Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

新たなイントラクライン機構を用いた加齢性眼疾患治療へ --眼局所のホルモンの加齢変化とサーカディアンリズムが鍵--. 京都大学プレスリリース. 2022-02-14.Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD+)-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD+ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction

Real-world effectiveness and safety analysis of carfilzomib-lenalidomide-dexamethasone and carfilzomib-dexamethasone in relapsed/refractory multiple myeloma: a multicenter retrospective analysis

Background: Little is known about the real-world survival benefits and safety profiles of carfilzomib-lenalidomide-dexamethasone (KRd) and carfilzomib-dexamethasone (Kd). Methods: We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database. Results: A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia. Conclusion: Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered

Corosolic acid ameliorates vascular remodeling in pulmonary arterial hypertension via the downregulation of STAT3 signaling

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that is characterized by vascular remodeling of the pulmonary artery. PAH remodeling is primarily caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). Therefore, an inhibitory mechanism is expected as a target for the treatment of PAH. Corosolic acid (CRA) is a pentacyclic triterpenoid extracted from the leaves of Banaba (Lagerstroemia speciosa) that exerts anti-diabetic, anti-inflammatory, and anti-tumor effects. In the present study, the effects of CRA on PAH remodeling were examined using PASMCs from idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline (MCT)-induced pulmonary hypertensive (PH) rats. CRA inhibited the excessive proliferation of IPAH-PASMCs in a concentration-dependent manner (IC50 = 14.1 μM). It also reduced the migration of IPAH-PASMCs. The CRA treatment downregulated the expression of signal transducer and activator of transcription 3 (STAT3) in IPAH-PASMCs. In MCT-PH rats, the administration of CRA (1 mg/kg/day) attenuated increases in right ventricular systolic pressure, pulmonary vascular remodeling, and right ventricular hypertrophy. CRA also decreased the expression of STAT3 in pulmonary arterial smooth muscles from MCT-PH rats. In conclusion, the anti-proliferative and anti-migratory effects of CRA in PASMCs ameliorated PAH remodeling by downregulating STAT3 signaling pathways

Calcilytics inhibit the proliferation and migration of human prostate cancer PC-3 cells

The carcinogenesis and development of prostate cancer are mediated by enhanced Ca2+ signaling. In the present study, the pharmacological profile of the Ca2+-sensing receptor (CaSR) antagonists (calcilytics) was examined in human prostate cancer PC-3 cells. NPS2143 and Calhex 231 blocked extracellular Ca2+-induced increases in cytosolic [Ca2+]. NPS2143 and Calhex 231 inhibited cell proliferation (IC50 = 7.4 and 10.3 μM, respectively) and migration. The exposure to NPS2143 or Calhex 231 down-regulated CaSR protein expression. These results demonstrated that calcilytics inhibited cell proliferation/migration and down-regulated CaSR expression in human prostate cancer cells, suggesting their potential as novel therapeutic drugs for prostate cancer. Keywords: Calcium-sensing receptor, Calcilytic, Prostate cance