Rational design, synthesis, biological evaluation, and molecular modeling of novel naphthamide derivatives possessing potent, reversible, and competitive inhibitory mode of action over human monoamine oxidase.

Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC50 value of 0.294 µM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC50 value of 0.519 µM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future.

Genomic insights into inherited bone marrow failure syndromes in a Korean population.

Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next-generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field.

Genetic predisposition in chemotherapy-induced cardiomyopathy in a 65-year-old female with metastatic breast cancer.

The prevention and management of cancer therapy-related cardiac dysfunction (CTRCD) have become increasingly important. Recent studies have revealed the crucial role of genetics in determining the susceptibility to development of CTRCD. We present a case of a 65-year-old woman with breast cancer who developed recurrent CTRCD following low-dose chemotherapy, despite lacking conventional cardiovascular risk factors. Her medical history included anthracycline-associated cardiomyopathy, and her condition deteriorated significantly after treatment with HER2-targeted therapies. Through the use of multimodal imaging, we detected severe left ventricular systolic dysfunction. Further investigation with genetic testing revealed a likely pathogenic variant in the TNNT2 gene, suggesting a genetic predisposition to CTRCD. This case implies the potential role of genetic screening in identifying patients at risk for CTRCD and advocates for personalized chemotherapy and cardioprotective strategies.

Central retinal artery occlusion after intravitreal brolucizumab injection for treatment-naïve neovascular age-related macular degeneration; a case report.

BACKGROUND: To report a case of central retinal artery occlusion (CRAO) after intravitreal injection of brolucizumab for a treatment-naïve neovascular age-related macular degeneration (nAMD) patient without comorbid cardiovascular disease history. CASE PRESENTATION: A 79-year-old Asian male without a cardiovascular disease history such as diabetes or hypertension underwent three times of monthly consecutive intravitreal brolucizumab injections for treatment of progressed nAMD in his left eye. Two days after the third injection, the patient presented with acute painless visual loss. Typical retinal whitening with a cherry red spot was observed on the fundus photograph, and retinal swelling with hyper-reflectivity was also identified on the optical coherence tomography (OCT) scan. On the fundus fluorescein angiography, arm-to-retina time and arteriovenous transit time were remarkedly delayed, but clinical findings suggesting an intraocular inflammation (IOI) were not observed. Therefore, CRAO was diagnosed, and anterior chamber paracentesis was administrated immediately. However, there had been no improvement in visual acuity during the follow-up period of three months, despite prolonged oral steroid and anti-platelet agent medication. CONCLUSIONS: In rare cases, patients without cardiovascular comorbidities can develop CRAO after intravitreal brolucizumab injection without gross evidence of IOI. Therefore, CRAO should always be in consideration and careful observation is required after intravitreal brolucizumab injection for nAMD patients with old age, even if the patient does not have any other cardiovascular disease history.

Ethanol Extracts of Cornus alba Improve Benign Prostatic Hyperplasia by Inhibiting Prostate Cell Proliferation through Modulating 5 Alpha-Reductase/Androgen Receptor Axis-Mediated Signaling.

PURPOSE: The aim of this study was to investigate the efficacy of ethanol extracts of Cornus alba (ECA) against benign prostatic hyperplasia (BPH) in vitro and in vivo. MATERIALS AND METHODS: The prostate stromal cells (WPMY-1) and epithelial cells (RWPE-1) were used to examine the action mechanism of ECA in BPH in vitro. ECA efficacy was evaluated in vivo using a testosterone propionate (TP)-induced BPH rat model. RESULTS: Treatment with ECA inhibited the proliferation of prostate cells by inducing G1-phase cell cycle arrest through the regulation of positive and negative proteins. Treatment of prostate cells with ECA resulted in alterations in the mitogen-activated protein kinases and protein kinase B signaling pathways. The transcriptional binding activity of the NF-κB motif was suppressed in both ECA-treated prostate cells. In addition, treatment with ECA altered the level of BPH-associated axis markers (5α-reductase, fibroblast growth factor-2, androgen receptor, epidermal growth factor, Bcl-2, and Bax) in both cell lines. Finally, the administration of ECA attenuated the enlargement of prostatic tissues in the TP-induced BPH rat model, accompanied by histology, immunoblot, and serum dihydrotestosterone levels. CONCLUSIONS: These results demonstrated that ECA exerted beneficial effects on BPH both in vitro and in vivo and might provide valuable information in the development of preventive or therapeutic agents for improving BPH.

Cellular abundance-based prognostic model associated with deregulated gene expression of leukemic stem cells in acute myeloid leukemia.

Background: Previous studies have reported that genes highly expressed in leukemic stem cells (LSC) may dictate the survival probability of patients and expression-based cellular deconvolution may be informative in forecasting prognosis. However, whether the prognosis of acute myeloid leukemia (AML) can be predicted using gene expression and deconvoluted cellular abundances is debatable. Methods: Nine different cell-type abundances of a training set composed of the AML samples of 422 patients, were used to build a model for predicting prognosis by least absolute shrinkage and selection operator Cox regression. This model was validated in two different validation sets, TCGA-LAML and Beat AML (n = 179 and 451, respectively). Results: We introduce a new prognosis predicting model for AML called the LSC activity (LSCA) score, which incorporates the abundance of 5 cell types, granulocyte-monocyte progenitors, common myeloid progenitors, CD45RA + cells, megakaryocyte-erythrocyte progenitors, and multipotent progenitors. Overall survival probabilities between the high and low LSCA score groups were significantly different in TCGA-LAML and Beat AML cohorts (log-rank p-value = 3.3×10-4 and 4.3×10-3, respectively). Also, multivariate Cox regression analysis on these two validation sets shows that LSCA score is independent prognostic factor when considering age, sex, and cytogenetic risk (hazard ratio, HR = 2.17; 95% CI 1.40-3.34; p < 0.001 and HR = 1.20; 95% CI 1.02-1.43; p < 0.03, respectively). The performance of the LSCA score was comparable to other prognostic models, LSC17, APS, and CTC scores, as indicated by the area under the curve. Gene set variation analysis with six LSC-related functional gene sets indicated that high and low LSCA scores are associated with upregulated and downregulated genes in LSCs. Conclusion: We have developed a new prognosis prediction scoring system for AML patients, the LSCA score, which uses deconvoluted cell-type abundance only.

Influence of Post-Curing in Nitrogen-Saturated Condition on the Degree of Conversion and Color Stability of 3D-Printed Resin Crowns.

Post-curing is the process of applying extra light to complete the polymerization process of 3D printing. The mechanical properties of light-cured three-dimensional (3D) printed resin can be improved by decreasing the oxygen concentrations during post-curing, and nitrogen-saturated post-curing has been applied for this purpose. This study aimed to evaluate and compare the color stability of 3D-printed resin crowns that were post-cured in both normal air and nitrogen-saturated conditions. Crowns were fabricated with a 3D printer and post-cured in normal air (control group; air) or nitrogen-saturated conditions (experimental group; nitrogen). The specimens in each group were subdivided into four subgroups, each exposed to different discoloration agents: distilled water, coffee, wine, and curry. Post-immersion color changes were measured using a digital spectrophotometer and analyzed using repeated-measures ANOVA. Fourier transform infrared (FT-IR) spectroscopy evaluated the degree of conversion of resin over immersion times for both post-curing conditions. Upon comparing the effects of post-curing conditions, a significant difference between the control and experimental groups in terms of immersion time in the wine and curry subgroups was found. FT-IR analysis showed a significant difference in the degree of conversion between the air and nitrogen groups from 10 to 300 s. These findings suggest that nitrogen-saturated post-curing can potentially enhance the conversion rate of 3D-printed resin crowns, thereby improving their color stability.

Risk Factors for Infertility in Korean Women.

BACKGROUND: Female infertility is a crucial problem with significant implications for individuals and society. In this study, we explore risk factors for infertility in Korean women. METHODS: A total of 986 female patients who visited six major infertility clinics in Korea were recruited from April to December 2014. Fertile age-matched controls were selected from two nationwide survey study participants. Conditional logistic regression after age-matching was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of each risk factor for infertility. RESULTS: Women with a body mass index (BMI) < 18.5 kg/m² had 1.35 times higher odds of infertility (OR, 1.35; 95% CI, 1.03-1.77), while those with a BMI ≥ 25.0 kg/m² had even higher odds (OR, 2.06; 95% CI, 1.61-2.64) compared to women with a normal BMI (18.5 kg/m² ≤ BMI < 25 kg/m²). Ever-smokers exhibited 4.94 times higher odds of infertility compared to never-smokers (95% CI, 3.45-8.85). Concerning alcohol consumption, women who consumed ≥ 7 glasses at a time showed 3.13 times significantly higher odds of infertility than those who consumed ≤ 4 glasses at a time (95% CI, 1.79-5.48). Lastly, women with thyroid disease demonstrated 1.44 times higher odds of infertility compared to women without thyroid disease (95% CI, 1.00-2.08). CONCLUSION: Female infertility in Korea was associated with underweight, obesity, smoking, alcohol consumption, and thyroid disease.

Early-onset vasomotor symptoms and development of depressive symptoms among premenopausal women.

BACKGROUND: We investigated the association between vasomotor symptoms (VMSs) and the onset of depressive symptoms among premenopausal women. METHODS: This cross-sectional study included 4376 premenopausal women aged 42-52 years, and the cohort study included 2832 women without clinically relevant depressive symptoms at baseline. VMSs included the symptoms of hot flashes and night sweats. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale; a score of ≥16 was considered to define clinically relevant depressive symptoms. RESULTS: Premenopausal Women with VMSs at baseline exhibited a higher prevalence of depressive symptoms compared with women without VMSs at baseline (multivariable-adjusted prevalence ratio 1.76, 95 % confidence interval [CI] 1.47-2.11). Among the 2832 women followed up (median, 6.1 years), 406 developed clinically relevant depressive symptoms. Women with versus without VMSs had a significantly higher risk of developing clinically relevant depressive symptoms (multivariable-adjusted hazard ratio, 1.72; 95 % CI 1.39-2.14). VMS severity exhibited a dose-response relationship with depressive symptoms (P for trend <0.05). LIMITATIONS: Self-reported questionnaires were only used to obtain VMSs and depressive symptoms, which could have led to misclassification. We also could not directly measure sex hormone levels. CONCLUSIONS: Even in the premenopausal stage, women who experience hot flashes or night sweats have an increased risk of present and developed clinically relevant depressive symptoms. It is important to conduct mental health screenings and provide appropriate support to middle-aged women who experience early-onset VMSs.

Advancements in Human Embryonic Stem Cell Research: Clinical Applications and Ethical Issues.

BACKGROUND: The development and use of human embryonic stem cells (hESCs) in regenerative medicine have been revolutionary, offering significant advancements in treating various diseases. These pluripotent cells, derived from early human embryos, are central to modern biomedical research. However, their application is mired in ethical and regulatory complexities related to the use of human embryos. METHOD: This review utilized key databases such as ClinicalTrials.gov, EU Clinical Trials Register, PubMed, and Google Scholar to gather recent clinical trials and studies involving hESCs. The focus was on their clinical application in regenerative medicine, emphasizing clinical trials and research directly involving hESCs. RESULTS: Preclinical studies and clinical trials in various areas like ophthalmology, neurology, endocrinology, and reproductive medicine have demonstrated the versatility of hESCs in regenerative medicine. These studies underscore the potential of hESCs in treating a wide array of conditions. However, the field faces ethical and regulatory challenges, with significant variations in policies and perspectives across different countries. CONCLUSION: The potential of hESCs in regenerative medicine is immense, offering new avenues for treating previously incurable diseases. However, navigating the ethical, legal, and regulatory landscapes is crucial for the continued advancement and responsible application of hESC research in the medical field. Considering both scientific potential and ethical implications, a balanced approach is essential for successfully integrating hESCs into clinical practice.

Profiling the Phytochemicals of Orostachys margaritifolia: Biological Activities, LC-ESI/MS, and HPLC Analyses.

Orostachys margaritifolia Y. N. Lee (OMY) is an endemic Korean plant in the family Crassulaceae that is known to contain a variety of bioactive compounds. To assess the physiological activities of an OMY ethanol extract, ABTS+ and DPPH radical scavenging assays and a nitric oxide (NO) inhibition assay were conducted. The phytochemical makeup of the extract was profiled via liquid chromatography-mass spectrometry (LC-ESI/MS) and high-performance liquid chromatography with a photodiode array detector (HPLC/PDA). The OMY extract was found to have weaker ABTS+ and DPPH radical scavenging activities than the control group (green tea). In the NO inhibition assay, the OMY extract induced a significant increase in macrophage cell viability but showed a lower NO inhibitory activity than l-NAME, producing an IC50 value of 202.6 µg/mL. The LC-ESI/MS and HPLC/PDA analyses identified isoquercitrin and astragalin in the OMY extract, quantifying their contents at 3.74 mg/g and 3.19 mg/g, respectively. The study revealed possibilities for the utilization of OMY as a future source of drugs for alleviating inflammation and diseases related to reactive oxygen species.

Determination of the Absolute Configuration of Secondary Alcohols in a Compound Mixture via the Application of Competing Enantioselective Acylation Coupled with LC/MS Analysis.

The determination of natural product stereochemistry plays a significant role in drug discovery and development. Understanding the stereochemistry of natural products is essential for predicting and optimizing their interactions with biological targets, which, in turn, influences their therapeutic efficacy, safety, and overall impact on living organisms. Here, we present the first application of competitive enantioselective acylation (CEA) reactions in conjunction with LC/MS analysis for determining the absolute configuration of secondary alcohols in natural products which were purified as a mixture. This approach utilizes the enantiomeric pair of HBTM (homobenzotetramisole) catalysts, demonstrating sufficient kinetic resolution for the acylation of secondary alcohols. The rapid reaction kinetics were quantitatively estimated with LC/MS analysis as the characterization technique for the enantioselective transformations. Our study has expanded the application of the CEA reaction coupled with LC/MS analysis to mixtures. Utilizing LC/MS analysis, the CEA reaction offers a sensitive and simple method for stereochemistry determination. Additionally, the application of the CEA reaction is cost/time-effective since only small quantities of substrates and a short reaction time are required for characterizing the absolute configuration of secondary alcohols in natural products compared to other conventional methods.

Optimized treatment parameter by computer simulation for high-intensity focused ultrasound treatment of uterine adenomyosis: Short-term and long-term results.

This study aimed to investigate the efficacy and safety of using optimized parameters obtained by computer simulation for ultrasound-guided high-intensity focused ultrasound (HIFU) treatment of uterine adenomyosis in comparison with conventional parameters. We retrospectively assessed a single-institution, prospective study that was registered at Clinical Research Information Service (CRiS) of Republic of Korea (KCT0003586). Sixty-six female participants (median age: 44 years) with focal uterine adenomyosis were prospectively enrolled. All participants were treated with a HIFU system by using treatment parameters either for treating uterine fibroids (Group A, first 20 participants) or obtained via computer simulation (Group B, later 46 participants). To assess the treatment efficacy of HIFU, qualitative indices, including the clinically effective dysmenorrhea improvement index (DII), were evaluated up to 3 years after treatment, whereas quantitative indices, such as the nonperfused volume ratio and adenomyosis volume shrinkage ratio (AVSR), on MRI were evaluated up to 3 months after treatment. Quantitative/qualitative indices were compared between Groups A and B by using generalized linear mixed effect model. A safety assessment was also performed. Results showed that clinically effective DII was more frequently observed in Group B than in Group A (odds ratio, 3.69; P = 0.025), and AVSR were higher in Group B than in Group A (least-squares means, 21.61; P = 0.001). However, two participants in Group B developed skin burns at the buttock and sciatic nerve pain and required treatment. In conclusion, parameters obtained by computer simulation were more effective than the conventional parameters for treating uterine adenomyosis by using HIFU in terms of clinically effective DII and AVSR. However, care should be taken because of the risk of adverse events.

Enzyme Inhibition Assays for Monoamine Oxidase.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines with two isoforms, namely, MAO-A and MAO-B, in mitochondrial outer membranes. These two types of MAO-A and MAO-B participate in changes in levels of neurotransmitter such as serotonin (5-hydroxytryptamine) and dopamine. Selective MAO-A inhibitors have been targeted for anti-depression treatment, while selective MAO-B inhibitors are targets of therapeutic agents for Alzheimer's disease and Parkinson's disease. For this reason, study on the development of MAO inhibitors has recently become important. Here, we describe methods of MAO activity assay, especially continuous spectrophotometric methods, which give relatively high accuracy. MAO-A and MAO-B can be assayed using kynuramine and benzylamine as substrates, respectively, at 316 nm and 250 nm, respectively, to measure their respective products, 4-hydroxyquinoline and benzaldehyde. Inhibition degree and pattern can be analyzed by using the Lineweaver-Burk and secondary plots in the presence of inhibitor, and reversibility of inhibitor can be determined by using the dialysis method.

Delayed treatment of traumatic eyeball dislocation into the maxillary sinus and treatment algorithm: a case report and literature review.

Orbital floor fractures are commonly encountered, but the dislocation of the eyeball into the maxillary sinus is relatively rare. When it does occur, globe dislocation can have serious consequences, including vision loss, enucleation, and orbito-ocular deformity. Immediate surgical intervention is typically attempted when possible. However, severe comorbidities and poor general health can delay necessary surgery. In this report, we present the surgical outcomes of a 70-year-old woman who received delayed treatment for traumatic eyeball dislocation into the maxillary sinus due to a subarachnoid hemorrhage and hemopneumothorax. Additionally, we propose a treatment algorithm based on our clinical experience and a review of the literature.

Chronic ankle instability affects the association between knee joint angle and loading: musculoskeletal simulation study.

The purpose of this study was to calculate and compare (1) knee loads, (2) muscle-specific contributions to knee loads, and (3) effects of knee flexion angle on knee loads and muscle-specific load contributions during a forward jump-landing task in people with and without chronic ankle instability (CAI). Eight CAI patients and seven healthy controls performed a forward jump-landing task. We collected 3D kinematics, ground reaction force, and muscle activation and used musculoskeletal modeling. The results showed that only healthy controls exhibited an association between knee flexion angle and knee compressive impulse (r = 0.854, p = .014). The lack of association in CAI group may lead to knee instability and increase knee injury risk in people with CAI.

Porocarcinoma in a palm reconstructed with a full thickness skin graft: A case report.

BACKGROUND: Porocarcinoma is a rare type of skin cancer that originates from sweat gland tumors. It is an aggressive malignant skin cancer that is difficult to diagnose clinically owing to its rarity and similarity to squamous cell carcinoma (SCC). CASE SUMMARY: This case involved a 92-year-old woman, a farmer by profession, presented with an exophytic and verrucous mass on her left palm that had formed 2 years prior and caused chronic pain and frequent bleeding. Initially, the patient was diagnosed with SCC using a punch biopsy; however, a repeat biopsy with additional immunohistochemical tests was performed for porocarcinoma. Ultimately, the patient was diagnosed with porocarcinoma and reconstruction was planned using a full-thickness skin graft. After treatment, the range of motion of the palm was preserved, and the aesthetic outcome was favorable. At 6 mo of follow-up, the patient was satisfied with the outcome. CONCLUSION: Porocarcinoma is commonly misdiagnosed as SCC; therefore, clinicians should consider porocarcinomas when evaluating mass-like lesions on the hands.

Comprehensive workflow encompassing discovery, verification, and quantification of indicator peptide in snail mucin using LC-quadrupole Orbitrap high-resolution tandem mass spectrometry.

Peptidomics analysis was conducted using high-resolution tandem mass spectrometry (MS2) to determine the peptide profile of snail-derived mucin extract (SM). The study was also aimed to identify an indicator peptide and validate a quantification method for this peptide. The peptide profiling and identification were conducted using discovery-based peptidomics analysis employing data-dependent acquisition, whereas the selected peptides were verified and quantified using parallel reaction monitoring acquisition. Among the 16 identified peptides, the selected octapeptide (TEAPLNPK) was quantified via precursor ion ionization (m/z 435.2400), followed by quantification of the corresponding quantifier ion fragment (m/z 639.3824) using MS2. The quantification method was optimized and validated in terms of specificity, linearity, accuracy, precision, and limit of detection/quantification. The validated method accurately quantified the TEAPLNPK content in the SM as 7.5 ± 0.2 µg/g. Our study not only identifies an indicator peptide from SM but also introduces a novel validation method, involving precursor ion ionization and quantification of specific fragments. Our findings may serve as a comprehensive workflow for the monitoring, selection, and quantification of indicator peptides from diverse food resources.