Clinical correlates of pareidolias and color discrimination deficits in idiopathic REM sleep behavior disorder and Parkinson's disease.

Visuoperceptual dysfunction is common in Parkinson's disease (PD) and is also reported in its prodromal phase, isolated REM sleep behavior disorder (iRBD). We aimed to investigate color discrimination ability and complex visual illusions known as pareidolias in patients with iRBD and PD compared to healthy controls, and their associating clinical factors. 46 iRBD, 43 PD, and 64 healthy controls performed the Farnsworth-Munsell 100 hue test and noise pareidolia tests. Any relationship between those two visual functions and associations with prodromal motor and non-motor manifestations were evaluated, including MDS-UPDRS part I to III, Cross-Cultural Smell Identification Test, sleep questionnaires, and comprehensive neuropsychological assessment. iRBD and PD patients both performed worse on the Farnsworth-Munsell 100 hue test and had greater number of pareidolias compared to healthy controls. No correlations were found between the extent of impaired color discrimination and pareidolia scores in either group. In iRBD patients, pareidolias were associated with frontal executive dysfunction, while impaired color discrimination was associated with visuospatial dysfunction, hyposmia, and higher MDS-UPDRS-III scores. Pareidolias in PD patients correlated with worse global cognition, whereas color discrimination deficits were associated with frontal executive dysfunction. Color discrimination deficits and pareidolias are frequent but does not correlate with each other from prodromal to clinically established stage of PD. The different pattern of clinical associates with the two visual symptoms suggests that evaluation of both color and pareidolias may aid in revealing the course of neurodegeneration in iRBD and PD patients.

Antimicrobial Resistance Profiles and Molecular Characteristics of Extended-Spectrum ß-Lactamase-Producing Escherichia coli Isolated from Healthy Cattle and Pigs in Korea.

Antimicrobial-resistant bacteria isolated from food animals pose a major health threat to the public on this planet. This study aimed to determine the susceptibility profiles of Escherichia coli isolated from cattle and pig fecal samples and investigate the molecular characteristics of extended-spectrum ß-lactamase (ESBL)-producing E. coli using gene identification, conjugation, and Southern blot approach. Overall 293 E. coli were recovered from cattle (120 isolates) and pigs (173 isolates) in 7 provinces of Korea during 2017-2018. Ampicillin, chloramphenicol, streptomycin, and sulfisoxazole resistance rates were the highest in pigs' isolates (>60%, p ≤ 0.001) compared to that in cattle (3-39%). Multidrug resistance (MDR) was higher in pig isolates (73%) than in cattle (31%), and the MDR profile usually includes streptomycin, sulfisoxazole, and tetracycline. Resistance to critically important antimicrobials such as ceftiofur, colistin, and ciprofloxacin was higher in weaners than those from finishers in pigs. The qnrS gene was detected in 13% of the pig isolates. Eight isolates from pigs and one isolate from cattle were identified as ESBL-producers and ESBL genes belonged to blaCTX-M-55 (n = 4), blaCTX-M-14 (n = 3), and blaCTX-M-65 (n = 2). Notably, the blaCTX-M-65 and qnrS1 genes were found to be carried together in an identical plasmid (IncHI2) in two isolates from finisher pigs. The blaCTX-M-carrying isolates belonged to phylogenetic groups B1 (n = 4), B2 (n = 2), A (n = 2), and D (n = 1). The blaCTX-M genes and non-ß-lactam resistance traits were transferred to the E. coli J53 recipient from seven blaCTX-M-positive strains isolated from pigs. The blaCTX-M genes belonged to the IncI1α, IncFII, and IncHI2 plasmids and are also associated with the ISEcp1, IS26, IS903, and orf477 elements. These findings suggested the possibility of blaCTX-M-carrying E. coli transmission to humans through direct contact with cattle and pigs or contamination of food products.

Community Transmission of SARS-CoV-2 Omicron Variant, South Korea, 2021.

In South Korea, a November 2021 outbreak caused by severe acute respiratory syndrome coronavirus 2 Omicron variant originated from 1 person with an imported case and spread to households, kindergartens, workplaces, restaurants, and hospitals, resulting in 11 clusters within 3 weeks. An epidemiologic curve indicated rapid community transmission of the Omicron variant.

Antibiotic Resistance Profiles and Molecular Characteristics of blaCTX-M-15-Carrying Salmonella enterica Serovar Enteritidis Isolates from Healthy and Diseased Chickens in Korea.

Extended-spectrum ß-lactamase (ESBL)-producing Salmonella enterica serovar Enteritidis has emerged as a public health concern. The main objectives of this study were therefore to determine the antimicrobial susceptibility profiles of Salmonella Enteritidis and to investigate the molecular characteristics of identified ESBL-producing isolates. In the study, 237 Salmonella Enteritidis isolates (232 isolates from chickens, 4 from cattle, and 1 from a pig) were recovered from carcasses and fecal samples of healthy and diseased food animals between 2010 and 2017. Ceftiofur resistance was noted only in chicken isolates (43%, 102/237), with the highest in healthy chickens and their carcasses (48.3%, 83/172) compared with that in diseased chickens (31.7%, 19/60). All of the ceftiofur-resistant isolates exhibited resistance to multiple antimicrobials. Indeed, a relatively higher percentage of ceftiofur-resistant isolates demonstrated resistance to the tested aminoglycosides and tetracycline compared with the ceftiofur-susceptible strains. In this study, blaCTX-M-15 was the only ESBL gene detected in all of the ceftiofur-resistant isolates. The blaCTX-M-15-carrying isolates belonged to 11 different pulsotypes. The blaCTX-M-15 gene was transferred from 20.6% (21/102) of the blaCTX-M-15-harboring isolates to a recipient Escherichia coli J53. The coexistence of IncHI2/ST2 and IncFIIs/ST1 plasmids was noted in the majority (81.8%, 18/22) of the transconjugants. E. coli J53 transconjugants carrying blaCTX-M-15 gene showed distinct genetic environments, predominantly ISEcp1-blaCTX-M-15-orf477 (15/21, 71.4%). This study demonstrated that healthy chickens and their carcasses act as reservoirs of blaCTX-M-15-carrying Salmonella Enteritidis that can potentially be transmitted to humans.

Imaging the Substantia Nigra in Parkinson Disease and Other Parkinsonian Syndromes.

Parkinson disease is characterized by dopaminergic cell loss in the substantia nigra of the midbrain. There are various imaging markers for Parkinson disease. Recent advances in MRI have enabled elucidation of the underlying pathophysiologic changes in the nigral structure. This has contributed to accurate and early diagnosis and has improved disease progression monitoring. This article aims to review recent developments in nigral imaging for Parkinson disease and other parkinsonian syndromes, including nigrosome imaging, neuromelanin imaging, quantitative iron mapping, and diffusion-tensor imaging. In particular, this article examines nigrosome imaging using 7-T MRI and 3-T susceptibility-weighted imaging. Finally, this article discusses volumetry and its clinical importance related to symptom manifestation. This review will improve understanding of recent advancements in nigral imaging of Parkinson disease. Published under a CC BY 4.0 license.

Coexistence of dentatorubral-pallidoluysian atrophy and Parkinson's disease: An autopsy case report.

We report an autopsy case of a 56-year-old male patient with the coexistence of dentatorubral-pallidoluysian atrophy (DRPLA) and Parkinson's disease (PD). He presented with gait instability and dysarthria for 10 years. The removed brain showed general atrophy (988 g) with depigmentation of the substantia nigra. The neocortex and deep gray matter, including the red nucleus, subthalamic nuclei, and globus pallidus, were atrophic, and grumose degeneration of the cerebellar dentate nucleus was observed. Polyglutamine- and p62-positive neuronal inclusions were present and widespread in the areas mentioned above. Interestingly, this case also had brainstem-predominant PD pathology with α-synuclein-positive Lewy bodies and Lewy neurites. Generalized white matter atrophy with patchy loss of astrocytes in the white matter suggested glial dysfunction by elongated CAG repeats in the atrophin 1 gene (atrophin 1). Polymerase chain reaction (PCR) fragment analysis revealed increased CAG repeats (61) on atrophin 1 encoding atrophin 1. The patient had a family history of DRPLA, including his daughter, who was confirmed positive on genetic testing (CAG repeat: 65). His father, brother, and niece were suspected of having the disease. Clinicopathologically, all of the above findings are consistent with the coexistence of DRPLA and PD. So far, various overlapping neurodegenerative disorders have been reported, but the coexistence of DRPLA and PD has never been demonstrated in the published literature. Even though the exact time of PD development is unknown in this case, PD might develop after DRPLA, and the overwhelming symptoms of DRPLA might mask those of PD. Here, we report a clinicopathologically definite case of the coexistence of DRPLA and PD. White matter degeneration with patchy loss of astrocytes was another remarkable finding of this case.

Short communication: First detection of Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus ST30 in raw milk taken from dairy cows with mastitis in South Korea.

We identified 199 Staphylococcus aureus isolates from quarter milk samples of 1,289 dairy cattle between 2014 and 2018. About 66% of the isolates were resistant to at least 1 antimicrobial agent; the highest rate of resistance was to penicillin, followed by resistance to ampicillin, erythromycin, and sulfadimethoxine. We obtained 30 methicillin-resistant S. aureus (MRSA) strains from 6 farms in 3 provinces. The MRSA strains exhibited a significantly higher resistance rate to most of the tested antimicrobials than the oxacillin-susceptible strains. The MRSA strains represented 5 genotypes: ST72-t324-SCCmec IV (n = 14), ST30-t1752-SCCmec IV (n = 8), ST188-t189-SCCmec NT (n = 6), ST188-t2284-SCCmec NT (n = 1), and NT-NT-SCCmec IV (n = 1). One of the ST188 MRSA strains represented a novel staphylococcal protein A (spa) type (t2284). In addition, 7 of the 8 ST30 MRSA strains were Panton-Valentine leukocidin (PVL)-positive and carried various staphylococcal enterotoxin encoding genes. This is the first report of PVL-positive ST30 MRSA-t1752-SCCmec IV from bovine mastitis in Korea. All of ST72-t324-SCCmec IV MRSA strains carried staphylococcal enterotoxin and leukotoxin encoding genes. They were also sensitive to most of the tested non-ß-lactam antimicrobials. In contrast, ST188-t189 MRSA strains were resistant to multiple antimicrobials and predominantly carried the leukotoxin encoding gene. Taken together, these findings may indicate that dairy cows could be a major source for spreading MRSA strains, and contaminated milk could be a vehicle for transmission. Suitable hygienic measures should be established in dairy farms and processing plants to limit the likelihood of introducing MRSA into the food chain.

Nationwide Surveillance on Antimicrobial Resistance Profiles of Staphylococcus aureus Isolated from Major Food Animal Carcasses in South Korea During 2010-2018.

Contamination of meat with antimicrobial-resistant bacteria represents a major public health threat worldwide. In this study, we determined the antimicrobial resistance profiles and resistance trends of Staphylococcus aureus isolated from major food animal carcasses (408 cattle, 1196 pig, and 1312 chicken carcass isolates) in Korea from 2010 to 2018. Approximately 75%, 92%, and 77% of cattle, pig, and chicken carcass isolates, respectively, were resistant to at least one antimicrobial agent. Resistance to penicillin (62.1%) was the highest, followed by resistance to tetracycline (42.1%) and erythromycin (28.2%). About 30% of pig and chicken isolates were resistant to ciprofloxacin. We observed linezolid resistance only in pig isolates (2.3%). However, all S. aureus isolates were sensitive to rifampin and vancomycin. We noted an increasing but fluctuating trend of kanamycin and penicillin resistance in cattle isolates. Similarly, the chloramphenicol, ciprofloxacin, tetracycline, and trimethoprim resistance rates were increased but fluctuated through time in pig isolates. Methicillin-resistant S. aureus (MRSA) accounted for 5%, 8%, and 9% of the cattle, pig, and chicken isolates, respectively. The MRSA strains exhibited significantly high resistance rates to most of the tested antimicrobials, including ciprofloxacin, erythromycin, and tetracycline compared with methicillin-susceptible S. aureus (MSSA) strains. Notably, a relatively high percentage of MRSA strains (5.2%) recovered from pig carcasses were resistant to linezolid compared with MSSA strains (2.1%). In addition, almost 37% of the isolates were multi-drug resistant. S. aureus isolates recovered from major food animal carcasses in Korea exhibited resistance to clinically important antimicrobials, posing a public health risk.

Cardioprotective effects of genetically engineered cardiac stem cells by spheroid formation on ischemic cardiomyocytes.

BACKGROUND: Sca-1+ cardiac stem cells and their limited proliferative potential were major limiting factors for use in various studies. METHODS: Therefore, the effects of sphere genetically engineered cardiac stem cells (S-GECS) inserted with telomerase reverse transcriptase (TERT) were investigated to examine cardiomyocyte survival under hypoxic conditions. GECS was obtained from hTERT-immortalized Sca-1+ cardiac stem cell (CSC) lines, and S-GECS were generated using poly-HEMA. RESULTS: The optimal conditions for S-GECS was determined to be 1052 GECS cells/mm2 and a 48 h culture period to produce spheroids. Compared to adherent-GECS (A-GECS) and S-GECS showed significantly higher mRNA expression of SDF-1α and CXCR4. S-GECS conditioned medium (CM) significantly reduced the proportion of early and late apoptotic cardiomyoblasts during CoCl2-induced hypoxic injury; however, gene silencing via CXCR4 siRNA deteriorated the protective effects of S-GECS against hypoxic injury. As downstream pathways of SDF-1α/CXCR4, the Erk and Akt signaling pathways were stimulated in the presence of S-GECS CM. S-GECS transplantation into a rat acute myocardial infarction model improved cardiac function and reduced the fibrotic area. These cardioprotective effects were confirmed to be related with the SDF-1α/CXCR4 pathway. CONCLUSIONS: Our findings suggest that paracrine factors secreted from transplanted cells may protect host cardiomyoblasts in the infarcted myocardium, contributing to beneficial left ventricle (LV) remodeling after acute myocardial infarction (AMI).

Double-Blind, Randomized, Placebo-Controlled Trial of DA-9701 in Parkinson's Disease: PASS-GI Study.

OBJECTIVES: This study aimed to assess the efficacy of DA-9701 on gastrointestinal symptom-related quality of life in patients with Parkinson's disease on stable dopaminergic medications. METHODS: This multicenter, double-blind, placebo-controlled, phase 4 trial included a total of 144 patients with Parkinson's disease with gastrointestinal dysfunctions based on predefined criteria. Participants were randomized to take either DA-9701 or placebo for 4 weeks, and then both groups were administered DA-9701 for an additional 8 weeks while antiparkinsonian medications were unchanged. The primary outcome measure was gastrointestinal symptoms and related quality-of-life changes assessed on the Korean Nepean dyspepsia index after 4 and 12 weeks of therapy. We also evaluated the impact of DA-9701 therapy on parkinsonian motor symptoms at each time point. RESULTS: The gastrointestinal symptom-related quality-of-life score significantly improved in the DA-9701-treated group compared with the placebo-treated group after 4weeks (adjusted P = 0.012 by linear mixed effect model analysis). The overall gastrointestinal symptom and dyspepsia sum scores improved at 12 weeks after intervention in the DA-9701-first treated group (adjusted P = 0.002 and 0.014, respectively) and also in the placebo-first treated group (adjusted P = 0.019 and 0.039) compared with the baseline. Parkinsonian motor severity was not significantly affected by DA-9701 treatment in both groups at 4 and 12 weeks after intervention. There were no drug-related serious adverse events throughout the trial. CONCLUSIONS: DA-9701 therapy improved gastrointestinal symptom-related quality of life, and 12 weeks of daily administration can relieve the overall severity of gastrointestinal symptoms in patients with Parkinson's disease without affecting motor symptoms. (Clinical trial identifier: NCT02775591.) © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Sicyos angulatus Prevents High-Fat Diet-Induced Obesity and Insulin Resistance in Mice.

Obesity is a medical condition in which excess body fat has accumulated to a serious extent. It is a chronic disease that can lead to dyslipidemia, insulin resistance, and type 2 diabetes. In the present study, we investigated the anti-obesity effects of Sicyos angulatus (SA) extract on a high-fat diet (HFD)-induced C57BL/6J obese mice. The mice were divided into vehicle and three SA groups (25, 50, and 100 mg/kg body weight). The mice were fed a HFD with or without SA for 12 weeks. The oral administration of SA reduced body and adipose tissue weight in HFD-fed mice compared to those in the vehicle group (p<0.05). Adipocyte size and inflammation significantly decreased in the SA-administered groups in a dose-dependent manner. In particular, adipocytes larger than 5000 µm2 were remarkably reduced by around 50% in the SA-treated groups (p<0.05). In addition, SA contributes towards reducing insulin resistance (measured as the HOMA-IR index) and glucose intolerance in HFD-induced obese mice (p<0.05; Vehicle 21.5±3.1 vs. SA100 4.7±0.4). These beneficial effects of SA on obesity may be linked to the suppression of lipogenesis and stimulating energy metabolism in white adipose tissue and muscle. In white adipose tissue and muscle, the administration of SA activated AMPK pathway, leading to the inhibition of the development of pathophysiological conditions associated with obesity, including lipogenesis and inflammation. These findings suggest that SA may prevent obesity through inhibiting fat accumulation in HFD-induced obese mice. Therefore, SA is able to exert metabolic benefits in the prevention of obesity and insulin resistance.

Clinical Perspectives of Parkinson's Disease for Ophthalmologists, Otorhinolaryngologists, Cardiologists, Dentists, Gastroenterologists, Urologists, Physiatrists, and Psychiatrists.

Parkinson's disease (PD) is a multisystemic disorder characterized by various non-motor symptoms (NMS) in addition to motor dysfunction. NMS include sleep, ocular, olfactory, throat, cardiovascular, gastrointestinal, genitourinary, or musculoskeletal disorders. A range of NMS, particularly hyposmia, sleep disturbances, constipation, and depression, can even appear prior to the motor symptoms of PD. Because NMS can affect multiple organs and result in major disabilities, the recognition and multidisciplinary and collaborative management of NMS by physicians is essential for patients with PD. Therefore, the aim of this review article is to provide an overview of the organs that are affected by NMS in PD together with a brief review of pathophysiology and treatment options.

Correction to: Licochalcone A induces apoptosis through endoplasmic reticulum stress via a phospholipase Cγ1-, Ca2+-, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells.

The original version of this article contained mistakes in figures. The western blot data for pro-caspase-3 and cleaved caspase-3 (Fig. 1d), ß-actin (Fig. 1d), PLCγ1 (Fig. 5d), and eIF2α (Fig. 7d) are incorrect. The corrected Figs. 1d, 5d, and 7d are shown below. The corrections do not influence either the validity of the published data or the conclusion described in the article.

Correction to: Apicidin induces endoplasmic reticulum stress- and mitochondrial dysfunction-associated apoptosis via phospholipase Cγ1- and Ca2+-dependent pathway in mouse Neuro-2a neuroblastoma cells.

The original version of this article contained a mistake in the figure. The Ca2 + confocal image for the 2-APB/Apicidin-120 min in Fig. 5d is incorrect. The correction does not influence either the validity of the published data or the conclusion described in the article. The corrected Fig. 5d is given below.

Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing.

Inherited disorders of spasticity or ataxia exist on a spectrum with overlapping causative genes and phenotypes. We investigated the use of whole-genome sequencing (WGS) to detect a genetic cause when considering this spectrum of disorders as a single group. We recruited 18 Korean individuals with spastic paraplegia with or without cerebellar ataxia in whom common causes of hereditary cerebellar ataxia and hereditary spastic paraplegia had been excluded. We performed WGS with analysis for single nucleotide variants, small insertions and deletions, copy number variants (CNVs), structural variants (SVs) and intronic variants. Disease-relevant variants were identified in ABCD1 (n = 3), CAPN1 (n = 2), NIPA1 (n = 1) and PLA2G6 (n = 1) for 7/18 patients (38.9%). A 'reverse phenotyping' approach was used to clarify the diagnosis in individuals with PLA2G6 and ABCD1 variants. One of the ABCD1 disease-relevant variants was detected on analysis for intronic variants. No CNV or SV causes were found. The two males with ABCD1 variants were initiated on monitoring for adrenal dysfunction. This is one of only a few studies to analyse spastic-ataxias as a continuous spectrum using a single approach. The outcome was improved diagnosis of unresolved cases for which common genetic causes had been excluded. This includes the detection of ABCD1 variants which had management implications. Therefore, WGS may be particularly relevant to diagnosing spastic ataxias given the large number of genes associated with this condition and the relatively high diagnostic yield.

Various Motor and Non-Motor Symptoms in Early Multiple System Atrophy.

BACKGROUND: Multiple system atrophy (MSA) patients pre-sent a variety of symptoms other than autonomic dysfunctions, parkinsonism, and cerebellar ataxia. The aim of this study was to evaluate the frequency of various motor and non-motor symptoms including so-called "red flags" in patients with early MSA and to determine whether the frequency of these symptoms was different between the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes. METHODS: Sixty-one probable or possible MSA patients with disease duration of 3 years or less were included. Patients were classified into MSA-P, MSA-C, and MSA-PC. The frequency of 13 features including various motor and non-motor symptoms that commonly occur in MSA was assessed. RESULTS: Dysarthria was the most prevalent feature (98.4%) followed by sexual dysfunction (95.1%). Probable REM sleep behavior disorder was present in 90.2%. The frequency of constipation (82.0%), dysphagia (68.9%), and snoring (70.5%) was also high. Stridor was present in 42.6% and more common in MSA-C than in MSA-P. CONCLUSIONS: Increasing awareness of various motor and non-motor symptoms may assist clinicians to make an early, accurate diagnosis and to improve management of patients with MSA. We suggest that the diagnostic accuracy can be improved if these features are appropriately reflected in the new diagnostic criteria for MSA.

Neuropsychiatric Traits Associated with Refractory Impulse Control Disorder in Parkinson's Disease.

INTRODUCTION: Impulse control disorder (ICD) in Parkinson's disease (PD) is a critical nonmotor symptom with personality or neuropsychiatric traits contributing to ICD. OBJECTIVE: This study aimed to identify predictive traits for persistent or paradoxical aggravation of ICD after dopamine agonist substitution therapy for ICD in PD. METHODS: We conducted a case-control study using a database of a multicenter intervention trial for ICD in PD. The poor-outcome group was defined by showing paradoxical increases in ICD behaviors after the substitution of dopamine agonists with levodopa. We analyzed the pre-intervention personality traits associated with the poor outcome and also evaluated the risk traits for refractory ICD using a receiver-operating characteristic (ROC) curve analysis. RESULTS: The poor-outcome group showed higher levels of anger expression (p =0.007) and obsessive-compulsive traits (p =0.009) compared with the good-outcome group at the pre-intervention state. In the ROC curve analysis, the Obsessive-Compulsive Inventory showed the highest area under the curve with 80.0% sensitivity and 74.3% specificity in discriminating against the poor-outcome group. CONCLUSIONS: Our results suggest that assessment of obsessive compulsiveness may be useful for predicting the refractoriness of ICD behaviors in planning an interventional treatment for ICD in PD.

GADD45ß plays a protective role in acute lung injury by regulating apoptosis in experimental sepsis in vivo.

Sepsis is a systemic inflammatory response syndrome due to microbial infection. Growth arrest and DNA-damage-inducible 45 beta (GADD45ß) are induced by genotoxic stress and inflammatory cytokines. However, the role of GADD45ß during bacterial infection remains unclear. This study was aimed at investigating the role of GADD45ß in sepsis. We used GADD45ß-knockout (KO) mice and C57BL/6J wild-type (WT) mice. Experimental sepsis was induced by lipopolysaccharide (LPS) administration or cecal ligation and puncture (CLP). Sepsis-induced mortality was higher in GADD45ß-KO mice than in WT mice. Histopathological data demonstrated LPS treatment markedly increased lung injury in GADD45ß-KO mice as compared to that in WT mice; however, no significant difference was observed in the liver and kidney. Further, mRNA levels of inflammatory cytokines, such as Il-1ß, Il-6, Il-10, and Tnf-α, were higher in the lungs of LPS-treated GADD45ß-KO mice than in WT mice. Interestingly, plasma levels of these inflammatory cytokines were decreased in LPS-administered GADD45ß-KO mice. A significant increase in lung cell apoptosis was observed at early time points in GADD45ß-KO mice after administration of LPS as compared to that in WT mice. In line with LPS-induced apoptosis, JNK, and p38 activity was higher in the lung of GADD45ß-KO mice at 3 hr after LPS treatment than that in WT mice. In summary, this study is the first to demonstrate the protective role of GADD45ß in sepsis and the results suggest that GADD45ß could be used as a novel therapeutic target to cure sepsis.

Hepatocyte SHP deficiency protects mice from acetaminophen-evoked liver injury in a JNK-signaling regulation and GADD45ß-dependent manner.

Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure. Prolonged c-Jun N-terminal kinase (JNK) activation plays a central role in APAP-induced liver injury; however, growth arrest and DNA damage-inducible 45 beta (GADD45ß) is known to inhibit JNK phosphorylation. The orphan nuclear receptor small heterodimer partner (SHP, NR0B2) acts as a transcriptional co-repressor of various genes. The aim of the present study was to investigate the role of SHP in APAP-evoked hepatotoxicity. We used lethal (750 mg/kg) or sublethal (300 mg/kg) doses of APAP-treated wild-type (WT), Shp knockout (Shp-/-), hepatocyte-specific Shp knockout (Shphep-/-), and Shp and Gadd45ß double knockout (Shp-/-Gadd45ß-/-) mice for in vivo studies. Primary mouse hepatocytes were used for a comparative in vitro study. SHP deficiency protected against APAP toxicity with an increased survival rate, decreased liver damage, and inhibition of prolonged hepatic JNK phosphorylation in mice, which was independent of APAP metabolism regulation. Furthermore, Shphep-/- mice showed diminished APAP hepatotoxicity compared with WT mice. SHP-deficient primary mouse hepatocytes also showed decreased cell death and inhibition of sustained JNK phosphorylation following toxic APAP treatment. While SHP expression declined, GADD45ß expression increased after APAP treatment in WT mice. In Shp-/- mice, APAP-evoked GADD45ß induction was significantly enhanced. Notably, the ameliorative effects of SHP deficiency on APAP-induced liver injury were abolished in Shp-/-Gadd45ß-/- mice. The current study is the first to demonstrate that hepatocyte-specific SHP deficiency protects against APAP overdose-evoked hepatotoxicity in a JNK signaling regulation and GADD45ß dependent manner. SHP is suggested to be a novel therapeutic target for APAP overdose treatment.

Fluoxetine induces apoptosis through endoplasmic reticulum stress via mitogen-activated protein kinase activation and histone hyperacetylation in SK-N-BE(2)-M17 human neuroblastoma cells.

Fluoxetine (FLX) is an antidepressant drug that belongs to the class of selective serotonin reuptake inhibitors. FLX is known to induce apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti-cancer effects of FLX were investigated in SK-N-BE(2)-M17 human neuroblastoma cells. FLX induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by treatment with the ER stress inhibitors, salubrinal and 4-phenylbutyric acid or CHOP siRNA transfection reduced FLX-induced cell death. FLX induced phosphorylation of mitogen-activated protein kinases (MAPKs) family, p38, JNK, and ERK, and an upstream kinase apoptosis signal kinase 1 (ASK1). Inhibition of MAPKs and ASK1 reduced FLX-induced cell death and CHOP expression. We then showed that FLX reduced mitochondrial membrane potential (MMP) and ER stress inhibitors as well as MAPK inhibitors ameliorated FLX-induced loss of MMP. Interestingly, FLX induced hyperacetylation of histone H3 and H4, upregulation of p300 histone acetyltransferase (HAT), and downregulation of histone deacetylases (HDACs). Treatment with a HAT inhibitor anacardic acid or p300 HAT siRNA transfection blocked FLX-induced apoptosis in SK-N-BE(2)-M17 cells. However, FLX did not induce histone acetylation and anacardic acid had no protective effect on FLX-induced cell death and CHOP expression in MYCN non-amplified SH-SY5Y human neuroblastoma and MYCN knockdowned SK-N-BE(2)-M17 cells. These findings suggest that FLX induces apoptosis in neuroblastoma through ER stress and mitochondrial dysfunction via the ASK1 and MAPK pathways and through histone hyperacetylation in a MYCN-dependent manner.