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Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V2receptor (V2R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V2R. Among these derivatives, compound 25exhibited potent binding affinity to the V2R (Ki= 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC50= 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound 25in a murine model of ADPKD demonstrated a significantly improved in vivoefficacy compared with the reference compound tolvaptan. Overall, compound 25holds therapeutic potential for the treatment of ADPKD.

Bone-related diseases like osteoarthritis and osteoporosis impact millions globally, affecting quality of life. Osteoporosis considerably enhances the probability of bone fractures of the wrist, hip, and spine. Enhancement and acceleration of functional bone development can be achieved through the sustained delivery of growth factors (GFs) and cells in biomaterial carriers. The delivery of bioactive compounds in a targeted, spatiotemporal way that most closely resembles the natural defect repair process can be achieved by designing the carrier system with established release kinetics. Furthermore, the carrier can serve as a substrate that mimics the extracellular matrix, facilitating osteoprogenitor cell infiltration and growth for integrative tissue healing. In this report, we explore the significance of GFs within the realm of bone and cartilage tissue engineering, encompassing their encapsulation and delivery methodologies, the kinetics of release, and their amalgamation with biomaterials and stem cells (SCs) to facilitate the mending of bone fractures. Moreover, the significance of GFs in evaluating the microenvironment of bone tissue through reciprocal signaling with cells and biomaterial scaffolds is emphasized which will serve as the foundation for prospective advances in bone and cartilage tissue engineering as well as therapeutic equipment. Nanoparticles are being used in regenerative medicine to promote bone regeneration and repair by delivering osteoinductive growth factors like BMP-2, VEGF, TGF-β. These nanocarriers allow controlled release, minimizing adverse effects and ensuring growth factors are concentrated at the injury site. They are also mixed with mesenchymal stem cells (MSCs) to improve their engraftment, differentiation, and survival. This approach is a key step in developing multi-model systems that more efficiently facilitate bone regeneration. Researchers are exploring smart nanoparticles with immunomodulatory qualities to improve bonre regeneration and reduce inflammation in injury site . Despite promising preclinical results, challenges include cost management, regulatory approval, and long term safety. However, incorporating stem cell transport and growth factors in nanoparticles could revolutionize bone regeneration and offer more personalized therapies for complex bone disorders and accidents.

The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V2receptor (V2R) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved V2R antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class V2R antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide V2R antagonists. Peptide 33exhibited a high binding affinity for the V2R (Ki= 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide 33exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.