Uncovering the colorectal cancer immunotherapeutic potential: Evening primrose (Oenothera biennis) root extract and its active compound oenothein B targeting the PD-1/PD-L1 blockade.

BACKGROUND: The emergence of immune checkpoint inhibitors, a novel class of immunotherapy drugs, represents a major breakthrough in cancer immunotherapy, substantially improving patient survival post-treatment. Blocking programmed death-ligand 1 (PD-L1) and programmed death protein-1 (PD-1) has demonstrated promising clinical results in various human cancer types. The US FDA has recently permitted only monoclonal antibody (mAb)-based PD-L1 or PD-1 blockers. Although these antibodies exhibit high antitumor efficacy, their size- and affinity-induced side effects limit their applicability. PURPOSE: As small-molecule-based PD-1/PD-L1 blockers capable of reducing the side effects of antibody therapies are needed, this study focuses on exploring natural ingredient-based small molecules that can target hPD-L1/PD-1 using herbal medicines and their components. METHODS: The antitumor potential of evening primrose (Oenothera biennis) root extract (EPRE), a globally utilized traditional herbal medicine, folk remedy, and functional food, was explored. A coculture system was established using human PD-L1-expressed murine MC38 cells (hPD-L1-MC38s) and CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) expressing humanized PD-1. The in vivo experiments utilized a colorectal cancer (CRC) C57BL/6 J mouse model bearing MC38 cells expressing humanized PD-L1 and PD-1 proteins. RESULTS: EPRE and its active compound oenothein B effectively hindered the molecular interaction between hPD-L1 and hPD-1. EPRE stimulated tumor-specific T lymphocytes of a hPD-L1/PD-1 CRC mice. This action resulted in the elevated infiltration of cytotoxic CD8+T lymphocytes and subsequent tumor growth reduction. Moreover, the combined therapy of oenothein B, a PD-1/PD-L1 blocker, and FOLFOX (5-fluorouracil plus oxaliplatin) cooperatively suppressed hPD-L1-MC38s growth in the ex vivo model through activated CD8+ TIL antitumor immune response. Oenothein B exhibited a high binding affinity for hPD-L1 and hPD-1. We believe that this study is the first to uncover the inhibitory effects of EPRE and its component, oenothein B, on PD-1/PD-L1 interactions. CONCLUSION: This study identified a promising small-molecule candidate from natural products that blocks the hPD-L1/PD-1 signaling pathway. These findings emphasize the potential of EPRE and oenothein B as effective anticancer drugs.

Anti-Atopic Effect of Isatidis Folium Water Extract in TNF-α/IFN-γ-Induced HaCaT Cells and DNCB-Induced Atopic Dermatitis Mouse Model.

Isatidis folium or Isatis tinctoria L. is a flowering plant of the Brassicaceae family, commonly known as woad, with an ancient and well-documented history as an indigo dye and medicinal plant. This study aimed to evaluate the anti-atopic dermatitis (AD) effects of Isatidis folium water extract (WIF) using a 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mouse model and to investigate the underlying mechanism using tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-activated HaCaT cells. Oral administration of WIF reduced spleen weight, decreased serum IgE and TNF-α levels, reduced epidermal and dermal thickness, and inhibited eosinophil and mast cell recruitment to the dermis compared to DNCB-induced control groups. Furthermore, oral WIF administration suppressed extracellular signal-regulated kinase and p38 mitogen-activated protein kinase protein expression levels, p65 translocation from the cytoplasm to the nucleus, and mRNA expression of TNF-α, IFN-γ, interleukin (IL)-6, and IL-13 in skin lesion tissues. In HaCaT cells, WIF suppressed the production of regulated upon activation, normal T cell expressed and secreted (RANTES), thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), MCP-1, and MIP-3a, which are inflammatory cytokines and chemokines related to AD, and inhibited the mRNA expression of RANTES, TARC, and MDC in TNF-α/IFN-γ-stimulated HaCaT cells. Overall, the results revealed that WIF ameliorated AD-like skin inflammation by suppressing proinflammatory cytokine and chemokine production via nuclear factor-κB pathway inhibition, suggesting WIF as a potential candidate for AD treatment.

An optimized herbal medicine containing Scutellaria baicalensis Georgi, Alisma orientale Juzepzuk, and Atractylodes japonica Koidzumi has potent antiplatelet and antithrombotic activities.

Background and aim: Platelet-derived thrombosis is important in the pathogenesis of cardiovascular diseases. HTB is an optimized herbal medicine including Scutellaria baicalensis Georgi, Alisma orientale Juzepzuk, and Atractylodes japonica Koidzumi. It is widely used in traditional medicine due to its anti-inflammatory and antioxidant effects. However, its antiplatelet and antithrombotic activities have not been completely validated. The current study aimed to examine the inhibitory effect of the novel herb formula HTB against platelet activation and thrombus formation. Experimental procedure: The antiplatelet activities of HTB via platelet aggregation, granule secretion, reactive oxygen species generation, and intracellular calcium mobilization were evaluated. Moreover, the antithrombotic effect of HTB via FeCl3-induced arterial thrombus formation in vivo in mice was assessed. The inhibitory effect of HTB against primary hemostasis was investigated based on transection tail bleeding time. Results and conclusion: HTB treatment significantly inhibited glycoprotein VI-mediated platelet aggregation, granule secretion, reactive oxygen species generation, and intracellular calcium mobilization. Biochemical studies revealed that HTB inhibited glycoprotein VI-mediated platelet signal transduction during cell activation. Further, its antioxidant effect might be derived by reducing the phosphorylation of the p47phox/Hic5 axis signalosome. Oral HTB treatment was effective in decreasing FeCl3-induced arterial thrombus formation without prolonging the tail bleeding time. HTB can be an effective therapeutic agent against thrombotic diseases.

Sinomenium acutum Modulates Platelet Aggregation and Thrombus Formation by Regulating the Glycoprotein VI-Mediated Signalosome in Mice.

Sinomenium acutum (SA) has long been used as a traditional medicine in China, Japan, and Korea to treat a wide range of diseases. It has been traditionally used to ameliorate inflammation and improve blood circulation. However, its role in platelet activation has not been thoroughly investigated. Hence, we conducted this study to assess the potential inhibitory effect of SA on platelet aggregation and thrombus formation. The antiplatelet activities of SA were evaluated by assessing platelet aggregation, granular secretion, intracellular Ca2+ mobilization, and the Glycoprotein (GP) VI-mediated signalosome. The thrombosis and bleeding time assays were used to investigate the effect of SA (orally administered at 50 and 100 mg/kg for seven days) in mice. SA treatment at concentrations of 50, 100, and 200 µg/mL significantly reduced GPVI-mediated platelet aggregation, granular secretion, and intracellular Ca2+ mobilization. Further biochemical studies revealed that SA inhibited spleen tyrosine kinase, phospholipase Cγ2, phosphatidylinositol 3-kinase, and AKT phosphorylation. Interestingly, oral administration of SA efficiently ameliorated FeCl3-induced arterial thrombus formation without prolonging the tail bleeding time. These findings suggest that SA has beneficial effects in thrombosis and hemostasis. Therefore, SA holds promise as an effective therapeutic agent for the treatment of thrombotic diseases.

Neuroprotective and Anti-Neuroinflammatory Properties of Vignae Radiatae Semen in Neuronal HT22 and Microglial BV2 Cell Lines.

The important factors in the pathogenesis of neurodegenerative disorders include oxidative stress and neuron-glia system inflammation. Vignae Radiatae Semen (VRS) exhibits antihypertensive, anticancer, anti-melanogenesis, hepatoprotective, and immunomodulatory properties. However, the neuroprotective effects and anti-neuroinflammatory activities of VRS ethanol extract (VRSE) remained unknown. Thus, this study aimed to investigate the neuroprotective and anti-inflammatory activities of VRSE against hydrogen peroxide (H2O2)-induced neuronal cell death in mouse hippocampal HT22 cells and lipopolysaccharide (LPS)-stimulated BV2 microglial activation, respectively. This study revealed that VRSE pretreatment had significantly prevented H2O2-induced neuronal cell death and attenuated reactive oxygen species generations in HT22 cells. Additionally, VRSE attenuated the apoptosis protein expression while increasing the anti-apoptotic protein expression. Further, VRSE showed significant inhibitory effects on LPS-induced pro-inflammatory cytokines in BV2 microglia. Moreover, VRSE pretreatment significantly activated the tropomyosin-related kinase receptor B/cAMP response element-binding protein, brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor 2, and heme oxygenase-1 signaling pathways in HT22 cells exposed to H2O2 and inhibited the activation of the mitogen-activated protein kinase and nuclear factor-κB mechanism in BV2 cells stimulated with LPS. Therefore, VRSE exerts therapeutic potential against neurodegenerative diseases related to oxidative stress and pathological inflammatory responses.

Synthesis of Vacancy-Controlled Copper Iodide Semiconductor for High-Performance p-Type Thin-Film Transistors.

Copper iodide (CuI) has emerged as a promising p-type semiconductor material owing to its excellent carrier mobility, high transparency, and solution processability. Although CuI has potential for numerous applications, including perovskite solar cells, photovoltaic devices, and thin-film transistors (TFTs), the close relationship between the anion vacancy generation and the charge transport mechanism in CuI-based devices is underexplored. In this study, we propose solution-processed p-type CuI TFTs which were subject to the thermal annealing process in air and vacuum atmospheres at temperatures of 100, 200, and 300 °C. The chemical states and surface morphologies of the CuI thin films were systematically investigated, revealing the generation of iodine vacancy states and the reduction of carrier concentration, as well as increased film density and grain size according to the annealing condition. Further, the effective role of the Al2O3 passivation layer on the electrical characteristics of the solution-processed CuI TFTs is demonstrated for the first time, where the Al2O3 precursor greatly enhanced the electrical performance of the CuI TFTs, exhibiting a field-effect mobility of 4.02 cm2/V·s, a subthreshold swing of 0.61 V/decade, and an on/off current ratio of 1.12 × 104, which exceed the values of CuI TFTs reported so far. Based on the synergistic effects of the annealing process and the passivation layer that engineered the iodine vacancy state and morphology of CuI, the proposed CuI TFTs with the Al2O3 passivation layer showed excellent reliability under 100 times repeated operation and long-term stability over 216 h, where the transfer curves slightly shifted in the positive direction of 1.36 and 1.88 V measured at a current level of 10-6 A for the reliability and stability tests, respectively. Thus, this work opens a new window for solution-processed p-type CuI TFTs with excellent stability for developing next-generation complementary logic circuits.

Selaginella tamariscina Inhibits Glutamate-Induced Autophagic Cell Death by Activating the PI3K/AKT/mTOR Signaling Pathways.

Glutamate-induced neural toxicity in autophagic neuron death is partially mediated by increased oxidative stress. Therefore, reducing oxidative stress in the brain is critical for treating or preventing neurodegenerative diseases. Selaginella tamariscina is a traditional medicinal plant for treating gastrointestinal bleeding, hematuria, leucorrhea, inflammation, chronic hepatitis, gout, and hyperuricemia. We investigate the inhibitory effects of Selaginella tamariscina ethanol extract (STE) on neurotoxicity and autophagic cell death in glutamate-exposed HT22 mouse hippocampal cells. STE significantly increased cell viability and mitochondrial membrane potential and decreased the expression of reactive oxygen species, lactate dehydrogenase release, and cell apoptosis in glutamate-exposed HT22 cells. In addition, while glutamate induced the excessive activation of mitophagy, STE attenuated glutamate-induced light chain (LC) 3 II and Beclin-1 expression and increased p62 expression. Furthermore, STE strongly enhanced the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) phosphorylation activation. STE strongly inhibited glutamate-induced autophagy by activating the PI3K/Akt/mTOR signaling pathway. In contrast, the addition of LY294002, a PI3K/Akt inhibitor, remarkably suppressed cell viability and p-Akt and p62 expression, while markedly increasing the expression of LC3 II and Beclin-1. Our findings indicate that autophagy inhibition by activating PI3K/Akt/mTOR phosphorylation levels could be responsible for the neuroprotective effects of STE on glutamate neuronal damage.

Inhibitory effect of Isatis tinctoria L. water extract on DNCB-induced atopic dermatitis in BALB/c mice and HaCaT cells.

BACKGROUND: Isatis tinctoria L (PLG) is a medicinal herb from the roots of Isatis indigotica Fort (Family Cruciferae). Previous studies have shown that PLG has anti-inflammatory and therapeutic effects against conditions such as acute and chronic hepatitis, various respiratory inflammations, and cancer. The purpose of this study was to define the pharmacological effects of PLG on inflammatory reactions and skin hyperkeratosis, which are the main symptoms of atopic dermatitis (AD), in vivo and in vitro. METHODS: For the AD in vivo experiment, 2,4-dinitrochlorobenzene (DNCB) induction and oral administration of PLG were performed on male BALB/c mice for four weeks. For in vitro experiments, keratinocytes were activated using TNF-α/IFN-γ in cultured human keratinocyte (HaCaT) cells. PLG inhibited inflammatory chemokine production and blocked the nuclear translocation of NF-κB p65 in activated keratinocytes. RESULTS: As a result of oral administration of PLG, dermis and epidermis thickening, as well as eosinophil and mast cell infiltration, were attenuated in AD skin lesions. In addition, the levels of immunoglobulin E (IgE), pro-inflammatory cytokines, and the MAPK/NF-κB signaling pathway were decreased in serum and dorsal skin tissues. Furthermore, PLG inhibited inflammatory chemokine production and blocked the nuclear translocation of NF-κB p65 in activated keratinocytes. In addition, epigoitrin and adenosine, the standard compounds of PLG, were identified as candidate AD compounds. CONCLUSIONS: These results indicate that PLG is a potent therapeutic agent for attenuating symptoms of AD.

Synergistic effects of novel herbal decoctions from Panax ginseng and Morus alba on tyrosinase activity and melanogenesis in vitro.

Many medicinal plants such as a Panax ginseng and Morus alba (mulberry tree) have been widely used as depigmenting agents in Asia. To maximize their synergistic effects on melanogenesis, new herbal decoctions were created by mixing Ginseng Radix Alba (GR) and Mori Radicis Cortex (MC) at a ratio of 3:2 which called GMC decoction. A decoction of GR and Mori Ramulus (MR), which called GMR, was also formulated in order to compare the anti-melanogenic capacity. Combined decoctions, GMC and GMR, significantly decreased mushroom tyrosinase activity in vitro; however, single extracts, including MC and MR, showed weaker inhibitory activity. Melanin content assay and Fontana-Masson staining confirmed that two decoctions showed stronger inhibitory effects on the forskolin-induced melanin level in B16 cells, without cytotoxicity. Our findings suggest that ginseng in combination with mulberry tree enhances the anti-melanogenic effect in vitro.

Indigo Pulverata Levis (Chung-Dae, Persicaria tinctoria) Alleviates Atopic Dermatitis-like Inflammatory Responses In Vivo and In Vitro.

Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with a type 2 T helper cell (Th2) immune response. The IndigoPulverata Levis extract (CHD) is used in traditional Southeast Asian medicine; however, its beneficial effects on AD remain uninvestigated. Therefore, we investigated the therapeutic effects of CHD in 2,4-dinitrochlorobenzene (DNCB)-induced BALB/c mice and tumor necrosis factor (TNF)-α- and interferon gamma (IFN)-γ-stimulated HaCaT cells. We evaluated immune cell infiltration, skin thickness, and the serum IgE and TNF-α levels in DNCB-induced AD mice. Moreover, we measured the expression levels of pro-inflammatory cytokines, mitogen-activated protein kinase (MAPK), and the nuclear factor-kappa B (NF-κB) in the mice dorsal skin. We also studied the effect of CHD on the translocation of NF-κB p65 and inflammatory chemokines in HaCaT cells. Our in vivo results revealed that CHD reduced the dermis and epidermis thicknesses and inhibited immune cell infiltration. Furthermore, it suppressed the proinflammatory cytokine expression and MAPK and NF-κB phosphorylations in the skin tissue and decreased serum IgE and TNF-α levels. In vitro results indicated that CHD downregulated inflammatory chemokines and blocked NF-κB p65 translocation. Thus, we deduced that CHD is a potential drug candidate for AD treatment.

Chrysanthemum indicum Prevents Hydrogen Peroxide-Induced Neurotoxicity by Activating the TrkB/Akt Signaling Pathway in Hippocampal Neuronal Cells.

Oxidative stress-mediated neuronal damage is associated with the pathogenesis and development of neurodegenerative diseases. Chrysanthemum indicum has antioxidant properties. However, the neuroprotective effects and the cellular mechanism of C. indicum ethanol extract (CIE) against oxidative damage in hippocampal neuronal cells have not been clearly elucidated. Therefore, this study investigated whether CIE has protective effects against hydrogen peroxide (H2O2)-induced oxidative toxicity in HT22 cells. CIE pretreatment significantly improved neuronal cell viability. Moreover, the formation of intracellular reactive oxygen species and apoptotic bodies, and mitochondrial depolarization were significantly reduced in HT22 cells with H2O2-induced oxidative toxicity. Furthermore, CIE increased the phosphorylation of tropomyosin-related kinase receptor B (TrkB), protein kinase B (Akt), cAMP response element-binding protein, the expression of brain-derived neurotrophic factor, antioxidant enzymes, and the nuclear translocation of nuclear factor erythroid 2-related factor 2 by activating the TrkB/Akt signaling pathway. In contrast, the addition of K252a, a TrkB inhibitor, or MK-2206, an Akt-selective inhibitor, reduced the neuroprotective and antioxidant effects of CIE. Taken together; CIE exhibits neuroprotective and antioxidant effects against oxidative damage. Therefore, it can be a potential agent for treating oxidative stress-related neurodegenerative diseases.

Sanguisorbae Radix Suppresses Colorectal Tumor Growth Through PD-1/PD-L1 Blockade and Synergistic Effect With Pembrolizumab in a Humanized PD-L1-Expressing Colorectal Cancer Mouse Model.

Immune checkpoints such as programmed death-1 (PD-1) have been proven as antitumor targets by enhancing cytotoxic T cell activity. All immune checkpoint blockades are antibody therapeutics that have large size and high affinity, as well as known immune-related side effects and low responses. To overcome the limitation of antibody therapeutics, we have explored PD-1/PD-L1 (programmed death-ligand 1) blockades in traditional oriental medicine, which has a long history but has not yet studied PD-1/PD-L1 blockades. Sanguisorbae Radix extract (SRE) blocked PD-1 and PD-L1 binding in competitive ELISA. SRE effectively inhibited the PD-1/PD-L1 interaction, thereby improving T cell receptor (TCR) signaling and the NFAT-mediated luciferase activity of T cells. SRE treatment reduced tumor growth in the humanized PD-L1 MC38 cell allograft humanized PD-1 mouse model. Additionally, the combination of SRE and pembrolizumab (anti-PD-1 antibody) suppressed tumor growth and increased infiltrated cytotoxic T cells to a greater extent did either agent alone. This study showed that SRE alone has anticancer effects via PD-1/PD-L1 blockade and that the combination therapy of SRE and pembrolizumab has enhanced immuno-oncologic effects.

Forsythia Fruit Prevents Fulminant Hepatitis in Mice and Ameliorates Inflammation in Murine Macrophages.

Forsythia Fruit (FF), the fruit of Forsythia suspensa, has been used since ancient times as an herbal medication in East Asia to treat inflammation, gonorrhea, and pharyngitis. However, the efficacy of FF against liver damage due to inflammation has not been studied. Here, we explored the protective effects of FF in a mouse hepatitis model induced by lipopolysaccharide (LPS)/D-galactosamine (GalN) treatment. We measured inflammatory cytokine and aminotransferase levels in mouse blood and analyzed the effects of FF on inflammatory gene and protein expression levels in liver tissue. Our results show that FF treatment effectively lowers inflammatory cytokine and serum aminotransferase levels in mice and inhibits the expression of hepatic cytokine mRNA and inflammatory proteins. Furthermore, treatment with FF activated the antioxidant pathway HO-1/Nrf-2 and suppressed severe histological alteration in the livers of LPS/D-GalN-treated mice. Further investigation of the effects of FF on inflammatory reactions in LPS-stimulated macrophages showed that pretreatment with FF inhibits inflammatory mediator secretion and activation of inflammatory mechanisms both in a mouse macrophage RAW 264.7 cells and in primary peritoneal macrophages. These results show that FF has potential worth as a candidate for the treatment of fulminant inflammatory reactions and subsequent liver injury.

Mori ramulus and its Major Component Morusin Inhibit Herpes Simplex Virus Type 1 Replication and the Virus-Induced Reactive Oxygen Species.

Herpes simplex virus type 1 (HSV-1) is ubiquitous in many populations despite the use of acyclovir or related nucleoside analogs for treating infection. Drug resistance impairs the treatment of HSV-infected individuals who have immune deficits, underscoring the need for new safe and effective antiviral agents. Mori ramulus (the young twig of Morus alba L.) has long been used to treat diseases in Korea, Japan, and China. Recent studies have reported multiple pharmacological activities of Mori ramulus and its constituent morusin, but their effects on HSV-1 remain unknown. Here, we found that treatment with Mori ramulus ethanol extract (MRE) significantly reduced the replication of fluorescently labeled HSV-1 in Vero cells and inhibited the expression of HSV-1 envelope glycoprotein D (gD) and tegument protein VP16. MRE, furthermore, blocked HSV-1-induced production of reactive oxygen species (ROS), and this mediated the inhibition of viral replication. We identified morusin as the active antiviral component of MRE and found that morusin post-treatment was sufficient to inhibit viral gD and VP16 in addition to HSV-1-induced ROS production. Therefore, the inhibition of HSV-1-induced ROS may explain the antiviral activity of MRE against HSV-1. MRE or its component morusin may be potentially developed for anti-HSV-1 agents.

Anticancer Effect of Salvia plebeia and Its Active Compound by Improving T-Cell Activity via Blockade of PD-1/PD-L1 Interaction in Humanized PD-1 Mouse Model.

Immune checkpoint inhibitors, increasingly used to treat malignant tumors, are revolutionizing cancer treatment by improving the patient survival expectations. Despite the high antitumor efficacy of antibody therapeutics that bind to PD-1/PD-L1, study on small molecule-based PD-1/PD-L1 inhibitors is required to overcome the side effects of antibody therapeutics caused by their size and affinity. Herein, we investigated antitumor potential of Salvia plebeia R. Br. extract (SPE), which has been used as a traditional oriental medicine and food in many countries, and its components by the blockade of PD-1/PD-L1 interaction. SPE and its component cosmosiin effectively blocked the molecular interaction between PD-1 and PD-L1. SPE also inhibited tumor growth by increasing CD8+ T-cells in the tumor through the activation of tumor-specific T-cells in a humanized PD-1 mouse model bearing hPD-L1 knock-in MC38 colon adenocarcinoma tumor. This finding presents a preclinical strategy to develop small molecule-based anticancer drugs targeting the PD-1/PD-L1 immune checkpoint pathway.

Unripe Black Raspberry (Rubus coreanus Miquel) Extract and Its Constitute, Ellagic Acid Induces T Cell Activation and Antitumor Immunity by Blocking PD-1/PD-L1 Interaction.

Rubus coreanus Miquel (R. coreanus) is a unripen fruit of black raspberry native to eastern Asia. It is used as traditional oriental medicine and supplementary foods for centuries. Previous studies have shown that the R. coreanus extract (RCE) and its main constitute ellagic acid possess diverse biological activities. However, the effects of RCE on antitumor immunity and T cell function were not fully understood. The present study describes the anti-tumor effect of RCE in humanized PD-1 mice by blocking PD-1/PD-L1 interaction. Competitive enzyme-linked immunosorbent assay (ELISA) and pull down assay were performed to elucidate the binding properties of RCE in vitro. Cellular PD-1/PD-L1 blockade activities were measured by T cell receptor (TCR)-induced nuclear factor of activated T cells-luciferase activity in co-cultured cell models with PD-1/NFAT Jurkat and PD-L1/aAPC CHO-K1 cells. The in vivo efficacy of RCE was confirmed in humanized PD-1 mice bearing MC38 colorectal tumor. RCE and ellagic acid dose-dependently block the binding of PD-1 to PD-L1. Moreover, oral administration of RCE showed the potent anti-tumor activity similar to anti-PD-1 antibody. The present study suggests that RCE possesses potent anti-tumor effect via PD-1/PD-L1 blockade, and ellagic acid is the main compound in RCE. Thus, we provide new aspects of RCE as an immunotherapeutic agent.

Immune Checkpoint PD-1/PD-L1 CTLA-4/CD80 are Blocked by Rhus verniciflua Stokes and its Active Compounds.

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.

DNA Topoisomerase Inhibitory Activity of Constituents from the Fruits of Illicium verum.

Three new compounds, a sesquilignan (1) and two glucosylated phenylpropanoids (2, 3), and seven known compounds (4-10), were isolated from the fruits of Illicium verum HOOK. FIL. (Illiciaceae). The structures of 1-3 were determined based on one and two dimensional (1D- and 2D-) NMR data and electronic circular dichroism (ECD) spectra analyses. Compounds 3, 5, 6, and 8-10 exhibited potent inhibitory activities against topoisomerase II with IC50 values of 54.6, 25.5, 17.9, 12.1, 0.3 and 1.0 µM, respectively, compared to etoposide, the positive control, with an IC50 of 43.8 µM.

Nonablative fractional laser-assisted daylight photodynamic therapy with topical methyl aminolevulinate for moderate to severe facial acne vulgaris: Results of a randomized and comparative study.

BACKGROUND: Photodynamic therapy (PDT) has been reported as an effective alternative treatment for patients with acne. PURPOSE: To evaluate the efficacy and safety of DL-PDT in moderate to severe acne and to compare outcomes with those of laser-assisted daylight photodynamic therapy. METHODS: Patients were randomly assigned to either a DL-PDT group (D group) or a fractional laser-assisted DL-PDT group (F group). The outcomes were assessed by measuring acne lesion counts and severity grade at 4, 8, 12, and 16 weeks after therapy commenced. RESULTS: Twenty-eight subjects completed the study. Compared with baseline, the mean inflammatory lesion counts significantly decreased by 36.0% in the D group and 51.8% in the F group at 8 weeks (P<.001). The mean acne severity grades in both groups significantly decreased starting at 4 weeks (P=.012), and the beneficial effects lasted 16 weeks. CONCLUSION: DL-PDT with MAL shows clinically good responses to inflammatory lesions and is well tolerated in patients with moderate to severe acne.

The efficacy and safety of subcision using CO2 gas combined with fractional laser for acne scars: Clinical and microscopic evaluation.

BACKGROUND: Various modalities have been used to treat acne scars. CO2 fractional laser is an effective and commonly used treatment. CO2 gas injection into the dermis by needle with high pressure can cause fibrotic collagen breakage, producing the effects of subcision. CO2 also stimulates collagen synthesis by increasing neovascularization and releasing oxygen. OBJECTIVE: This study evaluated the efficacy and the safety of the combined treatment with CO2 gas subcision and CO2 fractional laser for acne scars. METHODS AND MATERIALS: Fourteen patients with acne scars were treated with three sessions of CO2 gas subcision at 2-week intervals and two sessions of fractional laser at 4-week interval. The clinical improvement was assessed using a 4-point scale. For histologic analysis, punch biopsy was performed before and after treatment in 10 patients. RESULTS: All patients experienced clinical improvements. Excellent, marked, moderate, and mild response was achieved in 1 (7%), 8 (57%), 4 (29%), and 1 patient (7%), respectively. Histologic evaluation of the biopsy specimens showed increased dermal collagen with dermal thickening and elastic fiber straightening in the reticular dermis after the treatment. CONCLUSION: The combination therapy with CO2 gas subcision and fractional laser was satisfactory and safe for treating acne scars. Abbreviation and acronym: CO2: Carbon dioxide GAS: Global assessment scale H&E: hematoxylin and eosin; SD: standard deviation.