Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists.

Orphan G-protein-coupled receptor 84 (GPR84) is a receptor that has been linked to cancer, inflammatory, and fibrotic diseases. We have reported DL-175 as a biased agonist at GPR84 which showed differential signaling via Gαi/cAMP and ß-arrestin, but which is rapidly metabolized. Herein, we describe an optimization of DL-175 through a systematic structure-activity relationship (SAR) analysis. This reveals that the replacement of the naphthalene group improved metabolic stability and the addition of a 5-hydroxy substituent to the pyridine N-oxide group, yielding compounds 68 (OX04528) and 69 (OX04529), enhanced the potency for cAMP signaling by 3 orders of magnitude to low picomolar values. Neither compound showed detectable effects on ß-arrestin recruitment up to 80 µM. Thus, the new GPR84 agonists 68 and 69 displayed excellent potency, high G-protein signaling bias, and an appropriate in vivo pharmacokinetic profile that will allow investigation of GPR84 biased agonist activity in vivo.

A computer-aided insight into the identification of significant therapeutic flavone as a promising agent for sarcopenic obesity.

Polyphenols, the important secondary metabolites, consist of multiple phytochemicals and show numerous physiological effects. Flavones play a significant role in various chronic disorders such as diabetes.. In this study, all the flavones were encountered, and it was further filtered based on their drug-likeness properties and pharmacokinetic parameters. Existing literature confirms that flavone-based compounds are suitable as the drug of choice in sarcopenic obesity. A molecular docking study was performed toward the myostatin inhibition profile of the flavones using PDB:3HH2 as a target site. This computer-aided drug design helps select lead molecules in novel drug discovery.

Different Treatments for Sugarcane Juice Preservation.

This investigation aimed to optimize the time, pH, pressure, and temperature of sugarcane juice pasteurization and to develop a "ready to serve" bottled sugarcane juice with a high preservation efficiency. Fresh sugarcane juice was extracted from sugarcane genotype Co 89003, and beverage samples were collected using three different treatments: sulphitation of juice with the addition of potassium metabisulphite (KMS-25, 50, 100, and 150 ppm), acidification of juice (addition of citric acid, to reduce the pH of the juice to 4.8, 4.5, and 4.25), and steam treatment of the canes (5 min, 10, and 15 min at 7 psi). In all treatments, the juice was pasteurized in glass bottles @ 65 °C for 25 min and stored at low temperature (5 °C) in pre-sterilized glass bottles. Juice properties such as the ˚Brix, total sugar, pH, and total phenolic content decreased with storage, whereas the microbial count, titrable acidity, and reducing sugar content significantly increased during storage. The addition of KMS, citric acid, and the steam treatment reduced the browning of juice and maintained the color of juice during storage, by inhibiting the polyphenol oxidase enzyme activity, from 0.571 unit/mL to 0.1 unit/mL. Among the selected treatments, sugarcane juice with KMS (100 and 150 ppm) and steam treatment of the canes for 5 and 10 min at 7 psi showed the minimum changes in physico-chemical properties, sensory qualities, and restricted microbial growth. Thesulphitation treatment with pasteurization proved best for increasing the shelf life of sugarcane juice upto 90 days with refrigeration. Similarly, the steam-subjected cane juice (10 and 15 min at 7 psi) could be effectively preserved for upto 30 days with refrigeration, without any preservative.

Integrated Approach in Genomic Selection to Accelerate Genetic Gain in Sugarcane.

Marker-assisted selection (MAS) has been widely used in the last few decades in plant breeding programs for the mapping and introgression of genes for economically important traits, which has enabled the development of a number of superior cultivars in different crops. In sugarcane, which is the most important source for sugar and bioethanol, marker development work was initiated long ago; however, marker-assisted breeding in sugarcane has been lagging, mainly due to its large complex genome, high levels of polyploidy and heterozygosity, varied number of chromosomes, and use of low/medium-density markers. Genomic selection (GS) is a proven technology in animal breeding and has recently been incorporated in plant breeding programs. GS is a potential tool for the rapid selection of superior genotypes and accelerating breeding cycle. However, its full potential could be realized by an integrated approach combining high-throughput phenotyping, genotyping, machine learning, and speed breeding with genomic selection. For better understanding of GS integration, we comprehensively discuss the concept of genetic gain through the breeder's equation, GS methodology, prediction models, current status of GS in sugarcane, challenges of prediction accuracy, challenges of GS in sugarcane, integrated GS, high-throughput phenotyping (HTP), high-throughput genotyping (HTG), machine learning, and speed breeding followed by its prospective applications in sugarcane improvement.

Covid-19 presenting as isolated severe thrombocytopenia in an HIV-lymphoma survivor.

Coronavirus disease has myriad manifestations and can present with predominantly extrapulmonary manifestations. We describe a 50-year-old man, a person living with HIV (PLHA), a non-Hodgkin lymphoma survivor, who presented with isolated severe thrombocytopenia. He was found to have immune-mediated thrombocytopenia, and showed excellent response to intravenous immunoglobulins.

Identification of Transthyretin Tetramer Kinetic Stabilizers That Are Capable of Inhibiting the Retinol-Dependent Retinol Binding Protein 4-Transthyretin Interaction: Potential Novel Therapeutics for Macular Degeneration, Transthyretin Amyloidosis, and Their Common Age-Related Comorbidities.

Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of proamyloidogenic monomers, which underlies TTR amyloidosis (ATTR) pathophysiology. ATTR is a progressive disease resulting from the deposition of toxic fibrils in tissues that predominantly presents clinically as amyloid cardiomyopathy and peripheral polyneuropathy. Ligands that bind to and kinetically stabilize TTR tetramers prohibit their dissociation and may prevent ATTR onset. Drawing from clinically investigated AG10, we designed a constrained congener (14) that exhibits excellent TTR tetramer binding potency, prevents TTR aggregation in a gel-based assay, and possesses desirable pharmacokinetics in mice. Additionally, 14 significantly lowers murine serum retinol binding protein 4 (RBP4) levels despite a lack of binding at that protein's all-trans-retinol site. We hypothesize that kinetic stabilization of TTR tetramers via 14 is allosterically hindering all-trans-retinol-dependent RBP4-TTR tertiary complex formation and that the compound could present ancillary therapeutic utility for indications treated with RBP4 antagonists, such as macular degeneration.

Discovery of Bispecific Antagonists of Retinol Binding Protein 4 That Stabilize Transthyretin Tetramers: Scaffolding Hopping, Optimization, and Preclinical Pharmacological Evaluation as a Potential Therapy for Two Common Age-Related Comorbidities.

Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex. We previously identified selective RBP4 antagonists that dissociate circulating RBP4-TTR-retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We describe herein the identification of bispecific RBP4 antagonist-TTR tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based assay. This new class of bispecific compounds may be especially important as a therapy for dry AMD patients who have another common age-related comorbidity, senile systemic amyloidosis, a nongenetic disease associated with wild-type TTR misfolding.