Discovery of novel anticancer flavonoids as potential HDAC2 inhibitors: virtual screening approach based on molecular docking, DFT and molecular dynamics simulations studies.

Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected flavonoids were screened based on molecular docking studies, as they have higher binding affinities than the standard drugs vorinostat and panobinostat. All screened compounds occupying the catalytic site of HDAC2 showed important molecular interaction with Zn2+ and other important amino acids in the binding pocket. The screened compounds were validated using ADMET filtration and bioactivity prediction from which we obtained six compounds, NPACT00270, NPACT00676, NPACT00700, NPACT001008, NPACT001054, and NPACT001407, which were analyzed using DFT studies. DFT studies were performed for all six screened flavonoids. In DFT studies, three flavonoids, NPACT00700, NPACT001008, and NPACT001407, were found to be better based on HOMO-LUMO and molecular electrostatic potential (MEP) analyses. Furthermore, MD simulations were performed for 100 ns for the three compounds. In the MD analysis, NPACT001407 was found to be more stable in the active site of HDAC2 as zinc formed a coordination bond with ASP181, HIS183, ASP269, and GLY305, along with two hydroxyl groups of the ligand. Our findings reveal that these flavonoids can interact as ligands with the active site of HDAC2. Because of the absence of a hydroxamate group in flavonoids, there are no possibilities for the formation of isocyanate. This suggests that the major drawback of current HDACs inhibitors may be solved. Further experimental validation is needed to understand the selectivity of flavonoids as HDAC2 inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03912-5.

TREATMENT PATTERNS AND 2-YEAR VISION OUTCOMES WITH BEVACIZUMAB IN DIABETIC MACULAR EDEMA: An Analysis From a Large U.S. Integrated Health Care System.

PURPOSE: To assess health care utilization and vision outcomes over 2 years in patients receiving bevacizumab treatment in clinical practice for diabetic macular edema. METHODS: Patients with newly diagnosed diabetic macular edema who received an intravitreal bevacizumab injection within 12 months of initial diagnosis were identified from Kaiser Permanente's 350,000 patients with diabetes mellitus treated between 2008 and 2013. Snellen best-corrected visual acuity (BCVA), number of intravitreal injections, and patient characteristics were abstracted from the electronic record. The main outcome measure was change in BCVA. RESULTS: Three hundred and nine patients met the inclusion criteria and had 2 years of follow-up after their first bevacizumab injection. These patients had a mean of 3.1 injections (range, 1-17) during the 2-year follow-up. Mean BCVA improvement was 5.4 letters at 12 months and 5.3 letters at 24 months. Only 29.8% of patients demonstrated ≥3 lines of vision improvement from baseline, whereas 12.3% had ≥3 lines of vision loss from baseline at 24 months. CONCLUSION: This is the largest U.S. clinical practice-based study of bevacizumab use in diabetic macular edema. Consistent with national studies, the frequency of injection was low. Average BCVA improvement was lower than in anti-vascular endothelial growth factor trials. Significant BCVA improvement was achieved in approximately 30% of patients with newly diagnosed diabetic macular edema.

Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors.

We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.

Calcium affects on vascular endpoints.

Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, calcium is now recognized as a key component of many physiologic pathways necessary for optimum health including cardiovascular, neurological, endocrine, renal, and gastrointestinal systems. A recent meta-analysis published in August 2011 showed a potential increase in cardiovascular events related to calcium supplementation. The possible mechanism of action of this correlation has not been well elucidated. This topic has generated intense interest due to the widespread use of calcium supplements, particularly among the middle aged and elderly who are at the most risk from cardiac events. Prior studies did not control for potential confounding factors such as the use of statins, aspirin or other medications. These controversial results warrant additional well-designed studies to investigate the relationship between calcium supplementation and cardiovascular outcomes. The purpose of this review is to highlight the current literature in regards to calcium supplementation and cardiovascular health; and to identify areas of future research.

Psoriasis treatment patterns: results of a cross-sectional survey of dermatologists.

OBJECTIVE: The study evaluated community physician prescribing patterns for patients with psoriasis. METHODS: US dermatologists actively practicing general dermatology and treating 10 or more patients with psoriasis/mo were interviewed (n = 90) in April and June 2006 and they recruited 8 to 10 consecutive patients for record review (n = 895, mean age = 46 years, 51% men). Proportion of patients treated with systemic, biologic, or topical therapy as reported by the dermatologist and recorded in the records was assessed by psoriasis severity. RESULTS: Among patients with severe psoriasis (body surface area affected > 10%), 56% to 63% received systemic therapy (including biologics) or phototherapy and 37% to 44% received topical therapy only. Dermatologists reported prescribing biologics to 41% of patients with severe disease compared with patient records where 27% to 34% of body surface area = 11% to 40% and 36% of body surface area greater than 40% patients received biologics. LIMITATIONS: Because of the small sample, eligibility criteria, and voluntary interview, selection bias may have occurred. CONCLUSIONS: Some dermatologists are prescribing systemic therapy for the majority of their patients with severe psoriasis but a gap in treatment remains for about 40% who received topical therapy alone.

Are patients with psoriasis undertreated? Results of National Psoriasis Foundation survey.

OBJECTIVE: We sought to assess whether patients with psoriasis with moderate or severe disease are being treated with systemic therapy. METHODS: Participants were identified from a random sample of the National Psoriasis Foundation contact database who were 18 years and older, with severe psoriasis (>10% body surface area) and moderate psoriasis (3%-10% body surface area); respondents with psoriatic arthritis were excluded. RESULTS: In all, 1657 respondents with psoriasis completed the survey (28% severe, 41% moderate). A total of 39% of respondents with severe psoriasis and 37% with moderate psoriasis were not currently receiving any treatment. Among respondents currently receiving therapy, only 43% of respondents with severe psoriasis received either traditional systemic therapy, biologic therapy, or phototherapy. LIMITATIONS: Respondents were from the National Psoriasis Foundation contact database and reported their current severity, which may be affected by their treatment. Body surface area as a measure of patient-reported severity has not been validated but has been used in several published studies. CONCLUSIONS: Almost 40% of respondents with psoriasis were currently not receiving treatment. For respondents with severe psoriasis, 26% were treated with systemic therapy, phototherapy, or both; 39% were not in treatment; and 35% were treated with topical therapy alone.