Search Results (5)

We previously reported that 3-(trihydroxygermyl)propanoic acid (THGP) suppresses inflammasome activation in THP-1 cells following stimulation with lipopolysaccharide (LPS) and ATP (signals 1 and 2) by forming a complex with ATP, thereby inhibiting IL-1β secretion. Our findings also suggested that THGP inhibits inflammasome activation through mechanisms independent of ATP complex formation. This study investigated the anti-inflammatory effects of THGP on signal 1 (ATP-independent) of inflammasome activation. THGP suppressed NF-κB nuclear translocation in LPS-stimulated THP-1 cells, which reduced the mRNA expression of the proinflammatory cytokines TNF-α and IL-6, as well as IL-1β secretion. This mechanism was mediated by the formation of a THGP–adenosine complex, which inhibited adenosine degradation and subsequently activated adenosine–NR4A2 signaling. Thus, THGP exerts anti-inflammatory effects by forming a complex with adenosine, leading to adenosine–NR4A2 signaling pathway activation. This mechanism is distinct from the ATP-dependent pathway by which THGP was previously reported to function. By targeting both ATP-dependent and ATP-independent inflammasome activation pathways, THGP has potential as a broad-spectrum therapeutic agent for various inflammatory diseases. Full article

M1 macrophages are an important cell type related to tumor immunology and are known to phagocytose cancer cells. In previous studies, the organogermanium compound poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) and its hydrolysate, 3-(trihydroxygermyl) propanoic acid (THGP), have been reported to exert antitumor effects by activating NK cells and macrophages through the induction of IFN-γ activity in vivo. However, the detailed molecular mechanism has not been clarified. In this study, we found that macrophages differentiate into the M1 phenotype via NF-κB activation under long-term culture in the presence of THGP in vitro and in vivo. Furthermore, long-term culture with THGP increases the ability of RAW 264.7 cells to suppress B16 4A5 melanoma cell proliferation. These mechanisms indicate that THGP promotes the M1 polarization of macrophages and suppresses the expression of signal-regulatory protein alpha (SIRP-α) in macrophages and CD47 in cancers. Based on these results, THGP may be considered a new regulatory reagent that suppresses tumor immunity. Full article

Inflammasome activity is a key indicator of inflammation. The inflammasome is activated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which activate the p38-NF-κB pathway and promote IL-1β transcription (signaling step 1). Next, extracellular adenosine triphosphate (ATP) activates the inflammasome (a protein complex consisting of a signal recognition protein, an adapter protein, and Caspase-1) and secretion of inflammatory cytokines such as IL-1β (signaling step 2). Inflammasome activation causes excessive inflammation, leading to inflammasome-active diseases such as atherosclerosis and type 2 diabetes. A hydrolysate of the organogermanium compound Ge-132, 3-(Trihydroxygermyl) propanoic acid (THGP) can form a complex with a cis-diol structure. We investigated the inhibitory effect of THGP on inflammasome activity in human THP-1 monocytes. THGP inhibited IL-1β secretion and caspase-1 activation (signaling step 2) in an ATP-dependent manner. On the other hand, THGP did not suppress IL-1β secretion induced by only lipopolysaccharide (LPS) stimulation. In addition, as IL-6 is an ATP-independent inflammatory cytokine, THGP did not decrease its secretion. THGP also suppressed pyroptosis, which is a caspase-1 activity-dependent form of cell death. Therefore, THGP is expected to become a new therapeutic or prophylactic agent for inflammasome-associated diseases. Full article

The interaction of viral nucleic acid with protein factors is a crucial process for initiating viral polymerase-mediated viral genome replication while activating pattern recognition receptor (PRR)-mediated innate immune responses. It has previously been reported that a hydrolysate of Ge-132, 3-(trihydroxygermyl) propanoic acid (THGP), shows a modulatory effect on microbial infections, inflammation, and immune responses. However, the detailed mechanism by which THGP can modify these processes during viral infections remained unknown. Here, we show that THGP can specifically downregulate type I interferon (IFN) production in response to stimulation with a cytosolic RNA sensor RIG-I ligand 5′-triphosphate RNA (3pRNA) but not double-stranded RNA, DNA, or lipopolysaccharide. Consistently, treatment with THGP resulted in the dose-dependent suppression of type I IFN induction upon infections with influenza virus (IAV) and vesicular stomatitis virus, which are known to be mainly sensed by RIG-I. Mechanistically, THGP directly binds to the 5′-triphosphate moiety of viral RNA and competes with RIG-I-mediated recognition. Furthermore, we found that THGP can directly counteract the replication of IAV but not EMCV (encephalitismyocarditis virus), by inhibiting the interaction of viral polymerase with RNA genome. Finally, IAV RNA levels were significantly reduced in the lung tissues of THGP-treated mice when compared with untreated mice. These results suggest a possible therapeutic implication of THGP and show direct antiviral action, together with the suppressive activity of innate inflammation. Full article

The organogermanium compound 3-(trihydroxygermyl)propanoic acid (THGP) has various biological activities. We previously reported that THGP forms a complex with cis-diol structures. L-3,4-Dihydroxyphenylalanine (L-DOPA), a precursor of melanin, contains a cis-diol structure in its catechol skeleton, and excessive melanin production causes skin darkening and staining. Thus, the cosmetic field is investigating substances that suppress melanin production. In this study, we investigated whether THGP inhibits melanin synthesis via the formation of a complex with L-DOPA using mushroom tyrosinase and B16 4A5 melanoma cells. The ability of THGP to interact with L-DOPA was analyzed by ¹H-NMR, and the influence of THGP and/or kojic acid on melanin synthesis was investigated. We also examined the effect of THGP on cytotoxicity, tyrosinase activity, and gene expression and found that THGP interacted with L-DOPA, a precursor of melanin with a cis-diol structure. The results also showed that THGP inhibited melanin synthesis, exerted a synergistic effect with kojic acid, and did not affect tyrosinase activity or gene expression. These results suggest that THGP is a useful substrate that functions as an inhibitor of melanogenesis and that its effect is enhanced by combination with kojic acid. Full article