Glucocorticoid receptor modulators CpdX and CpdX-D3 exhibit the same in vivo antiinflammatory activities as synthetic glucocorticoids.

We previously reported that the nonsteroidal compound CpdX, which was initially characterized 20 y ago as a possible gestagen and, shortly afterward, as a possible drug for treatments of inflammatory diseases, selectively triggers the NFκB/AP1-mediated tethered indirect transrepression function of the glucocorticoid receptor (GR), and could therefore be a selective glucocorticoid receptor agonistic modulator (SEGRAM). We now demonstrate that, upon administration to the mouse, CpdX and one of its deuterated derivatives, CpdX-D3, repress as efficiently as a synthetic glucocorticoid (e.g., Dexamethasone) an induced skin atopic dermatitis, an induced psoriasis-like inflammation, a house dust mite (HDM)-induced asthma-like allergic lung inflammation, a collagen-induced arthritis, an induced ulcerative colitis, and an ovalbumin-induced allergic conjunctivitis. Interestingly, in the cases of an HDM-induced asthma-like allergic lung inflammation and of a collagen-induced arthritis, the CpdX antiinflammatory activity was selectively exerted by one of the two CpdX enantiomers, namely, CpdX(eA) or CpdX-D3(eA).

The glucocorticoid receptor agonistic modulators CpdX and CpdX-D3 do not generate the debilitating effects of synthetic glucocorticoids.

Seventy years after the discovery of their anti-inflammatory properties, glucocorticoids (GCs) remain the mainstay treatment for major allergic and inflammatory disorders, such as atopic dermatitis, asthma, rheumatoid arthritis, colitis, and conjunctivitis, among others. However, their long-term therapeutical administration is limited by major debilitating side effects, e.g., skin atrophy, osteoporosis, Addison-like adrenal insufficiency, fatty liver, and type 2 diabetes syndrome, as well as growth inhibition in children. These undesirable side effects are mostly related to GC-induced activation of both the direct transactivation and the direct transrepression functions of the GC receptor (GR), whereas the activation of its GC-induced indirect tethered transrepression function results in beneficial anti-inflammatory effects. We have reported in the accompanying paper that the nonsteroidal compound CpdX as well as its deuterated form CpdX-D3 selectively activate the GR indirect transrepression function and are as effective as synthetic GCs at repressing inflammations generated in several mouse models of major pathologies. We now demonstrate that these CpdX compounds are bona fide selective GC receptor agonistic modulators (SEGRAMs) as none of the known GC-induced debilitating side effects were observed in the mouse upon 3-mo CpdX treatments. We notably report that, unlike that of GCs, the administration of CpdX to ovariectomized (OVX) mice does not induce a fatty liver nor type 2 diabetes, which indicates that CpdX could be used in postmenopausal women as an efficient "harmless" GC substitute.

Application of Chitosan in Bone and Dental Engineering.

Chitosan is a deacetylated polysaccharide from chitin, the natural biopolymer primarily found in shells of marine crustaceans and fungi cell walls. Upon deacetylation, the protonation of free amino groups of the d-glucosamine residues of chitosan turns it into a polycation, which can easily interact with DNA, proteins, lipids, or negatively charged synthetic polymers. This positive-charged characteristic of chitosan not only increases its solubility, biodegradability, and biocompatibility, but also directly contributes to the muco-adhesion, hemostasis, and antimicrobial properties of chitosan. Combined with its low-cost and economic nature, chitosan has been extensively studied and widely used in biopharmaceutical and biomedical applications for several decades. In this review, we summarize the current chitosan-based applications for bone and dental engineering. Combining chitosan-based scaffolds with other nature or synthetic polymers and biomaterials induces their mechanical properties and bioactivities, as well as promoting osteogenesis. Incorporating the bioactive molecules into these biocomposite scaffolds accelerates new bone regeneration and enhances neovascularization in vivo.

Difficulties and Psychological Impact of the SARS-CoV-2 Pandemic in Patients with Systemic Lupus Erythematosus: A Nationwide Patient Association Study.

OBJECTIVES: We aimed to evaluate the difficulties encountered by systemic lupus erythematosus (SLE) patients during the early COVID-19 pandemic and to evaluate their impact on patient mental health. METHODS: We conducted a nationwide survey including SLE patients from France, recruited by their treating specialist or through a patient association. The survey was administered online or in paper form between November 2020 and April 2021 and included questions aiming at evaluating the difficulties encountered during the early COVID-19 pandemic (March to August 2020). The impact on mental health was evaluated using the Hospital Anxiety and Depression Scale (HADS) and the Post-Traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5). RESULTS: 536 SLE patients (91.9% women) of mean age 50 (±14.1) years responded to the survey. The main reported difficulties were issues regarding access to medical care (n = 136, 25.4%) or hydroxychloroquine treatment (n = 98/389, 25.2%), the loss of employment (n = 85/349, 24.4%), and financial difficulties (n = 75/536, 11%). In 328 patients with complete mental health assessments, 161 (47.2%) screened positive for anxiety, 141 (41.2%) screened positive for depressive syndrome, and 128 (38.7%) screened positive for PTSD. The multivariate analysis showed that female sex (OR = 4.29 [95%CI: 1.39-13.24]), financial issues (OR = 2.57 [1.27-5.22]), and difficulties accessing medical care (OR = 2.15 [1.26-3.69]) or hydroxychloroquine treatment (OR = 1.90 [1.06-3.40]) were independently associated with a positive screening for PTSD. CONCLUSIONS: The COVID-19 pandemic resulted in a severe burden in SLE patients, including difficulties accessing care and treatment along with high psychological distress. Better understanding these difficulties will allow for better prevention and care in times of crisis.

Biological Characteristics and Patterns of Codon Usage Evolution for the African Genotype Zika Virus.

We investigated temporal trends of codon usage changes for different host species to determine their importance in Zika virus (ZIKV) evolution. Viral spillover resulting from the potential of codon adaptation to host genome was also assessed for the African genotype ZIKV in comparison to the Asian genotype. To improve our understanding on its zoonotic maintenance, we evaluated in vitro the biological properties of the African genotype ZIKV in vertebrate and mosquito cell lines. Analyses were performed in comparison to Yellow fever virus (YFV). Despite significantly lower codon adaptation index trends than YFV, ZIKV showed evident codon adaptation to vertebrate hosts, particularly for the green African monkey Chlorocebus aethiops. PCA and CAI analyses at the individual ZIKV gene level for both human and Aedes aegypti indicated a clear distinction between the two genotypes. African ZIKV isolates showed higher virulence in mosquito cells than in vertebrate cells. Their higher replication in mosquito cells than African YFV confirmed the role of mosquitoes in the natural maintenance of the African genotype ZIKV. An analysis of individual strain growth characteristics indicated that the widely used reference strain MR766 replicates poorly in comparison to African ZIKV isolates. The recombinant African Zika virus strain ArD128000*E/NS5 may be a good model to include in studies on the mechanism of host tropism, as it cannot replicate in the tested vertebrate cell line.

Polymer-Based Instructive Scaffolds for Endodontic Regeneration.

The challenge of endodontic regeneration is modulated by clinical conditions which determine five kinds of tissue requirements: pulp connective-tissue formation, dentin formation, revascularization, reinnervation and radicular edification. Polymer scaffolds constitute keystone of the different endodontic regenerative strategies. Indeed, scaffolds are crucial for carrying active molecules and competent cells which optimize the regeneration. Hydrogels are very beneficial for controlling viscosity and porosity of endodontic scaffolds. The nanofibrous and microporous scaffolds mimicking extracellular matrix are also of great interest for promoting dentin-pulp formation. Two main types of polymer scaffolds are highlighted: collagen and fibrin. Collagen scaffolds which are similar to native pulp tissue, are adequate for pulp connective tissue formation. Functionnalization by active biomolecules as BMP, SDF-1, G-CSF enhances their properties. Fibrin or PRF scaffolds present the advantage of promoting stem cell differentiation and concomitant revascularisation. The choice of the type of polymers (polypeptide, PCL, chitosan) can depend on its ability to deliver the active biomolecule or to build as suitable hydrogel as possible. Since 2010s, proposals to associate different types of polymers in a same scaffold have emerged for adding advantages or for offsetting a disadvantage of a polymer. Further works would study the synergetic effects of different innovative polymers composition.