Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury by Inhibiting Ferroptosis

Cisplatin is widely used in the treatment of solid tumors, but its application is greatly limited due to its nephrotoxicity; thus, there is still no effective medicine for the treatment of cisplatin-induced acute kidney injury (Cis-AKI). We previously identified that polydatin (PD) exerts nephroprotective effects by antioxidative stress in AKI models. Recent evidence suggests that oxidative stress-induced molecular events overlap with the process of ferroptosis and that there are common molecular targets, such as glutathione (GSH) depletion and lipid peroxidation. Nevertheless, whether the nephroprotective effect of PD is related to anti-ferroptosis remains unclear. In this study, the inhibitory effect of PD on ferroptosis was observed in both cisplatin-treated HK-2 cells (20 μM) in vitro and a Cis-AKI mouse model (20 mg/kg, intraperitoneally) in vivo, characterized by the reversion of excessive intracellular free iron accumulation and reactive oxygen species (ROS) generation, a decrease in malondialdehyde (MDA) content and GSH depletion, and an increase in glutathione peroxidase-4 (GPx4) activity. Remarkably, PD dose-dependently alleviated cell death induced by the system Xc− inhibitor erastin (10 μM), and the effect of the 40 μM dose of PD was more obvious than that of ferrostatin-1 (1 μM) and deferoxamine (DFO, 100 μM), classical ferroptosis inhibitors. Our results provide insight into nephroprotection with PD in Cis-AKI by inhibiting ferroptosis via maintenance of the system Xc−-GSH-GPx4 axis and iron metabolism.

Preferential Effects of Cariprazine on Counteracting the Disruption of Social Interaction and Decrease in Extracellular Dopamine Levels Induced by the Dopamine D3 Receptor Agonist, PD-128907 in Rats: Implications for the Treatment of Negative and Depressive Symptoms of Psychiatric Disorders

The negative and cognitive symptoms of schizophrenia and related disorders may be due to reduced dopaminergic tone in cortical brain areas. Alteration in the function of dopamine (DA) D3 receptors may play a role in this cortical hypofunctionality and underlie the deficits in social behaviors and cognitive functions in schizophrenia. Cariprazine is a potent DA D3-preferring D3/D2 receptor partial agonist that is approved for the treatment of schizophrenia and bipolar disorder. The objective of the study was to compare the abilities of cariprazine, aripiprazole (another DA receptor partial agonist with more D2 receptor preference), and ABT-925 (a selective DA D3 antagonist) to counteract the social deficit and neurochemical alterations induced by the D3 receptor-preferring agonist (+)-PD 128907 (PD) in rats. Administration of PD (0.16 mg/kg; s.c.) induced a marked (−72%) but short-lasting disruption of the defensive social aggregation behavior (huddling) in the first 10-min period. Cariprazine at all doses (0.1, 0.3, 1 mg/kg; p.o.) almost completely abolished the PD-induced disruption of huddling. Likewise, ABT-925 (3 mg/kg; p.o.) and to a lesser extent aripiprazole (20 mg/kg; p.o.) were effective in blocking the PD-induced disruption of huddling. As measured by microdialysis, the highest dose of cariprazine prevented a PD-induced decrease in DA levels (40–80 min post PD dose) in the medial prefrontal cortex (mPFC), whereas aripiprazole did not have a significant effect. ABT-925 significantly counteracted the effect of PD at 80 min post-dose. In the nucleus accumbens (nAcc) shell, the highest dose of cariprazine, as well as ABT-925 and aripiprazole, significantly reversed the PD-induced decrease in DA levels. Taken together, these data provide behavioral and in vivo neurochemical evidence for the preferential DA D3 receptor action of cariprazine in the rat. This property of cariprazine may offer therapeutic benefits against the cognitive deficits and negative/depressive symptoms of schizophrenia and related disorders.

Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

Mirroring Emotions: Patients' Versus Caregivers' Perceptions of Sexual Experience in Parkinson's Disease

Background and aims: The need for intimacy and sexual expression is an essential dimension of quality of life. As patients with Parkinson's disease (PD) have to cope with essential changes in their global and sexual functioning, achieving a satisfying intimate and sexual relationship can be challenging. Sexual experience is a complex process that involves a dyadic relationship. In this study, we aimed to characterize the sexual experience of patients with Parkinson's disease and patients' vs caregivers' perceptions. Methods Twenty-seven PD patients and their caregivers were asked to complete the Arizona Sexual Experience Scale (ASEX) anonymously. They were instructed to refer to their sexual behavior over the past year and to consider behavioral changes that lasted for at least four consecutive weeks. Results Our data suggest that when considering sexual perceptions in PD, there is often agreement of judgment between patients and their partners. Overall, they have a rather good sex life, especially in the early stage of the disease, with similar behavior shown by men and women. Conclusions The effect of PD on the sexual and couple relationship challenges healthcare professionals to focus on the needs of both partners and to plan specific interventions in such a way as to prevent the deterioration of the couples' sexual wellbeing.

Deubiquitinating enzyme USP48 mediates pyroptosis and meliorates immune evasion in tumors by stabilizing GSDME expression

Pyroptosis is a kind of programmed cell death, which is characterized by the activation of inflammatory caspase and the cleavage of gasdermin proteins. It is widely involved in the occurrence and development of tumors. Studies have shown that ubiquitin related proteins play a key regulatory role in many biological processes. However, the role and molecular mechanism of ubiquitin-related proteins in pyroptosis have not been well identified. Here, using CRISPR-Cas9 screening, we identified a deubiquitinating enzyme (USP48) that has the most significant regulatory effect on cell pyroptosis. USP48 stabilizes GsderminE (GSDME) expression by causing deubiquitination of it, thereby achieving its regulatory effect on pyroptosis. USP48 prevents the degradation of GSDME by inhibiting K63-linked ubiquitination at positions K120 and K189 of GSDME. Clinical tissue testing confirmed that the expression of USP48 has a significant positive correlation with GSDME and pyroptosis-related factors. GSDME plays a crucial role in the regulation of cell pyroptosis by USP48. The single-cell sequencing results showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment are inhibited to varying degrees after USP48 gene knockout. Finally, the tumor formation experiment in mice confirmed that overexpression of USP48 could effectively improve the therapeutic effect of PD-1 inhibitors. These findings define a pyroptosis regulation pathway and indicate that activation of the pharmacological activity of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis-related immunotherapeutic resistance.