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Korean Circulation Journal Jun 2024Although the clinical consequences of advanced heart failure (HF) may be similar across different etiologies of cardiomyopathies, their proteomic expression may show...
BACKGROUND AND OBJECTIVES
Although the clinical consequences of advanced heart failure (HF) may be similar across different etiologies of cardiomyopathies, their proteomic expression may show substantial differences in relation to underlying pathophysiology. We aimed to identify myocardial tissue-based proteomic characteristics and the underlying molecular pathophysiology in non-ischemic cardiomyopathy with different etiologies.
METHODS
Comparative extensive proteomic analysis of the myocardium was performed in nine patients with biopsy-proven non-ischemic cardiomyopathies (3 dilated cardiomyopathy [DCM], 2 hypertrophic cardiomyopathy [HCM], and 4 myocarditis) as well as five controls using tandem mass tags combined with liquid chromatography-mass spectrometry. Differential protein expression analysis, Gene Ontology (GO) analysis, and Ingenuity Pathway Analysis (IPA) were performed to identify proteomic differences and molecular mechanisms in each cardiomyopathy type compared to the control. Proteomic characteristics were further evaluated in accordance with clinical and pathological findings.
RESULTS
The principal component analysis score plot showed that the controls, DCM, and HCM clustered well. However, myocarditis samples exhibited scattered distribution. IPA revealed the downregulation of oxidative phosphorylation and upregulation of the sirtuin signaling pathway in both DCM and HCM. Various inflammatory pathways were upregulated in myocarditis with the downregulation of Rho GDP dissociation inhibitors. The molecular pathophysiology identified by extensive proteomic analysis represented the clinical and pathological properties of each cardiomyopathy with abundant proteomes.
CONCLUSIONS
Different etiologies of non-ischemic cardiomyopathies in advanced HF exhibit distinct proteomic expression despite shared pathologic findings. The benefit of tailored management strategies considering the different proteomic expressions in non-ischemic advanced HF requires further investigation.
PubMed: 38956938
DOI: 10.4070/kcj.2024.0033 -
Current Topics in Medicinal Chemistry Jul 2024For many centuries, traditional medicine has played an essential role in health care. The treatment of many illnesses, including cancer, has greatly benefited from using...
For many centuries, traditional medicine has played an essential role in health care. The treatment of many illnesses, including cancer, has greatly benefited from using herbal remedies derived from traditional medicine. The bioactive compounds, such as curcumin, silibinin, berberine, ginseng, and others present in traditional medicine have shown a wide range of properties, such as anti-inflammatory, antimicrobial, anti-oxidant as well as potent anti-cancer properties both in laboratory studies and animal experiments (in vitro and in vivo). In this review, we mainly emphasized the anticancer role of bioactive compounds present in traditional medicine, such as curcumin, cardamonin, piperine, berberine, ginseng, silibinin, epigallocatechin gallate, and asafoetida. We also discussed molecular evidence of these compounds in chemoprevention and anticancer effects. These compounds have the potential to interfere with cancer growth, proliferation, metastasis, and angiogenesis and induce apoptosis by targeting different pathways and the cell cycle. This review article also focuses on how these compounds can help overcome drug resistance and enhance the availability of other clinically approved drugs. The usage of these compounds synergistically with other forms of treatment is also of great fascination to new and upcoming research. Finally, we have discussed the bioavailability of these compounds and strategies employed to improve them so their full potential can be exploited.
PubMed: 38956915
DOI: 10.2174/0115680266302556240620054134 -
Advanced Science (Weinheim,... Jul 2024Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the...
Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single-cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia-based intercellular communication hub consisting of malignant cells, ALCAM macrophages, and exhausted CD8 T cells around the tumor boundary. A hypoxic microenvironment promotes binding of HIF-1α complex is demonstrated to the ALCAM promoter therefore increasing its expression in macrophages, and the ALCAM macrophages co-localize with exhausted CD8 T cells in the tumor spatial microenvironment and promote T cell exhaustion. Preclinically, HIF-1ɑ inhibition reduces ALCAM expression in macrophages and exhausted CD8 T cells and potentiates T cell antitumor function to enhance immunotherapy efficacy. This study reveals the systematic landscape of hypoxia at single-cell resolution and spatial architecture and highlights the effect of hypoxia on immunotherapy resistance through the ALCAM macrophage-exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia-induced resistance in cancers.
PubMed: 38956900
DOI: 10.1002/advs.202309885 -
British Journal of Pharmacology Jul 2024Remote ischaemic preconditioning (rIPC) for cardioprotection is severely impaired in diabetes, and therapeutic options to restore it are lacking. The vascular...
BACKGROUND AND PURPOSE
Remote ischaemic preconditioning (rIPC) for cardioprotection is severely impaired in diabetes, and therapeutic options to restore it are lacking. The vascular endothelium plays a key role in rIPC. Given that the activity of endothelial nitric oxide synthase (eNOS) is inhibited by proline-rich tyrosine kinase 2 (Pyk2), we hypothesized that pharmacological Pyk2 inhibition could restore eNOS activity and thus restore remote cardioprotection in diabetes.
EXPERIMENTAL APPROACH
New Zealand obese (NZO) mice that demonstrated key features of diabetes were studied. The consequence of Pyk2 inhibition on endothelial function, rIPC and infarct size after myocardial infarction were evaluated. The impact of plasma from mice and humans with or without diabetes was assessed in isolated buffer perfused murine hearts and aortic rings.
KEY RESULTS
Plasma from nondiabetic mice and humans, both subjected to rIPC, caused remote tissue protection. Similar to diabetic humans, NZO mice demonstrated endothelial dysfunction. NZO mice had reduced circulating nitrite levels, elevated arterial blood pressure and a larger infarct size after ischaemia and reperfusion than BL6 mice. Pyk2 increased the phosphorylation of eNOS at its inhibitory site (Tyr656), limiting its activity in diabetes. The cardioprotective effects of rIPC were abolished in diabetic NZO mice. Pharmacological Pyk2 inhibition restored endothelial function and rescued cardioprotective effects of rIPC.
CONCLUSION AND IMPLICATIONS
Endothelial function and remote tissue protection are impaired in diabetes. Pyk2 is a novel target for treating endothelial dysfunction and restoring cardioprotection through rIPC in diabetes.
PubMed: 38956895
DOI: 10.1111/bph.16483 -
Ophthalmic Genetics Jul 2024Fleck corneal dystrophy (FCD) is a rare autosomal dominant disease that affects exclusively the corneal stroma. The disease is caused by heterozygous variants in...
BACKGROUND
Fleck corneal dystrophy (FCD) is a rare autosomal dominant disease that affects exclusively the corneal stroma. The disease is caused by heterozygous variants in PIKFYVE, a gene encoding a lipid kinase involved in multiple cellular pathways, primarily participating in membrane dynamics and signaling. This report describes a familial case of FCD caused by a complete deletion of the PIKFYVE gene.
MATERIAL AND METHODS
A clinical ophthalmic examination was performed on the proband and family members. Genetic testing included next-generation sequencing (multigene panel), and chromosomal microarray analysis. A quantitative PCR assay was designed in order to segregate the deletion.
RESULTS
A 19-year-old male, with no family or personal history of ocular disease, presented for evaluation due to an acute illness consisting of burning, foreign body sensation, and red eye. Slit lamp biomicroscopy revealed bilateral small pterygia and scattered bilateral white opacities in the corneal stroma, a very similar corneal phenotype was found in the 47-year-old father, who was asymptomatic. NGS detected a heterozygous deletion of the entire PIKFYVE coding sequence. CMA in DNA from the propositus indicated a 543 kb deletion in 2q33.3q34 spanning the entire PIKFYVE gene. The deletion was confirmed in the father.
CONCLUSIONS
We add to the molecular spectrum of FCD by describing a familial case of a whole PIKFYVE gene deletion in affected subjects. Our findings support that normal expression of PIKFYVE is necessary for corneal keratocytes homeostasis and normal corneal appearance. We conclude that PIKFYVE haploinsufficiency is the molecular mechanism underlying this familial case of FCD.
PubMed: 38956867
DOI: 10.1080/13816810.2024.2365737 -
Brain and Behavior Jul 2024High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor...
The protective effects of repetitive transcranial magnetic stimulation with different high frequencies on motor functions in MPTP/probenecid induced Parkinsonism mouse models.
BACKGROUND
High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor symptoms of Parkinson's disease (PD). However, whether the high frequency of rTMS positively correlates to the improvement of motor symptoms of PD is still undecided. By controlling for other parameters, a disease animal model may be useful to compare the neuroprotective effects of different high frequencies of rTMS.
OBJECTIVE
The current exploratory study was designed to compare the protective effects of four common high frequencies of rTMS (5, 10, 15, and 20 Hz) and iTBS (a special form of high-frequency rTMS) and explore the optimal high-frequency rTMS on an animal PD model.
METHODS
Following high frequencies of rTMS application (twice a week for 5 weeks) in a MPTP/probenecid-induced chronic PD model, the effects of the five protocols on motor behavior as well as dopaminergic neuron degeneration levels were identified. The underlying molecular mechanisms were further explored.
RESULTS
We found that all the high frequencies of rTMS had protective effects on the motor functions of PD models to varying degrees. Among them, the 10, 15, and 20 Hz rTMS interventions induced comparable preservation of motor function through the protection of nigrostriatal dopamine neurons. The enhancement of brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2) and the suppression of TNF-α and IL-1β in the nigrostriatum were involved in the process. The efficacy of iTBS was inferior to that of the above three protocols. The effect of 5 Hz rTMS protocol was weakest.
CONCLUSIONS
Combined with the results of the present study and the possible side effects induced by rTMS, we concluded that 10 Hz might be the optimal stimulation frequency for preserving the motor functions of PD models using rTMS treatment.
Topics: Animals; Transcranial Magnetic Stimulation; Mice; Male; Disease Models, Animal; Probenecid; Parkinsonian Disorders; Mice, Inbred C57BL; Brain-Derived Neurotrophic Factor; Motor Cortex; Dopaminergic Neurons; Dopamine Plasma Membrane Transport Proteins; Interleukin-1beta; Substantia Nigra; Corpus Striatum; Vesicular Monoamine Transport Proteins; MPTP Poisoning; Motor Activity; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
PubMed: 38956819
DOI: 10.1002/brb3.3605 -
Pediatric Blood & Cancer Jul 2024Direct oral anticoagulants (DOACs) have had significant impact on the management of venous thromboembolism (VTE) in adults, but these agents were not approved for use in...
BACKGROUND
Direct oral anticoagulants (DOACs) have had significant impact on the management of venous thromboembolism (VTE) in adults, but these agents were not approved for use in pediatric patients until 2021. Our objective was to analyze the characteristics of pediatric patients treated with DOACs prior to and following U.S. Food and Drug Administration (FDA) approval for children and evaluate their impact on hospital outcomes.
PROCEDURE
We utilized the Epic Cosmos dataset (Cosmos), a de-identified dataset of over 220 million patients, to identify patients aged 1-18 years admitted with a first-occurrence diagnosis of VTE between January 1, 2017 and June 30, 2023. Patients were grouped by anticoagulation received (unfractionated heparin, low molecular weight heparin, and/or DOACs).
RESULTS
Among 5138 eligible patients, 18.1% received DOACs as all or part of their anticoagulation treatment, while 81.9% received heparin therapies alone. Patients treated with DOACs were older than patients treated with heparin monotherapy at 17.4 and 13.0 years, respectively. Non-DOAC patients were more likely to have chronic conditions and were less likely to have pulmonary embolism. Patients treated with DOACs demonstrated shorter overall length of stay and duration of intensive care unit (ICU) admission.
CONCLUSIONS
DOACs remain infrequently utilized in pediatric patients, especially in those under 13 years old. Initiation on heparin therapy and transition to DOACs remains common, with 80.6% of DOAC patients receiving heparin during their hospitalization. While DOAC monotherapy is not currently endorsed as first-line therapy for DVT or PE in children, it is being used clinically. Further research is needed to clarify the impact of DOAC use on patient adherence, VTE recurrence, and healthcare cost.
PubMed: 38956808
DOI: 10.1002/pbc.31140 -
International Neurourology Journal Jun 2024Bladder cancer (BCa) is the most common malignancy of the urinary system. It has a high recurrence rate and requires longterm follow-up. Significant advances in BCa...
Bladder cancer (BCa) is the most common malignancy of the urinary system. It has a high recurrence rate and requires longterm follow-up. Significant advances in BCa research have been made in recent years; however, the initial diagnosis and follow-up of BCa relies on cystoscopy, which is an invasive and expensive procedure. Over the past decade, liquid biopsies (e.g., blood and urine) have proven to be highly efficient methods for the discovery of BCa biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into body fluids and enables serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers have been studied extensively and have shown promising results in the clinical applications of BCa, including early detection, microscopic residual disease detection, recurrence prediction, and treatment response. Therefore, this review aims to provide an update on various new liquid biopsy markers and the advantages and current limitations of liquid biopsy in the diagnosis of BCa.
PubMed: 38956768
DOI: 10.5213/inj.2448198.099 -
Annals of Pediatric Endocrinology &... Jun 2024Recent advances in long-read next-generation sequencing (NGS) have enabled researchers to identify several pathogenic variants overlooked by short-read NGS, array-based...
Recent advances in long-read next-generation sequencing (NGS) have enabled researchers to identify several pathogenic variants overlooked by short-read NGS, array-based comparative genomic hybridization, and other conventional methods. Long-read NGS is particularly useful in the detection of structural variants and repeat expansions. Furthermore, it can be used for mutation screening in difficultto- sequence regions, as well as for DNA-methylation analyses and haplotype phasing. This mini-review introduces the usefulness of long-read NGS in the molecular diagnosis of pediatric endocrine disorders.
PubMed: 38956752
DOI: 10.6065/apem.2448028.014 -
Annals of Pediatric Endocrinology &... Jun 2024
PubMed: 38956750
DOI: 10.6065/apem.24224014edi03