scholarly journals Evaluation of the Inhibitory Effects of (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (DiNap), a Natural Product Analog, on the Replication of Type 2 PRRSV In Vitro and In Vivo

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 887
Author(s):  
Amina Khatun ◽  
Sun Park ◽  
Nadeem Shabir ◽  
Salik Nazki ◽  
A-Rum Kang ◽  
...  
Keyword(s):  
Natural Product ◽  
Control Measure ◽  
Virus Transmission ◽  
Pharmacological Intervention ◽  
Respiratory Syndrome Virus ◽  
Dependent Manner ◽  
Swine Industry

DiNap [(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one], an analog of a natural product (the chalcone flavokawain), was synthesized and characterized in this study. Porcine reproductive and respiratory syndrome virus (PRRSV) is the most challenging threat to the swine industry worldwide. Currently, commercially available vaccines are ineffective for controlling porcine reproductive and respiratory syndrome (PRRS) in pigs. Therefore, a pharmacological intervention may represent an alternative control measure for PRRSV infection. Hence, the present study evaluated the effects of DiNap on the replication of VR2332 (a prototype strain of type 2 PRRSV). Initially, in vitro antiviral assays against VR2332 were performed in MARC-145 cells and porcine alveolar macrophages (PAMs). Following this, a pilot study was conducted in a pig model to demonstrate the effects of DiNap following VR2332 infection. DiNap inhibited VR2332 replication in both cell lines in a dose-dependent manner, and viral growth was completely suppressed at concentrations ≥0.06 mM, without significant cytotoxicity. Consistent with these findings, in the pig study, DiNap also reduced viral loads in the serum and lungs and enhanced the weight gain of pigs following VR2332 infection, as indicated by comparison of the DiNap-treated groups to the untreated control (NC) group. In addition, DiNap-treated pigs had fewer gross and microscopic lesions in their lungs than NC pigs. Notably, virus transmission was also delayed by approximately 1 week in uninfected contact pigs within the same group after treatment with DiNap. Taken together, these results suggest that DiNap has potential anti-PRRSV activity and could be useful as a prophylactic or post-exposure treatment drug to control PRRSV infection in pigs.

scholarly journals Platycodin D Suppresses Type 2 Porcine Reproductive and Respiratory Syndrome Virus In Primary and Established Cell Lines

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 657 ◽  
Author(s):  
Mingxin Zhang ◽  
Taofeng Du ◽  
Feixiang Long ◽  
Xia Yang ◽  
Yankuo Sun ◽  
...  
Keyword(s):  
Virus Production ◽  
In Vivo Studies ◽  
Progeny Virus ◽  
Respiratory Syndrome Virus ◽  
Dependent Manner ◽  
Triterpenoid Saponins ◽  
Platycodin D

Porcine reproductive and respiratory syndrome virus (PRRSV) is a continuous threat to the pork industry as it continues to cause significant economic loss worldwide. Currently, vaccination strategies provide very limited protection against PRRSV transmission. Consequently, there is an urgent need to develop new antiviral strategies. Platycodin D (PD) is one of the major bioactive triterpenoid saponins derived from Platycodon grandiflorum, a traditional Chinese medicine used as an expectorant for pulmonary diseases and a remedy for respiratory disorders. Here, we demonstrate that PD exhibits potent activity against PRRSV infection in Marc-145 cells and primary porcine alveolar macrophages. PD exhibited broad-spectrum inhibitory activities in vitro against high pathogenic type 2 PRRSV GD-HD strain and GD-XH strain as well as classical CH-1a and VR2332 strains. PD at concentrations ranging 1–4 μM significantly inhibited PRRSV RNA synthesis, viral protein expression and progeny virus production in a dose-dependent manner. EC50 values of PD against four tested PRRSV strains infection in Marc-145 cells ranged from 0.74 to 1.76 μM. Mechanistically, PD inhibited PRRSV replication by directly interacting with virions therefore affecting multiple stages of the virus life cycle, including viral entry and progeny virus release. In addition, PD decreased PRRSV- and LPS-induced cytokine (IFN-α, IFN-β, IL-1α, IL-6, IL-8 and TNF-α) production in PAMs. Altogether, our findings suggested that PD is a potent inhibitor of PPRSV infection in vitro. However, further in vivo studies are necessary to confirm PD as a potential novel and effective PPRSV inhibitor in swine.

scholarly journals Meteorin-like (Metrnl) adipomyokine improves glucose tolerance in type 2 diabetes via AMPK pathway

2018 ◽  
Author(s):  
Jung Ok Lee ◽  
Hye Jeong Lee ◽  
Yong Woo Lee ◽  
Jeong Ah Han ◽  
Min Ju Kang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Beneficial Effects ◽  
Ampk Pathway

AbstractMeteorin-like (metrnl) is a recently identified adipomyokine that has beneficial effects on glucose metabolism. However, its underlying mechanism of action is not completely understood. In this study, we have shown that a level of metrnl increase in vitro under electrical-pulse-stimulation (EPS) and in vivo in exercise mice, suggesting that metrnl is an exercise-induced myokine. In addition, metrnl increases glucose uptake through the calcium-dependent AMPK pathway. Metrnl also increases the phosphorylation of HDAC5, a transcriptional repressor of GLUT4, in an AMPK-dependent manner. Phosphorylated HDAC5 interacts with 14-3-3 proteins and sequesters them in the cytoplasm, resulting in the activation of GLUT4 transcription. The intraperitoneal injection of recombinant metrnl improves glucose tolerance in mice with high fat-induced obesity or type 2 diabetes (db/db), but this is not seen in AMPK β1β2 muscle-specific null mice (AMPK β1β2 MKO). In conclusion, we have demonstrated that metrnl induces beneficial effects on glucose metabolism via AMPK and is a promising therapeutic candidate for glucose-related diseases such as type 2 diabetes.

scholarly journals Ginsenoside Rg1 Suppresses Type 2 PRRSV Infection via NF-κB Signaling Pathway In Vitro, and Provides Partial Protection against HP-PRRSV in Piglet

Viruses ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1045 ◽  
Author(s):  
Yu ◽  
Yi ◽  
Ma ◽  
Wei ◽  
Cai ◽  
...  
Keyword(s):  
Respiratory Syndrome Virus ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Ginsenoside Rg1 ◽  
Virus Attachment ◽  
Current Vaccine ◽  
Anti Oxidant ◽  
Signaling Activation

Porcine reproductive and respiratory syndrome virus (PRRSV) is a huge threat to the modern pig industry, and current vaccine prevention strategies could not provide full protection against it. Therefore, exploring new anti-PRRSV strategies is urgently needed. Ginsenoside Rg1, derived from ginseng and notoginseng, is shown to exert anti-inflammatory, neuronal apoptosis-suppressing and anti-oxidant effects. Here we demonstrate Rg1-inhibited PRRSV infection both in Marc-145 cells and porcine alveolar macrophages (PAMs) in a dose-dependent manner. Rg1 treatment affected multiple steps of the PRRSV lifecycle, including virus attachment, replication and release at concentrations of 10 or 50 µM. Meanwhile, Rg1 exhibited broad inhibitory activities against Type 2 PRRSV, including highly pathogenic PRRSV (HP-PRRSV) XH-GD and JXA1, NADC-30-like strain HNLY and classical strain VR2332. Mechanistically, Rg1 reduced mRNA levels of the pro-inflammatory cytokines, including IL-1β, IL-8, IL-6 and TNF-α, and decreased NF-κB signaling activation triggered by PRRSV infection. Furthermore, 4-week old piglets intramuscularly treated with Rg1 after being challenged with the HP-PRRSV JXA1 strain display moderate lung injury, decreased viral load in serum and tissues, and an improved survival rate. Collectively, our study provides research basis and supportive clinical data for using Ginsenoside Rg1 in PRRSV therapies in swine.

scholarly journals (−)-Epigallocatechin-3-Gallate Inhibits the Life Cycle of Pseudorabies Virus In Vitro and Protects Mice Against Fatal Infection

2021 ◽  
Vol 10 ◽  
Author(s):  
Changchao Huan ◽  
Weiyin Xu ◽  
Tingting Guo ◽  
Haochun Pan ◽  
Hengyue Zou ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Pseudorabies Virus ◽  
Antiviral Agent ◽  
Economic Cost ◽  
Dependent Manner ◽  
Swine Industry ◽  
Effective Prevention ◽  
Dose Dependent

A newly emerged pseudorabies virus (PRV) variant with enhanced pathogenicity has been identified in many PRV-vaccinated swine in China since 2011. The PRV variant has caused great economic cost to the swine industry, and measures for the effective prevention and treatment of this PRV variant are still lacking. (–)-Epigallocatechin-3-gallate (EGCG) exhibits antiviral activity against diverse viruses and thus in this study, we investigated the anti-PRV activity of EGCG in vitro and in vivo. EGCG significantly inhibited infectivity of PRV Ra and PRV XJ5 strains in PK15 B6 cells and Vero cells. The anti-PRV activity of EGCG was dose-dependent, and 50 μM EGCG could completely block viral infection at different multiplicities of infection. We next revealed that EGCG blocked PRV adsorption and entry to PK15 B6 cells in a dose-dependent manner, but inhibition of PRV entry by EGCG was not as efficient as its inhibition of PRV adsorption. PRV replication was suppressed in PK15 B6 cells treated with EGCG post-infection. However, EGCG did not affect PRV assembly and could promote PRV release. Furthermore, 40 mg/kg EGCG provided 100% protection in BALB/c mice challenged with PRV XJ5, when EGCG was administrated both pre- and post-challenge. These results revealed that EGCG exhibits antiviral activity against PRV mainly by inhibiting virus adsorption, entry and replication in vitro. Meanwhile, EGCG increased the survival of mice challenged with PRV. Therefore, EGCG might be a potential antiviral agent against PRV infection.

Abstract 110: Reduced Expression, Knockout, and Pharmacological Intervention of Arhgef11 -RhoA Pathway Significantly Attenuates Renal Injury and Blood Pressure

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ashley C Johnson ◽  
David S Pasco ◽  
Michael R Garrett
Keyword(s):  
Genetic Analysis ◽  
Natural Product ◽  
Renal Injury ◽  
Substantial Reduction ◽  
Kidney Injury ◽  
Pharmacological Intervention ◽  
Nucleotide Exchange ◽  
Low Salt

Through genetic analysis of the Dahl salt-sensitive (SS) rat, a model of hypertension and chronic kidney disease (CKD), Arhgef11, a Rho guanine nucleotide exchange factor was implicated in kidney injury. Arhgef11, via exchange of GDP for GTP, plays a role in the activation of RhoA signaling cascades through a number of cell stimuli that impact cytoskeletal structure and influence cell-cell contacts and promotes cell transformation. Previously, we demonstrated that reduced Arhgef11 expression/protein function in an SS- Arhgef11 SHR -minimal congenic strain resulted in significantly decreased proteinuria, fibrosis, and improved renal hemodynamics compared to SS-WT, without impacting BP. More recently, an SS-Arhgef11 -/- knockout rat model was studied. On low-salt (0.3% NaCl), SS-Arhgef11 -/- animals demonstrated reduced proteinuria and renal injury, with no impact on BP versus SS-WT. In contrast, SS-Arhgef11 -/- animals on an elevated-salt diet (2% NaCl) demonstrated a significant (p<0.001) attenuation of proteinuria (41±7.9 mg/24 hrs.), along with a substantial reduction in BP (124±2.6 mm Hg) compared to SS-WT (119±15.3 mg/24 hrs. and 151±5.9 mm Hg). This data suggests that reduced expression/loss of Arhgef11 (on low-salt) similarly leads to renoprotection, whereas the loss of Arhgef11 (vs reduced expression) leads to blunting of salt-induced elevations in BP vs SS-WT. These animal studies, in combination with in vitro work, suggest that inhibition of Arhgef11-RhoA could be an effective therapeutic for CKD. Using an in vitro cell screen, several hundred natural product compounds were tested for ability to inhibit Arhgef11/RhoA activity and identified 3 compounds. A pilot study done using one compound (sufficient for a one-week study) was very encouraging as animals treated with XTL-019-G7 (20mg/kg/day) exhibited an ~25% reduction in proteinuria compared to vehicle (VEH) treated animals (70±8.5 versus 95±9.6 mg/24hours, p=0.07), demonstrating that in vivo testing is feasible and that the compound warrants further testing. In summary, genetic analysis of a model of CKD identified a gene/pathway involved in kidney injury that served as a target to screen natural product derived small molecules, and may ultimately lead to a new treatment for CKD.

scholarly journals Bariatric surgery reveals a gut-restricted TGR5 agonist that exhibits anti-diabetic effects

2020 ◽  
Author(s):  
Snehal N. Chaudhari ◽  
David A. Harris ◽  
Hassan Aliakbarian ◽  
Matthew T. Henke ◽  
Renuka Subramaniam ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Bile Acids ◽  
Dependent Manner ◽  
Gi Tract ◽  
Incretin Hormone ◽  
Insulin Resistant ◽  
Target Effects

AbstractBariatric surgery, the most effective treatment for obesity and type 2 diabetes, is consistently associated with increased levels of the incretin hormone GLP-1 and changes in overall levels of circulating bile acids. The levels of individual bile acids in the GI tract following surgery, however, have remained largely unstudied. Using UPLC-MS-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a TGR5 agonist that induces GLP-1 secretion in vitro and in vivo and that CA7S administration increases glucose tolerance in insulin-resistant mice in a GLP-1 receptor-dependent manner. CA7S remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into circulation. By studying changes in individual metabolites following surgery, this study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.

scholarly journals Magnolia officinalisExtract Contains Potent Inhibitors against PTP1B and Attenuates Hyperglycemia in db/db Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jing Sun ◽  
Yongsen Wang ◽  
Xueqi Fu ◽  
Yingli Chen ◽  
Deli Wang ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
C2c12 Myotubes ◽  
Dependent Manner ◽  
Inhibitory Potential ◽  
Magnolia Officinalis ◽  
Kinetics Of ◽  
Dose Dependent

Protein tyrosine phosphatase 1B (PTP1B) is an established therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. The aim of this study was to investigate the inhibitory activity ofMagnolia officinalisextract (ME) on PTP1B and its anti-T2DM effects. Inhibition assays and inhibition kinetics of ME were performedin vitro. 3T3-L1 adipocytes and C2C12 myotubes were stimulated with ME to explore its bioavailability in cell level. Thein vivostudies were performed on db/db mice to probe its anti-T2DM effects. In the present study, ME inhibited PTP1B in a reversible competitive manner and displayed good selectivity against PTPsin vitro. Furthermore, ME enhanced tyrosine phosphorylation levels of cellular proteins, especially the insulin-induced tyrosine phosphorylations of insulin receptorβ-subunit (IRβ) and ERK1/2 in a dose-dependent manner in stimulated 3T3-L1 adipocytes and C2C12 myotubes. Meanwhile, ME enhanced insulin-stimulated GLUT4 translocation. More importantly, there was a significant decrease in fasting plasma glucose level of db/db diabetic mice treated orally with 0.5 g/kg ME for 4 weeks. These findings indicated that improvement of insulin sensitivity and hypoglycemic effects of ME may be attributed to the inhibition of PTP1B. Thereby, we pioneered the inhibitory potential of ME targeted on PTP1B as anti-T2DM drug discovery.

scholarly journals Application of the Phage Lysin Ply5218 in the Treatment of Streptococcus suis Infection in Piglets

Viruses ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 715 ◽  
Author(s):  
Zhaofei Wang ◽  
Jingjiao Ma ◽  
Jian Wang ◽  
Denghui Yang ◽  
Licheng Kong ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Streptococcus Suis ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Dependent Manner ◽  
Swine Industry ◽  
A Cell ◽  
Triple Treatment

Streptococcus suis (S. suis) is a gram-positive bacterium and zoonotic pathogen. Currently it poses a serious problem in the swine industry due to the emergence of antibiotic-resistant bacteria. Thus, novel antimicrobials against S. suis infections are urgently needed. In the previous study, a cell wall hydrolase or lysin derived from Streptococcus prophage phi5218, termed Ply5218, was identified. This lysin showed strong bacteriolytic activity against S. suis. In the current study, the in vitro data showed that after incubation with pig serum, the bacteriolytic efficacy of Ply5218 declined in a time-dependent manner. The in vivo assays indicated that a Ply5218 triple treatment (6, 24, and 48 h post infection) was effective against various serotypes of S. suis in a murine infection model. This regimen also alleviated streptococcal-induced clinical symptoms in piglets and significantly reduced the bacterial burden and levels of interleukin 6, a proinflammatory cytokine. This study indicates that Ply5218 shows strong antibacterial activity in pigs and has the potential to be used as a treatment for infectious diseases caused by S. suis.

scholarly journals Replacement of Porcine CD163 Scavenger Receptor Cysteine-Rich Domain 5 with a CD163-Like Homolog Confers Resistance of Pigs to Genotype 1 but Not Genotype 2 Porcine Reproductive and Respiratory Syndrome Virus

2016 ◽  
Vol 91 (2) ◽  
Author(s):  
Kevin D. Wells ◽  
Rachel Bardot ◽  
Kristin M. Whitworth ◽  
Benjamin R. Trible ◽  
Ying Fang ◽  
...  
Keyword(s):  
Scavenger Receptor ◽  
Viral Disease ◽  
Respiratory Syndrome Virus ◽  
Swine Industry ◽  
Srcr Domain ◽  
Rich Domain ◽  
Genotype 2

ABSTRACT CD163 knockout (KO) pigs are resistant to infection with genotype 2 (type 2) porcine reproductive and respiratory syndrome virus (PRRSV). Furthermore, the substitution of CD163 scavenger receptor cysteine-rich (SRCR) domain 5 with a homolog of human CD163-like (hCD163L1) SRCR 8 domain confers resistance of transfected HEK cells to type 1 PRRSV. As a means to understand the role of domain 5 in PRRSV infection with both type 1 and type 2 viruses, pigs were genetically modified (GM) to possess one of the following genotypes: complete knockout (KO) of CD163, deletions within SRCR domain 5, or replacement (domain swap) of SRCR domain 5 with a synthesized exon encoding a homolog of hCD163L1 SRCR domain 8. Immunophenotyping of porcine alveolar macrophages (PAMs) showed that pigs with the KO or SRCR domain 5 deletion did not express CD163. When placed in culture, PAMs from pigs with the CD163 KO phenotype were completely resistant to a panel consisting of six type 1 and nine type 2 isolates. PAMs from pigs that possessed the hCD163L1 domain 8 homolog expressed CD163 and supported the replication of all type 2 isolates, but no type 1 viruses. Infection of CD163-modified pigs with representative type 1 and type 2 viruses confirmed the in vitro results. The results confirm that CD163 is the likely receptor for all PRRS viruses. Even though type 1 and type 2 viruses are considered phenotypically similar at several levels, there is a distinct difference between the viral genotypes in the recognition of CD163. IMPORTANCE Genetic modification of the CD163 gene creates the opportunity to develop production animals that are resistant to PRRS, the costliest viral disease to ever face the swine industry. The results create further opportunities to develop refinements in the modification of CD163 with the goal of making pigs refractory to infection while retaining important CD163 functions.

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