening, caspase-3, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay), decreased intracellular ROS levels (2',7'-dichlorodihydrofluorescein diacetate and MitoSOX assays), and decreased protein nitroxidation (nitrotyrosine [NT] expression) and DNA oxidation (8-hydroxy-deoxyguanosine levels). Of note, ZnII(Me2DO2A) had no protective effect. The mechanism of MnII(Me2DO2A) relies on concentration-dependent removal of harmful O2• generated at reoxygenation from dysfunctional mitochondria in hypoxia-induced cells, as indicated by the MitoSOX assay. This study suggests that MnII(Me2DO2A) is a promising antioxidant drug capable of reducing O2•-mediated cell oxidative stress which occurs at reoxygenation after hypoxia. In perspective, MnII(Me2DO2A) might be used to reduce ischemia-reperfusion organ damage in acute vascular diseases, as well as to extend the viability of explanted organs before transplantation. [ABSTRACT FROM AUTHOR]

The aim of this study was to prove the effectiveness of MatriDerm® combined with skin grafting versus skin grafting alone in post-traumatic wounds treatment. At the Department of Plastic and Reconstructive Surgery of the University of Rome Tor Vergata, we treated 60 patients: 30 patients with dermal substitutes (MatriDerm®) combined with autologous skin graft and 30 with skin graft alone. Two weeks after the first treatment, 95% of wounds treated with MatriDerm®and skin graft showed a re-epithelisation, whereas it was 75DS80% in the control group. We used the Manchester Scar Scale (MSS) and patient's self-estimation scale to assess the outcomes. MannDSWhitney U test was performed for the five items of the MSS and the results were combined to those of patient's self-estimation scale and the re-epithelialisation percentage to test the significance between the two groups. These data confirm the evidence of the clinical use of MatriDerm® technology in the healing of soft tissue wounds and prove the effectiveness of combining MatriDerm® and skin grafting for the first time. Furthermore, we observed a percentage reduction of wound contraction and in the same time an improvement of elasticity, quality of scars tissue and dermal architecture. [ABSTRACT FROM AUTHOR]

Background: The aim of this report was to analyze the results obtained with the ReCell® system for the surgical treatment of stable vitiligo hands. Materials and Methods: One patient with stable vitiligo of the hands was admitted at the Department of Plastic and Reconstructive Surgery, University of Rome Tor Vergata. The patient underwent to ReCell® system for the treatment of stable vitiligo hands. Results: The repigmentation was assessed using the Vitiligo Area Scoring Index (VASI). The extent of pigmentation was scored as excellent, good, fair, and poor depending on the percentage of the repigmentation in the previously depigmented site. The color of the repigmented area was compared with the adjacent normally pigmented area. The patient had an excellent repigmentation. Conclusions: ReCell&® system is a simple, safe and feasible technique. The method that uses noncultured autologous epidermal suspension is simpler, cheaper, less time consuming and does not require sophisticated laboratory facilities, when compared with methods employing cultured melanocytes. [ABSTRACT FROM AUTHOR]

The aim of our case report was to analyse the results obtained with the Matriderm(R) system and autologous skin grafting for the surgical treatment of diabetic ulcers. We recruited one patient with diabetic ulcers admitted at the Department of Plastic and Reconstructive Surgery, University of Rome 'Tor Vergata'. The patient underwent Matriderm(R) system and autologous skin grafting for diabetic ulcer treatment. After just a single treatment, we obtained reduction in ulcer after 15 days from the surgical treatment. We achieved a reduction in pain and exudate secretion of the ulcer. We noticed an almost complete restoration of the missing volume and good quality of skin. Matriderm(R) system and autologous skin grafting is a simple, safe and feasible technique. This method, when compared with other methods of treatment, is simple, cheap, less time consuming and does not require sophisticated laboratory facilities. [ABSTRACT FROM AUTHOR]

Labial fusion is defined as either partial or complete adherence of the labia minora (1), and also called vulvar fusion, adhesions of the labia minor or conglutination of the labia minora and sinechia of the vulva. The complete and severe labial fusion is a rare pathology with a small number of cases reported in the literature in adults. We present a case report of a postmenopausal woman who presented with voiding difficulty and incontinence and was treated by surgical division of the adhesions and immediate resolution of the urinary incontinence confirmed by multichannel urodynamic test postoperatively. [ABSTRACT FROM AUTHOR]

A series of 2,4-dichloro-5-{[4-(phenylsulfonyl)piperazin-1-yl]carbonyl}benzenesulfonamides were designed and synthesized through amidation of Lasamide 1 with substituted piperazines. The newly obtained compounds demonstrated remarkable inhibition potency and selectivity for the human (h) expressed Carbonic Anhydrase (CA; EC 4.2.1.1) II isoform. Selected compounds 7 and 9 were investigated in an in vivo model of glaucoma and showed relevant performances, with the latter being able to last the effect up to 4 hours. The results herein reported are in sustainment of Lasamide derivatives as a new class of compounds potentially exploitable for the management of uncontrolled intra ocular pressure (IOP)., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Glaucoma is a degenerative optic neuropathy in which the degeneration of optic nerve and blindness occur. The main cause is a malfunction of ciliary processes (protrusions of the ciliary bodies) resulting in increased intraocular pressure (IOP). Ocular hypertension (OHT) causes ischemic events leading to retinal ganglion cell (RGC) depletion and blindness. Histaminergic and nitrergic systems are involved in the regulation of IOP. Therefore, we developed novel hybrid compounds that target histamine H 3 receptor (H 3 R) with nitric oxide (NO) releasing features (ST-1989 and ST-2130). After H 3 R binding was proven in vitro, we investigated their effects in two OHT models in New Zealand White rabbits. Compound ST-1989 showed the highest NO elevation, together with antioxidative and anti-inflammatory features partly superior to the co-administered H 3 R antagonist (ciproxifan) and NO donor (molsidomine). This hybrid compound demonstrated IOP reduction in both OHT models induced by intravitreal injection of hypertonic saline and carbomer into the anterior chamber of the eye, respectively. Ocular perfusion and photoreceptor neuroprotection were evaluated in a model of ischemia/reperfusion (I/R) of the ophthalmic artery induced by repeated sub-tenon injections of endothelin-1 (ET-1), twice a week for six weeks. Compound ST-1989 counteracts retinal degeneration reducing ophthalmic artery resistance index and increasing photoreceptor responses, thus rescuing RGCs. Our results indicate that compound ST-1989 is a promising molecule with long-lasting hypotensive effects and good effectiveness in reducing inflammation, oxidative stress, and RGCs apoptosis. In conclusion, these hybrid compounds could be a novel strategy to combat glaucomatous blindness and RGC depletion for ocular diseases involving retinal damage., 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. Mohammad A. Khanfar reports financial support was provided by Alexander von Humboldt Foundation. Holger Stark reports financial support was provided by German Research Council. Laura Lucarini reports financial support was provided by Fondazione Cassa di Risparmio di Firenze. If there are other authors, they 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 © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study introduces (S)-Opto-prop-2, a second-generation photoswitchable ligand designed for precise modulation of β 2 -adrenoceptor (β 2 AR). Synthesised by incorporating an azobenzene moiety with propranolol, (S)-Opto-prop-2 exhibited a high PSS cis (photostationary state for cis isomer) percentage (∼90 %) and a favourable half-life (>10 days), facilitating diverse bioassay measurements. In vitro, the cis-isomer displayed substantially higher β 2 AR binding affinity than the trans-isomer (1000-fold), making (S)-Opto-prop-2 one of the best photoswitchable GPCR (G protein-coupled receptor) ligands reported so far. Molecular docking of (S)-Opto-prop-2 in the X-ray structure of propranolol-bound β 2 AR followed by site-directed mutagenesis studies, identified D113 3.32 , N312 7.39 and F289 6.51 as crucial residues that contribute to ligand-receptor interactions at the molecular level. In vivo efficacy was assessed using a rabbit ocular hypertension model, revealing that the cis isomer mimicked propranolol's effects in reducing intraocular pressure, while the trans isomer was inactive. Dynamic optical modulation of β 2 AR by (S)-Opto-prop-2 was demonstrated in two different cAMP bioassays and using live-cell confocal imaging, indicating reversible and dynamic control of β 2 AR activity using the new photopharmacology tool. In conclusion, (S)-Opto-prop-2 emerges as a promising photoswitchable ligand for precise and reversible β 2 AR modulation with light. The new tool shows superior cis-on binding affinity, one of the largest reported differences in affinity (1000-fold) between its two configurations, in vivo efficacy, and dynamic modulation. This study contributes valuable insights into the evolving field of photopharmacology, offering a potential avenue for targeted therapy in β 2 AR-associated pathologies., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glaucoma, a leading cause of irreversible vision loss worldwide, is characterized by elevated intraocular pressure (IOP), a well-established risk factor across all its forms. We present the design and synthesis of 39 novel carbonic anhydrase inhibitors by a dual-tailed approach, strategically crafted to interact with distinct hydrophobic and hydrophilic pockets of CA active sites. The series was investigated against the CA isoforms implicated in glaucoma (hCA II, hCA IV, and hCA XII), and the X-ray crystal structures of compounds 25a , 25f , and 26a with CA II, along with 14b in complex with a hCA XII mimic, were determined. Selected compounds ( 14a , 25a , and 26a ) underwent evaluation for their ability to reduce IOP in rabbits with ocular hypertension. Derivative 26a showed significant potency and sustained IOP-lowering effects, surpassing the efficacy of the drugs dorzolamide and bimatoprost. This positions compound 26a as a promising candidate for the development of a novel anti-glaucoma medication.

Introduction: This study investigates the interactions between histaminergic system and glucocorticoid-induced leucin zipper (GILZ) in the inflammatory process and glucocorticoid modulation in lung fibrosis., Methods: Wild-type (WT) and GILZ Knock-Out (KO) mice were treated with bleomycin (0.05 IU) or saline, delivered by intra-tracheal injection. After surgery, mice received a continuous infusion of JNJ7777120 (JNJ, 2 mg/kg b.wt.) or vehicle for 21 days. Lung function was studied by measuring airway resistance to air insufflation through the analysis of pressure at airway opening (PAO). Lung samples were collected to evaluate the expression of histamine H 4 R, Anx-A1, and p65-NF-kB, the activity of myeloperoxidase (MPO), and the production of pro-inflammatory cytokines., Results: Airway fibrosis and remodeling were assessed by measuring TGF-β production and α-SMA deposition. JNJ reduces PAO in WT but not in GILZ KO mice (from 22 ± 1 mm to 15 ± 0.5 and from 24 ± 1.5 to 19 ± 0.5 respectively), MPO activity (from 204 ± 3.13 pmol/mg to 73.88 ± 2.63 in WT and from 221 ± 4.46 pmol/mg to 107 ± 5.54 in GILZ KO), the inflammatory response, TGF-β production, and α-SMA deposition in comparison to WT and GILZ KO vehicle groups., Conclusion: In conclusion, the role of H 4 R and GILZ in relation to glucocorticoids could pave the way for innovative therapies to counteract pulmonary fibrosis., (© 2023. The Author(s).)

Purpose: The purpose of this study was to assess the retinal protective activity and ocular hemodynamics after NCX 470 (0.1%) compared to bimatoprost administered as the US Food and Drug Administration (FDA)-approved drug (Lumigan - 0.01% ophthalmic solution, LUM) and at an equimolar dose (0.072%, BIM) to that released by NCX 470., Methods: Endothelin-1 (ET-1) induced ischemia/reperfusion injury model in rabbits was used. ET-1 was injected nearby the optic nerve head (ONH) twice/week for 6 weeks. Starting on week 3, the animals received vehicle (VEH), NCX 470, LUM, or BIM (30 µL/eye, twice daily, 6 days/week) until the end of ET-1 treatment. Intraocular pressure (IOP), ophthalmic artery resistive index (OA-RI), and electroretinogram (ERG) data were collected prior to dosing and at different time points postdosing. Reduced glutathione, 8-Hydroxy 2-deoxyguanosine, and Caspase-3 were determined in the retina of treated eyes. DNA fragmentation was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining., Results: ET-1 increased IOP (VEHIOP_Baseline = 20.5 ± 0.8 and VEHIOP_Week6 = 24.8 ± 0.3 mmHg) and OA-RI (VEHOA-RI_Baseline = 0.36 ± 0.02 and VEHOA-RI_Week6 = 0.55 ± 0.01) and reduced rod/cone responses over time. Oxidative stress, inflammation, and apoptotic markers increased in ET-1-treated eyes. NCX 470 prevented IOP (NCX 470IOP_Week6 = 18.1 ± 0.6 mmHg) and OA-RI changes (NCX 470OA-RI_Week6 = 0.33 ± 0.01) and restored ERG amplitude leaving unaltered the respective latency; these effects were only partially demonstrated by LUM or BIM. Additionally, NCX 470 reduced oxidative stress, inflammation, and apoptosis in the retinas of treated eyes. BIM and LUM were numerically less effective on these parameters., Conclusions: NCX 470 repeated ocular dosing ameliorates ocular hemodynamics and retinal cell dysfunction caused by ischemia/reperfusion via nitric oxide- and bimatoprost-mediated mechanisms., Translational Relevance: If confirmed in clinical setting our data may open new therapeutic opportunities to reduce visual field loss in glaucoma.