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Biological & Pharmaceutical Bulletin 2024The emergence of coronavirus disease 2019 (COVID-19), a novel identified pneumonia resulting from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus,...
The emergence of coronavirus disease 2019 (COVID-19), a novel identified pneumonia resulting from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has significantly impacted and posed significant challenges to human society. The papain-like protease (PLpro) found in the nonstructural protein 3 of SARS-CoV-2 plays a vital role in viral replication. Moreover, PLpro disrupts the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 from host proteins. Consequently, PLpro has emerged as a promising drug target against SARS-CoV-2 infection. Computational studies have reported that ciclesonide can bind to SARS-CoV-2 PLpro. However, the inhibitory effects of ciclenoside on the PLpro have not been experimentally evaluated. Here, we evaluated the inhibitory effects of synthetic glucocorticoids (sGCs), including ciclesonide, on SARS-CoV-2 PLpro in vitro assay. Ciclesonide significantly inhibited the enzymatic activity of PLpro, compared with other sGCs and its IC was 18.4 ± 1.89 µM. These findings provide insights into the development of PLpro inhibitors.
Topics: Pregnenediones; SARS-CoV-2; Humans; COVID-19 Drug Treatment; Coronavirus Papain-Like Proteases; Antiviral Agents; Molecular Docking Simulation; Coronavirus 3C Proteases; Glucocorticoids; COVID-19
PubMed: 38763750
DOI: 10.1248/bpb.b24-00038 -
Molecular Metabolism May 2024The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed....
OBJECTIVE
The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice.
METHODS
C57Bl/6 mice (8-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis.
RESULTS
We found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice.
CONCLUSIONS
Collectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis.
PubMed: 38763495
DOI: 10.1016/j.molmet.2024.101958 -
Cancer Letters May 2024Venetoclax is a BCL2-targeted drug employed in treating various cancers, particularly hematologic malignancies. Venetoclax combination therapies are increasingly...
Venetoclax is a BCL2-targeted drug employed in treating various cancers, particularly hematologic malignancies. Venetoclax combination therapies are increasingly recognized as promising treatment strategies for acute myeloid leukemia (AML). In this study, we conducted an unbiased drug screen and identified anlotinib, a promising multi-targeted receptor tyrosine kinase inhibitor with oral activity currently utilized in the treatment of solid tumor, as a potent enhancer of venetoclax's anticancer activity in AML. Our investigation encompassed AML cell lines, primary cells, and mouse models, demonstrating effective low-dose combination therapy of anlotinib and venetoclax with minimal cytopenia or organ damage. Proteomic analysis revealed abnormal mitotic signals induced by this combination in AML cells. Mechanistically, anlotinib synergized with venetoclax by suppressing ARPP19 protein, leading to sustained activation of PP2A-B55δ. This inhibited AML cells from entering the mitotic phase, culminating in mitotic catastrophe and apoptosis. Additionally, we identified a specific synthetic lethal vulnerability in AML involving an ARPP19 mutation at S62 phosphorylation. These findings underscore the therapeutic potential of anlotinib and venetoclax combination therapy in AML, warranting further clinical investigation.
PubMed: 38763475
DOI: 10.1016/j.canlet.2024.216970 -
Neurobiology of Disease May 2024CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss of function leads to neuronal ceroid lipofuscinosis. CLN8 has been...
CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss of function leads to neuronal ceroid lipofuscinosis. CLN8 has been linked to autophagy and lipid metabolism, but much remains to be learned, and there are no therapies acting on the molecular signatures in this disorder. The present study aims to characterize the molecular pathways involved in CLN8 disease and, by pinpointing altered ones, to identify potential therapies. To bridge the gap between cell and mammalian models, we generated a new zebrafish model of CLN8 deficiency, which recapitulates the pathological features of the disease. We observed, for the first time, that CLN8 dysfunction impairs autophagy. Using autophagy modulators, we showed that trehalose and SG2 are able to attenuate the pathological phenotype in mutant larvae, confirming autophagy impairment as a secondary event in disease progression. Overall, our successful modeling of CLN8 defects in zebrafish highlights this novel in vivo model's strong potential as an instrument for exploring the role of CLN8 dysfunction in cellular pathways, with a view to identifying small molecules to treat this rare disease.
PubMed: 38763444
DOI: 10.1016/j.nbd.2024.106536 -
Radiotherapy and Oncology : Journal of... May 2024Deep learning can automate delineation in radiation therapy, reducing time and variability. Yet, its efficacy varies across different institutions, scanners, or...
PURPOSE
Deep learning can automate delineation in radiation therapy, reducing time and variability. Yet, its efficacy varies across different institutions, scanners, or settings, emphasizing the need for adaptable and robust models in clinical environments. Our study demonstrates the effectiveness of the transfer learning (TL) approach in enhancing the generalizability of deep learning models for auto-segmentation of organs-at-risk (OARs) in cervical brachytherapy.
METHODS
A pre-trained model was developed using 120 scans with ring and tandem applicator on a 3 T magnetic resonance (MR) scanner (RT3). Four OARs were segmented and evaluated. Segmentation performance was evaluated by Volumetric Dice Similarity Coefficient (vDSC), 95 % Hausdorff Distance (HD95), surface DSC, and Added Path Length (APL). The model was fine-tuned on three out-of-distribution target groups. Pre- and post-TL outcomes, and influence of number of fine-tuning scans, were compared. A model trained with one group (Single) and a model trained with all four groups (Mixed) were evaluated on both seen and unseen data distributions.
RESULTS
TL enhanced segmentation accuracy across target groups, matching the pre-trained model's performance. The first five fine-tuning scans led to the most noticeable improvements, with performance plateauing with more data. TL outperformed training-from-scratch given the same training data. The Mixed model performed similarly to the Single model on RT3 scans but demonstrated superior performance on unseen data.
CONCLUSIONS
TL can improve a model's generalizability for OAR segmentation in MR-guided cervical brachytherapy, requiring less fine-tuning data and reduced training time. These results provide a foundation for developing adaptable models to accommodate clinical settings.
PubMed: 38763356
DOI: 10.1016/j.radonc.2024.110332 -
The Journal of Biological Chemistry May 2024ASCT2 (alanine serine cysteine transporter 2), a member of the SLC1 (solute carrier 1) family, mediates Na-dependent exchange of small neutral amino acids across cell...
ASCT2 (alanine serine cysteine transporter 2), a member of the SLC1 (solute carrier 1) family, mediates Na-dependent exchange of small neutral amino acids across cell membranes. ASCT2 was shown to be highly expressed in tumor cells, making it a promising target for anti-cancer therapies. In this study, we explored the binding mechanism of the high-affinity competitive inhibitor Lc-BPE with ASCT2, using electrophysiological and rapid kinetic methods. Our investigations reveal that Lc-BPE binding requires one or two Na ions initially bound to the apo-transporter with high affinity, with Na1 site occupancy being more critical for inhibitor binding. In contrast to the amino acid substrate bound form, the final, third Na ion cannot bind, due to distortion of its binding site (Na2), thus preventing the formation of a translocation-competent complex. Based on the rapid kinetic analysis, the application of Lc-BPE generated outward transient currents, indicating that, despite its net neutral nature, the binding of Lc-BPE in ASCT2 is weakly electrogenic, most likely because of asymmetric charge distribution within the amino acid moiety of the inhibitor. The pre-incubation with Lc-BPE also led to a decrease of the turnover rate of substrate exchange and a delay in the activation of substrate-induced anion current, indicating relatively slow Lc-BPE dissociation kinetics. Overall, our results provide new insight into the mechanism of binding of a prototypical competitive inhibitor to the ASCT transporters.
PubMed: 38763337
DOI: 10.1016/j.jbc.2024.107382 -
Arquivos de Neuro-psiquiatria May 2024Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that causes progressive dementia,...
BACKGROUND
Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that causes progressive dementia, seizures, movement disorders, language delay/regression, progressive visual failure, and early death. Neuronal ceroid lipofuscinosis type 2 (CLN2), caused by biallelic pathogenic variants of the gene, is the only NCL with an approved targeted therapy. The laboratory diagnosis of CLN2 is established through highly specific tests, leading to diagnostic delays and eventually hampering the provision of specific treatment for patients with CLN2. Epilepsy is a common and clinically-identifiable feature among NCLs, and seizure onset is the main driver for families to seek medical care.
OBJECTIVE
To evaluate the results of the Latin America Epilepsy and Genetics Program, an epilepsy gene panel, as a comprehensive tool for the investigation of CLN2 among other genetic causes of epilepsy.
METHODS
A total of 1,284 patients with epilepsy without a specific cause who had at least 1 symptom associated with CLN2 were screened for variants in 160 genes associated with epilepsy or metabolic disorders presenting with epilepsy through an epilepsy gene panel.
RESULTS
Variants of the gene were identified in 25 individuals (1.9%), 21 of them with 2 variants. The 2 most frequently reported variants were p.Arg208* and p.Asp276Val, and 2 novel variants were detected in the present study: p.Leu308Pro and c.89 + 3G > C Intron 2.
CONCLUSION
The results suggest that these genetic panels can be very useful tools to confirm or exclude CLN2 diagnosis and, if confirmed, provide disease-specific treatment for the patients.
Topics: Humans; Neuronal Ceroid-Lipofuscinoses; Tripeptidyl-Peptidase 1; Female; Male; Epilepsy; Aminopeptidases; Serine Proteases; Child; Adolescent; Adult; Young Adult; Child, Preschool; Telomere-Binding Proteins; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Mutation; Genetic Testing; Middle Aged; Infant
PubMed: 38763144
DOI: 10.1055/s-0044-1786854 -
Heart Rhythm May 2024Implantable cardioverter-defibrillators last longer, and interest in reliable leads with targeted lead placement is growing. The OmniaSecure defibrillation lead is a...
BACKGROUND
Implantable cardioverter-defibrillators last longer, and interest in reliable leads with targeted lead placement is growing. The OmniaSecure defibrillation lead is a novel, small-diameter, catheter-delivered lead designed for targeted placement, based on the established SelectSecure SureScan MRI Model 3830 lumenless pacing lead platform.
OBJECTIVE
This trial assessed safety and efficacy of the OmniaSecure defibrillation lead.
METHODS
The worldwide LEADR pivotal clinical trial enrolled patients indicated for de novo implantation of a primary or secondary prevention implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator, all of whom received the study lead. The primary efficacy end point was successful defibrillation at implantation per protocol. The primary safety end point was freedom from study lead-related major complications at 6 months. The primary efficacy and safety objectives were met if the lower bound of the 2-sided 95% credible interval was >88% and >90%, respectively.
RESULTS
In total, 643 patients successfully received the study lead, and 505 patients have completed 12-month follow-up. The lead was placed in the desired right ventricular location in 99.5% of patients. Defibrillation testing at implantation was completed in 119 patients, with success in 97.5%. The Kaplan-Meier estimated freedom from study lead-related major complications was 97.1% at 6 and 12 months. The trial exceeded the primary efficacy and safety objective thresholds. There were zero study lead fractures and electrical performance was stable throughout the mean follow-up of 12.7 ± 4.8 months (mean ± SD).
CONCLUSION
The OmniaSecure lead exceeded prespecified primary end point performance goals for safety and efficacy, demonstrating high defibrillation success and a low occurrence of lead-related major complications with zero lead fractures.
PubMed: 38762820
DOI: 10.1016/j.hrthm.2024.04.067 -
BMC Sports Science, Medicine &... May 2024Reference values (RVs) for knee function tests have been reported in perioperative patients with knee osteoarthritis (KOA); however, such values for practical use in...
BACKGROUND
Reference values (RVs) for knee function tests have been reported in perioperative patients with knee osteoarthritis (KOA); however, such values for practical use in outpatient setting has yet to be determined. Therefore, we aimed to establish the reference intervals (RIs) for outpatients with mild to moderate KOA.
METHODS
This cross-sectional study enrolled 202 outpatients with KOA from 8 Japanese orthopedic clinics and measured knee extensor/flexor muscle strength (MS) and knee extension/flexion range of motion (ROM). We used multiple regression analysis to evaluate the sources of variation, including sex, age, body mass index, Kellgren-Lawrence (K-L) classification, bilateral KOA, and exercise habits. Magnitude of between-subgroup differences is expressed as standard deviation ratio (SDR) based on a three-level nested analysis of variance, with SDR ≥ 0.4 as the threshold for requiring RIs specific for subgroups. RIs were calculated parametrically using two-parameter Box-Cox formula if Gaussian transformation of RVs was successful, otherwise calculated nonparametrically.
RESULTS
Partitioning was required by sex for extensor and flexor MS (SDR = 0.65, 0.57, respectively) and by K-L classification for flexion ROM (SDR = 0.54). RIs were determined parametrically for extensor MS as 0.27-2.09 (male) and 0.27-1.54 (female) Nm/kg and for flexor MS 0.18-1.20 (male) and 0.13-0.79 (female) Nm/kg. On the other hand, RIs for extension and flexion ROM were determined nonparametrically due to discrete nature of their RVs. The RIs determined for extension ROM were -15°-0° and for flexion ROM were 105°-150° (for K-L grade I/II) and 95°-140° (for K-L grade III/IV).
CONCLUSIONS
The ranges of RIs determined specifically for patients with mild to moderate KOA were in-between those of age-matched healthy controls and pre-surgical KOA patients, both of which we had reported for use in physiotherapeutic management of KOA patients undergone total knee arthroplasty. The newly derived RIs will provide an objective benchmark for physiotherapy targeting outpatients with mild to moderate KOA.
PubMed: 38762745
DOI: 10.1186/s13102-024-00901-w -
BMC Women's Health May 2024Cervical cancer continues to pose a major public health challenge in low-income countries. Cervical cancer screening programs enable early detection and effectively...
INTRODUCTION
Cervical cancer continues to pose a major public health challenge in low-income countries. Cervical cancer screening programs enable early detection and effectively reduce the incidence of cervical cancer as well as late-stage diagnosis and mortality. However, screening uptake remains suboptimal in Uganda. This study assessed correlates of intention to screen for cervical cancer among women in the Kyotera district of Central Uganda.
METHODS
We analyzed cross-sectional data collected to determine the effectiveness of community audio towers (CATs) as a modality of health communication to support cervical cancer prevention. Women (n = 430) aged 21-60 years without a prior history of cervical cancer screening were surveyed about demographics, sources of health information and cervical cancer screening intentions in 2020. We used generalized linear modelling with modified Poisson regression and backwards variable elimination to identify adjusted prevalence ratios and 95% confidence intervals (CI) to determine factors associated with intention to screen for cervical cancer.
RESULTS
Half (50.2%) of the participants had intentions to screen for cervical cancer within twelve months and 26.5% had moderate knowledge about cervical cancer. Nearly half (46.0%) considered themselves at risk of cervical cancer. Compared to residents who primarily received their health information from social media and radio, participants who received health information primarily from CATs (aPR:0.64, 95% CI:0.52-0.80, p < 0.001) and TV (aPR:0.52, 95% CI:0.34-0.82, p = 0.005) had a lower prevalence of intention to screen for cervical cancer. The prevalence of intentions to screen for cervical cancer in twelve months was higher among those resided in town councils (aPR:1.44, 95% CI:1.12-1.86, p = 0.004) compared to rural areas, and higher among those who considered themselves to be at risk of cervical cancer (aPR:1.74, 95% CI:1.28-2.36, p < 0.001) compared to those who did not.
CONCLUSIONS
We found suboptimal prevalence of intentions to screen for cervical cancer among women in central Uganda. Additional research and implementation projects are needed to increase cervical cancer screening. Targeting risk perceptions and behavioral approaches to increase intentions could be effective in future intervention work. Based on urban-rural differences, additional work is needed to support equitable sharing of information to support cancer prevention messaging; CATs and TV may best help reach those with lower intentions to screen based on our research.
Topics: Humans; Female; Uterine Cervical Neoplasms; Cross-Sectional Studies; Uganda; Adult; Middle Aged; Early Detection of Cancer; Intention; Health Knowledge, Attitudes, Practice; Patient Acceptance of Health Care; Young Adult; Mass Screening
PubMed: 38762723
DOI: 10.1186/s12905-024-03129-5