Repurposing of Agrochemicals as ATTRv Amyloidosis Inhibitors.

Transthyretin (TTR), a plasma protein, undergoes transformation into amyloid fibers, leading to ATTRv amyloidosis, a disease characterized by organ deposition of TTR amyloid fibrils and subsequent organ failure. Developing compounds that bind and kinetically stabilize TTR is a crucial strategy in the treatment of ATTRv amyloidosis. In this study, we narrowed 651 pesticide-related compounds down to 14 possible TTR binders through in silico screening; subsequent in vitro analysis revealed that 7 of them exhibited amyloid fibril formation inhibition activity.

Successful management of immunotherapy-resistant respiratory failure in anti-mitochondrial M2 antibody-positive myositis by modified lung volume recruitment therapy: A case report.

Rationale: Anti-mitochondrial antibodies (AMA) M2-positive myositis can lead to severe respiratory failure. Traditional immunotherapies sometimes fail to address respiratory failure. Herein, this CARE-compliant case report described a patient with AMA-M2-positive myositis who recovered from ventilation with tracheostomy owing to immunotherapy-resistant respiratory failure to spontaneous breathing after modified lung volume recruitment (mLVR) therapy.

SIRT5 mutants reveal the role of conserved asparagine and glutamine residues in the NAD-binding pocket.

SIRT5, one of the mammalian sirtuins, specifically recognizes succinyl-lysine residues on proteins and catalyzes the desuccinylation reaction. In this study, we characterized SIRT5 mutants with hydrophobic amino acid substitutions at Q140 and N141, in addition to the catalytic residue H158, known as an active site residue, by the Michaelis-Menten analysis and X-ray crystallography. Kinetic analysis showed that the catalytic efficiency (k/K) of the Q140L and N141V mutants decreased to 0.

Nicotinamide phosphoribosyl transferase in mammary gland epithelial cells is required for nicotinamide mononucleotide production in mouse milk.

Tissue-specific deficiency of nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD)-salvage pathway, causes a decrease of NAD in the tissue, resulting in functional abnormalities. The NAD-salvage pathway is drastically activated in the mammary gland during lactation, but the significance of this has not been established. To investigate the impact of NAD perturbation in the mammary gland, we generated two new lines of mammary gland epithelial-cell-specific Nampt-knockout mice (MGKO).

Sex-Specific Left Ventricular and Aorta Size Cut-Off Values for Hemodynamically Significant Chronic Aortic Regurgitation - Implications for Treatment in Asian Populations.

Background: There are no sex-specific guidelines for chronic aortic regurgitation (AR). This retrospective study examined sex-specific differences and propose treatment criteria from an Asian AR cohort.

Methods and results: Consecutive 1,305 patients with moderate-severe AR or greater at 3 tertiary centers in Taiwan and Japan (2008-2022) were identified.

Development of Benziodarone Analogues with Enhanced Potency for Selective Binding to Transthyretin in Human Plasma.

Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma.

Enzymatic activity of cGAS in the presence of three types of DNAs: limited cGAS stimulation by single-stranded HIV-1 SL2 DNA.

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is activated by binding to DNA. Activated cGAS produces 2'3'-cGAMP, which subsequently binds to the adaptor protein STING (stimulator of interferon genes). This interaction triggers the cGAS/STING signaling pathway, leading to the production of type I interferons.

A unique case of a typical pancreatic ductal adenocarcinoma that initially presented with a cystic component but underwent morphological changes.

A 66-year-old man was initially suspected of having a microcystic serous cystic neoplasm based on magnetic resonance imaging findings of a multifocal mass measuring 46 mm in the pancreatic head, with a cystic component showing a high signal on T2-weighted images. The tumor marker levels were within normal limits. However, contrast-enhanced computed tomography revealed thick cyst walls with delayed staining, which was atypical for serous cystic neoplasms; therefore, the patient was followed up closely.

Potential Effects of Mild Atrial Secondary Mitral Regurgitation in Patients With Isolated Atrial Fibrillation.

Background: Patients with only moderate atrial secondary mitral regurgitation (asMR) frequently develop heart failure (HF). Mechanisms of HF with moderate asMR and the impact of mild asMR remain unclarified. Although mild/moderate primary mitral regurgitation is compensated by left ventricular (LV) dilatation, the LV is not dilated in asMR.

Prognostic value of right ventricular free-wall longitudinal strain in patients with pulmonary hypertension: systematic review and meta-analyses.

Background: Right ventricular (RV) dysfunction is associated with adverse outcomes in patients with pulmonary hypertension (PH). This systematic review and meta-analysis evaluated the prognostic value of RV free-wall longitudinal strain (RVfwLS), compared with other RV parameters in PH.

Methods: We searched for articles presenting the HR of two-dimensional RVfwLS in PH.

Trypsin-induced aggregation of transthyretin Valine 30 variants associated with hereditary amyloidosis.

Amyloid fibrils of transthyretin (TTR) consist of full-length TTR and C-terminal fragments starting near residue 50. However, the molecular mechanism underlying the production of the C-terminal fragment remains unclear. Here, we investigated trypsin-induced aggregation and urea-induced unfolding of TTR variants associated with hereditary amyloidosis.

Prognostic value of right ventricular free-wall longitudinal strain in aortic stenosis: A systematic review and meta-analysis.

Background: Assessment of right ventricular (RV) function in aortic stenosis (AS) may improve risk stratification. However, whether the prognostic value of RV free-wall longitudinal strain (RVfwLS) is better than that of other right heart or pulmonary circulation parameters remains uncertain. This study assessed and compared the prognostic value of RVfwLS with traditional parameters in the AS population using a systematic review and meta-analysis.

Resveratrol Derivatives Inhibit Transthyretin Fibrillization: Structural Insights into the Interactions between Resveratrol Derivatives and Transthyretin.

Hereditary ATTR amyloidosis is a disease caused by the deposition of amyloid fibrils formed by mutated transthyretin (TTR), a protein that binds to thyroid hormone in the serum, in the organs. The development of a small molecule that binds to and stabilizes TTR is a promising strategy for the treatment of ATTR amyloidosis. In the present study, we demonstrated that the resveratrol derivatives including pterostilbene available as a dietary supplement inhibit the fibrillization of V30M-TTR to the same extent as the approved drug tafamidis.

Improving lysosomal ferroptosis with NMN administration protects against heart failure.

Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure from dilated cardiomyopathy.

Trial sequential analysis of efficacy and safety of direct oral anticoagulants and vitamin K antagonists against left ventricular thrombus.

Meta-analysis may increase the risk of random errors. Trial sequential analysis (TSA) has been developed to adjust for these random errors. We conducted TSA on the efficacy and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in left ventricular thrombus (LVT) patients in order to estimate how many additional patients should be required to draw definite conclusions.

Preventive effect of aripiprazole once monthly on rehospitalization for bipolar disorder: A multicenter 1-year retrospective mirror image study.

Aim: We conducted a 1-year retrospective mirror-image study to investigate the effect of aripiprazole once monthly (AOM) on rehospitalization for bipolar disorder.

Methods: Participants were recruited from psychiatric emergency and acute care hospitals in western Japan. We included 39 participants with bipolar disorder who had been administered AOM for at least 1 year with no missing medical records during the observational period.

Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity.

GLS1 is an attractive target not only as anticancer agents but also as candidates for various potential pharmaceutical applications such as anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor.

Feto-maternal cholesterol transport regulated by β-Klotho-FGF15 axis is essential for fetal growth.

β-Klotho (β-KL) is indispensable to regulate lipid, glucose, and energy metabolism in adult animals. β-KL is highly expressed in the yolk sac, but its role in the developmental stages has not been established. We hypothesized that β-KL is required for metabolic regulation in the embryo and aimed to clarify the role of β-KL during development.

Rafoxanide, a salicylanilide anthelmintic, interacts with human plasma protein transthyretin.

Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small molecules that compete with T for binding to TTR should be carefully studied, these small molecules can also serve as anti-ATTR amyloidosis drugs by stabilizing the TTR structure. Here, we demonstrated that rafoxanide, an EU-approved anthelmintic drug for domesticated animals, binds to the T -binding site of TTR.