scholarly journals Duple extinguishment of COVID-19: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

2020 ◽  
Author(s):  
Zhesheng He ◽  
Fei Ye ◽  
Zhongying Du ◽  
Chunyu Zhang ◽  
Wencong Zhao ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Gold Cluster ◽  
Bronchial Epithelial Cell ◽  
Gold Compound ◽  
Inflammatory Injury ◽  
Main Protease ◽  
Nfκb Pathway ◽  
Direct Suppression

AbstractThe virus replication and lung inflammation are basic targets for COVID-19 treatment. To effectively treat COVID-19, the best chemical drug should combine inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokine expression together. Our SARS-CoV-2 main protease (Mpro) crystal structure studies revealed Au(I), derived from auranofin (AF) or gold cluster (GA), could specifically bind thiolate of Cys145 of SARS-CoV-2 Mpro. GA or AF could well inhibit Mpro activity and significantly decrease SARS-CoV-2 replication in cell. Cell studies showed that either AF or GA could down-regulate NFκB pathway, therefore significantly inhibit inflammatory cytokine level of IL-6, IL-1β, TNF-α in macrophage and bronchial epithelial cell, respectively. The lung viral load in GA treated COVID-19 mice (15mg/kg.bw) is significantly lower than that in normal saline (NS, 0.9% NaCl) treated COVID-19 mice, and pathological studies revealed GA treatment (score ~1.8) significantly reduced lung inflammatory injury compared with NS treated COVID-19 mice (score ~3). After normal mice were treated by GA (15mg/kg), the Au ingredient well distributed into lungs and there are no pathological changes in main organs when compared with control mice. The toxicity results revealed GA is more safety than auranofin for cell/mice/rat. The rat pharmacokinetics studies show GA is with high bioavailability (> 90%) in vivo.One Sentence SummarySingle gold compound not only significantly inhibits SARS-CoV-2 replication in lung and but also directly suppress lung inflammatory injury in COVID-19 mice, it is with great potential to effectively treat COVID-19.

In vivo and in vitro effects of fluoroquinolones on lipopolysaccharide-induced pro-inflammatory cytokine production

2009 ◽  
Vol 15 (3) ◽  
pp. 168-173 ◽  
Author(s):  
Hiromi Ogino ◽  
Miho Fujii ◽  
Mariko Ono ◽  
Kayoko Maezawa ◽  
Junko Kizu ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Cytokine Production ◽  
In Vitro Effects

scholarly journals An In-Silico Study on Selected Organosulfur Compounds as Potential Drugs for SARS-CoV-2 Infection via Binding Multiple Drug Targets

2020 ◽  
Author(s):  
Liya Thurakkal ◽  
Satyam Singh ◽  
Sushabhan Sadhukhan ◽  
Mintu Porel
Keyword(s):  
Drug Targets ◽  
Target Prediction ◽  
Multiple Drug ◽  
Organosulfur Compounds ◽  
Potential Candidate ◽  
Health Crisis ◽  
Drug Molecules ◽  
Main Protease

The emerging paradigm shift from ‘one molecule, one target, for one disease’ towards ‘multi-targeted small molecules’ has paved an ingenious pathway in drug discovery in recent years. This idea has been extracted for the investigation of competent drug molecules for the unprecedented COVID-19 pandemic which became the greatest global health crisis now. Perceiving the importance of organosulfur compounds against SARS-CoV-2 from the drugs under clinical trials, a class of organosulfur compounds effective against SARS-CoV were selected and studied the interaction with multiple proteins of the SARS-CoV-2. One compound displayed inhibition against five proteins (both structural and non-structural) of the virus namely, main protease, papain-like protease, spike protein, helicase and RNA dependent RNA polymerase. Consequently, this compound emanates as a potential candidate for treating the virulent disease. The pharmacokinetics, ADMET properties and target prediction studies carried out in this work further inflamed the versatility of the compound and urge to execute <i>in-vitro</i> and <i>in-vivo</i> analysis on SARS-CoV-2 in the future.<br>

Abstract 3: Apolipoprotein A-I Inhibits Streptococcal Cell Wall-Induced Arthritis in the Rat in an ABCA1-dependent Manner

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Ben J Wu ◽  
Kwok L Ong ◽  
Sudichhya Shrestha ◽  
Kang Chen ◽  
Philip J Barter ◽  
...  
Keyword(s):  
Cell Wall ◽  
Inflammatory Cytokine ◽  
Density Lipoprotein ◽  
Joint Inflammation ◽  
Chronic Inflammatory Disease ◽  
Dependent Manner ◽  
Tlr2 Expression ◽  
Streptococcal Cell Wall

Introduction. Arthritis is a chronic inflammatory disease characterized by joint inflammation and destruction, reduced high-density lipoprotein (HDL) levels, and increased cardiovascular risk. Objective To determine if apolipoprotein (apo) A-I, the main HDL apolipoprotein, prevents joint inflammation in arthritis. Methods and Results In vivo: Arthritis was induced in female Lewis rats with a single 15 mg/kg intraperitoneal streptococcal cell wall peptidoglycan-polysaccharide (PG-PS) injection and quantified as a combined forepaw and hindpaw inflammation score. Arthritis progressed from an initial, acute phase of joint inflammation during the first 4 days post-PG-PS administration to remission by day 8, followed by chronic joint inflammation up to sacrifice at day 21. Two intravenous infusions of lipid-free apoA-I (8 mg/kg) 24 h pre- and 24 h post-PG-PS injection reduced the acute and chronic joint inflammation by 63±9% at day 3 and by 61±8% at day 21. Infusion of apoA-I at days 7, 9 and 11 post-PG-PS injection reduced the chronic response by 43±11% at day 21. ApoA-I infusions at 24 h prior to and at days 1, 7, 9, 11 post-PG-PS injection reduced joint inflammation by 61±5% at day 3 and by 90±5% at day 21 (p<0.05 for all vs saline infusion). These beneficial effects of apoA-I were accompanied by a reduced inflammatory white blood cell count, reduced pro-inflammatory cytokine levels in synovial fluid, and reduced macrophage accumulation, toll-like receptor 2 (TLR2) and inflammatory cytokine expression in synovial tissue. In vitro: Human monocyte-derived macrophages (HMDMs) were pre-incubated with lipid-free apoA-I, then stimulated with PG-PS (20 μg/mL). Pre-incubation with apoA-I inhibited PG-PS-induced TLR2 and MyD88, a TLR2 adapter protein, expression. Nuclear factor-κB activation and pro-inflammatory cytokine production were also attenuated. These anti-inflammatory effects of apoA-I were abolished in HMDMs transfected with ATP-binding cassette transporter 1 (ABCA1) siRNA. Conclusions These findings establish that apoA-I attenuates PG-PS induced arthritis in the rat. These effects may involve ABCA-1 and inhibition of TLR2 expression and activation.

Interleukin-27 Inhibits Epithelial-Mesenchymal Transition in Ovalbumin-Induced Mice Bronchial Epithelial Cells

2021 ◽  
Vol 11 (6) ◽  
pp. 1129-1137
Author(s):  
Yuanyuan Liu ◽  
Chao He ◽  
Xin Li ◽  
Zewen Zhang ◽  
Ju Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Airway Remodeling ◽  
Bronchial Epithelial Cell ◽  
Phenotypic Marker ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Stat3 Phosphorylation

The epithelial-mesenchymal transition (EMT) of bronchial epithelial cells is a critical mechanism involved in transforming growth factor beta 1 (TGF-β1) induced asthma airway remodeling. Previous study has shown that interleukin 27 (IL-27) attenuates EMT in alveolar epithelial cells, but its effects on the BEAS-2B human bronchial epithelial cell line EMT remain unknown. Herein, we explored the effects of IL-27 on BEAS-2B EMT in vivo and in vitro. In the in vivo experiments, we found that IL-27 nose-drip therapy alleviated airway remodeling, increased the epithelial phenotypic marker epithelial-cadherin (E-cadherin), and decreased the mesenchymal phenotypic marker alpha-smooth muscle actin (α-SMA) compared with the asthmatic control group. We also found that IL-27 suppressed the signal transducer and activator of transcription (STAT3) in the lung tissue of asthmatic mice. in vitro, TGF-β1-induced EMT changes, including downregulation of E-cadherin and upregulation of α-SMA, were suppressed by IL-27 treatment. Additionally, STAT3 phosphorylation was activated by TGF-β1, whereas IL-27 inhibited the activation of TGF-β1 induced STAT3 phosphorylation. Our findings indicated that IL-27 could inhibit airway remodeling by attenuating bronchial epithelial cell EMT in vivo and in vitro. Therefore, IL-27 may be a beneficial therapeutic option targeting asthmatic airway remodeling.

scholarly journals HIF-1α contributes to Ang II-induced inflammatory cytokine production in podocytes

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hao Huang ◽  
Yanqin Fan ◽  
Zhao Gao ◽  
Wei Wang ◽  
Ning Shao ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Inflammatory Factors ◽  
Ang Ii ◽  
Angiotensin System ◽  
Inflammatory Injury ◽  
Tnf Α

Abstract Background Studies have indicated that changed expression of hypoxia-inducible factor-1α (HIF-1α) in epithelial cells from the kidney could affect the renal function in chronic kidney disease (CKD). As Angiotensin II (Ang II) is a critical active effector in the renin-angiotensin system (RAS) and was proved to be closely related to the inflammatory injury. Meanwhile, researchers found that Ang II could alter the expression of HIF-1α in the kidney. However, whether HIF-1α is involved in mediating Ang II-induced inflammatory injury in podocytes is not clear. Methods Ang II perfusion animal model were established to assess the potential role of HIF-1α in renal injury in vivo. Ang II stimulated podocytes to observe the corresponding between HIF-1α and inflammatory factors in vitro. Results The expression of inflammatory cytokines such as MCP-1 and TNF-α was increased in the glomeruli from rats treated with Ang II infusion compared with control rats. Increased HIF-1α expression in the glomeruli was also observed in Ang II-infused rats. In vitro, Ang II upregulated the expression of HIF-1α in podocytes. Furthermore, knockdown of HIF-1α by siRNA decreased the expression of MCP-1 and TNF-α. Moreover, HIF-1α siRNA significantly diminished the Ang II-induced overexpression of HIF-1α. Conclusion Collectively, our results suggest that HIF-1α participates in the inflammatory response process caused by Ang II and that downregulation of HIF-1α may be able to partially protect or reverse inflammatory injury in podocytes.

scholarly journals A Potential Peptide From Soy Cheese Produced Using Lactobacillus delbrueckii WS4 for Effective Inhibition of SARS-CoV-2 Main Protease and S1 Glycoprotein

2020 ◽  
Vol 7 ◽  
Author(s):  
Rounak Chourasia ◽  
Srichandan Padhi ◽  
Loreni Chiring Phukon ◽  
Md Minhajul Abedin ◽  
Sudhir P. Singh ◽  
...  
Keyword(s):  
Drug Targets ◽  
Docking Studies ◽  
Lactobacillus Delbrueckii ◽  
Amino Acid Residues ◽  
Main Protease ◽  
Effective Inhibition ◽  
Cheese Peptides ◽  
Potential Inhibitors

The COVID-19 pandemic caused by novel SARS-CoV-2 has resulted in an unprecedented loss of lives and economy around the world. In this study, search for potential inhibitors against two of the best characterized SARS-CoV-2 drug targets: S1 glycoprotein receptor-binding domain (RBD) and main protease (3CLPro), was carried out using the soy cheese peptides. A total of 1,420 peptides identified from the cheese peptidome produced using Lactobacillus delbrueckii WS4 were screened for antiviral activity by employing the web tools, AVPpred, and meta-iAVP. Molecular docking studies of the selected peptides revealed one potential peptide “KFVPKQPNMIL” that demonstrated strong affinity toward significant amino acid residues responsible for the host cell entry (RBD) and multiplication (3CLpro) of SARS-CoV-2. The peptide was also assessed for its ability to interact with the critical residues of S1 RBD and 3CLpro of other β-coronaviruses. High binding affinity was observed toward critical amino acids of both the targeted proteins in SARS-CoV, MERS-CoV, and HCoV-HKU1. The binding energy of KFVPKQPNMIL against RBD and 3CLpro of the four viruses ranged from −8.45 to −26.8 kcal/mol and −15.22 to −22.85 kcal/mol, respectively. The findings conclude that cheese, produced by using Lb. delbrueckii WS4, could be explored as a prophylactic food for SARS-CoV-2 and related viruses. In addition, the multi-target inhibitor peptide, which effectively inhibited both the viral proteins, could further be used as a terminus a quo for the in vitro and in vivo function against SARS-CoV-2.

scholarly journals Rationally synthesized coumarin based pyrazolines ameliorate carrageenan induced inflammation through COX-2/pro-inflammatory cytokine inhibition

MedChemComm ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 421-430 ◽  
Author(s):  
Priyanka Chandel ◽  
Anoop Kumar ◽  
Nishu Singla ◽  
Anshul Kumar ◽  
Gagandeep Singh ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Inhibition ◽  
Cox 2 ◽  
Anti Inflammatory

In the present work, coumarin based pyrazolines (7a–g) have been synthesized and investigated for their in vitro and in vivo anti-inflammatory potential.

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