Primary cilia mediate sonic hedgehog signaling to regulate neuronal-like differentiation of bone mesenchymal stem cells for resveratrol induction in vitro.

Mesenchymal stem cells (MSCs) can differentiate into neuronal-like cell types under specific conditions. The classical antioxidant inducers such as ß-mercaptoethanol (BME), butylated hydroxyanisol (BHA), and dimethylsulfoxide (DMSO) are limited in clinical because of toxicity. Resveratrol, a safer, natural antioxidant, can stimulate osteoblastic differentiation of MSCs. However, its effect of inducing MSCs to differentiate into neuronal-like cells is less well studied, and its differentiated mechanisms are not well understood. Sonic hedgehog (Shh) signaling, mediated by the primary cilia, is crucial for embryonic development and tissue differentiation, but relatively little is known about the role of Shh signaling and primary cilia in neuronal-like differentiation of MSCs. Here we show that primary cilia, harboring patched 1 (Ptc1), are present in growth-arrested MSCs and that smoothened (Smo) and Gli1 are present in cytoplasm of MSCs, which are important components of the Shh signaling pathway. After resveratrol induction, MSCs acquire neuronal-like cell morphologies and phenotypes, Smo translocates to the primary cilia, Gli1 enters the nucleus, and expressions of Smo and Gli1 proteins increase, which can be inhibited by cyclopamine, a Smo antagonist. Meanwhile, Smo agonist (SAG) attains similar effects compared with the resveratrol group. These data indicate that resveratrol can induce MSCs to differentiate into neuronal-like cells and activate Shh signaling pathway in the primary cilia. Moreover, the primary cilia and Shh signaling are essential for resveratrol inducing neuronal-like differentiation of MSCs. Our finding is important for understanding the neuronal-like differentiation mechanism of MSCs for resveratrol and promoting its clinical therapeutic utility.

Efficacy and safety of antibody-drug conjugates in the treatment of urothelial cell carcinoma: a systematic review and meta-analysis of prospective clinical trials.

Introduction: Urothelial carcinoma (UC) is a refractory disease for which achieving satisfactory outcomes remains challenging with current surgical interventions. Antibody-drug conjugates (ADCs) are a novel class of targeted therapeutics that have demonstrated encouraging results for UC. Although there is a limited number of high-quality randomized control trials (RCTs) examining the use of ADCs in patients with UC, some prospective non-randomized studies of interventions (NRSIs) provide valuable insights and pertinent information. We aim to assess the efficacy and safety of ADCs in patients with UC, particularly those with locally advanced and metastatic diseases. Methods: A systematic search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science databases to identify pertinent studies. Outcomes, such as the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events (AEs), and treatment-related adverse events (TRAEs), were extracted for further analyses. Results: Twelve studies involving 1,311 patients were included in this meta-analysis. In terms of tumor responses, the pooled ORR and DCR were 40% and 74%, respectively. Regarding survival analysis, the pooled median PFS and OS were 5.66 months and 12.63 months, respectively. The pooled 6-month PFS and OS were 47% and 80%, while the pooled 1-year PFS and OS were 22% and 55%, respectively. The most common TRAEs of the ADCs were alopecia (all grades: 45%, grades ≥ III: 0%), decreased appetite (all grades: 34%, grades ≥ III: 3%), dysgeusia (all grades: 40%, grades ≥ III: 0%), fatigue (all grades: 39%, grades ≥ III: 5%), nausea (all grades: 45%, grades ≥ III: 2%), peripheral sensory neuropathy (all grades: 37%, grades ≥ III: 2%), and pruritus (all grades: 32%, grades ≥ III: 1%). Conclusion: The meta-analysis in this study demonstrates that ADCs have promising efficacies and safety for patients with advanced or metastatic UC. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023460232.

Chronic kidney disease--is it a true risk factor of reduced clopidogrel efficacy in elderly patients with stable coronary artery disease?

BACKGROUND: Chronic kidney disease (CKD) is an established predictor of recurrent ischemic events in patients with coronary artery disease (CAD). This association has been partially ascribed to high post-treatment platelet reactivity (HPPR) according to platelet function testing. However, the influencing factors of HPPR are assay-dependent, and the relevant data of elderly patients with stable CAD are absent. PATIENTS AND METHODS: 310 elderly patients (>80years of age) with stable CAD taking prolonged maintenance clopidogrel (75mg/day) were studied. Maximal platelet aggregation rate (MPA%) with light transmittance aggregometry and Platelet Reactive Units (PRU) with VerifyNow (VN) P2Y12 system were obtained. Markers of platelet activation, including PAC-1 and CD62P, were also determined. RESULTS: Patients on different stages of CKD presented similar MPA% and expression of PAC-1 and CD62P. Although severe CKD patients were more likely to present HPPR identified by VNP2Y12 (odds ratio: 1.85, p=0.038), multiple logistic regression diminished this effect (adjusted odds ratio: 1.19, p=0.642), and revealed anemia as a possible predictor of HPPR (adjusted odds ratio: 5.92, p=0.001). However, in a parallel way, hemoglobin correlated with baseline PRU values as well as with post-treatment values (r=-0.624 and r=-0.463, respectively, p<0.001). Association between hemoglobin and PRU inhibition rate was not found. Moreover, hemoglobin exerted no influence on MPA% at all. CONCLUSION: CKD is not necessarily associated with reduced antiplatelet effects of clopidogrel in elderly patients with stable CAD taking prolonged maintenance clopidogrel, and the seemingly influence of CKD on HPPR assessed by VNP2Y12 assay may be due to the artifactual effect of hemoglobin on VNP2Y12.

[Effect of non-contact coculture on bone marrow stromal cells and neural stem cells].

OBJECTIVE: To observe the effect of non-contact coculture on bone marrow stromal cells (MSCs) and neural stem cells (NSCs) in neural stem cell culture medium. METHODS: MSCs and NSCs were cultured in non-contact coculture in Transwell plate, and cell morphology and immunocytochemical profile were investigated. RESULTS: In the coculture, the NSCs showed adhering growth and extended long processes, and the migrating cells formed a network of cells within 7 days. The cells differentiated into neurons, astrocytes and oligodendrocytes as shown by immunocytochemistry. Most of the MSCs grew in a non-adherent manner, giving rise to large spherical cell masses which expressed neuronal, astrocyte, and oligodendrocyte phenotypes. In the control group, the NSCs grew in suspension, some of MSCs formed small non-adherent spherical cell masses, while some cells showed adherent growth. CONCLUSION: MSCs and NSCs in the non-contact coculture can mutually promote the cell differentiation into neural cells in neural stem cell culture medium, indicating that both MSCs and NSCs can secrete some neurotrophic factors to provide a microenvironment suitable for survival and differentiation for each other.