RNA vaccines based on Lipid nanoparticles (LNP) were put into practical use within only one year after the global outbreak of the coronavirus disease 2019 (COVID-19). This success of RNA vaccine highlights the utility of an mRNA delivery system as a vaccination strategy. Potent immunostimulatory activity of LNPs (i.e., inflammation occurring at the injection site and the production of inflammatory cytokines) have recently been reported. However, we have only limited knowledge concerning which cells are responsible for responding to the LNPs. We report herein on in vitro chemokine production from non-immune cells in response to exposure to LNPs. In this study, SM-102, an ionizable lipid that is used in the approved RNA vaccine for the clinical usage of COVID-19 mRNA vaccine, was used. Immortalized mouse lymphatic endothelial cells (mLECs) or professional antigen presenting cells (APCs) such as RAW 264.7 monocyte/macrophage cells were incubated with LNPs that contained no mRNA. As a result, chemokines involved in the recruitment of monocytes/neutrophils were produced only by the mLECs following the LNP treatment. These findings indicate that LEC appear to serve as the cell that sends out initial signals to response LNPs.
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by Editor-in-Chief]
The study
examined which cells are responsible for
responding to the LNPs used in the approved COVID-19 mRNA vaccine. In this
study, the authors incubated immortalized
mouse lymphatic endothelial cells (mLECs) or professional antigen presenting
cells (APCs) such as RAW 264.7 monocyte/macrophage cells with SM-102 LNPs that contained no
mRNA. As a result, chemokines involved in the recruitment of
monocytes/neutrophils were produced only by the mLECs following the empty LNP
treatment. These findings indicate that LECs appear to serve as the cells that
send out initial signals to response LNPs.
Recently, mitochondrial dysfunction has gained attention as a causative factor in the pathogenesis and progression of age-related macular degeneration (AMD). Mitochondrial damage plays a key role in metabolism and disrupts the balance of intracellular metabolic pathways, such as oxidative phosphorylation (OXPHOS) and glycolysis. In this study, we focused on oxidized low-density lipoprotein (ox-LDL), a major constituent of drusen that accumulates in the retina of patients with AMD, and investigated whether it could be a causative factor for metabolic alterations in retinal pigment epithelial (RPE) cells. We found that prolonged exposure to ox-LDL induced changes in fatty acid β-oxidation (FAO), OXPHOS, and glycolytic activity and increased the mitochondrial reactive oxygen species production in RPE cells. Notably, the effects on metabolic alterations varied with the concentration and duration of ox-LDL treatment. In addition, we addressed the limitations of using ARPE-19 cells for retinal disease research by highlighting their lower barrier function and FAO activity compared to those of induced pluripotent stem cell-derived RPE cells. Our findings can aid in the elucidation of mechanisms underlying the metabolic alterations in AMD.
Mitochondrial dysfunction is recognized as a key factor in the pathological progression of age-related macular degeneration (AMD) and can disrupt the balance of intracellular metabolic pathways (e.g., oxidative phosphorylation and glycolysis). The authors focused on oxidized low-density lipoprotein (ox-LDL), reported to a primary component accumulated in the retina of AMD patients, and elucidated its effect on metabolic alterations with increased mitochondrial reactive oxygen species production in retinal pigment epithelial cells. It was discovered that prolonged exposure to ox-LDL is crucial for the induction of these metabolic alterations. These significantly contribute to understanding the mechanisms underlying AMD metabolic alterations.
Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory complete response (CR) rate of ≥90%. However, the control rate after 24 h in the delayed period is unsatisfactory. This study compared the efficacy of fosnetupitant (F-NTP), a neurokinin 1 receptor antagonist, with that of fosaprepitant (F-APR) and aprepitant (APR) in the treatment of patients with cancer at high emetic risk due to chemotherapy. In this retrospective case-control study involving patients receiving cisplatin-containing regimens and neurokinin 1 receptor antagonists, patients were divided into three groups based on prophylactic antiemetic therapy: F-NTP, F-APR, and APR. The CR rate was evaluated for each period up to 168 h and further subdivided into acute (0–24 h), delayed (24–120 h), overall (0–120 h), and beyond-delayed (120–168 h) periods. Eighty-eight patients were included in the F-NTP group, 66 in the F-APR group, and 268 in the APR group. The CR rates at 0–168 and 120–168 h after cisplatin administration were significantly higher in the F-NTP group than in the F-APR and APR groups. After adjusting for confounding factors, F-NTP use was an independent factor in the multivariate analysis. Prophylactic antiemetic therapy, including F-NTP, was effective and well-tolerated during the delayed period. The efficacy of F-NTP in managing chemotherapy-induced nausea and vomiting was superior to those of F-APR and APR during the study period.
Management of chemotherapy-induced nausea and vomiting (CINV) after delayed periods presents a significant challenge in cancer chemotherapy. This study represents the first attempt to compare the administration of fosnetupitant (F-NTP), fosaprepitant (F-APR), or aprepitant (APR) from 0 to 168 hours following the initial doses of cisplatin-based regimens. The authors demonstrated that F-NTP was significantly more effective than F-APR and APR in reducing CINV after anticancer drug administration from 0 to 168 hours, without significant side effects. The efficacy of F-NTP was particularly effective in the beyond-delayed periods (120-168 hours), which is the focus of attention of the revised Japanese antiemetic guidelines.
Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78–20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52–19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.
The authors mainly investigated the risk factors and preventive strategies of cetuximab-induced hypomagnesemia in head and neck cancer (HNC) patients. Their results indicated that a low pre-treatment serum magnesium level emerges as the only risk factor, and this risk can be effectively mitigated through intravenous prophylactic magnesium sulfate administration from initiating cetuximab treatment. This preventive intervention exhibits minimal adverse events and is thus recommended for managing cetuximab-induced hypomagnesemia. Given that cetuximab interruption due to adverse events directly impacts prognosis, the insights gleaned from their study hold significant relevance for the optimal care of HNC patients undergoing cetuximab treatment.
Patients with diabetes exhibit altered taste sensitivity, but its details have not been clarified yet. Here, we examined alteration of sweet taste sensitivity with development of glucose intolerance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of non-insulin-dependent diabetes mellitus. Compared to the cases of Long Evans Tokushima Otsuka (LETO) rats as a control, glucose tolerance of OLETF rats decreased with aging, resulting in development of diabetes at 36-weeks-old. In brief-access tests with a mixture of sucrose and quinine hydrochloride, OLETF rats at 25 or more-weeks-old seemed to exhibit lower sweet taste sensitivity than age-matched LETO ones, but the lick ratios of LETO, but not OLETF, rats for the mixture and quinine hydrochloride solutions decreased and increased, respectively, aging-dependently. Expression of sweet taste receptors, T1R2 and T1R3, in circumvallate papillae (CP) was almost the same in LETO and OLETF rats at 10- and 40-weeks-old, while expression levels of a bitter taste receptor, T2R16, were greater in 40-weeks-old rats than in 10-weeks-old ones in both strains. There was no apparent morphological alteration in taste buds in CP between 10- and 40-weeks-old LETO and OLETF rats. Metagenomic analysis of gut microbiota revealed strain- and aging-dependent alteration of mucus layer-regulatory microbiota. Collectively, we concluded that the apparent higher sweet taste sensitivity in 25 or more-weeks-old OLETF rats than in age-matched LETO rats was due to the aging-dependent increase of bitter taste sensitivity in LETO rats with alteration of the gut microbiota.
Diabetes patients are well-known to exhibit alteration of taste sensitivity, but the alteration profiles have not been clarified in detail yet. In brief-access tests with a mixture of sucrose and quinine hydrochloride, the lick ratios of control, but not non-insulin-dependent diabetes mellitus (NIDDM)-model, rats for the mixture and quinine hydrochloride solutions decreased aging-dependently. Metagenomic analysis of gut microbiota revealed strain- and aging-dependent alteration of mucus layer-regulatory microbiota. These findings suggested that control, but not NIDDM-model, rats exhibited an aging-dependent increase of bitter taste sensitivity with alteration of gut microbiota.
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