Sumitomo Chemical Co., Ltd.

Glutathione accumulated in tertiary lymphoid structures (TLS), where dendritic cells and fibroblasts specifically expressed cystine/glutamate transporter.Pharmacologic inhibition of the cystine/glutamate transporter prevented the formation of TLS.Urinary glutathione concentrations efficiently detected the presence of TLS in the kidney in mice and humans.

Tertiary lymphoid structure (TLS), an ectopic lymphoid tissue induced under chronic inflammation, develops in various kidney diseases and is associated with poor prognosis. The immune system requires metabolic resources to support immune function and lymphocyte proliferation. Hence, dramatic metabolic alterations presumably occur during the formation of TLS. However, it remains unclear whether metabolic remodeling occurs during this formation and its underlying mechanism.

In a murine model of TLS in the kidney, we used imaging mass spectrometry and metabolome analysis to investigate the metabolic pathway that characterizes TLS. We also performed in situ hybridization with immunofluorescence and pharmacologic inhibition to explore the expression and function of the key molecules governing the pivotal metabolic pathway. We analyzed urine samples from mice and humans to explore the metabolites estimating the presence of TLS in the kidney.

Significant glutathione accumulation and depletion of cysteine, which is essential for glutathione synthesis, was observed specifically within TLS. The kidneys with TLS exhibited higher glutathione concentrations than healthy kidneys. TLS also showed significant accumulation of 4-hydroxynonenal and 8-hydroxy-2′ -deoxyguanosine, markers of oxidative stress. Dendritic cells and fibroblasts within TLS expressed the cystine/glutamate transporter, which regulates glutathione synthesis, and supplied synthesized glutathione to lymphocytes, which lacked its expression. Pharmacologic inhibition of the cystine/glutamate transporter prevented the formation of TLS in the kidney. Furthermore, enhanced glutathione synthesis within TLS was reflected in elevated urinary glutathione concentrations in both mice and humans, which effectively detected the presence of TLS in the kidney in IgA nephropathy patients.

Glutathione significantly accumulated within TLS in the kidney. Inhibition of the cystine/glutamate transporter prevented the formation of TLS. Urinary glutathione served as a biomarker to detect TLS in the kidney.

Antipsychotics increase metabolic syndrome ( MetSyn ) and diabetes risk. Preclinical and translational research data suggest that ulotaront, an investigational trace amine‐associated receptor 1 (TAAR1) agonist, may have beneficial metabolic effects. This Phase 1b study collected pilot data on 4‐week ulotaront exposure and weight‐associated metabolic markers.

A double‐blind, randomised, multiple‐dose within subject trial compared ulotaront to continued prior antipsychotic ( PA ) on metabolic markers in schizophrenia patients at high diabetes risk (presence of MetSyn and prediabetes). Metabolic characteristics of patients at check‐in were compared to a matched historical cohort without schizophrenia or antipsychotic exposure.

When compared to PA , ulotaront treatment showed improvement trends for high glucose clamp, low glucose clamp, liver fat, liver fibro‐inflammation, back muscle fat infiltration, pancreas fat and pancreas volume. Visceral adipose tissue and weight changes favoured ulotaront treatment ( p  < 0.001, p  = 0.047). Liver fibro‐inflammation distinguished antipsychotic‐induced metabolic changes from the historical cohort ( p  = 0.002).

Despite the sample size constraints due to early study termination, all key endpoint trends and statistically significant differences favoured ulotaront over previous antipsychotics, lending support that ulotaront may improve antipsychotic‐induced weight‐associated markers. Liver fibro‐inflammation may serve as a potential marker for antipsychotic‐induced MetSyn and prediabetes, and possible treatment target. Further research is needed to build on these findings.

Permethrin increases the incidence of bronchiolo-alveolar adenomas in female mice. The proposed mode of action (MOA) for permethrin-induced lung tumorigenesis involves increased mitogenesis in Club cells. Additionally, CYP2F2, which is particularly expressed in mouse lung Club cells and different from human CYP2F1, is considered to be a key factor in mouse-specific lung tumorigenesis. In this study, we investigated the relationship between permethrin-induced mouse lung tumorigenesis and CYP2F2 in CYP2f2 knockout (KO) mice. Fluensulfone and isoniazid were selected as positive controls. We showed that the increased proliferation of Club cells and increased proliferation of smooth endoplasmic reticulum (SER) within them were abolished in permethrin-treated CYP2f2 KO mice, while these changes were clearly observed in permethrin- and positive control-treated wild type mice. Additionally, the disappearance of the Club cell reaction was also observed in positive control-treated CYP2f2 KO mice. Based on these results, it was concluded that CYP2F2 is essential in the MOA of mouse lung tumorigenesis by permethrin, also suggesting that permethrin metabolism by CYP2F2 corresponds to a chain of early key events, including the molecular initiating event (MIE). Furthermore, the data suggested that CYP2F2 played a crucial role in mouse lung tumorigenesis induced by isoniazid, which is known to cause lung tumors in mice but not in humans. The collective data on permethrin-treated mouse lung tumorigenesis, including findings from this study, would lead to the conclusion that the lung tumors induced by permethrin treatment are mouse-specific and not relevant to human lung cancer risk.