Pharmacological Basis for Use of a Novel Compound in Hyperuricemia: Anti-Hyperuricemic and Anti-Inflammatory Effects
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE186871 | GEO | 2021/12/01
REPOSITORIES: GEO
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Project description:Pharmacological Basis for Use of a Novel Compound in Hyperuricemia: Anti-Hyperuricemic and Anti-Inflammatory Effects
| PRJNA776623 | ENA
Project description:The root bark of Zizyphus nummularia (Rhamnaceae) is traditionally used as an anti-inflammatory agent. The current study aimed to explore the anti-inflammatory activity (in vivo) of a crude ethanolic extract (EE) and the pure identified octadecahydro-picene-2,3,14,15-tetranone (IC) in the root bark of Z. nummularia. IC was further subjected to suitable in vitro and in silico studies to find out the mechanistic pharmacology.EE (100 and 200 mg/kg, p.o.) and (IC) (400 and 600 ?g/kg, p.o.) were subjected to in vivo anti-inflammatory assays to evaluate the anti-inflammatory activity and predict the probable mechanism(s) of action. Suitable acute (carrageenan-induced paw edema, arachidonic acid-induced ear edema, xylene-induced ear edema) and chronic (cotton pellet granuloma) models were employed to investigate in vivo the anti-inflammatory activity. Based on in vivo observation, IC was further subjected to in vitro assays to estimate the inhibition of nitric oxide (NO), prostaglandin-E2 (PGE-2) and tumor necrosis factor-? (TNF-?) production in PBS stimulated RAW 264.7 cells. Based on the observation of in vitro studies, finally, ADME prediction and molecular docking studies of IC were performed for better understanding of interaction of IC with TNF-?.Oral administration of EE (100 and 200 mg/kg) exhibited significant inhibition of carrageenan (p?<?0.05) and arachidonic acid (p?<?0.05) induced oedema, and the reduced the granuloma tissue formation (p?<?0.05) in experimental mice. IC (400 and 600 ?g/kg, p.o.) exhibited significant (p?<?0.01) inhibition of carrageenan, xylene and arachidonic acid-induced edema, and reduced the granuloma tissue formation. In in vitro assays, IC caused a concentration-dependent inhibition of LPS stimulated NO (up to?~?67.4% at 50 ?M) and TNF-? (~84.5% at 50 ?M) production. However, the PGE-2 inhibition did not follow dose dependent pattern. Based on in vitro observations, the molecular docking has been performed on the basis of interaction with TNF-?. In in silico studies, it was observed that IC showed hydrogen bonding with GLN 47 amino acid residue of TNF-? protein.IC possibly produces anti-inflammatory activity through inhibition of TNF-? and NO production.
| S-EPMC4657250 | biostudies-literature
Project description:Inflammatory bowel diseases (IBDs) are chronic conditions of the gastrointestinal tract in which dysregulated immune responses cause persistent inflammation of the gut mucosa. Biologic therapy with anti-TNF blockers has revolutionized the therapeutic management of IBD for their remarkable efficacy and potential impact on disease course and for many years has represented the sole treatment option for patients refractory or intolerant to conventional therapy. In recent years, more molecules, both biologically and chemically synthetized, have been developed as potential therapeutic options for IBD that target different molecular pathways aside from TNF blockade, and which have been proposed as targets for novel drugs. This is particularly relevant for the present, as well as future, management of IBD, considering that some patients are refractory to anti-TNF. This review will summarize the pharmacological options, either currently available or in the pipeline, for market approval to treat IBD, besides anti-TNF strategies, based on their mechanism(s) of action. We will also analyze the current evidence for effectiveness and safety, as well as offer perspective, regarding the potential implementation for such therapies in the future.
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Project description:Glutaredoxin (Grx1) is a ubiquitously expressed thiol-disulfide oxidoreductase that specifically catalyzes reduction of S-glutathionylated substrates. Grx1 is known to be a key regulator of pro-inflammatory signaling, and Grx1 silencing inhibits inflammation in inflammatory disease models. Therefore, we anticipate that inhibition of Grx1 could be an anti-inflammatory therapeutic strategy. We used a rapid screening approach to test 504 novel electrophilic compounds for inhibition of Grx1, which has a highly reactive active-site cysteine residue (pKa 3.5). From this chemical library a chloroacetamido compound, CWR-J02, was identified as a potential lead compound to be characterized. CWR-J02 inhibited isolated Grx1 with an IC50 value of 32 μM in the presence of 1 mM glutathione. Mass spectrometric analysis documented preferential adduction of CWR-J02 to the active site Cys-22 of Grx1, and molecular dynamics simulation identified a potential non-covalent binding site. Treatment of the BV2 microglial cell line with CWR-J02 led to inhibition of intracellular Grx1 activity with an IC50 value (37 μM). CWR-J02 treatment decreased lipopolysaccharide-induced inflammatory gene transcription in the microglial cells in a parallel concentration-dependent manner, documenting the anti-inflammatory potential of CWR-J02. Exploiting the alkyne moiety of CWR-J02, we used click chemistry to link biotin azide to CWR-J02-adducted proteins, isolating them with streptavidin beads. Tandem mass spectrometric analysis identified many CWR-J02-reactive proteins, including Grx1 and several mediators of inflammatory activation. Taken together, these data identify CWR-J02 as an intracellularly effective Grx1 inhibitor that may elicit its anti-inflammatory action in a synergistic manner by also disabling other pro-inflammatory mediators. The CWR-J02 molecule provides a starting point for developing more selective Grx1 inhibitors and anti-inflammatory agents for therapeutic development.
| S-EPMC5695812 | biostudies-literature
Project description:Parenteral administration of human chorionic gonadotropin (hCG) or luteinizing hormone (LH) stimulates the production of testosterone in males and these gonadotropins can therefore be used by athletes to enhance muscle strength. However, they are more expensive and less efficient than testosterone and anabolic steroids. Therefore their main use is probably to stimulate gonadal testosterone production during and after self-administration of testosterone or anabolic steroids. A positive effect of hCG on muscle strength has not been demonstrated in women and elevated concentrations of hCG in females are often caused by pregnancy. The use of gonadotropins is therefore prohibited only in males but not in females. HCG occurs at low but measurable concentrations in plasma and urine of healthy males and can be measured by sensitive methods. However, the characteristics of the method to be used for doping control have not been defined. Virtually all commercially available hCG assays have been designed for determination of hCG in serum rather than urine, which is used for doping control. Methods based on mass spectrometric detection of fragments derived from hCG extracted from urine by immunoadsorption have been developed but their suitability for doping control remains to be determined. The concentrations of LH in serum and urine are variable and more then 10-fold higher than those hCG. It is therefore difficult to detect illicit use of LH. The characteristics and reference values for hCG and LH assays used in doping control and the cutoff values need to be defined.
| S-EPMC2439513 | biostudies-other
Project description:Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.
| S-EPMC9369167 | biostudies-literature
Project description:Rhus verniciflua Stokes (RVS) has been used as a traditional herbal medicine for its various biological activities including anti-adipogenic effects. Activity-guided separation led to the identification of the anti-adipogenic functions of butein. Butein, a novel anti-adipogenic compound, robustly suppressed lipid accumulation and inhibited expression of adipogenic markers. Molecular studies showed that activated transforming growth factor-? (TGF-?) and suppressed signal transducer and activator of transcription 3 (STAT3) signaling pathways were mediated by butein. Analysis of the temporal expression profiles suggests that TGF-? signaling precedes the STAT3 in the butein-mediated anti-adipogenic cascade. Small interfering RNA-mediated silencing of STAT3 or SMAD2/3 blunted the inhibitory effects of butein on adipogenesis indicating that an interaction between two signaling pathways is required for the action of butein. Upon butein treatments, stimulation of TGF-? signaling was still preserved in STAT3 silenced cells, whereas regulation of STAT3 signaling by butein was significantly impaired in SMAD2/3 silenced cells, further showing that TGF-? acts upstream of STAT3 in the butein-mediated anti-adipogenesis. Taken together, the present study shows that butein, a novel anti-adipogenic compound from RVS, inhibits adipocyte differentiation through the TGF-? pathway followed by STAT3 and peroxisome proliferator-activated receptor ? signaling, further implicating potential roles of butein in TGF-?- and STAT3-dysregulated diseases.
| S-EPMC3622332 | biostudies-other
Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.
2024-07-10 | GSE269511 | GEO
Project description:Flaviviruses comprise several medically important viruses, including Japanese encephalitis virus, West Nile virus, dengue virus (DENV), yellow fever virus, and Zika virus (ZIKV). A large outbreak of DENV and ZIKV occurred recently, leading to many cases of illness and death. However, despite decades of effort, we have no clinically specific therapeutic drugs against DENV and ZIKV. Previous studies showed that inflammatory responses play a critical role in dengue and Zika virus pathogenesis. Thus, in this study, we examined a series of novel anti-inflammatory compounds and found that treatment with compound 2d could dose dependently reduce viral protein expression and viral progeny production in HEK-293 and Raw264.7 cells infected with four serotypes of DENV and ZIKV. In addition, considering medication safety, compound 2d could not suppress cyclooxygenase-1 (COX-1) enzymatic activities and thus could prevent the side effect of bleeding. Moreover, compound 2d significantly inhibited COX-2 enzymatic activities and prostaglandin E2 levels, associated with viral replication, compared to results with a selective COX-2 inhibitor, celecoxib. Furthermore, administering 5?mg/kg compound 2d to DENV-2-infected AG129 mice prolonged survival and reduced viremia and serum cytokine levels. Overall, compound 2d showed therapeutic safety and efficacy in vitro and in vivo and could be further developed as a potential therapeutic agent for flavivirus infection.
| S-EPMC7187576 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective death of motor neurons in the central nervous system. The main cause of the disease remains elusive, but several mutations have been associated with the disease process. In particular, mutant superoxide dismutase 1 (SOD1) protein causes oxidative stress by activating glia cells and contributes to motor neuron degeneration. KCHO-1, a novel herbal combination compound, contains 30% ethanol and the extracts of nine herbs that have been commonly used in traditional medicine to prevent fatigue or inflammation. In this study, we investigated whether KCHO-1 administration could reduce oxidative stress in an ALS model. KCHO-1 administered to ALS model mice improved motor function and delayed disease onset. Furthermore, KCHO-1 administration reduced oxidative stress through gp91phox and the MAPK pathway in both classically activated microglia and the spinal cord of hSOD1G93A transgenic mice. The results suggest that KCHO-1 can function as an effective therapeutic agent for ALS by reducing oxidative stress.
| S-EPMC5746442 | biostudies-literature