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Selective autophagy controls cellular homeostasis by degrading unnecessary or damaged cellular components. Melanosomes are specialized organelles that regulate the biogenesis, storage, and transport of melanin in melanocytes. However, the mechanisms underlying melanosomal autophagy, known as the melanophagy pathway, are poorly understood. To better understand the mechanism of melanophagy, we screened an endocrine-hormone chemical library and identified nalfurafine hydrochlorides, a κ-opioid receptor agonist, as a potent inducer of melanophagy. Treatment with nalfurafine hydrochloride increased autophagy and reduced melanin content in alpha-melanocyte-stimulating hormone (α-MSH)-treated cells. Furthermore, inhibition of autophagy blocked melanosomal degradation and reversed the nalfurafine hydrochloride-induced decrease in melanin content in α-MSH-treated cells. Consistently, treatment with other κ-opioid receptor agonists, such as MCOPPB or mianserin, inhibited excessive melanin production but induced autophagy in B16F1 cells. Furthermore, nalfurafine hydrochloride inhibited protein kinase A (PKA) activation, which was notably restored by forskolin, a PKA activator. Additionally, forskolin treatment further suppressed melanosomal degradation as well as the anti-pigmentation activity of nalfurafine hydrochloride in α-MSH-treated cells. Collectively, our data suggest that stimulation of κ-opioid receptors induces melanophagy by inhibiting PKA activation in α-MSH-treated B16F1 cells. [ABSTRACT FROM AUTHOR]

Primary cilia help to maintain cellular homeostasis by sensing conditions in the extracellular environment, including growth factors, nutrients, and hormones that are involved in various signaling pathways. Recently, we have shown that enhanced primary ciliogenesis in dopamine neurons promotes neuronal survival in a Parkinson's disease model. Moreover, we performed fecal metabolite screening in order to identify several candidates for improving primary ciliogenesis, including L-carnitine and acetyl-L-carnitine. However, the role of carnitine in primary ciliogenesis has remained unclear. In addition, the relationship between primary cilia and neurodegenerative diseases has remained unclear. In this study, we have evaluated the effects of carnitine on primary ciliogenesis in 1-methyl-4-phenylpyridinium ion (MPP+)-treated cells. We found that both L-carnitine and acetyl-L-carnitine promoted primary ciliogenesis in SH-SY5Y cells. In addition, the enhancement of ciliogenesis by carnitine suppressed MPP+-induced mitochondrial reactive oxygen species overproduction and mitochondrial fragmentation in SH-SY5Y cells. Moreover, carnitine inhibited the production of pro-inflammatory cytokines in MPP+-treated SH-SY5Y cells. Taken together, our findings suggest that enhanced ciliogenesis regulates MPP+-induced neurotoxicity and inflammation. [ABSTRACT FROM AUTHOR]

Background: Patients with borderline resectable (BR) or locally advanced pancreatic cancer (LAPC) require complex management strategies. This study evaluated the prognostic significance of the perichemotherapy skeletal muscle index (SMI) and carbohydrate antigen 19-9 (CA 19-9) in patients with BRPC or LAPC treated with FOLFIRINOX., Methods: We retrospectively evaluated 227 patients with BR or LAPC who received at least four cycles of chemotherapy between 2015 and 2020. We analysed chemotherapy response, changes in SMI (ΔSMI, %) on computed tomography (CT) and CA19-9 to determine their impact on progression-free survival (PFS) and overall survival (OS). After the early application of loco-regional treatments (LRT) within 3 months after completing four cycles of chemotherapy, the outcomes were compared between ΔSMI and CA19-9 subgroups., Results: Among 227 patients (median age, 60 years; 124 [54.6%] male) with 97 BR and 130 LAPC, 50.7% showed partial response (PR) to chemotherapy, 44.5% showed stable disease and 4.8% showed progressive disease (PD). Post-chemotherapy CA19-9 levels were normalized in 41.0% of patients. The high and low ΔSMI groups (based on the gender-specific cut-off of -8.6% for males and -2.9% for females) comprised 114 (50.2%) and 113 (49.8%) patients, respectively. The high ΔSMI group had poorer survival rates than the low ΔSMI group in both PFS (HR = 1.32, p = 0.05) and OS (HR = 1.74, p = 0.001). Multivariable analysis showed that ΔSMI (high vs. low; PFS, HR = 1.39, p = 0.03; OS, HR = 1.82, p < 0.001) and post-chemotherapy response (PD vs. PR/SD; PFS, HR = 18.69, p < 0.001; OS, HR = 6.19, p < 0.001) were independently associated with both PFS and OS. Additionally, the post-chemotherapy CA19-9 (≥ 37 vs. < 37; HR = 1.48, p = 0.01) was an independent predictor for PFS. Early application of LRT after chemotherapy significantly improved PFS and OS in both ΔSMI groups (all p < 0.05). However, it was not beneficial in the group with high ΔSMI and post-chemotherapy CA19-9 ≥ 37 (PFS, p = 0.39 and OS, p = 0.33)., Conclusions: Progressive sarcopenic deterioration after four cycles of chemotherapy was associated with poor survival outcomes in patients with BR or LAPC after FOLFIRINOX. We also investigated the optimal clinical setting for the early application LRTs using the ΔSMI and post-chemotherapy CA 19-9., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)