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5. Inhibition of mannan-binding lectin associated serine protease (MASP)-2 reduces the cognitive deficits in a mouse model of severe traumatic brain injury

Author

Mercurio, D, Pischiutta, F, Seminara, S, Tribuzio, F, Lisi, I, Pasetto, L, Bonetto, V, De Simoni, M, Schwaeble, W, Yaseen, S, Dudler, T, Zanier, E, Fumagalli, S, Mercurio, Domenico, Pischiutta, Francesca, Seminara, Serena, Tribuzio, Francesca, Lisi, Ilaria, Pasetto, Laura, Bonetto, Valentina, De Simoni, Maria-Grazia, Schwaeble, Wilhelm, Yaseen, Sadam, Dudler, Thomas, Zanier, Elisa R., Fumagalli, Stefano, Mercurio, D, Pischiutta, F, Seminara, S, Tribuzio, F, Lisi, I, Pasetto, L, Bonetto, V, De Simoni, M, Schwaeble, W, Yaseen, S, Dudler, T, Zanier, E, Fumagalli, S, Mercurio, Domenico, Pischiutta, Francesca, Seminara, Serena, Tribuzio, Francesca, Lisi, Ilaria, Pasetto, Laura, Bonetto, Valentina, De Simoni, Maria-Grazia, Schwaeble, Wilhelm, Yaseen, Sadam, Dudler, Thomas, Zanier, Elisa R., and Fumagalli, Stefano

Abstract

The lectin pathway (LP) of complement mediates inflammatory processes linked to tissue damage and loss of function following traumatic brain injury (TBI). LP activation triggers a cascade of proteolytic events initiated by LP specific enzymes called MASPs (for Mannan-binding lectin Associated Serine Proteases). Elevated serum and brain levels of MASP-2, the effector enzyme of the LP, were previously reported to be associated with the severity of tissue injury and poor outcomes in patients with TBI. To evaluate the therapeutic potential of LP inhibition in TBI, we first conducted a pilot study testing the effect of an inhibitory MASP-2 antibody (alpha-MASP-2), administered systemically at 4 and 24 h post-TBI in a mouse model of controlled cortical impact (CCI). Treatment with alpha-MASP-2 reduced sensorimotor and cognitive deficits for up to 5 weeks post-TBI. As previous studies by others postulated a critical role of MASP-1 in LP activation, we conducted an additional study that also assessed treatment with an inhibitory MASP-1 antibody (alpha-MASP-1). A total of 78 mice were treated intraperitoneally with either alpha-MASP-2, or alpha-MASP-1, or an isotype control antibody 4 h and 24 h after TBI or sham injury. An amelioration of the cognitive deficits assessed by Barnes Maze, prespecified as the primary study endpoint, was exclusively observed in the alpha-MASP-2-treated group. The behavioral data were paralleled by a reduction of the lesion size when evaluated histologically and by reduced systemic LP activity. Our data suggest that inhibition of the LP effector enzyme MASP-2 is a promising treatment strategy to limit neurological deficits and tissue loss following TBI. Our work has translational value because a MASP-2 antibody has already completed multiple late-stage clinical trials in other indications and we used a clinically relevant treatment protocol testing the therapeutic mechanism of MASP-2 inhibition in TBI.

Published
2024

6. Inhibition of the Lectin Pathway of Complement Activation Reduces Acute Respiratory Distress Syndrome Severity in a Mouse Model of SARS-CoV-2 Infection

Author

Ali, Y, Carnell, G, Fumagalli, S, Mercurio, D, Seminara, S, Lynch, N, Khatri, P, Arachchilage, C, Mascheroni, L, Kaminski, C, George, C, Stewart, H, Yabuki, M, Demopulos, G, Heeney, J, Schwaeble, W, Ali, Youssif M, Carnell, George W, Fumagalli, Stefano, Mercurio, Domenico, Seminara, Serena, Lynch, Nicholas J, Khatri, Priyanka, Arachchilage, Chanuka H, Mascheroni, Luca, Kaminski, Clemens, George, Charlotte L, Stewart, Hazel, Yabuki, Munehisa, Demopulos, Gregory, Heeney, Jonathan L, Schwaeble, Wilhelm, Ali, Y, Carnell, G, Fumagalli, S, Mercurio, D, Seminara, S, Lynch, N, Khatri, P, Arachchilage, C, Mascheroni, L, Kaminski, C, George, C, Stewart, H, Yabuki, M, Demopulos, G, Heeney, J, Schwaeble, W, Ali, Youssif M, Carnell, George W, Fumagalli, Stefano, Mercurio, Domenico, Seminara, Serena, Lynch, Nicholas J, Khatri, Priyanka, Arachchilage, Chanuka H, Mascheroni, Luca, Kaminski, Clemens, George, Charlotte L, Stewart, Hazel, Yabuki, Munehisa, Demopulos, Gregory, Heeney, Jonathan L, and Schwaeble, Wilhelm

Abstract

Most patients with COVID-19 in the intensive care unit develop an acute respiratory distress syndrome characterized by severe hypoxemia, decreased lung compliance, and high vascular permeability. Activation of the complement system is a hallmark of moderate and severe COVID-19, with abundant deposition of complement proteins in inflamed tissue and on the endothelium during COVID-19. Using a transgenic mouse model of SARS-CoV-2 infection, we assessed the therapeutic utility of an inhibitory antibody (HG4) targeting MASP-2, a key enzyme in the lectin pathway. Treatment of infected mice with HG4 reduced the disease severity score and improved survival vs mice that received an isotype control antibody. Administration of HG4 significantly reduced the lung injury score, including alveolar inflammatory cell infiltration, alveolar edema, and alveolar hemorrhage. The ameliorating effect of MASP-2 inhibition on the severity of COVID-19 pathology is reflected by a significant reduction in the proinflammatory activation of brain microglia in HG4-treated mice.

Published
2024

7. The impact of Methoxypropylamino Cyclohexenylidene Ethoxyethylcyanoacetate (MCE) UVA1 filter on pigmentary and ageing signs: An outdoors prospective 8‐week randomized, intra‐individual comparative study in two populations of different genetic background

Author

Flament, F., primary, Mercurio, D. G., additional, Muller, B., additional, Li, J., additional, Tricaud, C., additional, Bernerd, F., additional, Roudot, A., additional, Candau, D., additional, and Passeron, T., additional

Published
2023
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10. The impact of methoxypropylamino cyclohexenylidene ethoxyethylcyanoacetate (MCE) UVA1 filter on pigmentary and ageing signs: An outdoor prospective 8‐week randomized, intra‐individual comparative study in two populations of different genetic background

Author

Flament, F., Mercurio, D. G., Muller, B., Li, J., Tricaud, C., Bernerd, F., Roudot, A., Candau, D., and Passeron, T.

Subjects
*SUNBURN, *SKIN aging, *SUNSCREENS (Cosmetics), *COMPARATIVE studies, *TERRESTRIAL radiation, *FOREARM, *MEMBRANE filters
Abstract

Background: Of all ultraviolet (UV) radiations reaching the earth, UVA1 rays have a higher potential of penetrating and producing clinically harmful consequences. While UV radiations up to 370 nm are well‐blocked by current sunscreens, a photoprotection gap remains for the UVA1 wavelengths between 370 and 400 nm. Objective: This study was to assess under outdoor summer conditions the impact on pigmentation and skin ageing signs of a protection against UVA1 using methoxypropylamino cyclohexenylidene ethoxyethylcyanoacetate (MCE) filter added to a reference SPF50 sunscreen, in comparison with the same sunscreen without the MCE filter. Materials and Methods: This prospective randomized comparative intra‐individual study was conducted in 113 women in Brazil and China. Subjects had their face and two forearms exposed twice‐daily to a 1‐h outdoor sunlight exposure over 8 weeks. Before exposure, the SPF50 sunscreen containing 3% MCE was applied on one half‐face and one forearm and the same reference product without MCE on the other half‐face and forearm. Primary study endpoint was skin colour changes (chromametry). Other endpoints included expert panel grading of pigmentation and facial skin ageing, and naïve panel assessment of facial skin radiance and homogeneity. Results: After 8 weeks, the skin was darker on both forearms but the increase in sun‐induced pigmentation was smaller with the SPF50/MCE sunscreen. Expert panel evaluations showed no change in severity scores for pigmentation and a decreased severity scores for facial skin ageing in areas protected with the SPF50/MCE product: severity scores in areas protected with the SPF50 alone were either increased (pigmentation) or unchanged (skin ageing). Naïve panel evaluations of skin radiance and homogeneity showed statistically significant superiority of the SPF50/MCE product. Conclusion: Overall, this study demonstrates that a protection with the SPF50/MCE sunscreen significantly reduces pigmentation and ageing signs compared to the same SPF50 sunscreen. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Impact on facial skin aging signs of a 1‐year standardized photoprotection over a classical skin care routine in skin phototypes II–VI individuals: A prospective randomized trial.

Author

Flament, F., Mercurio, D. G., Catalan, E., Bouhadanna, E., Delaunay, C., Miranda, D. F., and Passeron, T.

Subjects
*SKIN aging, *SKIN care, *BRAZILIANS, *SKIN cancer, *SUNBURN
Abstract

Background: Data reflecting the impact of photoprotection on cutaneous aging are scarce and mostly limited to fair skin. Objective: To assess the effectiveness of a photoprotective product in counteracting the photoaging process in different skin phototypes over 1 year compared against a classical routine. Materials and Methods: Two hundred and ninety Brazilian women aged 30–65 years, with skin phototype II–VI were equally randomized in two groups. Group 1 kept on their routine whereas Group 2 applied, twice daily, a photoprotective product (SPF 60, PPD = 24.1) replacing the one they routinely used. Volunteers reported the duration of their daily sun‐exposure. Standardized photographs taken at D0 and D365 were analysed by 15 dermatologists to assess eight wrinkles and pigmentation signs. Results: A global increase in severity was reported which was significant for Group 1. This increase was lower in Group 2 where only half the signs showed significant worsening. In Group 2 versus Group 1, the increase in forehead wrinkles, marionette lines, wrinkles created by ptosis and size of dark spot was significantly (p < 0.05) decreased by 30%–50%. Conclusion: Daily application of a high photoprotective product significantly decreases the progression of skin aging signs after 1 year in skin phototypes II–VI. [ABSTRACT FROM AUTHOR]

Published
2023
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13. Plasma-derived and recombinant C1 esterase inhibitor: Binding profiles and neuroprotective properties in brain ischemia/reperfusion injury

Author

Mercurio, D, Piotti, A, Valente, A, Oggioni, M, Ponstein, Y, Van Amersfoort, E, Gobbi, M, Fumagalli, S, De Simoni, M, Mercurio D., Piotti A., Valente A., Oggioni M., Ponstein Y., Van Amersfoort E., Gobbi M., Fumagalli S., De Simoni M. -G., Mercurio, D, Piotti, A, Valente, A, Oggioni, M, Ponstein, Y, Van Amersfoort, E, Gobbi, M, Fumagalli, S, De Simoni, M, Mercurio D., Piotti A., Valente A., Oggioni M., Ponstein Y., Van Amersfoort E., Gobbi M., Fumagalli S., and De Simoni M. -G.

Abstract

C1 esterase inhibitor (C1INH) is known to exert its inhibitory effect by binding to several target proteases of the contact and complement systems. One of C1INH's targets comprise mannose-binding lectin (MBL), a critical player in post-stroke pathophysiology. We therefore explored the effects of recombinant human (rh) and plasma derived (pd) C1INH in C57BL/6J mice subjected to transient occlusion of the middle cerebral artery (tMCAo), receiving 15 U/mouse of pd or rhC1INH intravenously, at reperfusion. We analyzed the compounds’ (i) neuroprotective effects, (ii) plasma presence, (iii) effects on circulating and brain MBL, (iv) time course of endothelial deposition, and (v) effects on the formation of active complement products. rhC1INH-treated mice had neuroprotective effects, including reduced behavioral deficits and neuronal loss, associated with decreased MBL brain deposition and decreased formation of complement C4b active fragments. In contrast, pdC1INH did not show these neuroprotective effects despite its longer plasma residence time. We also analyzed the response to tMCAo in C1INH-deficient mice, observing a poorer ischemic outcome compared to the wild type mice, which could be partially prevented by rhC1INH administration. In conclusion, we show that rhC1INH exhibits stronger neuroprotective effects than the corresponding plasma-derived protein after experimental ischemia/reperfusion injury in the brain, placing it as a promising drug for stroke. Differential effects are likely related to more effective MBL inhibition which further confirms it as a useful pharmacological target for stroke.

Published
2021

46. Cichorium intybus root extract: A “vitamin D-like” active ingredient to improve skin barrier function.

Author

Maia Campos, P. M. B. G., G. Mercurio, D., O. Melo, M., and Closs-Gonthier, B.

Subjects
*TREATMENT of skin aging, *CHICORY, *SODIUM dodecyl sulfate, *THERAPEUTIC use of vitamin D, *HOMEOSTASIS, *TREATMENT effectiveness, *THERAPEUTICS, THERAPEUTIC use of plant extracts
Abstract

During the aging process, the human skin suffers many alterations including dryness, skin barrier function damage. The skin barrier function is important to the prevention of skin alterations and maintenance of homeostasis. So, the objective of this study was to assess the clinical efficacy on skin barrier function ofCichorium intybusroot extract in cosmetic formulations with or without UV filters. Fifty women, aged between 45 and 60 years, were divided into two groups. One group received vehicle formulations containing UV filters, and the other group received formulations without UV filters. Both groups received a formulation containing the extract and the vehicle. The formulations were applied twice daily to the upper arms after washing with sodium lauryl sulphate. Transepidermal water loss (TEWL) and skin microrelief were evaluated before and after a 14- and 28-day period of treatment. The control regions and regions where the vehicles were applied showed an increase in the TEWL. For the formulations containing the extract, decreased TEWL and improved microrelief were observed when compared to the vehicle and control areas after a 28-day period. In conclusion,Cichorium intybusroot extract showed protective and restructuring effects on the skin and stands out as an innovative ingredient to improve skin barrier function. [ABSTRACT FROM PUBLISHER]

Published
2017
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