EHP-101 alleviates angiotensin II-induced fibrosis and inflammation in mice

Some cannabinoids showed anti-inflammatory and antifibrotic activities. EHP-101 is an oral lipidic formulation of the novel non-psychotropic cannabidiol aminoquinone VCE-004.8, which showed antifibrotic activity in murine models of systemic sclerosis induced by bleomycin. We herein examined the effect of EHP-101 on cardiac and other organ fibrosis in a mouse model induced by Angiotensin II. VCE-004.8 inhibited TGFβ- and Ang II-induced myofibroblast differentiation in cardiac fibroblasts detected by α-SMA expression. VCE-004.8 also inhibited Ang II-induced ERK 1 + 2 phosphorylation, NFAT activation and mRNA expression of IL1β, IL6, Col1A2 and CCL2 in cardiac fibroblasts. Mice infused with Ang II resulted in collagen accumulation in left ventricle, aortic, dermal, renal and pulmonary tissues; oral administration of EHP-101, Ajulemic acid and Losartan improved these phenotypes. In myocardial tissue, Ang II induced infiltration of T cells and macrophages together with the accumulation of collagen and Tenascin C; those were all reduced by either EHP-101 or Losartan treatment. Cardiac tissue RNA-Seq analyses revealed a similar transcriptomic signature for both treatments for inflammatory and fibrotic pathways. However, the gene set enrichment analysis comparing data from EHP-101 vs Losartan showed specific hallmarks modified only by EHP-101. Specifically, EHP-101 inhibited the expression of genes such as CDK1, TOP2A and MKi67 that are regulated to the E2 factor family of transcription factors. This study suggests that the oral administration of EHP-101 prevents and inhibits cardiac inflammation and fibrosis. Furthermore, EHP-101 inhibits renal, pulmonary and dermal fibrosis. EHP-101 could offer new opportunities in the treatment of cardiac fibrosis and other fibrotic diseases

SAR Studies on Curcumin's Pro-inflammatory Targets: Discovery of Prenylated Pyrazolocurcuminoids as Potent and Selective Novel Inhibitors of 5-Lipoxygenase.

The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), key enzymes linking inflammation with cancer, as high affinity targets. A comparative structure-activity study revealed three modifications dissecting mPGES-1/5-LO inhibition, namely (i) truncation of the acidic, enolized dicarbonyl moiety and/or replacement by pyrazole, (ii) hydrogenation of the interaryl linker, and (iii) (dihydro)prenylation. The prenylated pyrazole analogue 11 selectively inhibited 5-LO, outperforming curcumin by a factor of up to 50, and impaired zymosan-induced mouse peritonitis along with reduced 5-LO product levels. Other pro-inflammatory targets of curcumin (i.e., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-κB, nuclear factor-erythroid 2-related factor-2, and signal transducer and activator of transcription 3) were hardly affected by 11. The strict structural requirements for mPGES-1 and 5-LO inhibition strongly suggest that specific interactions rather than redox or membrane effects underlie the inhibition of mPGES-1 and 5-LO by curcumin

Etude biochimique de la pulpe dentaire de veau

A biochemical study of dental pulp of calves has been performed concerning:a) peroxydabilityb) A, E, C vitamins contentc) glutation (GSH) contentd) presence of paramagnetic compoundse) phosphorylation ratioThe dental pulp from incisives of 5 months old calves has been preserved. Immediately after decapitation the pulp was immersed in liquid nitrogen. Chromatographie (HPLC) and spectroscopic (NMR-ESR) techniques have been used.GSH in dental pulp are present and dosable (4.56 +/-0.08 n moles/mg prot.) and GSSG (1.05 +/-0.01 n moles/mg prot.).Because of blood traces in the extracted pulps, the AA. have determined the hemoglobin (Hb) dosage and GSH of erythrocytary derivation (Fig. 1).After deduction of GSH of erythrocytary derivation, the GSH really present in the pulp was 4.41 n moles/mg prot. and the GSSG was 0.90 n moles/mg prot.Peroxydability of the dental pulp has been evaluated with Lowry method with dental pulp homogenate and rat liver homogenate (see Table 1).The ESR spectre shows 4 resonances with the following values: g. 2.24 - 2.04 - 2.00 - 1.97; there are some free intermediary radicals (gr. - 2.00) (Fig.2).The NMR spectre shows the presence of ATP (0.22 n moles/g) of inorganic phosphate (16.58 n moles g) (Fig.3).The pulp seems to have a lot of antioxydant factors. The next researches will be to study E, A and C vitamins concentrations. This high presence of GSH and GSSG may be an embryonary peculiarity.Une étude biochimique de la pulpe dentaire a été entreprise pour étudier les propriétés antioxydantes et leurs interactions avec le métabolisme énergétique et les équilibres redox de la pulpe dentaire de veau. Le GSH réduit et oxydé (GSSG) a été mesuré et la spectroscopie avec ESR (Electron Spin Résonance) a été utilisée pour la recherche des substances paramagnétiques et la résonance magnétique nucléaire (NMR) pour la détermination des métabolites phosphorylés de petit poids moléculaire. Après la soustraction de la quantité de GSH érythrocytaire, le GSH présent dans la pulpe est resté identique 4,41 n moles/mg prot. (GSH) et 0.90 n moles/mg n moles/mg prot. (GSSG). La péroxydation lipidique de la pulpe dentaire a été étudiée. Le spectre ESR montre 4 résonances, respectivement de valeurs de G de 2.24, 2.04, 2.00, 1.97.L’analyse des résultats montre l’existence d’une petite quantité de radicaux libres intermédiaires (g-2.00) dépendant du métabolisme tissulaire. Le spectre NMR a montré la présence d’ATP (0.22 n moles/g) et de phosphate inorganique (16.50 n moles/g)

Analysis of Psychological Symptoms Following Disclosure of Amyloid-Positron Emission Tomography Imaging Results to Adults With Subjective Cognitive Decline

IMPORTANCE: Individuals who are amyloid-positive with subjective cognitive decline and clinical features increasing the likelihood of preclinical Alzheimer disease (SCD+) are at higher risk of developing dementia. Some individuals with SCD+ undergo amyloid-positron emission tomography (PET) as part of research studies and frequently wish to know their amyloid status; however, the disclosure of a positive amyloid-PET result might have psychological risks. OBJECTIVE: To assess the psychological outcomes of the amyloid-PET result disclosure in individuals with SCD+ and explore which variables are associated with a safer disclosure in individuals who are amyloid positive. DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter study was conducted as part of The Amyloid Imaging to Prevent Alzheimer Disease Diagnostic and Patient Management Study (AMYPAD-DPMS) (recruitment period: from April 2018 to October 2020). The setting was 5 European memory clinics, and participants included patients with SCD+ who underwent amyloid-PET. Statistical analysis was performed from July to October 2022. EXPOSURES: Disclosure of amyloid-PET result. MAIN OUTCOMES AND MEASURES: Psychological outcomes were defined as (1) disclosure related distress, assessed using the Impact of Event Scale-Revised (IES-R; scores of at least 33 indicate probable presence of posttraumatic stress disorder [PTSD]); and (2) anxiety and depression, assessed using the Hospital Anxiety and Depression scale (HADS; scores of at least 15 indicate probable presence of severe mood disorder symptoms). RESULTS: After disclosure, 27 patients with amyloid-positive SCD+ (median [IQR] age, 70 [66-74] years; gender: 14 men [52%]; median [IQR] education: 15 [13 to 17] years, median [IQR] Mini-Mental State Examination [MMSE] score, 29 [28 to 30]) had higher median (IQR) IES-R total score (10 [2 to 14] vs 0 [0 to 2]; P < .001), IES-R avoidance (0.00 [0.00 to 0.69] vs 0.00 [0.00 to 0.00]; P < .001), IES-R intrusions (0.50 [0.13 to 0.75] vs 0.00 [0.00 to 0.25]; P < .001), and IES-R hyperarousal (0.33 [0.00 to 0.67] vs 0.00 [0.00 to 0.00]; P < .001) scores than the 78 patients who were amyloid-negative (median [IQR], age, 67 [64 to 74] years, 45 men [58%], median [IQR] education: 15 [12 to 17] years, median [IQR] MMSE score: 29 [28 to 30]). There were no observed differences between amyloid-positive and amyloid-negative patients in the median (IQR) HADS Anxiety (-1.0 [-3.0 to 1.8] vs -2.0 [-4.8 to 1.0]; P = .06) and Depression (-1.0 [-2.0 to 0.0] vs -1.0 [-3.0 to 0.0]; P = .46) deltas (score after disclosure - scores at baseline). In patients with amyloid-positive SCD+, despite the small sample size, higher education was associated with lower disclosure-related distress (ρ = -0.43; P = .02) whereas the presence of study partner was associated with higher disclosure-related distress (W = 7.5; P = .03). No participants with amyloid-positive SCD+ showed probable presence of PTSD or severe anxiety or depression symptoms at follow-up. CONCLUSIONS AND RELEVANCE: The disclosure of a positive amyloid-PET result to patients with SCD+ was associated with a bigger psychological change, yet such change did not reach the threshold for clinical concern

Efficiency Potential and Voltage Loss of Inorganic CsPbI2Br Perovskite Solar Cells

Inorganic perovskite solar cells show excellent thermal stability, but the reported power conversion efficiencies are still lower than for organic inorganic perovskites. This is mainly caused by lower open circuit voltages VOCs . Herein, the reasons for the low VOC in inorganic CsPbI2Br perovskite solar cells are investigated. Intensity dependent photoluminescence measurements for different layer stacks reveal that n i p and p i n CsPbI2Br solar cells exhibit a strong mismatch between quasi Fermi level splitting QFLS and VOC. Specifically, the CsPbI2Br p i n perovskite solar cell has a QFLS e amp; 8201; VOC mismatch of 179 amp; 8201;meV, compared with 11 amp; 8201;meV for a reference cell with an organic inorganic perovskite of similar bandgap. On the other hand, this study shows that the CsPbI2Br films with a bandgap of 1.9 amp; 8201;eV have a very low defect density, resulting in an efficiency potential of 20.3 with a MeO 2PACz hole transporting layer and 20.8 on compact TiO2. Using ultraviolet photoelectron spectroscopy measurements, energy level misalignment is identified as a possible reason for the QFLS e amp; 8201; VOC mismatch and strategies for overcoming this VOC limitation are discussed. This work highlights the need to control the interfacial energetics in inorganic perovskite solar cells, but also gives promise for high efficiencies once this issue is resolve

Clinical Effect of Early vs Late Amyloid Positron Emission Tomography in Memory Clinic Patients: The AMYPAD-DPMS Randomized Clinical Trial

IMPORTANCE: Amyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect. OBJECTIVE: To assess the clinical effect of amyloid PET in memory clinic patients. DESIGN, SETTING, AND PARTICIPANTS: The AMYPAD-DPMS is a prospective randomized clinical trial in 8 European memory clinics. Participants were allocated (using a minimization method) to 3 study groups based on the performance of amyloid PET: arm 1, early in the diagnostic workup (within 1 month); arm 2, late in the diagnostic workup (after a mean [SD] 8 [2] months); or arm 3, if and when the managing physician chose. Participants were patients with subjective cognitive decline plus (SCD+; SCD plus clinical features increasing the likelihood of preclinical Alzheimer disease), mild cognitive impairment (MCI), or dementia; they were assessed at baseline and after 3 months. Recruitment took place between April 16, 2018, and October 30, 2020. Data analysis was performed from July 2022 to January 2023. INTERVENTION: Amyloid PET. MAIN OUTCOME AND MEASURE: The main outcome was the difference between arm 1 and arm 2 in the proportion of participants receiving an etiological diagnosis with a very high confidence (ie, ≥90% on a 50%-100% visual numeric scale) after 3 months. RESULTS: A total of 844 participants were screened, and 840 were enrolled (291 in arm 1, 271 in arm 2, 278 in arm 3). Baseline and 3-month visit data were available for 272 participants in arm 1 and 260 in arm 2 (median [IQR] age: 71 [65-77] and 71 [65-77] years; 150/272 male [55%] and 135/260 male [52%]; 122/272 female [45%] and 125/260 female [48%]; median [IQR] education: 12 [10-15] and 13 [10-16] years, respectively). After 3 months, 109 of 272 participants (40%) in arm 1 had a diagnosis with very high confidence vs 30 of 260 (11%) in arm 2 (P < .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%]; P < .001; MCI: 45/108 [42%] vs 9/102 [9%]; P < .001; dementia: 39/80 [49%] vs 16/80 [20%]; P < .001). CONCLUSION AND RELEVANCE: In this study, early amyloid PET allowed memory clinic patients to receive an etiological diagnosis with very high confidence after only 3 months compared with patients who had not undergone amyloid PET. These findings support the implementation of amyloid PET early in the diagnostic workup of memory clinic patients. TRIAL REGISTRATION: EudraCT Number: 2017-002527-21