Alzheimer’s disease (AD) is a severe neuroinflammatory disease. CD4+Foxp3+ regulatory T cells (Tregs) modulate various inflammatory diseases via suppressing Th cell activation. There are increasing evidences that Tregs have beneficial roles in neurodegenerative diseases. Previously, we found the population of Treg cells was significantly increased by bee venom phospholipase A2 (bvPLA2) treatment in vivo and in vitro. To examine the effects of bvPLA2 on AD, bvPLA2 was administered to 3xTg-AD mice, mouse model of Alzheimer’s disease. The levels of amyloid beta (Aβ) deposits in the hippocampus, glucose metabolism in the brain, microglia activation, and CD4+ T cell infiltration were analyzed to evaluate the neuroprotective effect of bvPLA2. bvPLA2 treatment significantly enhanced the cognitive function of the 3xTg-AD mice and increased glucose metabolism, as assessed with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) positron emission tomography (PET). The levels of Aβ deposits in the hippocampus were dramatically decreased by bvPLA2 treatment. This neuroprotective effect of bvPLA2 was associated with microglial deactivation and reduction in CD4+ T cell infiltration. Interestingly, the neuroprotective effects of bvPLA2 were abolished in Treg-depleted mice. The present studies strongly suggest that the increase of Treg population by bvPLA2 treatment might inhibit progression of AD in the 3xTg AD mice.

Previously, we found that Foxp3-expressing CD4⁺ regulatory T (Treg) cells attenuate cisplatin-induced acute kidney injury in mice and that bee venom and its constituent phospholipase A2 (PLA2) are capable of modulating Treg cells. Here we tested whether PLA2 could inhibit cisplatin-induced acute kidney injury. As a result of treatment with PLA2, the population of Treg cells was significantly increased, both in vivo and in vitro. PLA2-injected mice showed reduced levels of serum creatinine, blood urea nitrogen, renal tissue damage, and pro-inflammatory cytokine production upon cisplatin administration. These renoprotective effects were abolished by depletion of Treg cells. Furthermore, PLA2 bound to CD206 mannose receptors on dendritic cells, essential for the PLA2-mediated protective effects on renal dysfunction. Interestingly, PLA2 treatment increased the secretion of IL-10 in the kidney from normal mice. Foxp3⁺IL-10⁺ cells and CD11c⁺IL-10⁺ cells were increased by PLA2 treatment. The anticancer effects of repeated administrations of a low dose of cisplatin were not affected by PLA2 treatment in a tumor-bearing model. Thus, PLA2 may prevent inflammatory responses in cisplatin-induced acute kidney injury by modulating Treg cells and IL-10 through the CD206 mannose receptor.

Lactate dehydrogenase (LDH) is a crucial enzyme involved in energy metabolism and present in various cells throughout the body. Its diverse physiological functions encompass glycolysis, and its abnormal activity is associated with numerous diseases. Targeting LDH has emerged as a vital approach in drug discovery, leading to the identification of LDH inhibitors among natural compounds, such as polyphenols, alkaloids, and terpenoids. These compounds demonstrate therapeutic potential against LDH-related diseases, including anti-cancer effects. However, challenges concerning limited bioavailability, poor solubility, and potential toxicity must be addressed. Combining natural compounds with LDH inhibitors has led to promising outcomes in preclinical studies. This review highlights the promise of natural compounds as LDH inhibitors for treating cancer, cardiovascular, and neurodegenerative diseases.

Influenza viruses are a serious threat to human health, causing numerous deaths and pandemics worldwide. To date, neuraminidase (NA) inhibitors have primarily been used to treat influenza. However, there is a growing need for novel NA inhibitors owing to the emergence of resistant viruses. Geranii Herba (Geranium thunbergii Siebold et Zuccarini), which is edible, has long been used in a variety of disease treatments in Asia. Although recent studies have reported its various pharmacological activities, the effect of Geranii Herba and its components on influenza viruses has not yet been reported. In this study, Geranii Herba ethanol extract (GHE) and its component geraniin showed high antiviral activity against influenza A strain as well as influenza B strain, against which oseltamivir has less efficacy than influenza A strain, by inhibiting NA activity following viral infection in Madin–Darby canine kidney cells. Thus, GHE and its components may be useful for the development of anti-influenza drugs.

The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2) from bee venom against acetaminophen-induced hepatotoxicity through CD4⁺CD25⁺Foxp3⁺ T cells (Treg) in mice. Acetaminophen (APAP) is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10^−/−) mice were injected with PLA2 once a day for five days and sacrificed 24 h (h) after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO) compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10^−/− mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

The bark of Rhus verniciflua Stokes (RVS) has been used to treat cancer in Korean herbal medicine. When we screened for PD-1 and CTLA-4 immune checkpoint inhibitors (PD-1/PD-L1 CTLA-4/CD80) from around 800 herbal extracts using competitive Enzyme-Linked Immunosorbent Assay (ELISA), we found that RVS blocked both the PD-1/PD-L1 and the CTLA-4/CD80 interactions. To identify the active compounds from RVS, we performed bioactivity-guided fractionation, and the ethyl acetate (EtOAc) fraction of RVS proved to be the most effective at blocking the PD-1/PD-L1 and CTLA-4/CD80 interactions. In addition, we isolated and identified 20 major compounds in the EtOAc fraction of RVS and then examined the blocking effects of these 20 compounds on PD-1/PD-L1 and CTLA-4/CD80. Among them, four compounds [eriodictyol (7) > fisetin (9) > quercetin (18) > liquiritigenin (13)] blocked the interaction of PD-1/PD-L1 on competitive ELISA. In addition, four different compounds [protocatechuic acid (2) > caffeic acid (19) > taxifolin (5) > butin (6)] blocked the interaction of CTLA-4/CD80. Our findings suggest that RVS and its components could be used as a potential immune checkpoint inhibitor blockade and could be developed for immuno-oncological therapeutics.