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Ketone bodies, including 3HBA, are endogenous products of fatty acid oxidation, and Hmgcs2 is the first rate-limiting enzyme of ketogenesis. From database analysis and in vivo and in vitro experiments, we found that adipose tissue and adipocytes express Hmgcs2, and that adipocytes produce and secrete 3HBA. Treatment with 3HBA enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors in adipose tissue in vivo and in adipocytes in vitro, accompanied by reduced ROS levels. Knockdown of endogenous Hmgcs2 in adipocytes markedly decreased 3HBA levels in adipocytes and decreased the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors with increased ROS levels. Conversely, overexpression of Hmgcs2 in adipocytes increased 3HBA secretion from adipocytes and enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors. These results demonstrate that 3HBA plays significant roles in enhancing the physiological function of adipocytes.

Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long‐term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole‐body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3‐butanediol, a precursor of β‐hydroxybutyrate. Furthermore, feeding the 1,3‐butanediol‐containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE‐deficient mice. By contrast, an ad libitum low‐carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double‐edged sword with respect to survival, depending on the method of administration and health status. The present study demonstrates that endogenous ketogenesis is essential for long‐term mammalian survival, which was revealed by a study using Hmgcs2−/− mice, and that dietary administration of 1,3‐butanediol (1,3‐BD), a precursor of β‐OHB, increases midlife mortality in normal mice, but extends life span in aged mice or atherosclerotic mice. By contrast, ad libitum low‐carbohydrate ketogenic diet increases mortality in any mouse models. Thus, ketone bodies represent a double‐edged sword for mammalian survival.

Heading off heart failure Cardiac enlargement, or hypertrophy, is a physiological response to increased workload and helps to maintain cardiac function. If the condition is prolonged, however, it can develop into heart failure. New insight into how that transition occurs has been obtained in a study of a mouse model of cardiac hypertrophy. As the animal's heart enlarges, new blood vessels develop to support it. But after about two weeks, the tumour suppressor protein p53 accumulates in heart cells, angiogenesis is blocked and the mice suffer cardiac failure. Targeting this process by inhibiting p53 or by promoting angiogenesis may be a means of preventing the transition from cardiac hypertrophy to heart failure. Angiogenesis is involved in compensatory cardiac hypertrophy following pressure overload. However, the process also induces the accumulation of p53 which ultimately suppresses angiogenesis and thereby contributes to the transition from hypertrophy to heart failure. Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function 1 . However, prolonged cardiac hypertrophy causes heart failure 2 , and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.

The prognosis for patients with metastatic osteosarcoma is still poor despite the development of effective adjuvant and neoadjuvant chemotherapy regimens. We have developed caffeine-potentiated chemotherapy for treatment of high-grade bone and soft tissue sarcomas based on the ability of caffeine to enhance the cytocidal effects of anticancer drugs. We report results of caffeine-potentiated chemotherapy for patients with osteosarcoma with pulmonary metastases. We analyzed retrospectively overall survival and some prognostic factors for 41 patients with osteosarcoma/ pulmonary metastases who were treated with caffeine-potentiated chemotherapy between 1990 and 2006. The mean follow-up of all patients was 32.7 months. At the time of the final follow-up, 11 patients were alive and 30 had died of disease. Overall survival rates at 2 and 5 years were 38% and 28%, respectively. We identified the primary tumor site, the histological response to preoperative chemotherapy, the number of pulmonary nodules at initial identification, the timing of pulmonary metastasis identification, and the existence of extrapulmonary metastasis as prognostic factors. Especially, the number of pulmonary nodules at initial identification and the timing of pulmonary metastasis identification were independent, strong prognostic factors. Patients with solitary pulmonary metastasis had good prognoses, and their overall 5-year survival rate was 60%; in contrast, survival was 28% in patients with two to five pulmonary nodules, and no patients with more than six nodules survived 5 years. Patients with pulmonary metastasis identified after completion of treatment had the best prognosis, whereas patients with pulmonary metastases identified during treatment had the worst prognosis. Caffeine-potentiated chemotherapy prolonged survival of patients who had osteosarcoma with pulmonary metastasis. Especially, patients with pulmonary metastasis identified after completion of treatment or with a solitary pulmonary nodule had good prognoses.

Abstract Aims Immune checkpoint inhibitors (ICIs) are a cornerstone of cancer therapy; however, immune-related adverse events, including myocarditis, pose significant challenges. Furthermore, limited data exist on the pathology of mild or asymptomatic cases. This study aimed to characterize the clinical, biomarker, and pathological features of ICI-associated cardiac toxicity, comparing symptomatic and asymptomatic cases within a Japanese multicentre registry. Methods and results A nationwide, retrospective registry collected data from 90 patients across 23 hospitals between 2020 and 2022. Patients were classified according to the American Society of Clinical Oncology Clinical Practice Guidelines: Grade 1 (asymptomatic) and Grades 2–4 (symptomatic). Endomyocardial biopsy was performed in 24 patients (n = 19 symptomatic, n = 5 asymptomatic). Among the enrolled patients (mean age: 68 years; 76.7% male), 41.1% were classified as Grade 1, whereas 58.9% were symptomatic (Grades 2–4). Symptomatic cases exhibited significantly higher troponin I and creatine kinase levels at onset. Pathological analysis revealed more extensive lymphocytic infiltration (CD3+ T cells) in symptomatic cases, particularly with higher CD8+ and CD68+ cell counts. Continuation of ICI therapy was more frequent in the asymptomatic group, and only one patient experienced recurrence. In contrast, all seven myocarditis-related deaths occurred in symptomatic patients. Conclusion This study provides one of the largest pathological and biomarker-based comparisons of symptomatic and asymptomatic ICI-associated cardiac toxicity. Our findings suggest that asymptomatic cases may represent a distinct, less aggressive inflammatory phenotype, characterized by lower CD8+ infiltration and limited myocardial damage. Graphical Abstract Graphical Abstract For image description, please refer to the figure legend and surrounding text.

Sporophytic self-incompatibility (SSI) in the genus Ipomoea (Convolvulaceae) is controlled by a single polymorphic S locus. We have previously analyzed genomic sequences of an approximately 300 kb region spanning the S locus of the S1 haplotype and characterized the genomic structure around this locus. Here, we further define the physical size of the S locus region by mapping recombination breakpoints, based on sequence analysis of PCR fragments amplified from the genomic DNA of recombinants. From the recombination analysis, the S locus of the S1 haplotype was delimited to a 0.23 cM region of the linkage map, which corresponds to a maximum physical size of 212 kb. To analyze differences in genomic organization between S haplotypes, fosmid contigs spanning approximately 67 kb of the S10 haplotype were sequenced. Comparison with the S1 genomic sequence revealed that the S haplotype-specific divergent regions (SDRs) spanned 50.7 and 34.5 kb in the S1 and S10 haplotypes, respectively and that their flanking regions showed a high sequence similarity. In the sequenced region of the S10 haplotype, five of the 12 predicted open reading frames (ORFs) were found to be located in the divergent region and showed co-linear organization of genes between the two S haplotypes. Based on the size of the SDRs, the physical size of the S locus was estimated to fall within the range 34–50 kb in Ipomoea.