Hiroko Kishi

Background/Objectives: Circulating erythritol has been linked to cardiometabolic disorders, but its association with renal function decline remains unclear. We investigated this association in patients with type 2 diabetes and examined the effects of erythritol on interleukin-6 (IL-6) secretion from tubular cells. Methods: This retrospective study included 217 patients with baseline estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m². Plasma erythritol and IL-6 concentrations were measured. Renal outcomes were defined as an annual change in eGFR < −2.5 mL/min/1.73 m² and an eGFR reduction > 30%. Multivariable logistic regression analyses were performed. Human renal proximal tubular epithelial cells (RPTECs) were treated with erythritol for 24 h. Results: Median follow-up was 50 months. Plasma erythritol concentrations were positively correlated with cardio-ankle vascular index, total plaque score, and plasma IL-6 concentrations, and inversely correlated with baseline eGFR. Among 196 patients with eGFR ≥ 60 mL/min/1.73 m², higher erythritol concentrations were independently associated with Criterion 1 after adjustment for age, sex, body mass index, eGFR, and urinary albumin-to-creatinine ratio. Erythritol increased IL-6 secretion from RPTECs at 1 and 10 μmol/L. Conclusions: Plasma erythritol may serve as a functional biomarker and risk marker for subsequent renal function decline in patients with type 2 diabetes and relatively preserved kidney function. Its association with plasma IL-6 concentrations and its effects on RPTEC IL-6 secretion suggest a potential link between erythritol and renal tubular inflammation.

Vasospasm is a sustained abnormal contraction of vascular smooth muscle (VSM), which is commonly observed in the coronary and cerebral arteries. This abnormal VSM contraction leads to reduced blood flow to tissues or organs, ultimately causing severe diseases such as myocardial infarction and cerebral infarction. Studies have demonstrated that oxidative stress and sphingosylphosphorylcholine (SPC)-induced Rho-kinase signaling pathways are related to this abnormal contraction. Flavonoids, a class of natural compounds, are found in various plants, fruits, vegetables, and traditional Chinese medicines. They have anti-inflammatory, antioxidative, and anticarcinogenic properties. Recent studies have shown that some flavonoids strongly inhibit the abnormal contraction of VSM. This review explores the potential of flavonoids as candidate drugs for the treatment and prevention of vasospasm through oxidative stress and the SPC-induced Rho-kinase signaling pathway. Nevertheless, more extensive studies are required to fully elucidate the mechanism by which flavonoids exert their anti-vasospastic effects and explore their potential benefits as adjunctive therapy for critical cardiovascular and cerebrovascular diseases.

The plasma membrane covering the primary cilium has a diverse accumulation of receptors and channels. To ensure the sensor function of the cilia, the ciliary membrane has higher cholesterol content than other cell membrane regions. A peroxisomal biogenesis disorder, Zellweger syndrome, characterized by polycystic kidney, is associated with a reduced level of ciliary cholesterol in cells. However, the etiological mechanism by which ciliary cholesterol lowering causes polycystic kidney disease remains unclear. Here, we demonstrated that lowering ciliary cholesterol by either pharmacological treatment or genetic depletion of peroxisomes impairs the localization of a ciliary ion channel polycystin-2. We also generated cultured renal medullary cells and mice carrying a missense variant in the cholesterol-binding site of polycystin-2 detected in the patient database of autosomal dominant polycystic kidney disease. This missense protein showed normal channel activity but decreased localization to the ciliary membrane. The homozygous mice exhibited embryonic lethality and the ciliopathy spectrum conditions of situs inversus and polycystic kidney. Our results suggest that cholesterol controls the ciliary localization of polycystin-2 to prevent polycystic kidney disease.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous research indicated that theobromine (TB), a methylxanthine, enhances cognitive function in rodents via the PFC. This study investigates TB's effects on hyperactivity and cognitive function in stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received a diet containing 0.05% TB for 40 days, while control rats received normal diets. Age-matched male Wistar–Kyoto rats (WKY) served as genetic controls. During the TB administration period, we conducted open-field tests and Y-maze tasks to evaluate hyperactivity and cognitive function, then assessed dopamine concentrations and tyrosine hydroxylase (TH), dopamine receptor D1–5 (DRD1–5), dopamine transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), and brain-derived neurotrophic factor (BDNF) expressions in the PFC. Additionally, the binding affinity of TB for the adenosine receptors (ARs) was evaluated. Compared to WKY, SHR exhibited hyperactivity, inattention and working memory deficits. However, chronic TB administration significantly improved these ADHD-like behaviors in SHR. TB administration also normalized dopamine concentrations and expression levels of TH, DRD2, DRD4, SNAP-25, and BDNF in the PFC of SHR. No changes were observed in DRD1, DRD3, DRD5, DAT, and VMAT-2 expression between SHR and WKY rats, and TB intake had minimal effects. TB was found to have affinity binding to ARs. These results indicate that long-term TB supplementation mitigates hyperactivity, inattention and cognitive deficits in SHR by modulating dopaminergic nervous function and BDNF levels in the PFC, representing a potential adjunctive treatment for ADHD.

Metastasis is the leading cause of death in breast cancer patients due to the lack of effective therapies. Elevated levels of paxillin expression have been observed in various cancer types, with tyrosine phosphorylation shown to play a critical role in driving cancer cell migration. However, the specific impact of the distinct tyrosine phosphorylation events of paxillin in the progression of breast cancer remains to be fully elucidated. Here, we found that paxillin overexpression in breast cancer tissue is associated with a patient’s poor prognosis. Paxillin knockdown inhibited the migration and invasion of breast cancer cells. Furthermore, the phosphorylation of paxillin tyrosine residue 31 (Tyr31) was significantly increased upon the TGF-β1-induced migration and invasion of breast cancer cells. Inhibiting Fyn activity or silencing Fyn decreases paxillin Tyr31 phosphorylation. The wild-type and constitutively active Fyn directly phosphorylate paxillin Tyr31 in an in vitro system, indicating that Fyn directly phosphorylates paxillin Tyr31. Additionally, the non-phosphorylatable mutant of paxillin at Tyr31 reduces actin stress fiber formation, migration, and invasion of breast cancer cells. Taken together, our results provide direct evidence that Fyn-mediated paxillin Tyr31 phosphorylation is required for breast cancer migration and invasion, suggesting that targeting paxillin Tyr31 phosphorylation could be a potential therapeutic strategy for mitigating breast cancer metastasis.

Cardiovascular diseases are the leading cause of mortality and disability worldwide. We have previously found that sphingosylphosphorylcholine (SPC) is the key molecule leading to vasospasm. We have also identified the SPC/Src family protein tyrosine kinase Fyn/Rho-kinase (ROK) pathway as a novel signaling pathway for Ca²⁺ sensitization of vascular smooth muscle (VSM) contraction. This study aimed to investigate whether hesperetin can inhibit the SPC-induced contraction with little effect on 40 mM K⁺-induced Ca²⁺-dependent contraction and to elucidate the underlying mechanisms. Hesperetin significantly inhibited the SPC-induced contraction of porcine coronary artery smooth muscle strips with little effect on 40 mM K⁺-induced contraction. Hesperetin blocked the SPC-induced translocation of Fyn and ROK from the cytosol to the membrane in human coronary artery smooth muscle cells (HCASMCs). SPC decreased the phosphorylation level of Fyn at Y531 in both VSMs and HCASMCs and increased the phosphorylation levels of Fyn at Y420, myosin phosphatase target subunit 1 at T853, and myosin light chain (MLC) at S19 in both VSMs and HCASMCs, which were significantly suppressed by hesperetin. Our results indicate that hesperetin inhibits the SPC-induced contraction at least in part by suppressing the Fyn/ROK pathway, suggesting that hesperetin can be a novel drug to prevent and treat vasospasm.

To correctly understand various phenomena in living organisms, new insights can be obtained not only by relative observation but also by quantitative measurement of physical parameters.