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The resurgence of influenza viruses as a significant global threat emphasizes the urgent need for innovative antiviral strategies beyond existing treatments. Here, we present the development and evaluation of a novel super-multivalent sialyllactosylated filamentous phage, termed t-6SLPhage, as a potent entry blocker for influenza A viruses. Structural variations in sialyllactosyl ligands, including linkage type, valency, net charge, and spacer length, were systematically explored to identify optimal binding characteristics against target hemagglutinins and influenza viruses. The selected SLPhage equipped with optimal ligands, exhibited exceptional inhibitory potency in in vitro infection inhibition assays. Furthermore, in vivo studies demonstrated its efficacy as both a preventive and therapeutic intervention, even when administered post-exposure at 2 days post-infection, under 4 lethal dose 50% conditions. Remarkably, co-administration with oseltamivir revealed a synergistic effect, suggesting potential combination therapies to enhance efficacy and mitigate resistance. Our findings highlight the efficacy and safety of sialylated filamentous bacteriophages as promising influenza inhibitors. Moreover, the versatility of M13 phages for surface modifications offers avenues for further engineering to enhance therapeutic and preventive performance.
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Antivirales , Animales , Antivirales/farmacología , Antivirales/química , Humanos , Perros , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/virología , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/fisiología , Células de Riñón Canino Madin Darby , Inovirus/efectos de los fármacos , Oseltamivir/farmacología , Oseltamivir/química , Ratones , Gripe Humana/virología , Gripe Humana/tratamiento farmacológico , Ratones Endogámicos BALB C , Ácido N-Acetilneuramínico/química , Ácido N-Acetilneuramínico/metabolismo , FemeninoRESUMEN
BACKGROUND: Though observational evidence supports indirect effects of SARS-CoV-2 vaccines, randomised experiments are lacking. To address this gap, the double-blinded, prospective follow-up of the household contacts (HHCs) of Philippine participants of the individually-randomised, placebo-controlled trial of the adjuvanted-subunit protein COVID-19 vaccine, SCB-2019, (EudraCT, 2020-004272-17; ClinicalTrials.gov, NCT04672395) was analyzed in a cluster-randomised fashion. METHODS: Over an eight-week period, HHCs were followed by rRT-PCR and paired rapid antibody tests (RATs) to detect symptomatic (SCI, primary) and all (ACI, secondary) SARS-CoV-2 infection. A standard analysis estimated the indirect effectiveness of SCB-2019 for each endpoint, excluding HHC RAT-positive at enrollment. A secondary analysis employed enzyme-linked immunosorbent assay (ELISA) results to correct for suspected bias. FINDINGS: SCB-2019 (N=3470) and placebo (N = 3225) exposed HHCs contributed to at least one analysis. The standard analysis estimated that SCB-2019 reduced the risk of SCI by 83% (95% confidence/credible interval [CI: 32% to 96%), with no effect against ACI. The bias-corrected relative risk reduction was 97% (95% CI: 74% to 100%) for SCI and 79% (95% CI: 14% to 96%) for ACI, with an estimated one SARS-CoV-2 infection prevented per 4.8 households where one member received SCB-2019. INTERPRETATION: SCB-2019 demonstrated bias-corrected indirect effectiveness against SARS-CoV-2 infection among HHC, even at a modest coverage level in the household (approximately 25%). Further research into the indirect effects of SARS-CoV-2 vaccines is needed to optimize the impact of limited doses in low and middle-income settings. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.
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SARS-CoV-2 serological testing is useful to determine seroprevalence, epidemiological trends, and the extent of transmission. The collection and transport of serum samples can be logistically challenging, especially in remote underserved areas. Dried blood spots (DBSs) would allow easier sample collection and logistical handling compared with standard serum collection, particularly for extensive and repeated SARS-CoV-2 serosurveys. We evaluated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the IgG ELISA (Wantai, Beijing, China) using DBSs against sera for the quantitative detection of SARS-CoV-2 IgG antibody. The IgG ELISA was used to test paired sera and DBSs obtained from individuals with recent virologically confirmed COVID-19 illness and banked paired sera and DBSs collected before the COVID-19 pandemic. We found that 100/100 (100%) seropositive samples were positive using DBSs, and 193/194 (99%) seronegative samples were negative using DBSs. Compared with sera, the DBS method had a 100% sensitivity, 99% specificity, 99% PPV, and 100% NPV. Use of DBSs for SARS-CoV-2 household or population serosurveys may be considered in situations with limitations in sample collection, shipment, and storage.
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Anticuerpos Antivirales , Prueba Serológica para COVID-19 , COVID-19 , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina G , SARS-CoV-2 , Sensibilidad y Especificidad , Humanos , Inmunoglobulina G/sangre , SARS-CoV-2/inmunología , Anticuerpos Antivirales/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/sangre , COVID-19/inmunología , Prueba Serológica para COVID-19/métodos , Pruebas con Sangre Seca/métodos , Persona de Mediana Edad , Masculino , Femenino , Adulto , Estudios Seroepidemiológicos , Manejo de EspecímenesRESUMEN
Backgrounds: The age at menarche has decreased worldwide. Previous studies on Korean adolescents have reported a downward trend in age at menarche. This study aimed to investigate the current trends in age at menarche among Korean adolescents using nationally representative data. Materials and methods: The study used data from the Korea National Health and Nutrition Examination Survey 2007-2021. A total of 50,730 females born between 1927 and 2004 with information on age at menarche were included. The trend in age at menarche was analyzed according to 15 birth-year groups (with 5-year intervals) using quantile regression analysis. Results: The mean age at menarche decreased from 16.92 ± 0.06 years for females born before 1935 to 12.45 ± 0.04 years for females born between 2000 and 2004 (p <.001). According to the percentile group of age at menarche, mean menarche age decreased by -0.071 years per year (95% confidence interval [CI], -0.072 to -0.070) in total, -0.050 years per year (95% CI, -0.052 to -0.048) in the 3rd percentile group, -0.088 years per year (95% CI, -0.091 to -0.085) in the 97th percentile group (p <.001 for all). A decreasing trend of age at menarche was more prominent in the obesity group (-0.080 years per year, 95% CI, -0.082 to -0.078) compared to the non-obesity group (-0.069 years per year, 95% CI, -0.071 to -0.068) (p <.001 for both). Conclusion: Ongoing downward trend in age at menarche was observed in Korean females born until 2004, decreasing by 0.71 years per decade. The downward trend was faster in individuals with a higher percentile of age at menarche and in those with obesity.
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Menarquia , Humanos , Menarquia/fisiología , Femenino , República de Corea/epidemiología , Adolescente , Factores de Edad , Encuestas Nutricionales , NiñoRESUMEN
Ochratoxin A (OTA) is a widespread food toxin produced by Aspergillus ochraceus and other molds. In this study, we developed and established acute OTA toxicity conditions in mice, which received daily oral doses of OTA between 0.5 up to 8 mg/kg body weight up to 7 days and were subjected to histological and biochemical analysis to characterize renal and hepatic damage. Oral administration of OTA for 7 days resulted in loss of body weight in a dose-dependent manner and increased the levels of serum biomarkers of hepatic and renal damage. The kidney was more sensitive to OTA-induced damage than the liver. In addition to necrosis, OTA induced hepatic and renal apoptosis in dose- and time-dependent manners. Especially, a high dose of OTA (8 mg/kg body weight) administered for 7 days led to necroptosis in both liver and kidney tissues. OTA dose-dependently increased the oxidative stress levels, including lipid peroxidation, in the liver and kidneys. OTA disrupted mitochondrial dynamics and structure in hepatic and renal cells, leading to the dysregulation of mitochondrial homeostasis. OTA increased transferrin receptor 1 and decreased glutathione peroxidase 4 levels in a dose- and time-dependent manner. These results suggest the induction of ferroptosis. Collectively, this study highlighted the characteristics of acute OTA-induced hepatic and renal toxicity in mice in terms of oxidative stress, mitochondrial damage, and multiple cell death mechanisms, including necroptosis and ferroptosis.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Riñón , Hígado , Mitocondrias , Ocratoxinas , Estrés Oxidativo , Animales , Ocratoxinas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Ratones , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Relación Dosis-Respuesta a Droga , Apoptosis/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Necroptosis/efectos de los fármacosRESUMEN
Background and Objectives: Muscle atrophy occurs when protein degradation exceeds protein synthesis, resulting in imbalanced protein homeostasis, compromised muscle contraction, and a reduction in muscle mass. The incidence of muscle atrophy is increasingly recognized as a significant worldwide public health problem. The aim of the current study was to evaluate the effect of whey peptide (WP) on muscle atrophy induced by dexamethasone (DEX) in mice. Materials and Methods: C57BL/6 mice were divided into six groups, each consisting of nine individuals. WPs were orally administered to C57BL/6 mice for 6 weeks. DEX was administered for 5-6 weeks to induce muscle atrophy (intraperitoneal injection, i.p.). Results: Microcomputer tomography (CT) analysis confirmed that WP significantly increased calf muscle volume and surface area in mice with DEX-induced muscle atrophy, as evidenced by tissue staining. Furthermore, it increased the area of muscle fibers and facilitated greater collagen deposition. Moreover, WP significantly decreased the levels of serum biomarkers associated with muscle damage, kidney function, and inflammatory cytokines. WP increased p-mTOR and p-p70S6K levels through the IGF-1/PI3K/Akt pathway, while concurrently decreasing protein catabolism via the FOXO pathway. Furthermore, the expression of proteins associated with myocyte differentiation increased noticeably. Conclusions: These results confirm that WP reduces muscle atrophy by regulating muscle protein homeostasis. Additionally, it is believed that it helps to relieve muscle atrophy by regulating the expression of myocyte differentiation factors. Therefore, we propose that WP plays a significant role in preventing and treating muscle wasting by functioning as a supplement to counteract muscle atrophy.
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Dexametasona , Suero Lácteo , Ratones , Animales , Dexametasona/efectos adversos , Suero Lácteo/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Transducción de Señal/fisiología , Ratones Endogámicos C57BL , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/etiología , Músculo Esquelético/patología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Péptidos/efectos adversosRESUMEN
BACKGROUND: Bisphenol A (BPA) is known as an obesogenic endocrine disruptor. Bisphenol S (BPS) and F (BPF) are substitutes that have recently replaced BPA. OBJECTIVES: To investigate the relationships of urinary bisphenols (BPA, BPS and BPF) with adiposity measurements (obesity, BMI z-score, and fat mass), serum adipokine levels (adiponectin and leptin), and adiponectin/leptin ratio (A/L ratio) in 6- and 8-year-old children. METHODS: A total of 561 children who participated in the Environment and Development of Children cohort (482 and 516 children visited at age 6 and 8, respectively) at Seoul National University Children's Hospital during 2015-2019 were included. Urinary BPA levels were log-transformed. BPS levels were categorized into three groups (non-detected, lower-half, and higher-half of detected), and BPF levels were classified into two groups (non-detected and detected). RESULTS: The urinary BPS higher-half group had a higher BMI z-score (ß = 0.160, P= 0.044), higher fat mass (ß = 0.104, P< 0.001), lower adiponectin concentration (ß =- 0.069, P< 0.001), higher leptin concentration (ß = 0.360, P< 0.001), and lower A/L ratio (ß =- 0.428, P< 0.001) compared with the non-detected group. The urinary BPF-detected group had a higher fat mass (ß = 0.074, P< 0.001), lower adiponectin concentration (ß =- 0.069, P< 0.001), higher leptin concentration (ß = 0.360, P< 0.001), and lower A/L ratio (ß =- 0.428, P< 0.001) compared with the non-detected group. The BPA levels showed no consistent associations with outcomes, except for isolated associations of BPA at age 6 with a higher BMI z-score at age 6 (P= 0.016) and leptin at age 8 (P= 0.021). CONCLUSIONS: Increased exposure to BPS and BPF is associated with higher fat mass and leptin concentration, lower serum adiponectin, and lower A/L ratio in children. These findings suggest potential adverse effects of BPA substitutes on adiposity and adipokines. No consistent association of BPA exposure with outcomes could be partly explained by the decreasing BPA levels over time.
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Adiponectina , Leptina , Fenoles , Niño , Humanos , Compuestos de Bencidrilo/orina , Obesidad , AdipoquinasRESUMEN
Beckwith-Wiedemann syndrome (BWS) is an epigenetic overgrowth syndrome. Despite its distinctive growth pattern, the detailed growth trajectories of children with BWS remain largely unknown. We retrospectively analyzed 413 anthropometric measurements over an average of 4.4 years of follow-up in 51 children with BWS. We constructed sex-specific percentile curves for height, weight, and head circumference using a generalized additive model for location, scale, and shape. Males with BWS exhibited greater height at all ages evaluated, weight before the age of 10, and head circumference before the age of 9 than those of the general population. Females with BWS showed greater height before the age of 7, weight before the age of 4.5, and head circumference before the age of 7 than those of the general population. At the latest follow-up visit at a mean 8.4 years of age, bone age was significantly higher than chronological age. Compared to paternal uniparental disomy (pUPD), males with imprinting center region 2-loss of methylation (IC2-LOM) had higher standard deviation score (SDS) for height and weight, while females with IC2-LOM showed larger SDS for head circumference. These disease-specific growth charts can serve as valuable tools for clinical monitoring of children with BWS.
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Síndrome de Beckwith-Wiedemann , Masculino , Niño , Femenino , Humanos , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Metilación de ADN/genética , Impresión Genómica , Estudios Retrospectivos , Gráficos de Crecimiento , Trastornos del Crecimiento , República de Corea/epidemiologíaRESUMEN
Transcriptionally controlled tumor protein (TCTP) is a highly conserved protein performing a large number of cellular functions by binding with various partner proteins. The importance of its roles in many diseases requires an assay method to find regulatory compounds. However, the molecular characteristics of TCTP made it difficult to search for chemicals interacting with it. In this study, a tryptophan-based assay method was designed and Y151W mutant TCTP was constructed to search binding chemicals. Since there is no tryptophan in the native sequence of TCTP, the incorporation of tryptophan in the Y151W mutant was very effective to establish the method. A flavonoid library was employed to the assay with the method. With the native and Y151W mutant TCTPs, three flavonoids such as morin, myricetin and isobavachalcone have been found to interact with TCTP. Combined with native gel electrophoresis, the binding region of isobavachalcone was suggested to be the flexible loop of TCTP. This approach can be easily applicable to find binding compounds of proteins with similar molecular characteristics of TCTP.
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Neoplasias , Triptófano , Humanos , Biomarcadores de Tumor/metabolismo , Proteína Tumoral Controlada Traslacionalmente 1 , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismoRESUMEN
Gelatinase A (MMP-2) has been studied and proven to play a vital role in the intrusion and metastasis of cancer. Flavonoids influence on molecular and cellular functions of MMP-2 and thus a systematic investigation of flavonoids against the metalloproteolytic activity of MMP-2 has been performed in this study. A fluorescence resonance energy transfer method was used to investigate the inhibitory activities of various flavonoids. Flavone, flavonol and isobavachalcone derivatives showed their inhibitory activity against MMP-2. Surprisingly, the most effective inhibitor was Amentoflavone and its blocking function was superior to other flavonoids. Its IC50 value was 0.689 µM. An induced-fit docking study was carried out to survey its extraordinary activity. The binding mode of Amentoflavone is quite similar to that of (2 â¼ {S})-2-[2-[4-(4-methoxyphenyl) phenyl] sulfanylphenyl] pentanedioic acid complexed with MMP-9. Amentoflavone interacts with the functional zinc and catalytic residue, Glu202. Therefore, the docking study reasonably confirmed the strong inhibitory activity of Amentoflavone.
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Evidence suggests that the human respiratory tract, as with the gastrointestinal tract, has evolved to its current state in association with commensal microbes. However, little is known about how the airway microbiome affects the development of airway immune system. Here, we uncover a previously unidentified mode of interaction between host airway immunity and a unique strain (AIT01) of Staphylococcus epidermidis, a predominant species of the nasal microbiome. Intranasal administration of AIT01 increased the population of neutrophils and monocytes in mouse lungs. The recruitment of these immune cells resulted in the protection of the murine host against infection by Pseudomonas aeruginosa, a pathogenic bacterium. Interestingly, an AIT01-secreted protein identified as GAPDH, a well-known bacterial moonlighting protein, mediated this protective effect. Intranasal delivery of the purified GAPDH conferred significant resistance against other Gram-negative pathogens (Klebsiella pneumoniae and Acinetobacter baumannii) and influenza A virus. Our findings demonstrate the potential of a native nasal microbe and its secretory protein to enhance innate immune defense against airway infections. These results offer a promising preventive measure, particularly relevant in the context of global pandemics.
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The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.
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Diabetes Mellitus Tipo 2 , Masculino , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Pruebas Genéticas , Mutación , República de CoreaRESUMEN
Imprinted genes are regulated by DNA methylation of imprinted differentially methylated regions (iDMRs). An increasing number of patients with congenital imprinting disorders (IDs) exhibit aberrant methylation at multiple imprinted loci, multi-locus imprinting disturbance (MLID). We examined MLID and its possible impact on clinical features in patients with IDs. Genome-wide DNA methylation analysis (GWMA) using blood leukocyte DNA was performed on 13 patients with Beckwith-Wiedemann syndrome (BWS), two patients with Silver-Russell syndrome (SRS), and four controls. HumanMethylation850 BeadChip analysis for 77 iDMRs (809 CpG sites) identified three patients with BWS and one patient with SRS showing additional hypomethylation, other than the disease-related iDMRs, suggestive of MLID. Two regions were aberrantly methylated in at least two patients with BWS showing MLID: PPIEL locus (chromosome 1: 39559298 to 39559744), and FAM50B locus (chromosome 6: 3849096 to 3849469). All patients with BWS- and SRS-MLID did not show any other clinical characteristics associated with additional involved iDMRs. Exome analysis in three patients with BWS who exhibited multiple hypomethylation did not identify any causative variant related to MLID. This study indicates that a genome-wide approach can unravel MLID in patients with an apparently isolated ID. Patients with MLID showed only clinical features related to the original IDs. Long-term follow-up studies in larger cohorts are warranted to evaluate any possible phenotypic consequences of other disturbed imprinted loci.
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Metilación de ADN , Impresión Genómica , Humanos , Exoma , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 6RESUMEN
PURPOSE: The association between appendicular skeletal muscle mass (ASM) and cardiometabolic risk has been emphasized. We estimated reference values of the percentage of ASM (PASM) and investigated their association with metabolic syndrome (MS) in Korean adolescents. METHODS: Data from the Korea National Health and Nutrition Examination Survey performed between 2009 and 2011 were used. Tables and graphs of reference PASM were generated using 1,522 subjects, 807 of whom were boys aged 10 to 18. The relationship between PASM and each component of MS in adolescents was further analyzed in 1,174 subjects, 613 of whom were boys. Moreover, the pediatric simple MS score (PsiMS), the homeostasis model assessment of insulin resistance (HOMA-IR), and the triglyceride-glucose (TyG) index were analyzed. Multivariate linear and logistic regressions adjusting for age, sex, household income, and daily energy intake were performed. RESULTS: In boys, PASM increased with age; the trend was different in girls, in whom PASM declined with age. PsiMS, HOMA-IR, and TyG index showed inverse associations with PASM (PsiMS, ß=-0.105, P<0.001; HOMA-IR, ß=-0.104, P<0.001; and TyG index, ß=-0.013, P<0.001). PASM z-score was negatively associated with obesity (adjusted odds ratio [aOR], 0.22; 95% CI, 0.17-0.30), abdominal obesity (aOR, 0.27; 95% CI, 0.20-0.36), hypertension (aOR, 0.65; 95% CI, 0.52-0.80), and elevated triglycerides (aOR, 0.67; 95% CI, 0.56-0.79). CONCLUSION: The probability of acquiring MS and insulin resistance decreased as PASM values increased. The reference range may offer clinicians information to aid in the effective management of patients. We urge clinicians to monitor body composition using standard reference databases.
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BACKGROUND: Hypochondroplasia is a skeletal dysplasia caused by activating pathologic variants of FGFR3. The N540K variant accounts for 60-70% of reported cases and is associated with severe manifestations. Here, we analyze the clinical manifestations and outcomes of Korean patients with hypochondroplasia harboring the FGFR3 N540K variant. METHODS: Medical records of 20 unrelated patients with genetically confirmed N540K-related hypochondroplasia were retrospectively reviewed. All individuals were diagnosed with hypochondroplasia by Sanger sequencing for FGFR3, or target-panel sequencing for skeletal dysplasia. The effectiveness of growth hormone therapy was analyzed in 16 patients treated with growth hormones. RESULTS: Among 20 patients (7 men, 13 women), the mean age at first visit was 3.5±1.0 years, and the mean follow-up duration was 6.8±0.6 years. The patients presented with a short stature and/or short limbs. Genu varum, macrocephaly, and developmental delay were observed in 11 (55.0%), 9 (45.0%), and 5 (25.0%) patients, respectively. Of the 12 patients who underwent neuroimaging, five (41.7%) showed abnormal findings (one required operation for obstructive hydrocephalus). Among 16 growth-hormone-treated patients (two were growth-hormone deficient), the increase in height standard deviation scores was significant after a mean 5.4±0.7 years of treatment (+0.6 and+1.8 using growth references for healthy controls and achondroplasia children, respectively). Four patients underwent surgical limb lengthening at a mean age of 8.8±3.3 years. CONCLUSIONS: Neurodevelopmental abnormalities are frequently observed in patients with N540K-related hypochondroplasia. Close monitoring of skeletal manifestations and neurodevelopmental status is necessary for hypochondroplasia.
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Acondroplasia , Hormona de Crecimiento Humana , Osteocondrodisplasias , Masculino , Niño , Humanos , Femenino , Preescolar , Estudios Retrospectivos , Acondroplasia/tratamiento farmacológico , Acondroplasia/genética , Acondroplasia/diagnóstico , Osteocondrodisplasias/genética , República de Corea , Mutación , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
Osteoarthritis (OA) is a chronic, progressive joint disease associated with pain, functional impairment, and diminished quality of life in affected individuals. At a societal level, it also has a high economic burden. Boswellia serrata has been reported to have potent anti-inflammatory, antiarthritic, and analgesic effects. The aim of this study was to explore the therapeutic potential and possible underlying mechanism of 5-Loxin®, a standardized Boswellia serrata extract, in a rat model of OA. The OA model was established by the intra-articular injection of 50 µL of monosodium iodoacetate (MIA) (60 mg/mL). 5-Loxin® was administered orally, and efficacy was evaluated through serum analysis, real-time polymerase chain reaction (PCR), histologic staining, and micro-computed tomography (micro-CT). Results indicated that administration of 5-Loxin® can relieve OA joint pain through inhibition of both inflammatory processes and cartilage degeneration. In the group of rats treated with 5-Loxin®, the suppression of inflammatory enzymes such as cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) resulted in a significant reduction in the prostaglandin (PG) E2 and leukotriene (LT) B4 levels. Moreover, 5-Loxin® ameliorated the deterioration of the main components of the articular extracellular matrix (ECM), such as glycosaminoglycans (GAGs) and aggrecan, through the downregulation of matrix metalloproteinases (MMPs). These findings suggest that 5-Loxin® may be a potential therapeutic agent for the treatment of OA.
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Methionine (Met) can be oxidized to methionine sulfoxide (MetO), which exist as R- and S-diastereomers. Present in all three domains of life, methionine sulfoxide reductases (MSR) are the enzymes that reduce MetO back to Met. Most characterized among them are MSRA and MSRB, which are strictly stereospecific for the S- and R-diastereomers of MetO, respectively. While the majority of MSRs use a catalytic Cys to reduce their substrates, some employ selenocysteine. This is the case of mammalian MSRB1, which was initially discovered as selenoprotein SELR or SELX and later was found to exhibit an MSRB activity. Genomic analyses demonstrated its occurrence in most animal lineages, and biochemical and structural analyses uncovered its catalytic mechanism. The use of transgenic mice and mammalian cell culture revealed its physiological importance in the protection against oxidative stress, maintenance of neuronal cells, cognition, cancer cell proliferation, and the immune response. Coincident with the discovery of Met oxidizing MICAL enzymes, recent findings of MSRB1 regulating the innate immunity response through reversible stereospecific Met-R-oxidation of cytoskeletal actin opened up new avenues for biological importance of MSRB1 and its role in disease. In this review, we discuss the current state of research on MSRB1, compare it with other animal Msrs, and offer a perspective on further understanding of biological functions of this selenoprotein.
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Metionina Sulfóxido Reductasas , Selenocisteína , Actinas , Animales , Humanos , Mamíferos , Metionina/química , Metionina Sulfóxido Reductasas/genética , Ratones , Ratones Transgénicos , Selenoproteínas/genéticaRESUMEN
Mouse double minute 1 (Mdm1) might be involved in the function and structure of centrioles and age-related retinal degeneration. However, the mechanism by which Mdm1 deficiency causes retinal degeneration remains unknown. We confirmed that the Mdm1 protein is localized at the connecting cilium (CC) of photoreceptor cells in the retina. The electroretinograms of 6-week-old Mdm1-/- mice revealed decreased vision, which was eventually lost, and outer segment (OS) photoreceptor degeneration was evident on postnatal day 7, with complete loss of the outer nuclear layer (ONL) observed at 35 weeks. Mdm1-/- mouse retinas showed mislocalization of opsins in the photoreceptor cells, indicating particular intraflagellar transport (IFT) defects, and entrapment of the nuclei in the ONL by microvilli of retinal pigment epithelial cells, leading to apoptosis in the ONL. These results suggest that Mdm1 ablation causes specific IFT defects, which prevents the OS from continuously replenishing new discs, resulting in retinal degeneration.
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Degeneración Retiniana , Animales , Electrorretinografía , Ratones , Opsinas/metabolismo , Células Fotorreceptoras/metabolismo , Retina/metabolismo , Degeneración Retiniana/metabolismoRESUMEN
Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine-6-sulfatase, which results in skeletal and connective tissue abnormalities, as well as various non-skeletal manifestations. Although enzyme replacement therapy (ERT) is recommended as the first-line treatment, the outcomes of ERT on bone pathology remain controversial. We report clinical characteristics and outcomes of ERT in 9 patients with MPS IVA (6 males and 3 females) from 7 unrelated families. During ERT, results from pulmonary function tests, echocardiography, the 6-min walk test, and the Functional Independence Measure were monitored biannually. Anthropometric data were compared with previously reported growth charts of subjects with MPS IVA. Among the 9 patients (5 severe, and 4 slowly progressive form), 7 patients (5 severe, 2 slowly progressive) commenced ERT at a median age of 3.8 years (range: 0.8-13.7 years) and were treated for a median duration of 1.9 years (range: 1.2-5.7 years). Mean height standard deviation scores using MPS IVA growth charts were + 0.4 (+0.0 in severe phenotypes) at initiation and + 0.7 (+0.2 in severe phenotypes) at the last follow-up. Four patients with severe phenotypes underwent surgery for cervical myelopathy and 1 patient with a slowly progressive phenotype underwent a bilateral pelvic osteotomy for hip pain during ERT. The parameters of pulmonary and heart function, endurance, and Functional Independence Measure scores were maintained or increased after ERT. Overall, ERT was well tolerated without deterioration of cardiorespiratory and functional outcomes during treatment, although skeletal outcomes, including growth, were limited.