Fatigue Potentially Reduces the Effect of Transcranial Magnetic Stimulation on Depression Following COVID-19 and Its Vaccination.

COVID-19's long-term effects, known as Long-COVID, present psychiatric and physical challenges in recovered patients. Similarly, rare long-term post-vaccination side effects, resembling Long-COVID, are emerging (called Post-Vaccine). However, effective treatments for both conditions are scarce. Our clinical experience suggests that transcranial magnetic stimulation (TMS) often aids recovery in Long-COVID and Post-Vaccine patients. However, its effectiveness is reduced in patients with severe fatigue. Therefore, we retrospectively analysed Tokyo TMS Clinic's outpatient records (60 in total; mean age, 38 years) to compare Long-COVID and post-vaccine patients' characteristics and symptoms, assess the impact of TMS on their symptoms, and investigate the role of fatigue in depression recovery with TMS. The primary outcome was the regression coefficient of the initial fatigue score on depression score improvement using TMS. Secondary outcomes included psychiatric/physical scores before and after TMS and their improvement rates. We found no differences in the initial symptoms and background factors between Long-COVID and Post-Vaccine patients. After ten TMS sessions, all psychiatric and physical symptom scores improved significantly. TMS improves depression, insomnia, anxiety, and related neuropsychiatric symptoms, which were the primary complaints in this study. Thus, we conclude that TMS improves depression and anxiety. The effectiveness of TMS in treating depression in Long-COVID and Post-Vaccine patients decreased as fatigue severity increased. In conclusion, TMS relieved depressive symptoms following COVID-19 and vaccination; however, fatigue may hinder its effectiveness.

Targeted delivery to macrophages and dendritic cells by chemically modified mannose ligand-conjugated siRNA.

Extrahepatic delivery of small interfering RNAs (siRNAs) may have applications in the development of novel therapeutic approaches. However, reports on such approaches are limited, and the scarcity of reports concerning the systemically targeted delivery of siRNAs with effective gene silencing activity presents a challenge. We herein report for the first time the targeted delivery of CD206-targetable chemically modified mannose-siRNA (CMM-siRNA) conjugates to macrophages and dendritic cells (DCs). CMM-siRNA exhibited a strong binding ability to CD206 and selectively delivered contents to CD206-expressing macrophages and DCs. Furthermore, the conjugates demonstrated strong gene silencing ability with long-lasting effects and protein downregulation in CD206-expressing cells in vivo. These findings could broaden the use of siRNA technology, provide additional therapeutic opportunities, and establish a basis for further innovative approaches for the targeted delivery of siRNAs to not only macrophages and DCs but also other cell types.

PEG-modification on the endo-position of an antisense oligonucleotide increases tumor accumulation via the EPR effect.

Nucleic acid medicine is the next-generation therapeutic modality for refractory diseases with its unique mode of action as an alternative to traditional therapies. A nucleic acid delivery system targeted to liver was validated clinically; however, the delivery system of nucleic acids targeting solid tumors following systemic administration is not efficient enough for clinical use. In this study, we first utilized an antisense oligonucleotide (ASO) and polyethylene glycol (PEG) in one-to-one conjugation (PEG-ASO) at the endo-position of the ASO (endo-PEG-ASO). The effects of ASO modification position, PEG structure and molecular weight, and PEG-ASO tumor accumulation were evaluated in vivo. The endo-PEG-ASO showed prolonged pharmacokinetics and enhanced tumor accumulation compared with the conventional ASO and the PEG-ASO modified at the ASO exo-position (exo-PEG-ASO), indicating that the modification position of PEG is crucial for targeting tumors. We also observed that the endo-PEG-ASO indicated possibility of enhanced permeability inside the tumor. Further research is needed to optimize the linker in the endo-PEG-ASO for clinical application as a novel and promising therapeutic format for targeting solid tumors.

Delphinidin prevents disuse muscle atrophy and reduces stress-related gene expression.

Delphinidin is a member of the anthocyanidin class of plant pigments. We examined the effects of delphinidin on muscle atrophy. Oral administration of delphinidin suppressed the muscle weight loss induced by mechanical unloading. Microarray analysis showed that delphinidin suppresses the upregulation of oxidative stress-related gene expression, including the expression of Cbl-b. Thus, delphinidin may prevent unloading-mediated muscle atrophy.

Metabolomics-driven nutraceutical evaluation of diverse green tea cultivars.

BACKGROUND: Green tea has various health promotion effects. Although there are numerous tea cultivars, little is known about the differences in their nutraceutical properties. Metabolic profiling techniques can provide information on the relationship between the metabolome and factors such as phenotype or quality. Here, we performed metabolomic analyses to explore the relationship between the metabolome and health-promoting attributes (bioactivity) of diverse Japanese green tea cultivars. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the ability of leaf extracts from 43 Japanese green tea cultivars to inhibit thrombin-induced phosphorylation of myosin regulatory light chain (MRLC) in human umbilical vein endothelial cells (HUVECs). This thrombin-induced phosphorylation is a potential hallmark of vascular endothelial dysfunction. Among the tested cultivars, Cha Chuukanbohon Nou-6 (Nou-6) and Sunrouge (SR) strongly inhibited MRLC phosphorylation. To evaluate the bioactivity of green tea cultivars using a metabolomics approach, the metabolite profiles of all tea extracts were determined by high-performance liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical analyses, principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA), revealed differences among green tea cultivars with respect to their ability to inhibit MRLC phosphorylation. In the SR cultivar, polyphenols were associated with its unique metabolic profile and its bioactivity. In addition, using partial least-squares (PLS) regression analysis, we succeeded in constructing a reliable bioactivity-prediction model to predict the inhibitory effect of tea cultivars based on their metabolome. This model was based on certain identified metabolites that were associated with bioactivity. When added to an extract from the non-bioactive cultivar Yabukita, several metabolites enriched in SR were able to transform the extract into a bioactive extract. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that metabolic profiling is a useful approach for nutraceutical evaluation of the health promotion effects of diverse tea cultivars. This may propose a novel strategy for functional food design.