Biological & pharmaceutical bulletin最新文献

Ergothioneine (ERGO) has antioxidant and anti-inflammatory activities in UV-irradiated skin cells in vitro; however, there is no evidence about the effects of dietary ERGO on UV-induced skin damage or ERGO skin distribution in vivo. This study examined the protective effects of ERGO-rich edible mushrooms Pleurotus species against UVB-induced skin damage and the exposure to ERGO in the plasma and skin. Hos : HR-1 hairless mice were fed with or without freeze-dried cross-bred Pleurotus species (PS) or Pleurotus eringii (PE) and were exposed to UVB. Dietary intake of PS or PE significantly alleviated UVB-induced reductions in skin moisture content, increases in transepidermal water loss and oxidative stress markers, and epidermal thickening at plasma ERGO concentrations of 30-40 μM. Additionally, ingestion of PS significantly suppressed UVB-induced expression of pro-inflammatory cytokines. These results suggest that ingesting PS and PE may protect against UVB-induced skin disorders through antioxidant and anti-inflammatory activities at clinically relevant ERGO concentrations. Ingestion of PS and PE led to an increase in epidermal ERGO concentration to levels that were approx. 100 times higher than the ERGO concentration required for significant suppression of UVB-induced intracellular reactive oxygen species in immortalized human keratinocyte HaCaT cells. This suggests that the beneficial effects of PS and PE may be at least partly due to the antioxidant effects of ERGO in murine skin. Overall, ingestion of ERGO-rich Pleurotus species resulted in efficient distribution of ERGO to the skin and protective effects against UVB-induced skin damage, suggesting that these mushrooms may have beneficial effects in humans.

Adult T-cell leukemia/lymphoma (ATL) is a malignant tumor of mature T lymphocytes induced by human T-cell leukemia virus 1, and it has a poor prognosis. Brentuximab vedotin (BV) is included in the treatment of CD30-positive ATL, but there are no predictive biomarkers for the treatment effects of BV. Serum soluble CD30 (sCD30) concentrations are increased in aggressive ATL at the time of diagnosis, but the effect of extracellular CD30 on BV-induced cell death in ATL is unknown. Similarly, a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17 possess CD30 sheddase activity in anaplastic large cell lymphoma, but this activity is unclear in ATL. In this study, we showed that sCD30 concentrations were associated with BV activity in ATL-associated cell lines. Extracellular vesicles, such as exosomes containing CD30, also inhibited BV activity. Furthermore, knockdown of ADAM10/17 significantly reduced sCD30 concentrations and increased BV-induced cell death. These results suggest that ADAM10 and ADAM17 are involved in sCD30 production in ATL. Furthermore, endogenous extracellular CD30, such as sCD30 and CD30-positive extracellular vesicles shed by ADAM10/17, may be involved in BV-induced cell death. Taken together, our findings suggest that extracellular CD30 concentrations, including CD30 on extracellular vesicles, are a useful biomarker for BV therapy in ATL.

The non-canonical phosphorylation of the receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) at Ser-897 plays crucial roles in tumor progression in a tyrosine kinase-independent manner. This phosphorylation is catalyzed by p90 ribosomal S6 kinase (RSK), a kinase downstream of extracellular signal-regulated kinase (ERK). We recently reported that stress-responsive kinase mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), instead of ERK, regulates RSK under cellular stress conditions; however, the function of MK2 in ERK-activated cells is still unknown. We herein clarified that MK2 regulates the RSK-EphA2 axis in ERK-activated echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) lung cancer cells. In addition, an MK2 inhibitor blocked enhancements in cell motility induced by the constitutively activated RSK-EphA2 axis. The present results reveal the importance of MK2 in the ERK-activated non-canonical activation of EphA2.

Astragalus polysaccharide (APS) is a biologically active water-soluble polysaccharide extracted from stems or roots, which has been proven to have antiaging effects. The aim of this study was to investigate the effects of APS on cognitive function in d-galactose (d-gal)-induced aging rats and explore the potential underlying molecular mechanisms. The rats were induced to age by intraperitoneal injection with 400 mg/kg/d d-gal for 8 weeks. Aging of rats was assessed through the Morris water maze test, step-down test, open field test, and grip strength test. Pathological changes in the hippocampal CA3 and CA1 regions were determined by Hematoxylin and eosin and Nissl staining. The superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and total antioxidant capacity (T-AOC) in the serum were measured. Telomere length, dual oxidase 1 (Duox1), dual oxidase 2 (Duox2), peroxiredoxin 1 (Prdx1), p21, p16, p53, telomerase reverse transcriptase (TERT), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), nicotinamide phosphoribosyl transferase (NAMPT), and sirtuin 1 (SIRT1) were detected via real-time PCR, Western blotting, and immunohistochemical staining. The results indicated that APS ameliorated the general status in d-gal-induced aging rats, mitigated neuronal degeneration in the CA3 and CA1 regions, reduced the oxidative stress levels, modulated senescence-related β-GAL and protein expression, and maintained telomere length. Furthermore, APS significantly reduced p53 expression and increased p-PI3K, p-AKT, NAMPT, SIRT1, and TERT expression. Therefore, d-gal-induced aging and cognitive impairment in rats can be prevented by APS, likely through regulation of the TERT/p53 signaling axis via the PI3K/Akt and NAMPT/SIRT1 signaling pathways.

Herbal medicines are widely used in clinical practice. Several herbal medicines are prescribed in clinical practice to improve mental symptoms. Yokukansan is an effective prescription for irritability and aggression, which are behavioral and psychological symptoms of dementia (BPSD) or autism spectrum disorder (ASD). However, because herbal medicines contain many components, their pharmacological effects have not been analyzed in detail. Risperidone and quetiapine are prescribed in severe cases; however, their side effects of oversedation are problematic. Tokishigyakukagoshuyushokyoto (TSGST) is a herbal medicine prescribed to improve blood circulation and relieve headaches, back pain, or chilblains associated with hemodynamic insufficiency. Interestingly, most of the individual components of TSGST are known to exert sedative or analgesic effects. In this study, we investigated whether TSGST ameliorates aggressive behavior induced by social isolation in mice. The mice were isolated for 5 or 6 weeks immediately after weaning and given TSGST via a water bottle during this period. Long-term administration of TSGST suppressed the onset of aggression induced by isolation rearing. This aggressive phenotype was significantly reversed by intraperitoneal (i.p.) administration of the 5-hydroxytryptamine 1A (5-HT_1A) receptor antagonist WAY-100635 in TSGST-isolated mice. We also showed that TSGST had similar effects as risperidone, a commonly used antipsychotic for irritability and aggression. These results suggest that TSGST may be effective for irritability or aggression in BPSD or ASD.

Detecting low-frequency genetic mutations is crucial for genetic testing, especially in cancer diagnostics. Wild-type blocking PCR identifies these genetic mutations using a blocking oligonucleotide that is fully complementary to wild-type DNA. The blocking oligonucleotide selectively binds to wild-type DNA, inhibiting its amplification by DNA polymerase and allowing preferential amplification of mutant DNA. Bridged nucleic acids (BNAs), with high binding affinities for cDNA, are often incorporated into the blocking oligonucleotide to enhance inhibition. However, the effects of BNA positioning within the blocking oligonucleotide on wild-type DNA amplification inhibition are poorly understood. To address this issue, we evaluated the effects of different BNA positions on amplification inhibition efficacy by comparing blocking oligonucleotides with varying numbers of BNAs at the 5' end, 3' end, and central region. Results indicated that BNAs at the 5' end enhanced the inhibition efficacy, whereas BNAs at the 3' end notably diminished the inhibition efficacy. Likewise, increasing the number of BNAs in the central region generally decreased the inhibition efficacy. This is one of the first studies to report the importance of BNA positioning in the amplification inhibition efficacy of blocking oligonucleotides.

This study investigated the protective effects of metformin against combined high glucose (HG)- and UVA-induced cytotoxicity in fetal rat skin keratinocytes (FRSK cells), a model of diabetic photoaging. HG combined with UVA caused a synergistic loss of cell viability accompanied by marked increases in phosphorylation of AMP-activated protein kinase (p-AMPK), reactive oxygen species (ROS) generation, senescence-associated β-galactosidase (SA-β-Gal) activity, and Sirtuin 1 (SIRT1) expression. HG alone induced moderate cytotoxicity and senescence, whereas UVA alone under normal glucose conditions (NG + UVA) produced negligible ROS and minimal viability loss. Metformin improved cell viability under dual stress conditions in a dose-dependent manner, with maximal protection observed at 8 mM. In UVA-free cultures, metformin increased p-AMPK in both NG and HG, peaking at 8 mM. Under HG + UVA, p-AMPK was higher than in NG + UVA and HG alone, with no additional increase following metformin treatment. ROS accumulation occurred only under HG + UVA and was strongly suppressed by metformin, nearly to baseline at 8 mM. The HG + UVA-induced increases in SA-β-Gal activity and SIRT1 expression were reduced in parallel with ROS suppression. These findings suggest that metformin's cytoprotective effect in this model is primarily mediated by attenuation of ROS rather than by further AMPK activation, indicating an AMPK-independent antioxidant mechanism.

Endometriosis, a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, demonstrates malignant tumor-like properties including aggressive adhesion and invasiveness. Emerging evidence implicates roundabout guidance receptor 3 (ROBO3) in cellular pathophysiology, yet its role in endometriosis remains unexplored. In this study, we first found abnormally high ROBO3 expression in endometriosis by bioinformatics analysis. Next, functional assays revealed that ROBO3 is a key regulator promoting the invasion and migration of endometriotic stromal cells (ESCs) in vitro. Mechanistically, ROBO3 activates the Wnt/β-catenin signaling pathway, evidenced by increased phosphorylation of glycogen synthase kinase 3β, nuclear β-catenin accumulation, and upregulated c-myc expression. Pharmacological inhibition of Wnt/β-catenin with MSAB (5 μM) reversed ROBO3-mediated pro-invasive and pro-migratory effects. Furthermore, we discovered that ROBO3 enhances the secretion of chemokines CCL2 and CCL5 in ESCs, which subsequently promote macrophage polarization toward the M2 phenotype, as indicated through elevated expression of interleukin-10 and Arg-1. Collectively, our findings elucidate a dual mechanism whereby ROBO3 drives endometriosis progression through both intrinsic activation of Wnt/β-catenin signaling and extrinsic modulation of tumor-associated macrophages, underscoring ROBO3 as a promising therapeutic target for endometriosis.

The effect of transient receptor potential canonical-3 (TRPC3) channel inhibitor pyrazole-3 (Pyr3) on the stability of atrial fibrillation (AF) was analyzed in a rat model of chronic volume overload. Male Wistar rats underwent aorto-venocaval shunt (AVS) surgery and received Pyr3 treatment intraperitoneally for 12 weeks. Morphological and electrophysiological assessments were performed at the end of the treatment period. Longer P-wave duration, atrial conduction time, and AF duration, in addition to greater atrial tissue weight, were detected in AVS rats compared with sham rats. Chronic Pyr3 administration prevented AVS-induced prolongation of P-wave duration and atrial conduction time, partially prevented atrial weight increase, and abbreviated AVS-induced prolongation of AF duration to similar levels as those in sham rats, without affecting the atrial effective refractory period. These results suggest that the TRPC3 inhibitor Pyr3 can ameliorate sustained AF associated with chronic volume overload by improving atrial conduction defects in AVS rats. Pharmacological inhibition of TRPC3 channels by Pyr3 thus represents a promising therapeutic strategy for preventing AF development related to structural modeling.

FR429, an ellagitannin isolated and purified from the whole herb Polygonum capitatum (P. capitatum), possesses a robust pharmacological profile, which is particularly noteworthy for its anti-inflammatory and anticancer properties. Despite these established effects, its potential in mitigating hepatic injury remains to be fully explored. The present investigation delineates the hepatoprotective efficacy of FR429 and unveils its underlying molecular mechanisms. Initially, of the tested compounds, 10 compounds (specifically, compounds 2, 4, 5, 6, 7, 8, 9, 12, 13, and 14) exhibited significant protective effects at a concentration of 10 μM, elevating HepG2 (human liver cancer cell) cell viability from 43.4 to 70% following carbon tetrachloride (CCl₄) exposure. Among them, compounds 2 (FR429, half-maximum effective concentration (EC₅₀) = 6.46 μM) and 6 (2"-O-galloylquercitrin, EC₅₀ = 5.36 μM) demonstrated the highest cytoprotective activities. In the murine model, FR429 dramatically attenuated serum levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase, indicative of its hepatoprotective potential. Histopathological evaluation further substantiated these findings, as FR429 noticeably mitigated CCl₄-induced hepatic lesions, involving necrosis, ballooning degeneration, and neutrophil infiltration. Transcriptomic analysis unveiled 178 differentially expressed genes in FR429-treated mice liver tissue, with significant alterations indicative of a hepatoprotective response. Mechanistic investigations revealed that FR429's hepatoprotective effects involve modulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, evidenced by downregulation of toll-like receptor 2, phosphorylated PI3K, phosphorylated Akt, nuclear factor-kappa-B, interleukin-1 beta, and tumor necrosis factor-alpha expression. Furthermore, FR429 modulated the gene and protein expression levels of apoptotic markers (apoptotic protein (Bax) and B-lymphoblastoma-2 gene (Bcl2)), reinforcing its anti-hepatic damage efficacy. This study represents the first report establishing FR429 as an effective hepatoprotective compound, paving the way for further investigation into its therapeutic applications.