Matrine induces cardiotoxicity by promoting ferroptosis through the Nrf2 antioxidant system in H9c2 cells.

Matrine (MT) has shown promising efficacy in various cancers and chronic hepatitis; however, its clinical application is limited because of its side effects. Our previous studies have indicated that MT can induce severe hepatotoxicity and nephrotoxicity. The current study aimed to investigate its cardiotoxicity and potential underlying mechanisms in H9c2 cells. Our results showed that MT induced H9c2 cell death and disrupted the cellular membrane integrity. Moreover, MT decreased glutathione (GSH) and cysteine (Cys) levels, and increased Fe2+, lipid peroxidation, reactive oxygen species (ROS), and MDA levels, ultimately leading to ferroptosis. Interestingly, these phenomena were alleviated by the ferroptosis inhibitor Fer-1, whereas MT-induced ferroptosis was exacerbated by the ferroptosis agonist RSL3. In addition, MT significantly reduced FTH, Nrf2, xCT, GPX4, and FSP1 protein levels and inhibited the transcriptional activity of Nrf2 while increasing TFR1 protein levels. Supplementation with Nrf2 agonist (Dimethyl fumarate, DMF) or selenium (Sodium selenite, SS) and CoQ10 alleviated MT-induced cytotoxic effects in H9c2 cells. These results suggest that ferroptosis, which is mediated by an imbalance in the Nrf2 antioxidant system, is involved in MT-induced cardiac toxicity.

Emodin disrupts the Notch1/Nrf2/GPX4 antioxidant system and promotes renal cell ferroptosis.

Emodin has been demonstrated to possess multiple pharmacological activities. However, emodin has also been reported to induce nephrotoxicity at high doses and with long-term use, and the underlying mechanism has not been fully disclosed. The current study aimed to investigate the roles of oxidative stress and ferroptosis in emodin-induced kidney toxicity. Mice were intraperitoneally treated with emodin, and NRK-52E cells were exposed to emodin in the presence or absence of treatment with Jagged1, SC79, or t-BHQ. Emodin significantly upregulated the levels of blood urea nitrogen, serum creatinine, malondialdehyde, and Fe2+ , reduced the levels of superoxide dismutase and glutathione, and induced pathological changes in the kidneys in vivo. Moreover, the viability of NRK-52E cells treated with emodin was reduced, and emodin induced iron accumulation, excessive reactive oxygen species production, and lipid peroxidation and depolarized the mitochondrial membrane potential (ΔΨm). In addition, emodin treatment downregulated the activity of neurogenic locus notch homolog protein 1 (Notch1), reduced the nuclear translocation of nuclear factor erythroid-2 related factor 2 (Nrf2), and decreased glutathione peroxidase 4 protein levels. However, Notch1 activation by Jagged1 pretreatment, Akt activation by SC79 pretreatment, or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of emodin in NRK-52E cells. Taken together, these results revealed that emodin-induced ferroptosis triggered kidney toxicity through inhibition of the Notch1/Nrf2/glutathione peroxidase 4 axis.

Matrine-induced nephrotoxicity via GSK-3ß/nrf2-mediated mitochondria-dependent apoptosis.

INTRODUCTION: Matrine (MT), an ingredient extracted from the Chinese herb Sophora flavescens, can result in nephrotoxicity because of long-term exposure. However, the underlying mechanism by which MT leads to kidney injury remains unclear. This study aimed to investigate the roles of oxidative stress and mitochondria in MT-induced kidney toxicity both in vitro and in vivo. METHODS: Mice were exposed to MT for 20 days, and NRK-52E cells were exposed to MT with or without LiCl (a GSK-3ß inhibitor), tert-Butylhydroquinone (t-BHQ, an Nrf2 activator), or small interfering RNA. RESULTS: The results showed that MT caused nephrotoxicity accompanied by an increase in reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. Meanwhile, MT significantly upregulated glycogen synthase kinase-3ß (GSK-3ß) activity, released cytochrome c (Cyt C) and cleaved caspase-3, decreased the activity of nuclear factor-erythroid 2-related Factor 2 (Nrf2), and reduced the expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1), which led to the inactivation of antioxidant enzymes and the activation of apoptosis. In addition, GSK-3ß inhibition by LiCl or small interfering RNA pretreatment or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of MT in NRK-52E cells. CONCLUSIONS: Taken together, these results revealed that MT-induced apoptosis triggered kidney toxicity and that GSK-3ß or Nrf2 might serve as a promising nephroprotective target for MT-induced kidney injury.

Effects of self-management interventions for cancer patients with pain: A systematic review of randomised controlled trials.

AIMS: To evaluate the effects of self-management interventions targeting individuals with cancer-related pain on pain intensity, self-efficacy, quality of life (QoL), pain medication adherence, and pain-related knowledge and provide recommendations for the content and format of self-management interventions based on the existing evidence. DESIGN: A systematic review of randomised controlled trials (RCTs) and narrative synthesis. DATA SOURCES: A search of six electronic databases, including Medline, PsycINFO, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science and Scopus. REVIEW METHODS: This systematic review followed the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies published from January 2011 to March 2022 in English were retrieved. The Cochrane Risk of Bias Tool was used to assess quality. Data were summarised using narrative synthesis. RESULTS: This systematic review included six RCTs involving 748 patients with cancer-related pain. The results support the effectiveness of the intervention on QoL and pain-related knowledge. Mixed results were observed in the effectiveness on pain intensity, self-efficacy and medication adherence. Overall, the quality of the evidence was low. The content of self-management interventions varied across studies but with similar formats (face-to-face coaching and telephone follow-up). CONCLUSION: The existing evidence supports the effectiveness of self-management interventions on pain-related knowledge and QoL. Further high-quality RCTs are needed to determine the most effective interventions. RELEVANCE TO CLINICAL PRACTICE: Self-management is recommended to improve cancer patients' pain awareness, self-management behaviour and adaptability. Components for self-management of cancer pain, including patient attitude and knowledge assessment, nurse coaching and counselling, reinforcement during follow-up period, and provision of supplementary materials on pain management and medication adherence, could be covered in the intervention. In the future, it is worthwhile exploring an effective intervention using Internet-based information technology, for example WeChat, to aid the delivery of self-management intervention. NO PATIENT OR PUBLIC CONTRIBUTION: This systematic review does not necessarily involve patients or public members in this work.

Cdc42 signaling regulated by dopamine D2 receptor correlatively links specific brain regions of hippocampus to cocaine addiction.

BACKGROUND: Hippocampus plays critical roles in drug addiction. Cocaine-induced modifications in dopamine receptor function and the downstream signaling are important regulation mechanisms in cocaine addiction. Rac regulates actin filament accumulation while Cdc42 stimulates the formation of filopodia and neurite outgrowth. Based on the region specific roles of small GTPases in brain, we focused on the hippocampal subregions to detect the regulation of Cdc42 signaling in long-term morphological and behavioral adaptations to cocaine. METHODS: Genetically modified mouse models of Cdc42, dopamine receptor D1 (D1R) and D2 (D2R) and expressed Cdc42 point mutants that are defective in binding to and activation of its downstream effector molecules PAK and N-WASP were generated, respectively, in CA1 or dentate gyrus (DG) subregion. RESULTS: Cocaine induced upregulation of Cdc42 signaling activity. Cdc42 knockout or mutants blocked cocaine-induced increase in spine plasticity in hippocampal CA1 pyramidal neurons, leading to a decreased conditional place preference (CPP)-associated memories and spatial learning and memory in water maze. Cdc42 knockout or mutants promoted cocaine-induced loss of neurogenesis in DG, leading to a decreased CPP-associated memories and spatial learning and memory in water maze. Furthermore, by using D1R knockout, D2R knockout, and D2R/Cdc42 double knockout mice, we found that D2R, but not D1R, regulated Cdc42 signaling in cocaine-induced neural plasticity and behavioral changes. CONCLUSIONS: Cdc42 acts downstream of D2R in the hippocampus and plays an important role in cocaine-induced neural plasticity through N-WASP and PAK-LIMK-Cofilin, and Cdc42 signaling pathway correlatively links specific brain regions (CA1, dentate gyrus) to cocaine-induced CPP behavior.

Apigenin Attenuates Mesoporous Silica Nanoparticles-Induced Nephrotoxicity by Activating FOXO3a.

Mesoporous silica nanoparticles (MSNs) are widely used in many biomedical applications and clinical fields. However, the applications of MSNs are limited by their severe toxicity. Apigenin (AG) has demonstrated pharmacological effects with low toxicity. The aim of this study was to clarify the role of AG in the progression of MSNs-induced renal injury. BALB/c mice and NRK-52E cells were exposed to MSNs with or without AG. AG protected mice and NRK-52E cells from the MSNs-induced pathological variations in renal tissues and decreased cell viability. AG significantly reduced the levels of serum blood urea nitrogen (BUN) and serum creatinine (Scr), upregulated the levels of superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT), and improved the pathological changes of the kidney in MSNs-treated mice. The protective effects of AG were associated with its ability to increase the levels of antioxidants, reduce the accumulation of ROS, and inhibit the expression of the inflammatory mediators (TNF-α, IL-6). In addition, AG treatment upregulated the activity of FOXO3a, increased the level of IkBα, and reduced the nuclear translocation of NF-κB, which ultimately alleviated MSNs-induced inflammation. Nuclear FOXO3a translocation also triggered antioxidant gene transcription and protected nephrocyte from oxidative damage. However, knockdown of FOXO3a significantly blocked the protective effects of AG. These findings suggested that AG could be a promising therapeutic strategy for MSNs-induced nephrotoxicity, and this protective effect might be related to the suppression of oxidative stress and inflammation via the FOXO3a/NF-κB pathway.

Phillyrin ameliorates diabetic nephropathy through the PI3K/Akt/GSK-3ß signalling pathway in streptozotocin-induced diabetic mice.

Diabetic nephropathy is a progressive kidney disease resulting from long-term hyperglycaemia in diabetic patients, and the underlying mechanism is complex and lacks effective treatments. Various active ingredients in Chinese herbs have been shown to alleviate renal injury and improve DN in recent years. Phillyrin, a natural medicinal active compound extracted from the Oleaceae family, has various pharmacological effects, including antioxidative, antiapoptotic and antiobesity effects. However, the role of phillyrin and its underlying mechanism in DN have not yet been explored. To investigate the effects of phillyrin on DN and its potential mechanisms of action, we performed experiments using streptozotocin (STZ)-induced DN mice as models. Phillyrin significantly reduced the levels of fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c), downregulated the levels of serum blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine ß2-microglobulins (ß2-MG) and improved the pathological changes of the kidney in a DN mouse model. Phillyrin also increased the level of antioxidants and attenuated oxidative damage in DN model mice. In addition, phillyrin inhibited Glycogen synthase kinase-3ß (GSK-3ß) activity by activating the PI3K/Akt signalling pathway, increased the Bcl-2/Bax ratio, reduced the release of cytochrome c from the mitochondria to the cytoplasm, subsequently inhibited the activation of caspase-3 and ultimately suppressed renal cell apoptosis. These findings suggested that phillyrin could be a new promising therapeutic strategy for DN, and this protective effect might be related to suppressing oxidative stress and apoptosis via the PI3K/Akt/GSK-3ß pathway.

Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen.

Repeated exposure to cocaine was previously found to cause sensitized behavioral responses and structural remodeling on medium spiny neurons of the nucleus accumbens (NAc) and caudate putamen (CPu). Rac1 has emerged as a key integrator of environmental cues that regulates dendritic cytoskeletons. In this study, we investigated the role of Rac1 in cocaine-induced dendritic and behavioral plasticity in the CPu. We found that Rac1 activation was reduced in the NAc but increased in the CPu following repeated cocaine treatment. Inhibition of Rac1 activity by a Rac1-specific inhibitor NSC23766, overexpression of a dominant negative mutant of Rac1 (T17N-Rac1) or local knockout of Rac1 attenuated the cocaine-induced increase in dendrites and spine density in the CPu, whereas overexpression of a constitutively active Rac1 exert the opposite effect. Moreover, NSC23766 reversed the increased number of asymmetric spine synapses in the CPu following chronic cocaine exposure. Downregulation of Rac1 activity likewise attenuates behavioral reward responses to cocaine exposure, with activation of Rac1 producing the opposite effect. Thus, Rac1 signaling is differentially regulated in the NAc and CPu after repeated cocaine treatment, and induction of Rac1 activation in the CPu is important for cocaine exposure-induced dendritic remodeling and behavioral plasticity.

Activation of Dopamine D1 Receptors Regulates Dendritic Morphogenesis Through Rac1 and RhoA in Prefrontal Cortex Neurons.

Dopamine (DA) is an important regulator of neuronal plasticity in the prefrontal cortex (PFC) and plays a critical role in addiction-related neuroadaptation. The Rho GTPases, including Rac1, RhoA and Cdc42, are key regulators of actin cytoskeleton rearrangement that play important roles in dendritic morphogenesis. The goal of the current study was to use cultures of primary PFC neurons to gain a better understanding of the molecular mechanisms underlying DA-induced dendritic morphogenesis, a phenomenon that mimics the increase in DA synaptic transmission observed in the PFC of in vivo cocaine administration. We investigated the effects of repeated DA treatments on dendritic morphology changes in PFC neurons, and identified Rac1 and RhoA as downstream effectors of D1 receptors during the regulation of dendritic morphogenesis. Importantly, we found that D1 receptor-regulated Rac1 and RhoA have distinct roles in the regulation of dendritic morphogenesis after repeated DA treatments. Our data provide the first evidence that Rac1 and RhoA are effectors of D1 receptor signaling during dendritic morphogenesis and represent new signaling molecules involved in long-lasting neuroadaptation in the PFC.