SIGMAR1 targets AMPK/ULK1 pathway to inhibit SH-SY5Y cell apoptosis by regulating endoplasmic reticulum stress and autophagy.

Distal hereditary motor neuropathy (dHMN) is a progressive neurological disease characterized by distal limb muscle weakness and amyotrophy. Sigma 1 receptor (σ1R), a gene product of SIGMAR1, mutations have been reported to induce dHMN, but its mechanism remains unknown. This study aims to explore the effect of C238T and 31_50del mutations in σ1R on neuronal SH-SY5Y cell functions. The SH-SY5Y cells that overexpressed σ1R, C238T mutant σ1R (σ1RC238T) or 31_50del mutant σ1R (σ1R31_50del) were constructed by pEGFPN1 vectors. We used Western blot (WB) and immunofluorescence (IF) staining to detect the expression of σ1R and green fluorescent proteins (GFP). Then, we evaluated the impact of σ1R mutation on apoptosis, autophagy, endoplasmic reticulum stress, and the involvement of the unfolded protein response (UPR) pathway in SH-SY5Y cells. We found that σ1RC238T and σ1R31_50del downregulated σ1R and promoted the apoptosis of SH-SY5Y cells. σ1RC238T and σ1R31_50del increased p-PERK, p-eIF2α, p-JNK, BIP, ATF4, CHOP, ATF6, XBP1, Caspase3, Caspase12 expressions and Ca2+ concentration, whereas decreased ATP content in SH-SY5Y cells. Besides, the expressions of LC3B, Lamp1, ATG7, Beclin-1 and phosphorylation of AMPK and ULK1 were increased, while the p62 level decreased after C238T or 31_50del mutation of σ1R. Additionally, AMPK knockdown abolished the apoptosis mediated by σ1RC238T or σ1R31_50del in SH-SY5Y cells. Our results indicated that C238T or 31_50del mutation in σ1R promoted motor neuron apoptosis through the AMPK/ULK1 pathway in dHMN. This study shed light on a better understanding of the neurons pathological mechanisms mediated by σ1R C238T and σ1R 31-50del in dHMN.

Rationale, Design, and Interim Observations of the Steady Movement With Innovating Leadership for Heart Failure (SMILE HF) Registry: A Multicenter Prospective Cohort Registry for Patients With Acute Heart Failure.

Background and Objectives: Heart failure (HF) is a leading cause of hospitalization and death worldwide. The Steady Movement with Innovating Leadership for Heart Failure (SMILE HF) aims to evaluate the clinical characteristics, management, hospital course, and long-term outcomes of patients hospitalized for acute HF in South Korea. Methods: This prospective, observational multicenter cohort study was conducted on consecutive patients hospitalized for acute HF in nine university hospitals since September 2019. Enrolment of 2000 patients should be completed in 2024, and follow-up is planned through 2025. Results: Interim analysis of 1,052 consecutive patients was performed to understand the baseline characteristics. The mean age was 69±15 years; 57.6% were male. The mean left ventricular ejection fraction was 39±15%. The prevalences of HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction were 50.9%, 15.3%, and 29.2%. Ischemic cardiomyopathy (CMP) was the most common etiology (32%), followed by tachycardia-induced CMP (12.8%) and idiopathic dilated CMP (9.5%). The prescription rate of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers/angiotensin receptor/neprilysin inhibitor, beta-blockers, spironolactone, and sodium-glucose cotransporter-2 inhibitors at discharge were 76.8%, 66.5%, 50.0%, and 17.5%, respectively. The post-discharge 90-day mortality and readmission rates due to HF aggravation were 2.0% and 6.4%, respectively. Our analysis reveals the current state of acute HF in South Korea. Conclusions: Our interim analysis provides valuable insights into the clinical characteristics, management, and early outcomes of acute HF patients in South Korea, highlighting the current state and treatment patterns in this population.

The diagnostic value of bronchoalveolar lavage fluid metagenomic next-generation sequencing in critically ill patients with respiratory tract infections.

Metagenomic next-generation sequencing (mNGS) is an unbiased and rapid method for detecting pathogens. This study enrolled 145 suspected severe pneumonia patients who were admitted to the Affiliated Hospital of Jining Medical University. This study primarily aimed to determine the diagnostic performance of mNGS and conventional microbiological tests (CMTs) using bronchoalveolar lavage fluid samples for detecting pathogens. Our findings indicated that mNGS performed significantly higher sensitivity (97.54% vs 28.68%, P < 0.001), coincidence (90.34% vs 35.17%, P < 0.001), and negative predictive value (80.00% vs 13.21%, P < 0.001) but performed lower specificity than CMTs (52.17% vs 87.5%, P < 0.001). Streptococcus pneumoniae as the most common bacterial pathogen had the largest proportion (22.90%, 30/131) in this study. In addition to bacteria, fungi, and virus, mNGS can detect a variety of atypical pathogens such as Mycobacterium tuberculosis and non-tuberculous. Mixed infections were common in patients with severe pneumonia, and bacterial-fungal-viral-atypical pathogens were the most complicated infection. After adjustments of antibiotics based on mNGS and CMTs, the clinical manifestation improved in 139 (95.86%, 139/145) patients. Our data demonstrated that mNGS had significant advantage in diagnosing respiratory tract infections, especially atypical pathogens and fungal infections. Pathogens were detected timely and comprehensively, contributing to the adjustments of antibiotic treatments timely and accurately, improving patient prognosis and decreasing mortality potentially.IMPORTANCEMetagenomic next-generation sequencing using bronchoalveolar lavage fluid can provide more comprehensive and accurate pathogens for respiratory tract infections, especially when considering the previous usage of empirical antibiotics before admission or complicated clinical presentation. This technology is expected to play an important role in the precise application of antimicrobial drugs in the future.

Heart Failure Statistics 2024 Update: A Report From the Korean Society of Heart Failure.

Background and Objectives: The number of people with heart failure (HF) is increasing worldwide, and the social burden is increasing as HF has high mortality and morbidity. We aimed to provide updated trends on the epidemiology of HF in Korea to shape future social measures against HF. Methods: We used the National Health Information Database of the National Health Insurance Service to determine the prevalence, incidence, hospitalization rate, mortality rate, comorbidities, in-hospital mortality, and healthcare cost of patients with HF from 2002 to 2020 in Korea. Results: The prevalence of HF in the total Korean population rose from 0.77% in 2002 to 2.58% (1,326,886 people) in 2020. Although the age-standardized incidence of HF decreased over the past 18 years, the age-standardized prevalence increased. In 2020, the hospitalization rate for any cause in patients with HF was 1,166 per 100,000 persons, with a steady increase from 2002. In 2002, the HF mortality was 3.0 per 100,000 persons, which rose to 15.6 per 100,000 persons in 2020. While hospitalization rates and in-hospital mortality for patients with HF increased, the mortality rate for patients with HF did not (5.8% in 2020), and the one-year survival rate from the first diagnosis of HF improved. The total healthcare costs for patients with HF were approximately $2.4 billion in 2020, a 16-fold increase over the $0.15 billion in 2002. Conclusions: The study's results underscore the growing socioeconomic burden of HF in Korea, driven by an aging population and increasing HF prevalence.

Predicting amyloid-PET and clinical conversion in apolipoprotein E ε3/ε3 non-demented individuals with multidimensional factors.

The apolipoprotein E (APOE) ε4 is a well-established risk factor of amyloid-ß (Aß) in Alzheimer's disease (AD). However, because of the high prevalence of APOE ε3, there may be a large number of people with APOE ε3/ε3 who are non-demented and have Aß pathology. There are limited studies on assessing Aß status and clinical conversion in the APOE ε3/ε3 non-demented population. Two hundred and ninety-three non-demented individuals with APOE ε3/ε3 from ADNI database were divided into Aß-positron emission tomography (Aß-PET) positivity (+) and Aß-PET negativity (-) groups using cut-off value of >1.11. Stepwise regression searched for a single or multidimensional clinical variables for predicting Aß-PET (+), and the receiver operating characteristic curve (ROC) assessed the accuracy of the predictive models. The Cox regression model explored the risk factors associated with clinical conversion to mild cognitive impairment (MCI) or AD. The results showed that the combination of sex, education, ventricle and white matter hyperintensity (WMH) volume can accurately predict Aß-PET status in cognitively normal (CN), and the combination of everyday cognition study partner total (EcogSPTotal) score, age, plasma p-tau 181 and WMH can accurately predict Aß-PET status in MCI individuals. EcogSPTotal score were independent predictors of clinical conversion to MCI or AD. The findings may provide a non-invasive and effective tool to improve the efficiency of screening Aß-PET (+), accelerate and reduce costs of AD trial recruitment in future secondary prevention trials or help to select patients at high risk of disease progression in clinical trials.

Trends and focal points in pelvic floor reconstruction for pelvic organ prolapse: A bibliometric analysis.

OBJECTIVE: This study aims to investigate the current research trends and focal points in the field of pelvic floor reconstruction for the management of pelvic organ prolapse (POP). METHODS: To achieve this objective, a bibliometric analysis was conducted on relevant literature using the Citespace database. The analysis led to the creation of a knowledge map, offering a comprehensive overview of scientific advancements in this research area. RESULTS: The study included a total of 607 publications, revealing a consistent increase in articles addressing pelvic floor reconstruction for POP treatment. Most articles originated from the United States (317 articles), followed by Chinese scholars (40 articles). However, it is important to note that the overall number of articles remains relatively low. The organization with the highest publication frequency was the Cleveland Clinic in Ohio, where Matthew D. Barber leads the academic group. Barber himself has the highest number of published articles (18 articles), followed by Zhu Lan, a Chinese scholar (10 articles). Key topics with high frequency and mediated centrality include stress urinary incontinence, quality of life, impact, and age. The journal with the largest number of papers from both domestic and international researchers is INT UROGYNECOL J. The study's hotspots mainly focus on the impact of pelvic floor reconstruction on the treatment and quality of life of POP patients. The United States leads in this field, but there is a lack of cooperation between countries, institutions, and authors. Moving forward, cross-institutional, cross-national, and cross-disciplinary exchanges and cooperation should be strengthened to further advance the field of pelvic floor reconstructive surgery for POP research.

Incidence of atrial fibrillation in patients with renal infarction: A retrospective cohort analysis of the Korean national health insurance registry.

BACKGROUND: Regarding the pathophysiology of renal infarction (RI), cardioembolic causes could have large proportion. However, there are notable variations in prevalence of atrial fibrillation (AF) among patients with RI across different studies, ranging from 17 to 65%. The primary objective of this study is to analyze the incidence of AF in patients with RI. METHODS: This nationwide retrospective cohort study enrolled 5200 patients with RI from the Korean National Institute of Health Services database spanning the years 2013 to 2019. The study accessed the AF incidence rate within 12 months in patients without a prior history of AF. Events occurring within 3 months of RI diagnosis were excluded to mitigate cases diagnosed during the initial screening or those with AF diagnoses that were potentially overlooked in the past. RESULTS: AF occurred in 19.1% of patients with RI over the entire period (median: 2.5 years, interquartile range 1.04-4.25 years). The majority of AF cases (16.1%) occured within the first year, resulting in an overall incidence rate of 7.0 per 100 person-years. Patients with newly developed AF were, on average, older than those who did not develop AF (64.1 vs. 57.3 years, P < 0.001). The independent predictors of AF were identified as age, male sex, higher body mass index, current smoking, ischemic heart disease, and heart failure. CONCLUSIONS: Physicians should consider the implementation of active rhythm monitoring for patients with RI to identify potential occurrence of subclinical AF, even if not initially diagnosed during the initial screening after RI diagnosis.

Gamma-Aminobutyric Acid in Rice Bran Extract Exerts Antistress Effects in Mouse Models with Depressive-Like Behaviors.

Various neurotransmitters are involved in regulating stress systems. In this study, we investigated the effects of gamma-aminobutyric acid-rich rice bran extract (GRBe) in mice stressed by forced swimming and tail suspension tests. Four weeks of oral administration of GRBe (500-2000 mg/kg) reduced the levels of dopamine and corticosterone in the blood and brain while increasing serotonin levels. GRBe was involved not only in stress but also in regulating sleep and obesity-related genes. Modern society experiences diverse and tense lives because of urbanization and informatization, which cause excessive stress due to complicated interpersonal relationships, heavy work burden, and fatigue from the organized society. High levels of stress cause psychological instability and disrupt the balance in the autonomic nervous system, which maintains the body's equilibrium, resulting in cardiovascular and cerebrovascular diseases, hormonal imbalances, and sleep disorders. Therefore, our results suggest that GRBe is a useful substance that can relieve tension by ultimately influencing a depressive-like state by lowering the levels of neuronal substances, hormones, and cytokines involved in stress and sleep disorders.

Home Bioelectrical Impedance Analysis Management System in Patients With Heart Failure: Rationale and Study Design.

Body fluid monitoring and management are essential to control dyspnea and prevent re-hospitalization in patients with chronic heart failure (HF). There are several methods to estimate and monitor patient's volume status, such as symptoms, signs, body weight, and implantable devices. However, these methods might be difficult to use for reasons that are slow to reflect body water change, inaccurate in specific patients' condition, or invasive. Bioelectrical impedance analysis (BIA) is a novel method for body water monitoring in patients with HF, and the value in prognosis has been proven in previous studies. We aim to determine the efficacy and safety of home BIA body water monitoring-guided HF treatment in patients with chronic HF. This multi-center, open-label, randomized control trial will enroll patients with HF who are taking loop diuretics. The home BIA group patients will be monitored for body water using a home BIA device and receive messages regarding their edema status and direction of additional diuretics usage or behavioral changes through the linked application system once weekly. The control group patients will receive the usual HF management. The primary endpoint is the change in N-terminal prohormone of brain natriuretic peptide levels from baseline after 12 weeks. This trial will provide crucial evidence for patient management with a novel home BIA body water monitoring system in patients with HF.

Complement components regulates ferroptosis in CVB3 viral myocarditis by interatction with TFRC.

BACKGROUND: Dysregulated cell death machinery and an excessive inflammatory response in Coxsackievirus B3(CVB3)-infected myocarditis are hallmarks of an abnormal host response. Complement C4 and C3 are considered the central components of the classical activation pathway and often participate in the response process in the early stages of virus infection. METHODS: In our study, we constructed a mouse model of CVB3-related viral myocarditis via intraperitoneal injection of Fer-1 and detected myocarditis and ferroptosis markers in the mouse myocardium. Then, we performed co-IP and protein mass spectrometry analyses to explore which components interact with the ferroptosis gene transferrin receptor (TFRC). Finally, functional experiments were conducted to verify the role of complement components in regulating ferroptosis in CVB3 infection. RESULTS: It showed that the ferroptosis inhibitor Fer-1 could alleviate the inflammation in viral myocarditis as well as ferroptosis. Mechanistically, during CVB3 infection, the key factor TFRC was activated and inhibited by Fer-1. Fer-1 effectively prevented the consumption of complement C3 and overload of the complement product C4b. Interestingly, we found that TFRC directly interacts with complement C4, leading to an increase in the product of C4b and a decrease in the downstream complement C3. Functional experiments have also confirmed that regulating the complement C4/C3 pathway can effectively rescue cell ferroptosis caused by CVB3 infection. CONCLUSIONS: In this study, we found that ferroptosis occurs through crosstalk with complement C4 in viral myocarditis through interaction with TFRC and that regulating the complement C4/C3 pathway may rescue ferroptosis in CVB3-infected cardiomyocytes.

Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors.

The coexistence of ferroptosis and other modes of death has great advantages in the treatment of cancers. A series of glutathione peroxidase 4 (GPX4) and cyclin-dependent kinase (CDK) dual inhibitors were designed and synthesized, given the synergistic anticancer effect of ML162 (GPX4 inhibitor) in combination with indirubin-3'-oxime (IO) (CDK inhibitor). Compound B9 exhibited the highest potential cytotoxic activity against all four cell lines and displayed excellent inhibitory activity against GPX4 (IC50 = 542.5 ± 0.9 nM) and selective inhibition of CDK 4/6 (IC50 = 191.2 ± 8.7, 68.1 ± 1.4 nM). Mechanism research showed that B9 could simultaneously induce ferroptosis and arrest cells at the G1 phase in both MDA-MB-231 cells and HCT-116 cells. Compared with ML162 and IO, B9 showed much stronger cancer cell growth inhibition in vivo. These results proved that developing potent GPX4/CDK dual inhibitors is a promising strategy for the malignant cancer therapy.

Acetylation of FOXO1 activates Bim expression involved in CVB3 induced cardiomyocyte apoptosis.

Viral myocarditis (VMC) is the major reason for sudden cardiac death among both children and young adults. Of these, coxsackievirus B3 (CVB3) is the most common causative agent of myocarditis. Recently, the role of signaling pathways in the pathogenesis of VMC has been evaluated in several studies, which has provided a new perspective on identifying potential therapeutic targets for this hitherto incurable disease. In the present study, in vivo and in vitro experiments showed that CVB3 infection leads to increased Bim expression and triggers apoptosis. In addition, by knocking down Bim using RNAi, we further confirmed the biological function of Bim in apoptosis induced by CVB3 infection. We additionally found that Bim and forkhead box O1 class (FOXO1) inhibition significantly increased the viability of CVB3-infected cells while blocking viral replication and viral release. Moreover, CVB3-induced Bim expression was directly dependent on FOXO1 acetylation, which is catalyzed by the co-regulation of CBP and SirTs. Furthermore, the acetylation of FOXO1 was an important step in Bim activation and apoptosis induced by CVB3 infection. The findings of this study suggest that CVB3 infection induces apoptosis through the FOXO1 acetylation-Bim pathway, thus providing new insights for developing potential therapeutic targets for enteroviral myocarditis.

The Prevalence of Sensorineural Hearing Loss in β-thalassaemia patient treated with Desferrioxamine

Objective: This study aimed to evaluate the prevalence of sensorineural hearing loss (SNHL) in β-thalassaemia patients treated with Desferrioxamine (DFO) and determine the correlation of SNHL with average daily DFO dosage, serum ferritin level and Therapeutic index (T.I). Methods: This is a cross sectional descriptive study carried out for a period of 14 months and 54 patients were recruited. The recruited patients are transfusion dependant β- thalassaemia patient aged 3 years and above treated with DFO. An interview, clinical examination and hearing assessment, which included tympanogram, and Pure Tone Audiometry (PTA) or behaviour alaudiometry were performed. The data on age started on DFO, average daily DFO, duration of DFO intake, serum ferritin past 1 year and Therapeutic Index (T.I) were obtained from patients’ case notes. Results: The prevalence of SNHL was 57.4% and majority has mild hearing loss (93.6%). Fourteen patients (25.9%) have bilateral ear involvement and as many as 17 patients (31.5%) have SNHL in either ear. A total of 23 patients (42.6%) have normal hearing level. Although the prevalence of SNHL was 57.4%, only a small percentage of the patient noticed and complained of hearing loss (11.1%). There is no association between age started on DFO, average daily DFO and duration of DFO intake with normal hearing group and those patients with SNHL. Positive correlation was seen between average daily DFO with 2000 and 4000Hz on PTA in the left ear and between serum ferritin level past 1 year with 4000 and 8000Hz in the right ear and 8000Hz in the left ear. No significant correlation was seen between T.I on PTA. Conclusion: The prevalence of SNHL from hearing assessment is high in β-thalassaemia patients in this study. However, it is manifested clinically in a smaller percentage. We suggest a baseline hearing assessment should be carried on all β-thalassaemia patients prior to DFO chelation therapy.