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1.
Front Pediatr ; 12: 1336589, 2024.
Article in English | MEDLINE | ID: mdl-38390278

ABSTRACT

We encountered a pediatric case of pulmonary hypertension triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 14-year-old girl was brought to the emergency department of our hospital with fever, respiratory distress, and impaired consciousness. She tested positive for SARS-CoV-2 upon a polymerase chain reaction examination and had prolonged hypoxemia without pneumonia. An echocardiography revealed elevated right ventricular pressure. She was diagnosed with pilocytic astrocytoma at the age of 10 years and underwent a resection of a pituitary tumor. Hormone replacement therapy was administered postoperatively, but her growth hormones were not activated because of concerns about tumor recurrence. Echocardiography at the age of 13 years showed normal right ventricular pressure. On admission, she had an abnormal liver function, elevated liver fibrosis markers, a decreased platelet count, and hepatosplenomegaly, suggesting pulmonary and portal hypertension. The diagnosis was pulmonary hypertension associated with SARS-CoV-2 infection. The mechanism of the pulmonary hypertension was thought to be portal hypertension owing to growth hormone deficiency and SARS-CoV-2 infection. The patient's symptoms improved with oxygenation and bed rest without additional targeted pulmonary hypertension therapy, and her right ventricular pressure decreased. This case demonstrates that a pediatric patient with subclinical pulmonary hypertension may develop pulmonary hypertension triggered by SARS-CoV-2 infection.

2.
Front Genet ; 14: 1221745, 2023.
Article in English | MEDLINE | ID: mdl-37614820

ABSTRACT

Megalencephaly-capillary malformation syndrome (MCAP, OMIM # 602501) is caused by hyperactivity of the thephosphoinositide-3-kinase (PI3K)-Vakt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway, which results in megalencephaly, capillary malformations, asymmetrical overgrowth, and connective tissue dysplasia. Herein, we report the case of a 7-month-old girl with MCAP due to a PIK3CA somatic mosaic variant who presented with atrial tachycardia, finally diagnosed as pulmonary arterial hypertension (PAH). Oxygen therapy and sildenafil decreased pulmonary blood pressure and improved atrial tachycardia. Previous studies reported an association between the PI3K/AKT/mTOR pathway and abnormal pulmonary arterial smooth muscle cell proliferation, which may be associated with PAH. PAH should be considered a potentially lethal complication in MCAP patients, even when no structural cardiac abnormalities are identified in the neonatal period.

3.
J Pharmacol Sci ; 144(1): 16-22, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32653341

ABSTRACT

JPH203 is a novel anti-cancer drug targeting L-type amino acid transporter 1 (LAT1), which plays a primary role in the uptake of essential amino acids in tumor cells. Although a co-incubation inhibitory effect of JPH203 has been shown in a conventional uptake assay, its preincubation inhibitory effects have remained undetermined. Therefore, we aimed to characterize the preincubation inhibitory effects of JPH203 on LAT1 function using leucine uptake assays in LAT1-positive human colon cancer HT-29 cells. Preincubation of the cells with JPH203 (0.3 µM for 120 min) decreased the activity level to 30% of that in dimethylsulfoxide-treated cells. Similarly, in time-dependency analysis, preincubation of HT-29 cells with 10 µM JPH203 for 30, 60, and 120 min decreased the leucine uptake activity (42%, 32%, and 28% of that in control cells, respectively). Furthermore, the IC50 value of the combination of preincubation and co-incubation effects was lower than that of co-incubation inhibition alone (34.2 ± 3.6 nM vs. 99.2 ± 11.0 nM). In conclusion, we revealed that JPH203 has the capability to inhibit LAT1 function through preincubation effects. Moreover, preincubation synergistically enhances the co-incubation inhibitory effects. These findings provide a novel insight into the anti-cancer effects of JPH203 in cancer therapy.


Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Antineoplastic Agents/pharmacology , Benzoxazoles/pharmacology , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Drug Screening Assays, Antitumor/methods , Large Neutral Amino Acid-Transporter 1/metabolism , Tyrosine/analogs & derivatives , Dose-Response Relationship, Drug , HT29 Cells , Humans , Large Neutral Amino Acid-Transporter 1/physiology , Leucine/metabolism , Time Factors , Tyrosine/pharmacology
4.
Sci Rep ; 9(1): 16776, 2019 11 20.
Article in English | MEDLINE | ID: mdl-31748583

ABSTRACT

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.


Subject(s)
Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/metabolism , Large Neutral Amino Acid-Transporter 1/metabolism , Benzoxazoles/pharmacology , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Female , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Male , Middle Aged , Prognosis , Progression-Free Survival , Retrospective Studies , Tyrosine/analogs & derivatives , Tyrosine/pharmacology
5.
Pediatr Int ; 61(5): 438-443, 2019 May.
Article in English | MEDLINE | ID: mdl-30916859

ABSTRACT

BACKGROUND: There is still no definite treatment for refractory Kawasaki disease (KD). In this pilot study, we evaluated the safety and efficacy of a new protocol consisting of sivelestat sodium hydrate (SSH) combined with additional i.v. immunoglobulin (IVIG) for KD resistant to initial IVIG therapy. METHODS: This study is a prospective non-randomized, open-label and single-arm study undertaken in a population of refractory KD patients at Chiba University Hospital from December 2006 to March 2016. The subjects had KD resistant to initial IVIG (2 g/kg) and received SSH (0.2 mg/kg/h for 5 days) combined with additional IVIG (2 g/kg) as a second-line therapy. We evaluated the safety and efficacy of the treatment during the study period. RESULTS: Forty-six KD patients were enrolled in this study and no serious adverse event was noted. Of these, 45 patients were evaluated for the incidence of coronary artery lesions, which occurred in one patient (2.2%; 95% CI: 0.5-15.2). Twenty-eight (62.2%) responded promptly and were afebrile after the therapy. The median total duration of fever was 8 days (range, 6-28 days). CONCLUSIONS: Additional IVIG combined with SSH as a second-line therapy for KD refractory to initial IVIG therapy was safe and well tolerated and could be a promising option for severe KD. Further investigations are expected to clarify the safety and timing of SSH treatment for KD.


Subject(s)
Glycine/analogs & derivatives , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Mucocutaneous Lymph Node Syndrome/drug therapy , Serine Proteinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Adolescent , Child , Child, Preschool , Drug Therapy, Combination , Female , Glycine/therapeutic use , Humans , Infant , Male , Pilot Projects , Prospective Studies , Treatment Outcome
6.
Brain Dev ; 41(3): 310-312, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30314873

ABSTRACT

BACKGROUND: Peripheral facial nerve palsy is characterized by unilateral facial paresis due to ipsilateral facial nerve dysfunction. Most cases are idiopathic; however, some have specific etiologies, such as herpesvirus infection, immunological disorders, and hypertension. Atomoxetine is a norepinephrine reuptake inhibitor that is used in the treatment of attention deficit hyperactivity disorder (ADHD). This drug is known to cause adverse effects, such as nausea, appetite loss, headache, insomnia, and hypertension. CASE DESCRIPTION: We herein describe a case of sudden-onset right peripheral facial palsy in a 9-year-old Japanese boy. The patient's systolic blood pressure was as high as 200 mmHg, and he was therefore admitted to our hospital for investigation. Extensive surveillance including blood examination; endocrinological testing; imaging studies such as computed tomography, magnetic resonance imaging, and renography; and renal biopsy did not reveal any abnormalities. The patient had ADHD and was under treatment with atomoxetine. We discontinued treatment with atomoxetine; the patient showed gradual improvement. His hypertension and facial palsy resolved. We therefore diagnosed the patient with peripheral facial palsy associated with atomoxetine-induced hypertension. CONCLUSION: Although peripheral facial nerve palsy is usually benign and self-limiting, blood pressure should be monitored in children under treatment with atomoxetine and the possibility of drug-induced hypertension should be considered in order to prevent palsy associated with hypertension.


Subject(s)
Adrenergic Uptake Inhibitors/adverse effects , Atomoxetine Hydrochloride/adverse effects , Facial Paralysis/complications , Hypertension/chemically induced , Hypertension/complications , Attention Deficit Disorder with Hyperactivity/drug therapy , Child , Facial Paralysis/diagnostic imaging , Humans , Hypertension/diagnostic imaging , Male , Neuroimaging
7.
Anticancer Res ; 39(1): 159-165, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30591453

ABSTRACT

BACKGROUND/AIM: L-type amino acid transporter 1 (LAT1) is a promising molecular target for cancer therapy. The present study aimed to characterize the anti-cancer effects of JPH203, an LAT1-selective inhibitor, on gastrointestinal cancer cells. MATERIALS AND METHODS: Three esophageal, two gastric, and two colon cancer cell lines were used. Cytotoxic effects of JPH203 were assessed by a WST-8 assay. LAT1 mRNA levels were determined by quantitative PCR. The inhibitory property of JPH203 against LAT1 function was examined by a transport assay. RESULTS: JPH203 treatment significantly reduced the viability of all gastric and colon cancer cells. While LAT1 expression levels and inhibitory potencies of JPH203 on LAT1 functions were comparable among the cells, all the esophageal cells were resistant to JPH203. CONCLUSION: JPH203 was effective in reducing gastric and colon cancer cells. To clarify its cell type-dependent efficacy, identification of the causal factors for JPH203 resistance will be needed.


Subject(s)
Benzoxazoles/pharmacology , Colonic Neoplasms/drug therapy , Gastrointestinal Neoplasms/drug therapy , Large Neutral Amino Acid-Transporter 1/genetics , Tyrosine/analogs & derivatives , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Tyrosine/pharmacology
8.
Bioorg Med Chem Lett ; 28(23-24): 3708-3711, 2018 12 15.
Article in English | MEDLINE | ID: mdl-30389287

ABSTRACT

We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.


Subject(s)
Benzbromarone/analogs & derivatives , Benzbromarone/metabolism , Organic Anion Transporters/antagonists & inhibitors , Organic Cation Transport Proteins/antagonists & inhibitors , Uricosuric Agents/chemistry , Uricosuric Agents/metabolism , Activation, Metabolic , Animals , Benzbromarone/pharmacology , Benzbromarone/toxicity , Chemistry Techniques, Synthetic , HEK293 Cells , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Organic Anion Transporters/metabolism , Organic Cation Transport Proteins/metabolism , Rats , Uric Acid/metabolism , Uricosuric Agents/pharmacology , Uricosuric Agents/toxicity
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