Cordyceps militaris is rich in adenosine derivatives, including 3'-deoxyadenosine, also known as cordycepin. It has been reported for antitumor effects, but its underlying molecular mechanism has yet to be elucidated. We investigated how adenosine derivatives exerted antitumor effects against ovarian cancer using human ovarian cancer cells and a xenograft mouse model. Treatment with adenosine derivatives effectively resulted in cell death of ovarian cancer cells through AMPK activation and subsequently mTOR-mediated autophagic induction. Intriguingly, the effect required membrane transport of adenosine derivatives via ENT1, rather than ADORA-mediated cellular signaling. Our data suggest that adenosine derivatives may be an effective therapeutic intervention in ovarian cancer through induction of ENT1-AMPK-mTOR-mediated autophagic cell death.

The regulation of the circadian clock plays an important role in influencing physiological conditions. While it is reported that the timing and quantity of energy intake impact circadian regulation, the underlying mechanisms remain unclear. This study investigated the impact of dietary protein intake on peripheral clocks. Firstly, transcriptomic analysis was conducted to investigate molecular targets of low-protein intake. Secondly, mPer2::Luc knock-in mice, fed with either a low-protein, normal, or high-protein diet for 6 weeks, were analyzed for the oscillation of PER2 expression in peripheral tissues and for the expression profiles of circadian and metabolic genes. Lastly, the candidate pathway identified by the in vivo analysis was validated using AML12 cells. As a result, using transcriptomic analysis, we found that the low-protein diet hardly altered the circadian rhythm in the central clock. In animal experiments, expression levels and period lengths of PER2 were different in peripheral tissues depending on dietary protein intake; moreover, mRNA levels of clock-controlled genes and endoplasmic reticulum (ER) stress genes were affected by dietary protein intake. Induction of ER stress in AML12 cells caused an increased amplitude of Clock and Bmal1 and an advanced peak phase of Per2. This result shows that the intake of different dietary protein ratios causes an alteration of the circadian rhythm, especially in the peripheral clock of mice. Dietary protein intake modifies the oscillation of ER stress genes, which may play key roles in the regulation of the circadian clock.

High-grade serous ovarian cancer (HGSOC) is the predominant subtype of ovarian cancer and is characterized by a high rate of relapse after platinum-based chemotherapy. Herein, we present a comprehensive analysis of 111 Korean HGSOC samples using next-generation sequencing technology to elucidate their transcriptomic landscapes. Our investigation revealed the existence of four distinct transcriptional subtypes of ovarian cancer: immunoreactive, mesenchymal, proliferative, and differentiated, which is comparable to those of TCGA HGSOC transcriptional subgroups. Each subtype exhibited unique correlation networks and their immune cell composition was computationally determined. Notably, the immunoreactive cluster displayed the highest immune score, even in the context of pan solid-cancer types, accompanied by heightened expression of CD4⁺ and CD8⁺ T cells (P < 0.05), along with notable associations with neutrophil degranulation and antigen presentation pathways (FDR < 0.01). Conversely, the differentiated cluster demonstrated immunodepleted characteristics, featuring an elevated proportion of overexpressed cancer-germline antigens. We also identified several cancer-germline HGSOC antigens that could be further investigated as potential targets for immunological intervention in cancer.

Supplementation of nicotinamide adenine dinucleotide (NAD) precursors has been investigated for its potential to counteract age-related physiological decline. While decreased NAD⁺ level is associated with conditions such as obesity and dyslipidemia, few studies have explored its metabolic impact in relatively young animals. Here, we hypothesized that nicotinamide mononucleotide (NMN) could alleviate high-fat diet-induced metabolic stress in young mice and sought to elucidate the underlying mechanisms. We first conducted a secondary analysis of hepatic transcriptome datasets from multiple NMN intervention studies to identify target pathways. Next, 11-week-old lean and obese C57BL/6N mice administrated NMN (500 mg/kg/day) for 1 mon were analyzed for metabolic parameters and gene expression for the target pathways. In vitro study using AML12 cell line was then conducted to confirm the effects of NMN. Additionally, transcriptomic data from liver-specific nicotinamide phosphoribosyltransferase (NAMPT)-deficient mice were analyzed to examine the relationship between NAD⁺ metabolism, endoplasmic reticulum (ER) stress, and circadian rhythm. The secondary analysis of hepatic transcriptome datasets revealed potential target pathways related to circadian regulation and hepatic ER stress. In mouse study, short-term NMN administration significantly decreased body weight and fat mass. NMN also alleviated hepatic ER stress response in vivo and in vitro. Additional analysis revealed that the mice with diet-induced metabolic stress or NAMPT deficiency led to phase shifts of the hepatic circadian core clock oscillation by advancing the peak time, while time-restricted feeding shifted the opposite, indicating the metabolic regulation of the circadian phase. Short-term NMN administration effectively attenuated obese condition in young mice and mitigated hepatic ER stress. The altered ER stress was regulated by NAMPT, potentially through the phase shift of the hepatic circadian rhythm.