Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT. METHODS: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. RESULTS: Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation. INTERPRETATION: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2023;93:244-256.

Mild matters: parental insights into the conundrums of managing mild congenital hearing loss.

OBJECTIVE: To explore and describe parental experiences related to the management of mild bilateral congenital hearing loss in children. DESIGN: Using qualitative methods, we conducted semi-structured interviews with parents/caregivers until saturation of themes was achieved. We analysed transcripts using inductive content analysis. STUDY SAMPLE: Caregivers of children under 3-years-old with mild bilateral sensorineural hearing loss. RESULTS: We interviewed 12 parents. Parental perception of advice regarding hearing aid fitting was varied; almost all children were offered hearing aids. Perceived positives related to hearing aids: feeling empowered that action has been taken; improvements in the child's hearing perception and; facilitation of behavioural management. Perceived negatives of hearing aid use: difficulties with compliance resulting in parental frustration and guilt, damage/loss of equipment, discomfort, parental discord, altered quality of natural sound and potential bullying/stigma. Some parents were ambivalent about the effect of the hearing aids. Where hearing aids were offered and not fitted, there was significant ongoing uncertainty, and the family carried the burden of their decision. CONCLUSIONS: There was a wide variation in perceived advice regarding early hearing aid fitting in children with mild bilateral hearing loss. We identified parental perceptions of positive/negative impacts of hearing aid fitting and potential perceived harms from not fitting.

A Niemann-pick C1 disease child with BCG-itis: a case report and analysis.

BACKGROUND: Niemann-Pick C disease is a rare autosomal recessive lysosomal lipid storage disorder. Some primary immunodeficiency diseases patients developed regional disease or disseminated disease after vaccinating BCG. It is unclear whether NPC gene deficiency is associated with Mycobacteria infection. CASE PRESENTATION: We report and discuss a case of a child who presented at the age of 6 months with NPC1 and BCG-itis. The patient was treated with Miglustat and the symptom of lymphadenopathy was improved. CONCLUSIONS: We reasonably speculate that NPC1 is a susceptibility gene of Mtb infection and mainly affects innate immunity. Once diagnosed, the infant should not be vaccinated with BCG and early treated.

Application effect of diversified health-promoting models on rehabilitation exercises for cervical spondylotic myelopathy.

BACKGROUND: With improving living standards, the incidence of cervical spondylotic myelopathy (CSM) has become increasingly high. OBJECTIVE: The study aims to explore the effect of diversified health-promoting models on rehabilitation exercises in patients with CSM after an operation. METHOD: This was a randomized controlled trial, wherein 107 patients with CSM treated by neurosurgery were selected as the subjects. Of those, 52 patients in the control group adopted the conventional health-promoting model, while the remaining 55 patients in the intervention group adopted diversified health-promoting models. The effect of rehabilitation exercises in the two groups was evaluated according to the self-efficacy rehabilitation outcome scale, grip strength measurement of the affected limb, and Barthel index. RESULTS: At Day 3 post-operation and before discharge, the self-efficacy management of rehabilitation exercises in the intervention group was better than that of the control group (P< 0.05). The grip strength measurement of the affected limb, Japanese Orthopedic Association score of the cervical vertebra, and Barthel index of the two groups at Day 3 post-operation were lower than before the intervention and were not statistically significant (P> 0.05). However, these three items before discharge were improved when compared with those of before intervention and were statistically significant (P< 0.05). CONCLUSION: Postoperative rehabilitation exercises guided by the diversified health-promoting models for patients with CSM can improve the patients' self-efficacy management ability in rehabilitation exercises, help improve grip strength, and promote the recovery of cervical vertebra function, thereby improving the patients' quality of life.

EV-COMM: A database of interspecies and intercellular interactions mediated by extracellular vesicles.

Intra- and inter-organismal interactions play a crucial role in the maintenance and function of individuals, as well as communities. Extracellular vesicles (EVs) have been identified as effective mediators for the communication both within and between species. They can carry and transport molecular cargoes to transmit biological messages. Several databases (ExoBCD, ExoCarta, EVpedia, EV-TRACK, Vesiclepedia) complied the cargoes information including DNA, RNA, protein, lipid and metabolite associated with EVs. Databases that refer to the complete records on both donor and recipient information are warranted to facilitate the understanding of the interaction across cells and species. In this study, we developed a database that compiled the records equipped with a structured process of EV-mediated interaction. The sources of donor and recipient were classified by cell type, tissues/organs and species, thus providing an extended knowledge of cell-cell, species-species interaction. The isolation and identification methods were presented for assessing the quality of EVs. Information on functional cargoes was included, where microRNA was linked to a prediction server to broaden its potential effects. Physiological and pathological context was marked to show the environment where EVs functioned. At present, a total of 1481 data records in our database, including 971 cell-cell interactions belonging to more than 40 different tissues/organs, and 510 cross-species records. The database provides a web interface to browse, search, visualize and download the interaction records. Users can search for interactions by selecting the context of interest or specific cells/species types, as well as functional cargoes. To the best of our knowledge, the database is the first comprehensive database focusing on interactions between donor and recipient cells or species mediated by EVs, serving as a convenient tool to explore and validate interactions. The Database, shorten as EV-COMM (EV mediated communication) is freely available at http://sdc.iue.ac.cn/evs/list/ and will be continuously updated.

Association between metabolic syndrome severity score and cardiovascular disease: results from a longitudinal cohort study on Chinese adults.

Objective: This study aimed to quantify the severity of metabolic syndrome(MetS) and investigate its association with cardiovascular disease(CVD) risk on Chinese adults. Methods: 13,500 participants from the Zhejiang Adult Chronic Disease Study were followed up between 2010 and 2021. A continuous MetS severity score derived from the five components of MetS was used to quantify MetS severity, and the association between MetS severity and the risk of incident CVD was assessed using Cox proportional hazard and restricted cubic spline regression. Results: Both the presence and severity of MetS were strongly associated with CVD risk. MetS was related to an increased risk of CVD (hazard ratio(HR):1.700, 95% confidence interval(CI): 1.380-2.094). Compared with the hazard ratio for CVD in the lowest quartile of the MetS severity score, that in the second, third, and highest quartiles were 1.812 (1.329-2.470), 1.746 (1.265-2.410), and 2.817 (2.015-3.938), respectively. A linear and positive dose-response relationship was observed between the MetS severity and CVD risk (P for non-linearity = 0.437). Similar results were found in various sensitivity analyses. Conclusion: The MetS severity score was significantly associated with CVD risk. Assessing MetS severity and further ensuring intervention measures according to the different severities of MetS may be more useful in preventing CVD.

The association of body mass index and its interaction with family history of dyslipidemia towards dyslipidemia in patients with type 2 diabetes: a cross-sectional study in Zhejiang Province, China.

Objectives: This study aimed to investigate the association between body mass index (BMI) and dyslipidemia and to explore the interaction between BMI and family history of dyslipidemia towards dyslipidemia in patients with type 2 diabetes. Methods: This cross-sectional study was conducted between March and November 2018 in Zhejiang Province, China. A total of 1,756 patients with type 2 diabetes were included, physical examination data, fasting blood samples and face-to-face questionnaire survey data were collected. Restricted cubic spline analysis was used to evaluate the association between BMI and the risk of dyslipidemia. Unconditional multivariable logistic regression was used to estimate the interaction between BMI and family history of dyslipidemia towards dyslipidemia. Results: The prevalence of dyslipidemia was 53.7% in the study population. The risk of dyslipidemia elevated with increased BMI value (p for non-linearity <0.05). After adjusting for covariates, individuals with high BMI (≥24 kg/m2) and a family history of dyslipidemia had a 4.50-fold (95% CI: 2.99-6.78) increased risk of dyslipidemia compared to the normal reference group, which was higher than the risk associated with high BMI alone (OR = 1.83, 95% CI: 1.47-2.28) or family history of dyslipidemia alone (OR = 1.79 95% CI: 1.14-2.83). Significant additive interaction between high BMI and a family history of dyslipidemia was detected, with RERI, AP, and SI values of 1.88 (95% CI: 0.17-4.10), 0.42 (95% CI: 0.02-0.62), and 2.16 (95% CI: 1.07-4.37), respectively. However, stratified by status of diabetes control, this additive interaction was only find significant among patients with controlled diabetes. Conclusion: Both high BMI and a family history of dyslipidemia were related with high risk of dyslipidemia. Moreover, there were synergistic interaction between these two factors. Patients with type 2 diabetes who had a family history of dyslipidemia were more susceptible to the negative impact of being overweight or obesity on dyslipidemia.

Effects of ivabradine on ventricular electrophysiological remodeling after myocardial infarction in rats.

Introduction: This study aims to investigate the effects of ivabradine (IVA) on ventricular electrophysiological remodeling after myocardial infarction (MI) in rats. Material and methods: A total of 60 male Sprague-Dawley rats were randomly divided into five groups: an MI group, an IVA group, a metoprolol (MET) group, an IVA + MET group, and a sham group. After a four-week intervention, the ventricular electrophysiological parameters were detected by multichannel electrophysiological polygraph. Then, the morphological characteristics were evaluated using hematoxylin and eosin (H&E) and Masson's staining, and the expression of phosphorylated connexin 43 (p-Cx43) in the left ventricular wall was detected through immunohistochemistry and the Western blot test. Results: The electrophysiological examination revealed that the induction rate and fatality rate of ventricular tachycardia (VT)/ventricular fibrillation (VF) were lower in both the IVA and the MET group, compared with the MI group (6/12, 6/12 vs. 10/11; and 1/12, 1/12 vs. 5/11; all p < 0.05), as well as the IVA + MET group (1/11 vs. 10/11, p < 0.01; and 1/11 vs. 5/11, p < 0.05). The induction rate of VT/VF was lower in the IVA + MET group, compared to the MET group (1/11 vs. 6/12, p < 0.05). H&E and Masson's staining revealed that compared with the MI group, the left ventricular infarction area was lower in the IVA, MET, and IVA + MET groups (p < 0.05, p < 0.05, and p < 0.01, respectively), while collagen volume fraction (CVF) also was lower in the other groups (all p < 0.01). The left ventricular infarction area and CVF both were lower in the IVA + MET group, compared to the MET group (p < 0.05 and p < 0.01, respectively). The immunohistochemistry and Western blot revealed that p-Cx43 expression was higher in the treatment groups, compared with the MI group (all p < 0.01). Conclusions: IVA can reduce the incidence of ventricular arrhythmia after MI in male rats by improving both structural and electrical remodeling, and the combination of IVA and MET is even more effective.

Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice.

Recent studies have shown that chlorogenic acid (CGA), which is present in coffee, has protective effects on the nervous system. However, its role in neonatal hypoxic-ischemic brain injury remains unclear. In this study, we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA. We found that CGA intervention effectively reduced the volume of cerebral infarct, alleviated cerebral edema, restored brain tissue structure after injury, and promoted axon growth in injured brain tissue. Moreover, CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival. In addition, changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA. Furthermore, CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2. In summary, our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis, providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

A comparative analysis of 375 patients with lateral and medial medullary infarction.

BACKGROUND: Few studies have compared the etiology and clinical features between pure lateral medullary infarction (LMI) and pure medial medullary infarction (MMI). METHODS: All patients included were hospitalized at The First Affiliated Hospital and The Second Affiliated Hospital of Wenzhou Medical University from January 2015 to July 2020. Their risk factors, clinical manifestation, stroke mechanisms and short-term prognosis were analyzed retrospectively. RESULTS: Among the 387 patients enrolled, 266 (68.7%) had LMI, 109 (28.2%) had MMI, and 12 (3.1%) (nine men and three women) had LMI plus MMI. We analyzed the 375 patients of LMI and MMI. The average ages of LMI and MMI were 59.4 years and 62.69 years, respectively. Univariate analysis and multivariable logistic regression was used to investigate the existing risk factors of MMI relative to LMI. Prior infarction, poor glycemic control, and atherosclerosis were more frequently associated with MMI than with LMI. The clinical manifestation was significantly different between LMI and MMI. We used modified Rankin Scale (mRS) score as the short-term prognostic evaluation criteria, and MMI appeared worse than LMI. CONCLUSIONS: This study reveals that: (1) patients with MMI are older than those with LMI; (2) prior infarction, poor glycemic control, and atherosclerosis are independent risk factors of MMI than that of LMI; (3) the clinical manifestations of LMI and MMI are heterogeneous; (4) short-term prognosis of MMI is worse than LMI.

Comprehensive evaluation of intravitreal conbercept versus half-dose photodynamic therapy for chronic central serous chorioretinopathy.

AIM: To compare the safety and efficacy of conbercept intravitreal injection and half-dose photodynamic therapy (PDT) in treating chronic central serous chorioretinopathy (CSC). METHODS: This study was retrospective. Thirty-seven patients (37 eyes) with chronic CSC received conbercept injections while 57 patients (57 eyes) were treated with half-dose PDT. All subjects were followed in 6mo. Outcome measures included change in best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), and resolution of subretinal fluid (SRF). RESULTS: There was no adverse event observed in either treatment group. At the 6-month follow-up, 26 eyes (70.3%) in the conbercept group and 54 eyes (94.7%) in the half-dose PDT group (P<0.05) reached full resolution of SRF. The mean logarithm of the minimum angle of resolution (logMAR) BCVA significantly improved (P<0.001) in both treatment groups with better outcome at early phase in the half-dose PDT group (2wk, 1, and 2mo, P<0.05). All subjects experienced significant CMT improvement (P<0.001) with no statistical difference between the two groups (P>0.05). The SFCT also improved in all subjects (P<0.001) with better outcome in the half-dose PDT group (P<0.05). CONCLUSION: Both intravitreal conbercept and half-dose PDT are safe to use in treating chronic CSC. By 6mo, both treatment groups are efficacious in improving BCVA, reducing CMT and SFCT, and resolving SRF in eyes with chronic CSC. Half-dose PDT may show better outcome at initial phase of treatment in chronic CSC. Longer follow-up period is necessary to study for long-term effect and safety.

NALP3 orchestrates cellular bioenergetics to facilitate non-small cell lung cancer cell growth.

AIMS: Previous work has reported the closely correlation between inflammation and carcinogenesis, while the role of NALP3, the key component of inflammasome activation in NSCLC remains elusive. This study was to unravel the mechanism of NALP3 on modulating NSCLC cancer cell growth. METHODS: IHC and immuno-blot were performed to analyze expression of NALP3 and indicated molecules. CCK-8 and xenograft nude mice assay were used to evaluate cell growth in vitro and in vivo. Bioenergetics assay was performed to measure OXPHOS and aerobic glycolysis. siRNA and shRNA were constructed to knockdown endogenous NALP3 and DNMT1. Co-immunoprecipitation was applied to confirm the interaction between NALP3 and DMAP1. BioProfile FLEX analyzer and Lactate Reagent Kit were used to measure relative level glucose uptake and lactate production. KEY FINDINGS: We reported NALP3 were up-regulated in NSCLC tumor tissues. NALP3 depletion suppressed cancer cell growth in vitro and in vivo. Moreover, data showed depletion of NALP3 promoted cell bioenergetics switch from aerobic glycolysis to OXPHOS. Additionally, we found NALP3 interacted with DMAP1 and alteration of NALP3 increased DNMT1 level. Subsequently, we clarified depletion of DNMT1 significantly suppressed NSCLC cell growth and orchestrated cellular metabolism which was similar to the effects of NALP3 knockdown. Finally, our data showed high NALP3 was associated with poor outcomes, and correlated with TNM stage and differentiation. SIGNIFICANCE: Current study elucidated NALP3 could promote metabolic reprogramming to regulate NSCLC cell growth and suggested that NALP3 may be considered as a novel biomarker and therapeutic target for NSCLC patients.

Applying Lean Six Sigma to Reduce the Incidence of Unplanned Surgery Cancellation at a Large Comprehensive Tertiary Hospital in China.

Unplanned surgery cancellation (USC) was an important quality management issue in the course of medical care for surgical patients, which caused inappropriate use of hospital resources and had negative impacts on quality and safety. This study used Lean Six Sigma to reduce the incidence of USC. Following the Lean Six Sigma DMAIC (Define, Measure, Analyze, Improve, and Control) process, the main factors influencing the USC were identified, such as the time of informing patient admission, the time of submitting operation notice, and the management of test report follow-up. A series of measures were implemented including improving the health education content of virtual bed patients, standardizing the way of communication between the Admission Management Center and the patients, improving the timing of anesthesia evaluation, optimizing the process of operation notice with an information system, and implementing the regulations of virtual bed management. The incidence of USC reduced from 10.21% in Jan. 2016 to 3.8% in Dec. 2016, and the Z-score increased from 1.25 to 1.68, which improved patient safety and demonstrated that Lean Six Sigma was an effective method to solve cross-department issues in hospital.

Comparison of persistent submacular fluid in different preoperative macular status after vitrectomy for rhegmatogenous retinal detachment.

AIM: To compare the incidence of persistent submacular fluid (SMF) and visual outcome after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) in different preoperative macular status according to optical coherence tomography (OCT). METHODS: A non-randomized, retrospective review was performed for patients who underwent successful PPV for RRD. OCT exams were taken preoperatively and 1mo after surgery, until SMF disappeared. According to the preoperative macular status on OCT, patients were divided into two groups: macula-off RRD (Group A) and macula-on RRD (Group B). In Group A, there were two subgroups: macula partly detached (Group A1) and macula totally detached (Group A2). The main outcome measures were the presence of SMF on OCT 1mo after surgery, and the preoperative and postoperative best corrected visual acuities (BCVA), among the different groups and depending on the presence or absence of persistent SMF. RESULTS: A total of 139 eyes of 139 patients were included in the study. Persistent SMF at 1mo after surgery was 15.8% (22/139), all occurring in Group A (22/101); Group B had no SMF at 1mo after surgery (0/38, P=0.002). The incidence of persistent SMF at 1mo after surgery in Group A1 was 50% (14/28), and in Group A2 was 11.0% (8/73, P<0.001). Significant differences were shown between the presence and absence of persistent SMF on foveola-off RRD, the preoperative BCVA, the 1mo postoperative BCVA, and the degree of the BCVA improvement from 1mo postoperatively to the final follow-up (P<0.05). However, there were no significant differences in the final BCVA (P>0.05). CONCLUSION: Persistent SMF after PPV for retinal detachment is associated with preoperative macular status. Macula-uninvolving RRD shows no persistent SMF after PPV. Macular partly detached RRD has a higher incidence of SMF than macula totally detached RRD after PPV. The persistence of SMF may be responsible for the delayed visual recovery, whereas there were no significant differences in the final visual acuity.

Novel treatment strategies for patients with HER2-positive breast cancer who do not benefit from current targeted therapy drugs.

Human epidermal growth factor receptor-2 positive breast cancer (HER2+ BC) is characterized by a high rate of metastasis and drug resistance. The advent of targeted therapy drugs greatly improves the prognosis of HER2+ BC patients. However, drug resistance or severe side effects have limited the application of targeted therapy drugs. To achieve more effective treatment, considerable research has concentrated on strategies to overcome drug resistance. Abemaciclib (CDK4/6 inhibitor), a new antibody-drug conjugate (ADC), src homology 2 (SH2) containing tyrosine phosphatase-1 (SHP-1) and fatty acid synthase (FASN) have been demonstrated to improve drug resistance. In addition, using an effective vector to accurately deliver drugs to tumors has shown good application prospects. Many studies have also found that natural anti-cancer substances produced effective results during in vitro and in vivo anti-HER2+ BC research. This review aimed to summarize the current status of potential clinical drugs that may benefit HER2+ BC patients in the future.

Risk of gastrointestinal complications in breast cancer patients treated with neratinib: a meta-analysis.

BACKGROUNDS: Neratinib is a potent EGFR/HER2 kinase inhibitor. Gastrointestinal complications (i.e. diarrhea, vomiting and nausea) are the most common adverse events. In this study, we aimed to investigate (1) the overall incidence and relative risk (RR) of diarrhea, vomiting and nausea and (2) whether combination neratinib therapy increased the incidence of gastrointestinal complications versus neratinib alone. METHODS: Relevant studies were identified from the PubMed database, from abstracts presented at the American Society of Clinical Oncology annual conference and from the Web of Science database. Incidences, RRs, and 95% confidence intervals (CIs) were calculated. RESULTS: The incidences of all-grade diarrhea, vomiting and nausea in the neratinib groups were 89% (95% CI = 77-95%), 31% (95% CI = 25-37%) and 44% (95% CI = 33-55%), respectively. The neratinib arms significantly increased the risk of diarrhea and vomiting in comparison with the control groups (diarrhea: all-grade, RR = 2.06, 95% CI = 1.38-3.08, P = 0.0004; grade 3/4, RR = 8.77, 95% CI = 2.91-26.40, P = 0.0001; vomiting: all-grade, RR = 2.02, 95% CI = 1.10-3.71, P = 0.02; grade 3/4, RR = 7.10, 95% CI = 3.33-15.15, P < 0.00001). CONCLUSIONS: Our meta-analysis demonstrates that the neratinib arms are associated with a significantly increased risk of diarrhea and vomiting.

PTEN regulation by the Akt/GSK-3ß axis during RANKL signaling.

Phosphatase and tensin homolog (PTEN) negatively regulates phosphoinositide 3-kinase (PI3K)/Akt signaling as a lipid phosphatase for the second messenger phosphatidylinositol 3,4,5-triphosphate. We discovered recently that inactivating glycogen synthase kinase-3ß (GSK-3ß) via Akt plays an important role in receptor activator of nuclear factor κb ligand (RANKL)-induced osteoclastogenesis. However, the signaling link between GSK-3ß and PTEN in RANKL signaling has not been revealed. Downregulating PTEN by RNA interference increases Akt and GSK-3ß phosphorylation levels by RANKL, thereby promoting the formation of osteoclasts. PTEN phosphorylation at threonine 366 (T366) decreased gradually during RANKL-induced osteoclastogenesis, whereas PTEN protein levels were unaffected. Interestingly, the PTEN phosphorylation defective mutant (T366A) showed increased osteoclastogenesis, which is consistent with its lower phosphatase activity, compared to that of wild-type PTEN. Moreover, treatment with the GSK-3 inhibitor SB216763 suppressed PTEN phosphorylation levels and phosphatase activity and enhanced Akt phosphorylation. These data suggest that inhibiting GSK-3ß during RANKL-induced osteoclastogenesis decreases PTEN phosphorylation, leading to enhanced osteoclast differentiation through Akt activation.

Early estrogen-induced gene 1, a novel RANK signaling component, is essential for osteoclastogenesis.

The receptor activator of NF-κB (RANK) and immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors are essential factors involved in regulating osteoclast formation and bone remodeling. Here, we identify early estrogen-induced gene 1 (EEIG1) as a novel RANK ligand (RANKL)-inducible protein that physically interacts with RANK and further associates with Gab2, PLCγ2 and Tec/Btk kinases upon RANKL stimulation. EEIG1 positively regulates RANKL-induced osteoclast formation, likely due to its ability to facilitate RANKL-stimulated PLCγ2 phosphorylation and NFATc1 induction. In addition, an inhibitory peptide designed to block RANK-EEIG1 interaction inhibited RANKL-induced bone destruction by reducing osteoclast formation. Together, our results identify EEIG1 as a novel RANK signaling component controlling RANK-mediated osteoclast formation, and suggest that targeting EEIG1 might represent a new therapeutic strategy for the treatment of pathological bone resorption.

Protection effect of piper betel leaf extract against carbon tetrachloride-induced liver fibrosis in rats.

Piper betel leaves (PBL) are used in Chinese folk medicine for the treatment of various disorders. PBL has the biological capabilities of detoxication, antioxidation, and antimutation. In this study, we evaluated the antihepatotoxic effect of PBL extract on the carbon tetrachloride (CCl(4))-induced liver injury in a rat model. Fibrosis and hepatic damage, as reveled by histology and the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were induced in rats by an administration of CCl(4) (8%, 1 ml/kg body weight) thrice a week for 4 weeks. PBL extract significantly inhibited the elevated AST and ALT activities caused by CCl(4) intoxication. It also attenuated total glutathione S-transferase (GST) activity and GST alpha isoform activity, and on the other hand, enhanced superoxide dismutase (SOD) and catalase (CAT) activities. The histological examination showed the PBL extract protected liver from the damage induced by CCl(4) by decreasing alpha-smooth muscle actin (alpha-sma) expression, inducing active matrix metalloproteinase-2 (MMP2) expression though Ras/Erk pathway, and inhibiting TIMP2 level that consequently attenuated the fibrosis of liver. The data of this study support a chemopreventive potential of PBL against liver fibrosis.