Ultrasound-guided quadratus lumborum block provided more effective analgesia for children undergoing lower abdominal laparoscopic surgery: a randomized clinical trial.

BACKGROUND: Postoperative pain treatment for pediatrics is often inadequate and the evidence of pediatric postoperative analgesia is scarce. To our knowledge, no report regarding the comparison among caudal block, transversus abdominis plane (TAP) block and quadratus lumborum (QL) block for children undergoing lower abdominal laparoscopic surgery was found at present. Thus this trial aimed to compare the efficacies of them for children undergoing lower abdominal laparoscopic surgery. METHODS: One hundred and eighty children aged from 1 to 12 years undergoing lower abdominal laparoscopic surgery were included and randomized to receive caudal block, TAP block or QL block. The primary outcome was the Face, Legs, Activity, Cry, and Consolability (FLACC) score at 30 min, 1 h, 4 h, 8 h, 12 h, and 24 h and tramadol consumption during first 24 h postoperatively. Secondary outcomes included the number of children received tramadol, time to first tramadol request, parents' satisfaction and postoperative adverse reactions. RESULTS: The QLB group had lower postoperative FLACC scores at 8 h (median difference - 0.43, P = 0.03) than the Caudal group and at 4 h (median difference - 0.6, P = 0.001) and 8 h (median difference - 0.43, P = 0.03) than the TAPB group. The tramadol consumption was lower in the QLB group (28.43 ± 6.55) than the TAPB group (37.17 ± 6.12, P = 0.023). Although the number of children received tramadol did not differ among the three groups, the time to first tramadol request was longer in the QLB group (7.20 ± 0.79) than the caudal group (8.42 ± 0.61, P = 0.008). No statistical difference was observed concerning other secondary outcomes. CONCLUSIONS: QLB produced more effective postoperative analgesia for children undergoing laparoscopic abdominal surgery compared with the TAPB and caudal block.

Prediction of early recurrence of hepatocellular carcinoma after liver transplantation based on computed tomography radiomics nomogram.

BACKGROUND: Early recurrence results in poor prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). This study aimed to explore the value of computed tomography (CT)-based radiomics nomogram in predicting early recurrence of patients with HCC after LT. METHODS: A cohort of 151 patients with HCC who underwent LT between December 2013 and July 2019 were retrospectively enrolled. A total of 1218 features were extracted from enhanced CT images. The least absolute shrinkage and selection operator algorithm (LASSO) logistic regression was used for dimension reduction and radiomics signature building. The clinical model was constructed after the analysis of clinical factors, and the nomogram was constructed by introducing the radiomics signature into the clinical model. The predictive performance and clinical usefulness of the three models were evaluated using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA), respectively. Calibration curves were plotted to assess the calibration of the nomogram. RESULTS: There were significant differences in radiomics signature among early recurrence patients and non-early recurrence patients in the training cohort (P < 0.001) and validation cohort (P < 0.001). The nomogram showed the best predictive performance, with the largest area under the ROC curve in the training (0.882) and validation (0.917) cohorts. Hosmer-Lemeshow testing confirmed that the nomogram showed good calibration in the training (P = 0.138) and validation (P = 0.396) cohorts. DCA showed if the threshold probability is within 0.06-1, the nomogram had better clinical usefulness than the clinical model. CONCLUSIONS: Our CT-based radiomics nomogram can preoperatively predict the risk of early recurrence in patients with HCC after LT.

Selective Activation of Basal Forebrain Cholinergic Neurons Attenuates Polymicrobial Sepsis-Induced Inflammation via the Cholinergic Anti-Inflammatory Pathway.

OBJECTIVES: Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored. DESIGN: Animal research. SETTING: University research laboratory. SUBJECTS: Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice. INTERVENTIONS: The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used. MEASUREMENTS AND MAIN RESULTS: Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation. CONCLUSIONS: These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis.

Expression and cellular localization of hepcidin mRNA and protein in normal rat brain.

BACKGROUND: Hepcidin is a peptide hormone belonging to the defensin family of cationic antimicrobial molecules that has an essential role in systemic iron homeostasis. The peptide is synthesised by hepatocytes and transported in the circulation to target tissues where it regulates the iron export function of the ferrous iron permease, ferroportin. In the brain hepcidin protein has been identified using immuno-histochemistry and mRNA by real-time PCR but not by in situ hybridisation raising the question of whether there is measurable transcription of the hepcidin gene in the central nervous system. Alternatively hepcidin could be transported as a hormone to the brain via the circulation. RESULTS: By RT-PCR hepcidin mRNA was present at low level throughout normal rat brain while in situ hybridisation to detect low-abundant mRNA revealed that transcripts were restricted to endothelium of blood vessels and choroid plexus. In contrast, hepcidin protein analysed by immuno-histochemistry was highly expressed in blood vessels, in endothelium and in pericytes. Hepcidin was also present in glial cells and in the olfactory bulb, sub-ventricular zone and dentate gyrus, areas where neurogenesis and synaptic plasticity are maintained throughout adult life. The hepcidin species identified by Western blotting in sub-ventricular zone, cortex and hippocampus migrated as a ~2.8 kDa band, identical in size to hepcidin present in normal rat serum suggesting that hepcidin in brain was the full-length biologically active 25 amino acid peptide. Hepcidin co-localised with ferroportin in ependymal cells of the sub-ventricular zone and in the corpus callosum consistent with a regulatory role in iron metabolism at these sites. CONCLUSIONS: Hepcidin protein was widely expressed in brain parenchyma while levels of hepcidin gene transcription appeared to be below the limits of detection of the in situ hybridisation probes. This disparity suggests that not all hepcidin in the brain is transcribed in situ and may originate in part outside the brain. The properties of hepcidin as a cationic peptide hormone are reflected in the finding of hepcidin in the walls of blood vessels and in pericytes and glia, cells that may be involved in transporting the peptide into brain interstitium.

Cytoplasmic Escape of Mitochondrial DNA Mediated by Mfn2 Downregulation Promotes Microglial Activation via cGas-Sting Axis in Spinal Cord Injury.

Neuroinflammation is associated with poor outcomes in patients with spinal cord injury (SCI). Recent studies have demonstrated that stimulator of interferon genes (Sting) plays a key role in inflammatory diseases. However, the role of Sting in SCI remains unclear. In the present study, it is found that increased Sting expression is mainly derived from activated microglia after SCI. Interestingly, knockout of Sting in microglia can improve the recovery of neurological function after SCI. Microglial Sting knockout restrains the polarization of microglia toward the M1 phenotype and alleviates neuronal death. Furthermore, it is found that the downregulation of mitofusin 2 (Mfn2) expression in microglial cells leads to an imbalance in mitochondrial fusion and division, inducing the release of mitochondrial DNA (mtDNA), which mediates the activation of the cGas-Sting signaling pathway and aggravates inflammatory response damage after SCI. A biomimetic microglial nanoparticle strategy to deliver MASM7 (named MSNs-MASM7@MI) is established. In vitro, MSNs-MASM7@MI showed no biological toxicity and effectively delivered MASM7. In vivo, MSNs-MASM7@MI improves nerve function after SCI. The study provides evidence that cGas-Sting signaling senses Mfn2-dependent mtDNA release and that its activation may play a key role in SCI. These findings provide new perspectives and potential therapeutic targets for SCI treatment.

NONO promotes gallbladder cancer cell proliferation by enhancing oncogenic RNA splicing of DLG1 through interaction with IGF2BP3/RBM14.

Gallbladder cancer (GBC) is a highly malignant and rapidly progressing tumor of the human biliary system, and there is an urgent need to develop new therapeutic targets and modalities. Non-POU domain-containing octamer-binding protein (NONO) is an RNA-binding protein involved in the regulation of transcription, mRNA splicing, and DNA repair. NONO expression is elevated in multiple tumors and can act as an oncogene to promote tumor progression. Here, we found that NONO was highly expressed in GBC and promoted tumor cells growth. The dysregulation of RNA splicing is a molecular feature of almost all tumor types. Accordingly, mRNA-seq and RIP-seq analysis showed that NONO promoted exon6 skipping in DLG1, forming two isomers (DLG1-FL and DLG1-S). Furthermore, lower Percent-Spliced-In (PSI) values of DLG1 were detected in tumor tissue relative to the paraneoplastic tissue, and were associated with poor patient prognosis. Moreover, DLG1-S and DLG1-FL act as tumor promoters and tumor suppressors, respectively, by regulating the YAP1/JUN pathway. N6-methyladenosine (m6A) is the most common and abundant RNA modification involved in alternative splicing processes. We identified an m6A reader, IGF2BP3, which synergizes with NONO to promote exon6 skipping in DLG1 in an m6A-dependent manner. Furthermore, IP/MS results showed that RBM14 was bound to NONO and interfered with NONO-mediated exon6 skipping of DLG1. In addition, IGF2BP3 disrupted the binding of RBM14 to NONO. Overall, our data elucidate the molecular mechanism by which NONO promotes DLG1 exon skipping, providing a basis for new therapeutic targets in GBC treatment.

MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation.

Milk-fat globule EGF factor-8 (MFG-E8, SED1, lactadherin) is known to mediate the phagocytic removal of apoptotic cells by bridging phosphatidylserine (PS)-exposing cells and the vitronectin receptor (VR) on phagocytes. However, we show here that MFG-E8 can mediate phagocytosis of viable neurons during neuroinflammation induced by lipopolysaccharide (LPS), thereby causing neuronal death. In vitro, inflammatory neuronal loss is independent of apoptotic pathways, and is inhibited by blocking the PS/MFG-E8/VR pathway (by adding PS blocking antibodies, annexin V, mutant MFG-E8 unable to bind VR, or VR antagonist). Neuronal loss is absent in Mfge8 knock-out cultures, but restored by adding recombinant MFG-E8, without affecting inflammation. In vivo, LPS-induced neuronal loss is reduced in the striatum of Mfge8 knock-out mice or by coinjection of an MFG-E8 receptor (VR) inhibitor into the rat striatum. Our data show that blocking MFG-E8-dependent phagocytosis preserves live neurons, implying that phagocytosis actively contributes to neuronal death during brain inflammation.

Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death.

It is well-known that dead and dying neurons are quickly removed through phagocytosis by the brain's macrophages, the microglia. Therefore, neuronal loss during brain inflammation has always been assumed to be due to phagocytosis of neurons subsequent to their apoptotic or necrotic death. However, we report in this article that under inflammatory conditions in primary rat cultures of neurons and glia, phagocytosis actively induces neuronal death. Specifically, two inflammatory bacterial ligands, lipoteichoic acid or LPS (agonists of glial TLR2 and TLR4, respectively), stimulated microglial proliferation, phagocytic activity, and engulfment of ∼30% of neurons within 3 d. Phagocytosis of neurons was dependent on the microglial release of soluble mediators (and peroxynitrite in particular), which induced neuronal exposure of the eat-me signal phosphatidylserine (PS). Surprisingly, however, eat-me signaling was reversible, so that blocking any step in a phagocytic pathway consisting of PS exposure, the PS-binding protein milk fat globule epidermal growth factor-8, and its microglial vitronectin receptor was sufficient to rescue up to 90% of neurons without reducing inflammation. Hence, our data indicate a novel form of inflammatory neurodegeneration, where inflammation can cause eat-me signal exposure by otherwise viable neurons, leading to their death through phagocytosis. Thus, blocking phagocytosis may prevent some forms of inflammatory neurodegeneration, and therefore might be beneficial during brain infection, trauma, ischemia, neurodegeneration, and aging.

Acupuncture at Back-Shu point improves insomnia by reducing inflammation and inhibiting the ERK/NF-κB signaling pathway.

BACKGROUND: Insomnia is a disease where individuals cannot maintain a steady and stable sleep state or fail to fall asleep. Western medicine mainly uses sedatives and hypnotic drugs to treat insomnia, and long-term use is prone to drug resistance and other adverse reactions. Acupuncture has a good curative effect and unique advantages in the treatment of insomnia. AIM: To explore the molecular mechanism of acupuncture at Back-Shu point for the treatment of insomnia. METHODS: We first prepared a rat model of insomnia, and then carried out acupuncture for 7 consecutive days. After treatment, the sleep time and general behavior of the rats were determined. The Morris water maze test was used to assess the learning ability and spatial memory ability of the rats. The expression levels of inflammatory cytokines in serum and the hippocampus were detected by ELISA. qRT-PCR was used to detect the mRNA expression changes in the ERK/NF-κB signaling pathway. Western blot and immunohistochemistry were carried out to evaluate the protein expression levels of RAF-1, MEK-2, ERK1/2 and NF-κB. RESULTS: Acupuncture can prolong sleep duration, and improve mental state, activity, diet volume, learning ability and spatial memory. In addition, acupuncture increased the release of 1L-1ß, 1L-6 and TNF-α in serum and the hippocampus and inhibited the mRNA and protein expression of the ERK/NF-κB signaling pathway. CONCLUSION: These findings suggest that acupuncture at Back-Shu point can inhibit the ERK/NF-κB signaling pathway and treat insomnia by increasing the release of inflammatory cytokines in the hippo-campus.

Effect of Remimazolam on Postoperative Delirium in Older Adult Patients Undergoing Orthopedic Surgery: A Prospective Randomized Controlled Clinical Trial.

Background: Postoperative delirium is common in older adult patients and associated with a poor prognosis. The use of benzodiazepine was identified as an independent risk factor for delirium, but there is no randomized controlled trial regarding the relationship between remimazolam, a new ultra-short acting benzodiazepine, and postoperative delirium. We designed a randomized controlled trial to evaluate if remimazolam increases the incidence of postoperative delirium compared with propofol in older adult patients undergoing orthopedic surgery with general anesthesia. Patients and Methods: We enrolled 320 patients aged more than 60 with American Society of Anesthesiologists physical status I-III who underwent orthopedic surgery. Patients were randomized to two groups to receive intraoperative remimazolam or propofol, respectively. Our primary outcome was the incidence of delirium within 3 days after surgery. Secondary outcome was emergence quality including the incidence of emergence agitation, extubation time, and length of post-anesthesia care unit (PACU) stay. Adverse events were also recorded. Results: The incidence of postoperative delirium was 15.6% in the remimazolam group and 12.4% in the propofol group (Risk ratio, 1.26; 95% CI, 0.72 to 2.21; Risk difference, 3.2%; 95% CI, -4.7% to 11.2%; P = 0.42). No significant differences were observed for time of delirium onset, duration of delirium, and delirium subtype between the two groups. Patients in remimazolam group had a lower incidence of hypotension after induction and consumed less vasoactive drugs intraoperatively, but had a longer postoperative extubation time and PACU stay. Conclusion: General anesthesia with remimazolam was not associated with an increased incidence of postoperative delirium compared with propofol in older adult patients undergoing orthopedic surgery.

Robotic navigation during spine surgery: an update of literature.

INTRODUCTION: The application of robotic navigation during spine surgery has advanced rapidly over the past two decades, especially in the last 5 years. Robotic systems in spine surgery may offer potential advantages for both patients and surgeons. This article serves as an update to our previous review and explores the current status of spine surgery robots in clinical settings. AREAS COVERED: We evaluated the literature published from 2020 to 2022 on the outcomes of robotics-assisted spine surgery, including accuracy and its influencing factors, radiation exposure, and follow-up results. EXPERT OPINION: The application of robotics in spine surgery has driven spine surgery into a new era of precision treatment through a form of artificial intelligence assistance that compensates for the limitations of human abilities. Modularized robot configurations, intelligent alignment and planning incorporating multimodal images, efficient and simple human - machine interaction, accurate surgical status monitoring, and safe control strategies are the main technical features for the development of orthopedic surgical robots. The use of robotics-assisted decompression, osteotomies, and decision-making warrants further study. Future investigations should focus on patients' needs while continuing to explore in-depth medical - industrial collaborative development innovations that improve the overall utilization of artificial intelligence and sophistication in disease treatment.

Estimated glomerular filtration rate is a biomarker of cognitive impairment in Parkinson's disease.

Backgrounds: The relationship between kidney function and cognitive impairment in Parkinson's disease (PD) is poorly understood and underexplored. This study aims to explore whether renal indices can serve as indicators to monitor the cognitive impairment of PD. Methods: A total of 508 PD patients and 168 healthy controls from the Parkinson's Progression Markers Initiative (PPMI) were recruited, and 486 (95.7%) PD patients underwent longitudinal measurements. The renal indicators including serum creatinine (Scr), uric acid (UA), and urea nitrogen, as well as UA/Scr ratio and estimated glomerular filtration rate (eGFR), were measured. Cross-sectional and longitudinal associations between kidney function and cognitive impairment were evaluated using multivariable-adjusted models. Results: eGFR was associated with lower levels of cerebrospinal fluid (CSF) Aß1-42 (p = 0.0156) and α-synuclein (p = 0.0151) and higher serum NfL (p = 0.0215) in PD patients at baseline. Longitudinal results showed that decreased eGFR predicted a higher risk of cognitive impairment (HR = 0.7382, 95% CI = 0.6329-0.8610). Additionally, eGFR decline was significantly associated with higher rates of increase in CSF T-tau (p = 0.0096), P-tau (p = 0.0250), and serum NfL (p = 0.0189), as well as global cognition and various cognitive domains (p < 0.0500). The reduced UA/Scr ratio was also linked to higher NfL levels (p = 0.0282) and greater accumulation of T-tau (p = 0.0282) and P-tau (p = 0.0317). However, no significant associations were found between other renal indices and cognition. Conclusion: eGFR is altered in PD subjects with cognitive impairment, and predict larger progression of cognitive decline. It may assist identifying patients with PD at risk of rapid cognitive decline and have the potential to monitoring responses to therapy in future clinical practice.

Lipid-anchored proteasomes control membrane protein homeostasis.

Protein degradation in eukaryotic cells is mainly carried out by the 26S proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here, we show that N-myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system, and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation and membrane protein trafficking. Rpt2G2A/G2A homozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation by myristoyl-anchored proteasomes in health and disease.

GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.

[Impact of short-time treatment of prophylactic antibiotics for surgical site infection in cervical spinal surgery].

OBJECTIVES: This study is designed to determine the impact of the short-time usage of prophylactic antibiotics to prevent postoperative wound infection in spinal surgery. METHODS: The medical records of 965 patients who underwent cervical spinal operation between 2009 and 2011 were collected for the assessment. These patients were divided into two groups based on antibiotic selection and duration of prophylactic antibiotic treatment:234 patients treated with prophylactic antibiotics for a short period of time were set as Group A, whereas Group B included 731 patients treated with prophylactic antibiotics for experience-based length of time. All the patients' records, including personal information, preoperational medical records, surgical records, postoperative medical information and the development of surgical site infections, were collected for analysis. RESULTS: In Group A, 153 patients were treated by second generation cephalosporins and 81 patients were treated by clindamycin. The duration of treatment was 1.17 ± 0.38 days. In Group B, 41 patients were treated by penicillin, 375 and 2 patients were treated by second and third generation cephalosporins, respectively, 128 patients were treated by clindamycin, 42 patients were treated by cephamycin, 128 patients were treated by quinolone, other antibiotic was used by 1 patient and other 14 patients were treated by combinations of antibiotics. The duration of the treatment in Group B was 5.72 ± 1.63 days. The significant differences between the length of treatment time in Group A and B were observed (P < 0.001). There were no statistical differences of pre-/post-operational leukocytes number compared between Group A and B. In addition, although the neutrophils in Group A and B are 70.70% ± 9.71% and 67.09% ± 9.78% respectively, indicating a subtle difference (t = 2.921, P = 0.004), however, these numbers were in normal range; therefore, no clinical significance was found from the comparison of neutrophils in groups. A total of 7 cases (0.73%) of surgical site infection were recorded, including 4 cases (1.71%) in Group A and 3 cases (0.41%) in Group B, all of which were posterior laminoplasty. With Fisher analysis (P = 0.063), these infection rates were not statistically significant. CONCLUSIONS: An appropriate usage of prophylactic antibiotics in a short period of time in cervical spinal surgery did not increase the rate of surgical site infection.

Impaired metabolism of oligodendrocyte progenitor cells and axons in demyelinated lesion and in the aged CNS.

The key pathology of multiple sclerosis (MS) comprises demyelination, axonal damage, and neuronal loss, and when MS develops into the progressive phase it is essentially untreatable. Identifying new targets in both axons and oligodendrocyte progenitor cells (OPCs) and rejuvenating the aged OPCs holds promise for this unmet medical need. We summarize here the recent evidence showing that mitochondria in both axons and OPCs are impaired, and lipid metabolism of OPCs within demyelinated lesion and in the aged CNS is disturbed. Given that emerging evidence shows that rewiring cellular metabolism regulates stem cell aging, to protect axons from degeneration and promote differentiation of OPCs, we propose that restoring the impaired metabolism of both OPCs and axons in the aged CNS in a synergistic way could be a promising strategy to enhance remyelination in the aged CNS, leading to novel drug-based approaches to treat the progressive phase of MS.

Nrf2 signaling activation by a small molecule activator compound 16 inhibits hydrogen peroxide-induced oxidative injury and death in osteoblasts.

We explored the potential activity of compound 16 (Cpd16), a novel small molecule Nrf2 activator, in hydrogen peroxide (H2O2)-stimulated osteoblasts. In the primary murine/human osteoblasts and MC3T3-E1 murine osteoblastic cells, Cpd16 treatment at micro-molar concentrations caused disassociation of Keap1-Nrf2 and Nrf2 cascade activation. Cpd16 induced stabilization of Nrf2 protein and its nuclear translocation, thereby increasing the antioxidant response elements (ARE) reporter activity and Nrf2 response genes transcription in murine and human osteoblasts. Significantly, Cpd16 mitigated oxidative injury in H2O2-stimulited osteoblasts. H2O2-provoked apoptosis as well as programmed necrosis in osteoblasts were significantly alleviated by the novel Nrf2 activator. Cpd16-induced Nrf2 activation and osteoblasts protection were stronger than other known Nrf2 activators. Dexamethasone- and nicotine-caused oxidative stress and death in osteoblasts were attenuated by Cpd16 as well. Cpd16-induced osteoblast cytoprotection was abolished by Nrf2 short hairpin RNA or knockout, but was mimicked by Keap1 knockout. Keap1 Cys151S mutation abolished Cpd16-induced Nrf2 cascade activation and osteoblasts protection against H2O2. Importantly, weekly Cpd16 administration largely ameliorated trabecular bone loss in ovariectomy mice. Together, Cpd16 alleviates H2O2-induced oxidative stress and death in osteoblasts by activating Nrf2 cascade.

A nomogram based on iron metabolism can help identify apathy in patients with Parkinson's disease.

Backgrounds: Apathy is common in Parkinson's disease (PD) but difficult to identify. Growing evidence suggests that abnormal iron metabolism is associated with apathy in PD. We aimed to investigate the clinical features and iron metabolism of apathetic patients with PD, and construct a nomogram for predicting apathy in PD. Methods: Data of 201 patients with PD were analyzed. Demographic data, Apathy Scale (AS) assessments, and serum iron metabolism parameters were obtained. Spearman correlations were used to assess relationships between AS scores and iron metabolism parameters, separately for male and female patients. Additionally, a nomograph for detecting apathetic patients with PD was built based on the results of logistic regression analysis. Results: The serum transferrin (TRF, p < 0.0024) concentration and total iron binding capacity (TIBC, p < 0.0024) were lower in the apathetic group after Bonferroni correction, and they were negatively associated with AS scores in male participants with PD (TRF, r = -0.27, p = 0.010; TIBC, r = -0.259, p = 0.014). The nomogram was developed by incorporating the following five parameters: age, sex, serum iron concentration, TIBC and Hamilton Depression Rating Scale (HAMD) scores, which showed good discrimination and calibration, with a consistency index of 0.799 (95% confidence interval = 0.732-0.865). Conclusion: Abnormal iron metabolism may contribute to apathy in PD, especially among men. TIBC levels in combination with HAMD scores can be effectively used for the prediction of apathetic patients with PD.

Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-κB pathway.

Receptor interacting serine/threonine protein kinase 1 (RIPK1) activation and necroptosis have been genetically and mechanistically linked with human multiple sclerosis and neurodegenerative diseases for which demyelination is a common key pathology. Demyelination can be healed through remyelination which is mediated by new oligodendrocytes derived from the adult oligodendrocyte progenitor cells (OPCs). Unfortunately, the efficiency of remyelination declines with progressive aging partially due to the depletion of OPCs following chronic or repeated demyelination. However, to our knowledge, so far there is no drug which enhances proliferation of OPCs, and it is unknown whether inhibiting RIPK1 activity directly affect OPCs, the central player of remyelination. Using TNFα induced RIPK1-dependent necroptosis in Jurkat FADD-/- cells as a cell death assay, we screened from 2112 FDA-approved drugs and the drug candidates of new RIPK1 inhibitors selected by ourselves, and identified ZJU-37, a small molecule modified by introducing an amide bond to Nec-1s, is a new RIPK1 kinase inhibitor with higher potency than Nec-1s which has the best reported potency. We unveil in addition to protecting myelin from demyelination and axons from degeneration, ZJU-37 exhibits a new role on promoting proliferation of OPCs and enhancing remyelination by inhibiting RIPK1 kinase activity with higher potency than Nec-1s. Mechanistically, ZJU-37 promotes proliferation of OPCs by enhancing the transcription of platelet derived growth factor receptor alpha via NF-κB pathway. This work identifies ZJU-37 as a new drug candidate which enhances remyelination by promoting proliferation of OPCs, paving the way for a potential drug to enhance myelin repair.

A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway.

Neurofibromatosis type 2 is an autosomal dominant multiple neoplasia syndrome and is usually caused by mutations in the neurofibromin 2 (NF2) gene, which encodes a tumor suppressor and initiates the Hippo pathway. However, the mechanism by which NF2 functions in the Hippo pathway isn't fully understood. Here we identified a NF2 c.770-784del mutation from a neurofibromatosis type 2 family. MD simulations showed that this mutation significantly changed the structure of the F3 module of the NF2-FERM domain. Functional assays indicated that the NF2 c.770-784del variant formed LLPS in the cytoplasm with LATS to restrain LATS plasma membrane localization and inactivated the Hippo pathway. Besides, this deletion partly caused a skipping of exon 8 and reduced the protein level of NF2, collectively promoting proliferation and tumorigenesis of meningeal cells. We identified an unrecognized mechanism of LLPS and splicing skipping for the NF2-induced Hippo pathway, which provided new insight into the pathogenesis of neurofibromatosis type 2.