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1.
Antioxidants (Basel) ; 13(1)2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38247540

RESUMO

The common human coronavirus (HCoV) exhibits mild disease with upper respiratory infection and common cold symptoms. HCoV-OC43, one of the HCoVs, can be used to screen drug candidates against SARS-CoV-2. We determined the antiviral effects of FDA/EMA-approved drug anastrozole (AZ) on two human coronaviruses, HCoV-OC43 and HCoV-229E, using MRC-5 cells in vitro. The AZ exhibited antiviral effects against HCoV-OC43 and HCoV-229E infection. Subsequent studies focused on HCoV-OC43, which is related to the SARS-CoV-2 family. AZ exhibited anti-viral effects and reduced the secretion of inflammatory cytokines, TNF-α, IL-6, and IL-1ß. It also inhibited NF-κB translocation to effectively suppress the inflammatory response. AZ reduced intracellular calcium and reactive oxygen species (ROS) levels, including mitochondrial ROS and Ca2+, induced by the virus. AZ inhibited the expression of NLRP3 inflammasome components and cleaved IL-1ß, suggesting that it blocks NLRP3 inflammasome activation in HCoV-OC43-infected cells. Moreover, AZ enhanced cell viability and reduced the expression of cleaved gasdermin D (GSDMD), a marker of pyroptosis. Overall, we demonstrated that AZ exhibits antiviral activity against HCoV-OC43 and HCoV-229E. We specifically focused on its efficacy against HCoV-OC43 and showed its potential to reduce inflammation, inhibit NLRP3 inflammasome activation, mitigate mitochondrial dysfunction, and suppress pyroptosis in infected cells.

2.
Phytomedicine ; 125: 155370, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38266440

RESUMO

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.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Taninos Hidrolisáveis , Oenothera biennis , Humanos , Animais , Camundongos , Oenothera biennis/metabolismo , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Ligantes , Camundongos Endogâmicos C57BL , Antineoplásicos/farmacologia , Imunoterapia/métodos , Neoplasias Colorretais/tratamento farmacológico
3.
Antioxidants (Basel) ; 12(12)2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38136250

RESUMO

Immunotherapies, particularly those concerning immune checkpoint inhibitors, have transformed cancer treatment in recent years. Programmed death-ligand 1 (PD-L1) is a key target for immunotherapy that is overexpressed in the cells of colorectal cancer, a widespread malignant cancer that poses a significant healthcare challenge. This study investigated the effects of cosmosiin treatment on colorectal cancer cell lines. Cosmosiin is a naturally occurring flavone glycoside compound that has potential health benefits, including antioxidant and immunomodulatory effects. This study showed that cosmosiin effectively suppresses the expression of PD-L1 and triggers apoptosis, which is facilitated through pathways that are related to reactive oxygen species. These outcomes suggest that cosmosiin could be a promising candidate for an immune checkpoint inhibitor in the treatment of colorectal cancer.

4.
Antioxidants (Basel) ; 12(11)2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-38001788

RESUMO

Herpes simplex virus 1 (HSV-1) is double-stranded DNA virus that belongs to the Orthoherpesviridae family. It causes serious neurological diseases of the central nervous system, such as encephalitis. The current U.S. Food and Drug Administration (FDA)-approved drugs for preventing HSV-1 infection include acyclovir (ACV) and valacyclovir; however, their long-term use causes severe side effects and often results in the emergence of drug-resistant strains. Therefore, it is important to discover new antiviral agents that are safe and effective against HSV-1 infection. Korean chestnut honey (KCH) has various pharmacological activities, such as antioxidant, antibacterial, and anti-inflammation effects; however, antiviral effects against HSV-1 have not yet been reported. Therefore, we determined the antiviral activity and mechanism of action of KCH after HSV-1 infection on the cellular level. KCH inhibited the HSV-1 infection of host cells through binding and virucidal steps. KCH decreased the production of reactive oxygen species (ROS) and calcium (Ca2+) following HSV-1 infection and suppressed the production of inflammatory cytokines by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) activity. Furthermore, we found that KCH inhibited the expression of the nod-like receptor protein 3 (NLRP3) inflammasome during HSV-1 infection. Taken together, the antiviral effects of KCH occur through multiple targets, including the inhibition of viral replication and the ROS-mediated NLRP3 inflammasome pathway. Our findings suggest that KCH has potential for the treatment of HSV-1 infection and related diseases.

5.
Bioorg Chem ; 140: 106824, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37669581

RESUMO

Four new 26-carboxylated ergostane-type sterols (Sarcodonol A-D) were isolated from 70% ethanol extracts of dried fruiting bodies of Sarcodon imbricatus. Their chemical structures were elucidated using 1D- and 2D-nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry, and confirmed by comparison with previously reported data. As far as we know, this is the first instance of isolating a 26-carboxylated ergostane-type sterol from nature. The determined antiviral efficacy of sarcodonol A-D (1-4) against HCoV-OC43 in MRC-5 cells confirmed that sarcodonol D (4) had significant antiviral activity. Notably, sarcodonol D (4) potently blocked virus infection at low-micromolar concentration and showed high SI (IC50 = 2.26 µM; CC50 > 100 µM; SI > 44.2). In addition, this research shows that the antiviral effect of sarcodonol D (4) via reduced apoptosis increased by viral infection is through mitochondrial stress regulation. This suggests that sarcodonol D (4) is a potential candidate for use as an antiviral treatment.


Assuntos
Antivirais , Basidiomycota , Coronavirus Humano OC43 , Esteróis , Antivirais/química , Antivirais/farmacologia , Apoptose , Ácidos Carboxílicos , Carpóforos/química , Esteróis/química , Esteróis/farmacologia , Basidiomycota/química
6.
Front Immunol ; 14: 1157506, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37711616

RESUMO

Influenza is an acute respiratory disorder caused by the influenza virus and is associated with prolonged hospitalization and high mortality rates in older individuals and chronically ill patients. Vaccination is the most effective preventive strategy for ameliorating seasonal influenza. However, the vaccine is not fully effective in cases of antigenic mismatch with the viral strains circulating in the community. The emergence of resistance to antiviral drugs aggravates the situation. Therefore, developing new vaccines and antiviral drugs is essential. Castanea crenata honey (CH) is an extensively cultivated food worldwide and has been used as a nutritional supplement or herbal medicine. However, the potential anti-influenza properties of CH remain unexplored. In this study, the in vitro and in vivo antiviral effects of CH were assessed. CH significantly prevented influenza virus infection in mouse Raw264.7 macrophages. CH pretreatment inhibited the expression of the viral proteins M2, PA, and PB1 and enhanced the secretion of proinflammatory cytokines and type-I interferon (IFN)-related proteins in vitro. CH increased the expression of RIG-1, mitochondrial antiviral signaling (MAVS) protein, and IFN-inducible transmembrane protein, which interferes with virus replication. CH reduced body weight loss by 20.9%, increased survival by 60%, and decreased viral replication and inflammatory response in the lungs of influenza A virus-infected mice. Therefore, CH stimulates an antiviral response in murine macrophages and mice by preventing viral infection through the RIG-1-mediated MAVS pathway. Further investigation is warranted to understand the molecular mechanisms involved in the protective effects of CH on influenza virus infection.


Assuntos
Mel , Vacinas contra Influenza , Influenza Humana , Infecções por Orthomyxoviridae , Animais , Camundongos , Humanos , Imunidade Inata , Antivirais/farmacologia , Antivirais/uso terapêutico
7.
Int J Mol Sci ; 24(18)2023 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-37762216

RESUMO

Photodynamic therapy (PDT) has shown promise in reducing metastatic colorectal cancer (CRC); however, the underlying mechanisms remain unclear. Modulating tumor-infiltrating immune cells by PDT may be achieved, which requires the characterization of immune cell populations in the tumor microenvironment by single-cell RNA sequencing (scRNA-seq). Here, we determined the effect of Chlorin e6 (Ce6)-mediated PDT on tumor-infiltrating T cells using scRNA-seq analysis. We used a humanized programmed death-1/programmed death ligand 1 (PD-1/PD-L1) MC38 cell allograft mouse model, considering its potential as an immunogenic cancer model and in combination with PD-1/PD-L1 immune checkpoint blockade. PDT treatment significantly reduced tumor growth in mice containing hPD-1/PD-L1 MC38 tumors. scRNA-seq analysis revealed that the PDT group had increased levels of CD8+ activated T cells and CD8+ cytotoxic T cells, but decreased levels of exhausted CD8+ T cells. PDT treatment also enhanced the infiltration of CD8+ T cells into tumors and increased the production of key effector molecules, including granzyme B and perforin 1. These findings provide insight into immune-therapeutic modulation for CRC patients and highlight the potential of PDT in overcoming immune evasion and enhancing antitumor immunity.

8.
Acta Pharm Sin B ; 13(1): 174-191, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36815046

RESUMO

The development of drug-resistant influenza and new pathogenic virus strains underscores the need for antiviral therapeutics. Currently, neuraminidase (NA) inhibitors are commonly used antiviral drugs approved by the US Food and Drug Administration (FDA) for the prevention and treatment of influenza. Here, we show that vitisin B (VB) inhibits NA activity and suppresses H1N1 viral replication in MDCK and A549 cells. Reactive oxygen species (ROS), which frequently occur during viral infection, increase virus replication by activating the NF-κB signaling pathway, downmodulating glucose-6-phosphate dehydrogenase (G6PD) expression, and decreasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response activity. VB decreased virus-induced ROS generation by increasing G6PD expression and Nrf2 activity, and inhibiting NF-κB translocation to the nucleus through IKK dephosphorylation. In addition, VB reduced body weight loss, increased survival, decreased viral replication and the inflammatory response in the lungs of influenza A virus (IAV)-infected mice. Taken together, our results indicate that VB is a promising therapeutic candidate against IAV infection, complements existing drug limitations targeting viral NA. It modulated the intracellular ROS by G6PD, Nrf2 antioxidant response pathway, and NF-κB signaling pathway. These results demonstrate the feasibility of a multi-targeting drug strategy, providing new approaches for drug discovery against IAV infection.

9.
Int J Mol Sci ; 24(3)2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36768213

RESUMO

Blocking immune checkpoints, programmed death-1 (PD-1) and its ligand PD-L1, has proven a promising anticancer strategy for enhancing cytotoxic T cell activity. Although we previously demonstrated that ginsenoside Rg3, Rh2, and compound K block the interaction of PD-1 and PD-L1, the antitumor effect through blockade of this interaction by Korean Red Ginseng alone is unknown. Therefore, we determined the effects of Korean Red Ginseng extract (RGE) on the PD-1/PD-L1 interaction and its antitumor effects using a humanized PD-1/PD-L1-expressing colorectal cancer (CRC) mouse model. RGE significantly blocked the interaction between human PD-1 and PD-L1 in a competitive ELISA. The CD8+ T cell-mediated tumor cell killing effect of RGE was evaluated using murine hPD-L1-expressing MC38 cells and tumor-infiltrating hPD-1-expressing CD8+ T cells isolated from hPD-L1 MC38 tumor-bearing hPD-1 mice. RGE also reduced the survival of hPD-L1 MC38 cells in a cell co-culture system using tumor-infiltrating CD8+ T cells as effector cells combined with hPD-L1 MC38 target cells. RGE or Keytruda (positive control) treatment markedly suppressed the growth of hPD-L1 MC38 allograft tumors, increased CD8+ T cell infiltration into tumors, and enhanced the production of Granzyme B. RGE exhibits anticancer effects through the PD-1/PD-L1 blockade, which warrants its further development as an immunotherapy.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Animais , Humanos , Camundongos , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Receptor de Morte Celular Programada 1
10.
Nutrients ; 14(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36235822

RESUMO

Despite the recent development of RNA replication-targeted COVID-19 drugs by global pharmaceutical companies, their prescription in clinical practice is limited by certain factors, including drug interaction, reproductive toxicity, and drug resistance. COVID-19 drugs with multiple targets for the SARS-CoV-2 life cycle may lead to a successful reduction in drug resistance as well as enhanced therapeutic efficacy, and natural products are a potential source of molecules with therapeutic effects against COVID-19. In this study, we investigated the inhibitory efficacy of mulberrofuran G (MG), a component of Morus alba L., also known as mulberry, which has been used as food and traditional medicine, on the binding of the spike S1 receptor-binding domain (RBD) protein to the angiotensin-converting enzyme 2 (ACE2) receptor, which is the initial stage of the SARS-CoV-2 infection. In competitive enzyme-linked immunosorbent assays, MG effectively blocked the spike S1 RBD: ACE2 receptor molecular binding, and investigations using the BLItz system and in silico modeling revealed that MG has high affinity for both proteins. Finally, we confirmed that MG inhibits the entry of SARS-CoV-2 spike pseudotyped virus and a clinical isolate of SARS-CoV-2 into cells, suggesting that MG might be a promising therapeutic candidate for preventing SARS-CoV-2 binding to the cell surface during early infection.


Assuntos
Produtos Biológicos , Tratamento Farmacológico da COVID-19 , Morus , Enzima de Conversão de Angiotensina 2 , Benzofuranos , Humanos , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química , Terpenos
11.
Biomed Pharmacother ; 156: 113780, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36228379

RESUMO

Influenza viruses cause respiratory infections in humans with high morbidity and mortality rates. Neuraminidase inhibitors such as oseltamivir and peramivir are the most commonly used drugs for influenza virus infections. However, the emergence of resistant viruses necessitates the urgent need to develop next-generation anti-influenza drugs. Soybean (Glycine max L. Merr.) is widely cultivated and used as food worldwide. In addition, soybean has long been used as a nutritional supplement and herbal medicine. However, the potential anti-influenza properties of the soybean cultivar "GL 2626/96″ (SG2626) are yet to be investigated. Herein, we determined whether the ethanolic extract of SG2626 (SG2626E) has anti-viral activity through performing SG2626E pre-, co-, and post-treatment assays, using the influenza green fluorescent protein (GFP)-tagged influenza A/PR/8/34 (A/PR/8/34-GFP) virus. SG2626E showed anti-influenza virus activity in pre- and co-treated cells in a dose-dependent manner, but not in post-treated cells. SG2626E imparted a considerable inhibitory effect on influenza A virus (IAV) infection through blocking viral attachment. SG2626E inhibited the activity of viral hemagglutinin, but not viral neuraminidase of the IAV. SG2626E inhibited IAV infection by reducing intracellular calcium levels in infected human lung epithelial A549 cells. Additionally, SG2626E reduced body weight loss, decreased mortality, and increased the survival rate through reducing viral replication in the lungs of IAV-infected mice. Overall, these results suggest that SG2626E inhibits IAV infection and is a potential novel anti-influenza agent.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Influenza Humana , Humanos , Camundongos , Animais , Antivirais/farmacologia , Neuraminidase , Glycine max , Influenza Humana/tratamento farmacológico , Replicação Viral , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
12.
Int J Mol Sci ; 23(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36293371

RESUMO

There has been an immense effort by global pharmaceutical companies to develop anti-COVID-19 drugs, including small molecule-based RNA replication inhibitors via drug repositioning and antibody-based spike protein blockers related to cell entry by SARS-CoV-2. However, several limitations to their clinical use have emerged in addition to a lack of progress in the development of small molecule-based cell entry inhibitors from natural products. In this study, we tested the effectiveness of kuwanon C (KC), which has mainly been researched using in silico docking simulation and can serve as an effective building block for developing anti-COVID-19 drugs, in blocking the spike S1 RBD:ACE2 receptor interaction. KC is a natural product derived from Morus alba L., commonly known as mulberry, which has known antiviral efficacy. Molecular interaction studies using competitive ELISA and the BLItz system revealed that KC targets both the spike S1 RBD and the ACE2 receptor, successfully disrupting their interaction, as supported by the in silico docking simulation. Furthermore, we established a mechanism of action by observing how KC prevents the infection of SARS-CoV-2 spike pseudotyped virus in ACE2/TPRSS2-overexpressing HEK293T cells. Finally, we demonstrated that KC inhibits clinical isolates of SARS-CoV-2 in Vero cells. Future combinations of small molecule-based cell entry inhibitors, such as KC, with the currently prescribed RNA replication inhibitors are anticipated to significantly enhance the efficacy of COVID-19 therapies.


Assuntos
Produtos Biológicos , Tratamento Farmacológico da COVID-19 , Morus , Chlorocebus aethiops , Animais , Humanos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Morus/metabolismo , Células Vero , Células HEK293 , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , Antivirais/farmacologia , Preparações Farmacêuticas , RNA/metabolismo
13.
Cells ; 11(18)2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36139451

RESUMO

Immune checkpoint inhibitors (ICIs) have been shown to be extraordinarily effective in patients with colorectal cancer (CRC). However, the current ICIs still have adverse effects and limited efficacy of ICI monotherapy. We used a natural product to overcome the vulnerability of ICIs and tried a combination therapy with oxaliplatin to enhance the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade anticancer effect. In the present study, we evaluated the T cell-mediated antitumor immunity with Unripe Rubus coreanus Miquel extract (RCE), which exerts anticancer properties via PD-1/PD-L1 blockade, combined with oxaliplatin in a co-culture cell model and allograft tumor humanized PD-1 mice. We found that RCE plus oxaliplatin apparently activates hPD-1 tumor-infiltrating CD8+ T cells, resulting in elevations of released interleukin-2 (IL-2) and granzyme B (GrB), and kills hPD-L1 MC38 CRC cells. RCE plus oxaliplatin considerably reduced tumor growth in humanized PD-1/PD-L1-expressing mouse MC38 CRC allograft. Moreover, RCE plus oxaliplatin remarkably increased the infiltration of CD8+ T cells in tumor tissues, as well as increasingly produced GrB of tumor-infiltrating CD8+ T cells in the tumor microenvironment. Our study delineated combination therapy with RCE as a PD-1/PD-L1 blockade and oxaliplatin to improve the response to immune checkpoint blockade therapy in conjunction with standard chemotherapy regimens in CRC.


Assuntos
Produtos Biológicos , Neoplasias Colorretais , Rubus , Animais , Antígeno B7-H1 , Produtos Biológicos/uso terapêutico , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Granzimas , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Interleucina-2 , Camundongos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Receptor de Morte Celular Programada 1 , Microambiente Tumoral
14.
Antioxidants (Basel) ; 11(9)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36139847

RESUMO

Herpes simplex Type 1 (HSV-1) is a neurotropic virus that infects the peripheral and central nervous system. Usually, after primary infection in epithelial cells, HSV-1 migrates retrograde to the peripheral nervous system (PNS), where it establishes a latent infection. HSV-1 can remain latent in the nervous system, and its reactivation in the brain can rarely cause acute HSV-1 encephalitis, often a life-threatening condition, or asymptomatic reactivations that could lead to neuronal damage and ultimately neurodegenerative disorders. Acyclovir and related nucleoside analogs have been used as therapeutic agents for HSV-1 infection, but resistance to the drug can arise, and the protective effect of HSV-1 on brain cells is limited. Therefore, there is an urgent need for research into safe and effective new antiviral agents that can protect brain cells from the damage that is caused by HSV-1 infection. Vaccinium bracteatum Thunb. (VBT) is widely distributed in Korea and China, and has pharmacological actions such as anti-inflammatory, antioxidant, and antidiabetic activity. Studies on the antiviral effect of VBT on HSV-1 infection have not been reported so far. Therefore, we sought to determine the HSV-1 antiviral effect and molecular mechanism of VBT at the cellular level. We confirmed that VBT repressed the VP16 and IE genes in both Vero and SK-N-SH cells. We also found that the generation of HSV-1 virions was inhibited by VBT treatment. VBT inhibited the activities of the HSV-1-induced endoplasmic reticulum (ER) stressors PERK, ATF4, and CHOP. We confirmed that VBT inhibited the activity of apoptosis factors by regulating the expression of death receptor (DR) after HSV-1 infection. As HSV-1 is closely associated with brain diseases, the study of the antiviral drug effects and mechanism of VBT is meaningful. Further studies using animal models of infection will also be performed to determine the potential of VBT as an antiviral agent.

15.
Biomed Pharmacother ; 153: 113259, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35717782

RESUMO

Recently, attention has focused on the prevention and treatment of respiratory viruses including influenza viruses. We evaluated the antiviral effect of Tilia amurensis honey (TH) against influenza A virus in murine macrophages. Influenza A virus infection was reduced following pretreatment with TH. Pretreatment of murine macrophages with TH increased the production and secretion of type-1 interferon (IFN) and proinflammatory cytokines and increased phosphorylation of the type-1 IFN-related proteins, TANK-binding kinase (TBK), and STAT. Moreover, TH increased the expression of IFN-stimulating genes and increased the expression of IFN-inducible transmembrane (IFITM3), a protein that interferes with virus replication and entry. Taken together, these findings suggest that TH suppresses influenza A virus infection by regulating the innate immune response in macrophages. This supports the development of preventive and therapeutic agents for influenza A virus and enhances the economic value of TH.


Assuntos
Mel , Vírus da Influenza A , Influenza Humana , Interferon Tipo I , Animais , Humanos , Vírus da Influenza A/metabolismo , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Proteínas de Ligação a RNA/metabolismo , Tilia/metabolismo , Replicação Viral
16.
Front Pharmacol ; 12: 764297, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899320

RESUMO

OCD20015-V009 is an herbal mix of water-extracted Ginseng Radix, Poria (Hoelen), Rehmanniae Radix, Adenophorae Radix, Platycodi Radix, Crataegii Fructus, and Astragali Radix. In this study, its in vitro and in vivo antiviral activity and mechanisms against the influenza A virus were evaluated using a GFP-tagged influenza A virus (A/PR/8/34-GFP) to infect murine macrophages. We found that OCD20015-V009 pre-treatment substantially reduced A/PR/8/34-GFP replication. Also, OCD20015-V009 pre-treatment increased the phosphorylation of type-I IFN-related proteins TBK-1 and STAT1 and the secretion of pro-inflammatory cytokines TNF-α and IL-6 by murine macrophages. Moreover, OCD20015-V009 prophylactic administration increased IFN-stimulated genes-related 15, 20, and 56 and IFN-ß mRNA in vitro. Thus, OCD20015-V009 likely modulates murine innate immune response via macrophages. This finding is potentially useful for developing prophylactics or therapeutics against the influenza A virus. Furthermore, pre-treatment with OCD20015-V009 decreased the mortality of the mice exposed to A/PR/8/34-GFP by 20% compared to that in the untreated animals. Thus, OCD20015-V009 stimulates the antiviral response in murine macrophages and mice to viral infections. Additionally, we identified chlorogenic acid and ginsenoside Rd as the antiviral components in OCD20015-V009. Further investigations are needed to elucidate the protective effects of active components of OCD20015-V009 against influenza A viruses.

17.
Antioxidants (Basel) ; 10(10)2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34679772

RESUMO

HSV-1 is a neurotropic virus that replicates lytically during acute infection and establishes latency in peripheral neurons. Currently, the clinically approved compounds for the prevention of HSV-1 infection include acyclovir and penciclovir; however, long-term use of the drug is associated with serious side effects, and drug-resistant strains often appear. Therefore, it is important to find a safe and novel antiviral agent for HSV-1 infection. Quercus acuta Thunb. (Fagaceae) (QA) is widely distributed as an ornamental and dietary plant in Korea, Taiwan, China, and Japan. Thus far, the effects of QA extract and its active ingredients are known to have antioxidant, antibacterial, and anti-inflammatory activity, but studies of possible antiviral effects have not been reported. We studied the antiviral effects and molecular mechanism of QA after HSV-1 infection at the cellular level. We confirmed that QA suppresses ROS expression after HSV-1 infection and also suppresses inflammatory cytokine expression through inhibition of NF-кB activity. In addition, we found that QA increases the phosphorylation activity of IRF3 through induction of TBK1 activity during HSV-1 infection. QA exhibits an antiviral effect, and we confirmed through UPLC-DAD-mass spectrometer (MS)/MS analysis that it contains five main components: catechin, chlorogenic acid, fraxin, isoquercitrin, and taxifolin. Of these, isoquercitrin was confirmed to exhibit an antiviral effect on SK-N-SH cells through ICP27 inhibition. Overall, our results suggest that QA is a novel inhibitor with antiviral effects against HSV-1 infection and may be used specifically to prevent and treat of herpes simplex virus encephalitis infection.

18.
Front Immunol ; 12: 737076, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659228

RESUMO

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.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sanguisorba , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células CHO , Técnicas de Cocultura , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Cricetulus , Humanos , Células Jurkat , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Extratos Vegetais/isolamento & purificação , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Sanguisorba/química , Transdução de Sinais , Carga Tumoral
19.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445310

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the development of vaccines, the emergence of SARS-CoV-2 variants and the absence of effective therapeutics demand the continual investigation of COVID-19. Natural products containing active ingredients may be good therapeutic candidates. Here, we investigated the effectiveness of geraniin, the main ingredient in medical plants Elaeocarpus sylvestris var. ellipticus and Nephelium lappaceum, for treating COVID-19. The SARS-CoV-2 spike protein binds to the human angiotensin-converting enzyme 2 (hACE2) receptor to initiate virus entry into cells; viral entry may be an important target of COVID-19 therapeutics. Geraniin was found to effectively block the binding between the SARS-CoV-2 spike protein and hACE2 receptor in competitive enzyme-linked immunosorbent assay, suggesting that geraniin might inhibit the entry of SARS-CoV-2 into human epithelial cells. Geraniin also demonstrated a high affinity to both proteins despite a relatively lower equilibrium dissociation constant (KD) for the spike protein (0.63 µM) than hACE2 receptor (1.12 µM), according to biolayer interferometry-based analysis. In silico analysis indicated geraniin's interaction with the residues functionally important in the binding between the two proteins. Thus, geraniin is a promising therapeutic agent for COVID-19 by blocking SARS-CoV-2's entry into human cells.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/química , Glucosídeos/química , Humanos , Taninos Hidrolisáveis/química , Ligantes , Simulação de Dinâmica Molecular , Domínios e Motivos de Interação entre Proteínas , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/química
20.
Mediators Inflamm ; 2021: 6687089, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790692

RESUMO

The activation of microglial cells and their subsequent neuroinflammatory reactions are related to various degenerative brain diseases. Therefore, the regulation of microglial cell activation is an important point for the research of therapeutic agents for treating or preventing neurodegenerative disorders. Saussureae Radix (SR) is the root of Saussurea lappa Clarke, and it has been used for a long time as an herbal medicine in East Asia to treat indigestion and inflammation of the digestive system. In previous studies, however, the effect of SR ethanolic extract on microglial cell-mediated neuroinflammation was not fully explained. In this study, we explored the antineuroinflammatory activities and molecular mechanisms of SR in microglial cells stimulated with LPS (lipopolysaccharide). Our results illustrated that SR does not cause cytotoxicity and significantly weakens the production of nitric oxide (NO) and inflammatory cytokines. SR treatment also inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase- (COX-) 2, induced heme oxygenase- (HO-) 1, and activated the nuclear factor erythroid 2-related factor 2 (Nrf-2) pathway. In addition, SR significantly repressed the transcriptional activities of the nuclear factor- (NF-) κB and activator protein- (AP-) 1. Furthermore, SR effectively inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT). Isolation and high-performance liquid chromatography (HPLC) analysis indicated two major sesquiterpenoids (costunolide and dehydrocostuslactone). These compounds significantly inhibited the production of neuroinflammatory mediators and induced HO-1 expression. These findings show that SR could be a potential candidate for the treatment of inflammation-related degenerative brain diseases.


Assuntos
Lipopolissacarídeos , Microglia , Animais , Ciclo-Oxigenase 2/metabolismo , Heme Oxigenase-1/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/metabolismo , NF-kappa B/metabolismo , Doenças Neuroinflamatórias , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
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