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1.
Antioxidants (Basel) ; 13(8)2024 Aug 19.
Article in English | MEDLINE | ID: mdl-39199252

ABSTRACT

Resolvin D5 (RvD5) is a lipid mediator that has been reported to present anti-inflammatory and pro-resolution properties. Evidence also supports its capability to enhance reactive oxygen species (ROS) production during bacterial infections, which would be detrimental in diseases driven by ROS. The biological activity of RvD5 and mechanisms against UVB irradiation skin pathology have not been investigated so far. Female hairless mice were treated intraperitoneally with RvD5 before UVB stimulus. RvD5 reduced skin edema in a dose-dependent manner as well as oxidative stress by increasing antioxidants (endogenous tissue antioxidant scavenging of cationic radical, iron reduction, catalase activity and reduced glutathione levels) and decreasing pro-oxidants (superoxide anion and lipid peroxidation). RvD5 antioxidant activity was accompanied by enhancement of Nrf2, HO-1 and NQO1 mRNA expression. RvD5 reduced the production of IL-1ß, TNF-α, TGF-ß, and IL-10. RvD5 also reduced the inflammatory cell counts, including mast cells and neutrophils/macrophages. The reduction of oxidative stress and inflammation resulted in diminished matrix metalloproteinase 9 activity, collagen degradation, epidermal thickening and sunburn cell development. Therefore, this study demonstrates, to our knowledge, the first body of evidence that RvD5 can be used to treat UVB skin pathology and unveils, at least in part, its mechanisms of action.

2.
J Adv Res ; 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-39142441

ABSTRACT

INTRODUCTION: Endometriosis is a chronic inflammatory disease that affects âˆ¼10 % of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis. OBJECTIVES: We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice. METHODS: Peritoneal fluid was collected from endometriosis patients undergoing surgery and the levels of NGF and VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA. VEGFR1 regulator concentrations were used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibodies, and pharmacological approaches to specifically block neurotrophic ligands (NGF or BDNF) or receptors (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was measured using von Frey filaments, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Disease parameters were evaluated by lesion size and prevalence. To evaluate potential toxicity, we measured the effect of entrectinib dose and schedule on body weight, liver and kidney function, and bone structure (via micro-CT). RESULTS: We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though calculated receptor occupancy revealed that VEGFR1 agonist levels are sufficient to support signaling, blocking VEGFR1 via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Notably, changing dosing schedule to once weekly eliminated entrectinib-induced bone-loss without decreasing efficacy against pain. CONCLUSIONS: This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment.

3.
J Neurochem ; 2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38970456

ABSTRACT

Perineuronal nets (PNN) are highly specialized structures of the extracellular matrix around specific groups of neurons in the central nervous system (CNS). They play functions related to optimizing physiological processes and protection neurons against harmful stimuli. Traditionally, their existence was only described in the CNS. However, there was no description of the presence and composition of PNN in the enteric nervous system (ENS) until now. Thus, our aim was to demonstrate the presence and characterize the components of the PNN in the enteric nervous system. Samples of intestinal tissue from mice and humans were analyzed by RT-PCR and immunofluorescence assays. We used a marker (Wisteria floribunda agglutinin) considered as standard for detecting the presence of PNN in the CNS and antibodies for labeling members of the four main PNN-related protein families in the CNS. Our results demonstrated the presence of components of PNN in the ENS of both species; however its molecular composition is species-specific.

5.
Cell Calcium ; 119: 102870, 2024 May.
Article in English | MEDLINE | ID: mdl-38531262

ABSTRACT

In the 1990s, the identification of a non-selective ion channel, especially responsive to capsaicin, revolutionized the studies of somatosensation and pain that were to follow. The TRPV1 channel is expressed mainly in neuronal cells, more specifically, in sensory neurons responsible for the perception of noxious stimuli. However, its presence has also been detected in other non-neuronal cells, such as immune cells, ß- pancreatic cells, muscle cells and adipocytes. Activation of the channel occurs in response to a wide range of stimuli, such as noxious heat, low pH, gasses, toxins, endocannabinoids, lipid-derived endovanilloid, and chemical agents, such as capsaicin and resiniferatoxin. This activation results in an influx of cations through the channel pore, especially calcium. Intracellular calcium triggers different responses in sensory neurons. Dephosphorylation of the TRPV1 channel leads to its desensitization, which disrupts its function, while its phosphorylation increases the channel's sensitization and contributes to the channel's rehabilitation after desensitization. Kinases, phosphoinositides, and calmodulin are the main signaling pathways responsible for the channel's regulation. Thus, in this review we provide an overview of TRPV1 discovery, its tissue expression as well as on the mechanisms by which TRPV1 activation (directly or indirectly) induces pain in different disease models.


Subject(s)
Neuroimmunomodulation , Pain , TRPV Cation Channels , Humans , Calcium/metabolism , Capsaicin/pharmacology , Pain/metabolism , TRPV Cation Channels/metabolism , Animals
6.
Expert Opin Ther Targets ; 27(8): 679-703, 2023.
Article in English | MEDLINE | ID: mdl-37651647

ABSTRACT

INTRODUCTION: Gout arthritis (GA) is an intermittent inflammatory disease affecting approximately 10% of the worldwide population. Symptomatic phases (acute flares) are timely spaced by asymptomatic periods. During an acute attack, redness, joint swelling, limited movement, and excruciating pain are common symptoms. However, the current available therapies are not fully effective in reducing symptoms and offer numerous side effects. Therefore, unveiling new drug targets and effector molecules are required in developing novel GA therapeutics. AREAS COVERED: This review discusses the pathophysiological mechanisms of GA and explores potential pharmacological targets to ameliorate disease outcome. In addition, we listed promising pre-clinical studies demonstrating effector molecules with therapeutical potential. Among those, we emphasized the importance of natural products, including traditional Chinese medicine formulas and their multitarget mechanisms of action. EXPERT OPINION: In our search, we observed that there is a massive gap between pre-clinical and clinical knowledge. Only a minority (4.4%) of clinical trials aimed to intervene by applying natural products or current hot targets described herein. In this sense, we envisage four possibilities for GA therapeutics, which include the repurposing of existing therapies, ALX/FPR2 agonism for improvement in disease outcome, the use of multitarget drugs (e.g. natural products), and targeting the neuroinflammatory component of GA.


Subject(s)
Biological Products , Gout , Humans , Gout/drug therapy , Drug Delivery Systems , Biological Products/pharmacology , Biological Products/therapeutic use
7.
Molecules ; 28(13)2023 Jun 27.
Article in English | MEDLINE | ID: mdl-37446699

ABSTRACT

During an infection, inflammation mobilizes immune cells to eliminate the pathogen and protect the host. However, inflammation can be detrimental when exacerbated and/or chronic. The resolution phase of the inflammatory process is actively orchestrated by the specialized pro-resolving lipid mediators (SPMs), generated from omega-3 and -6 polyunsaturated fatty acids (PUFAs) that bind to different G-protein coupled receptors to exert their activity. As immunoresolvents, SPMs regulate the influx of leukocytes to the inflammatory site, reduce cytokine and chemokine levels, promote bacterial clearance, inhibit the export of viral transcripts, enhance efferocytosis, stimulate tissue healing, and lower antibiotic requirements. Metabolomic studies have evaluated SPM levels in patients and animals during infection, and temporal regulation of SPMs seems to be essential to properly coordinate a response against the microorganism. In this review, we summarize the current knowledge on SPM biosynthesis and classifications, endogenous production profiles and their effects in animal models of bacterial, viral and parasitic infections.


Subject(s)
Fatty Acids, Omega-3 , Parasitic Diseases , Animals , Inflammation/metabolism , Eicosanoids , Fatty Acids, Omega-3/pharmacology , Fatty Acids, Omega-3/metabolism , Cytokines , Inflammation Mediators/metabolism
8.
Int J Pharm ; 642: 123206, 2023 Jul 25.
Article in English | MEDLINE | ID: mdl-37419432

ABSTRACT

Improved therapies for inflammatory bowel diseases are sorely needed. Novel therapeutic agents and the development of controlled release systems for targeted tissue delivery are interesting approaches to overcome these barriers. We investigated the activity of trans-chalcone (T) in acetic acid-induced colitis in mice and developed, characterized, and determined the therapeutic effect of pectin/casein polymer microcapsules containing T (MT) in a colitis mouse model. In vitro, compound release was achieved in simulated intestinal fluid but not in the simulated gastric fluid. In vivo, since T at the dose of 3 mg/kg but not 0.3 mg/kg ameliorated colitis, we next tested the effects of MT at 0.3 mg/kg (non-effective dose). MT, but not free T at 0.3 mg/kg, significantly improved colitis outcomes such as neutrophil recruitment, antioxidant capacity, cytokine production, and NF-kB activation. This translated into reduced macro and microscopic damage in the colon. T release from the microcapsules is mediated by a pH-dependent and pectinase-regulated mechanism that provide controlled and prolonged release of T. Moreover, MT lowered the required dose for T therapeutic effect, indicating that could be a suitable pharmaceutical approach to colitis treatment. This is the first demonstration that T or MT is effective at reducing the signs of colitis.


Subject(s)
Chalcone , Chalcones , Colitis , Mice , Animals , Caseins , Chalcone/pharmacology , Capsules/pharmacology , Pectins , Colitis/chemically induced , Colitis/drug therapy , Colon , NF-kappa B , Disease Models, Animal
9.
Cells ; 12(4)2023 02 09.
Article in English | MEDLINE | ID: mdl-36831223

ABSTRACT

Chikungunya virus is an arthropod-borne infectious agent that causes Chikungunya fever disease. About 90% of the infected patients experience intense polyarthralgia, affecting mainly the extremities but also the large joints such as the knees. Chronic disease symptoms persist for months, even after clearance of the virus from the blood. Envelope proteins stimulate the immune response against the Chikungunya virus, becoming an important therapeutic target. We inactivated the Chikungunya virus (iCHIKV) and produced recombinant E2 (rE2) protein and three different types of anti-rE2 monoclonal antibodies. Using these tools, we observed that iCHIKV and rE2 protein induced mechanical hyperalgesia (electronic aesthesiometer test) and thermal hyperalgesia (Hargreaves test) in mice. These behavioral results were accompanied by the activation of dorsal root ganglia (DRG) neurons in mice, as observed by calcium influx. Treatment with three different types of anti-rE2 monoclonal antibodies and absence or blockade (AMG-9810 treatment) of transient receptor potential vanilloid 1 (TRPV1) channel diminished mechanical and thermal hyperalgesia in mice. iCHIKV and rE2 activated TRPV1+ mouse DRG neurons in vitro, demonstrating their ability to activate nociceptor sensory neurons directly. Therefore, our mouse data demonstrate that targeting E2 CHIKV protein with monoclonal antibodies and inhibiting TRPV1 channels are reasonable strategies to control CHIKV pain.


Subject(s)
Antibodies, Monoclonal , Chikungunya Fever , Chikungunya virus , Hyperalgesia , Viral Envelope Proteins , Animals , Mice , Antibodies, Monoclonal/pharmacology , Antibodies, Viral , Antineoplastic Agents , Hyperalgesia/drug therapy , TRPV Cation Channels , Viral Envelope Proteins/metabolism , Chikungunya Fever/drug therapy
10.
Molecules ; 28(2)2023 Jan 15.
Article in English | MEDLINE | ID: mdl-36677929

ABSTRACT

Arthroplasty is an orthopedic surgical procedure that replaces a dysfunctional joint by an orthopedic prosthesis, thereby restoring joint function. Upon the use of the joint prosthesis, a wearing process begins, which releases components such as titanium dioxide (TiO2) that trigger an immune response in the periprosthetic tissue, leading to arthritis, arthroplasty failure, and the need for revision. Flavonoids belong to a class of natural polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Hesperidin methyl chalcone's (HMC) analgesic, anti-inflammatory, and antioxidant effects have been investigated in some models, but its activity against the arthritis caused by prosthesis-wearing molecules, such as TiO2, has not been investigated. Mice were treated with HMC (100 mg/kg, intraperitoneally (i.p.)) 24 h after intra-articular injection of 3 mg/joint of TiO2, which was used to induce chronic arthritis. HMC inhibited mechanical hyperalgesia, thermal hyperalgesia, joint edema, leukocyte recruitment, and oxidative stress in the knee joint (alterations in gp91phox, GSH, superoxide anion, and lipid peroxidation) and in recruited leukocytes (total reactive oxygen species and GSH); reduced patellar proteoglycan degradation; and decreased pro-inflammatory cytokine production. HMC also reduced the activation of nociceptor-sensory TRPV1+ and TRPA1+ neurons. These effects occurred without renal, hepatic, or gastric damage. Thus, HMC reduces arthritis triggered by TiO2, a component released upon wearing of prosthesis.


Subject(s)
Arthritis , Chalcones , Hesperidin , Mice , Animals , Nociceptors/metabolism , Chalcones/therapeutic use , Inflammation/drug therapy , Inflammation/metabolism , Arthritis/drug therapy , Oxidative Stress , Antioxidants/pharmacology , Anti-Inflammatory Agents/pharmacology , Hyperalgesia/drug therapy , Cytokines/metabolism
11.
Brain Sci ; 12(9)2022 Sep 15.
Article in English | MEDLINE | ID: mdl-36138983

ABSTRACT

We standardized a model by injecting Ehrlich tumor cells into the paw to evaluate cancer pain mechanisms and pharmacological treatments. Opioid treatment, but not cyclooxygenase inhibitor or tricyclic antidepressant treatments reduces Ehrlich tumor pain. To best use this model for drug screening it is essential to understand its pathophysiological mechanisms. Herein, we investigated the contribution of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in the Ehrlich tumor-induced pain model. Dorsal root ganglia (DRG) neurons from the Ehrlich tumor mice presented higher activity (calcium levels using fluo-4 fluorescent probe) and an increased response to capsaicin (TRPV1 agonist) than the saline-injected animals (p < 0.05). We also observed diminished mechanical (electronic von Frey) and thermal (hot plate) hyperalgesia, paw flinching, and normalization of weight distribution imbalance in TRPV1 deficient mice (p < 0.05). On the other hand, TRPV1 deficiency did not alter paw volume or weight, indicating no significant alteration in tumor growth. Intrathecal injection of AMG9810 (TRPV1 antagonist) reduced ongoing Ehrlich tumor-triggered mechanical and thermal hyperalgesia (p < 0.05). Therefore, the contribution of TRPV1 to Ehrlich tumor pain behavior was revealed by genetic and pharmacological approaches, thus, supporting the use of this model to investigate TRPV1-targeting therapies for the treatment of cancer pain.

12.
Neuropharmacology ; 216: 109189, 2022 09 15.
Article in English | MEDLINE | ID: mdl-35820471

ABSTRACT

Maresin-2 (MaR2) is a specialized pro-resolution lipid mediator (SPM) that reduces neutrophil recruitment in zymosan peritonitis. Here, we investigated the analgesic effect of MaR2 and its mechanisms in different mouse models of pain. For that, we used the lipopolysaccharide (LPS)-induced mechanical hyperalgesia (electronic version of the von Frey filaments), thermal hyperalgesia (hot plate test) and weight distribution (static weight bearing), as well as the spontaneous pain models induced by capsaicin (TRPV1 agonist) or AITC (TRPA1 agonist). Immune cell recruitment was determined by immunofluorescence and flow cytometry while changes in the pro-inflammatory mediator landscape were determined using a proteome profiler kit and ELISA after LPS injection. MaR2 treatment was also performed in cultured DRG neurons stimulated with capsaicin or AITC in the presence or absence of LPS. The effect of MaR2 on TRVP1- and TRPA1-dependent CGRP release by cultured DRG neurons was determined by EIA. MaR2 inhibited LPS-induced inflammatory pain and changes in the cytokine landscape as per cytokine array assay. MaR2 also inhibited TRPV1 and TRPA1 activation as observed by a reduction in calcium influx in cultured DRG neurons, and the number of flinches and time spent licking the paw induced by capsaicin or AITC. In corroboration, MaR2 reduced capsaicin- and AITC-induced CGRP release by cultured DRG neurons and immune cell recruitment to the paw skin close the CGRP+ fibers. In conclusion, we show that MaR2 is an analgesic SPM that acts by targeting leukocyte recruitment, nociceptor TRPV1 and TRPA1 activation, and CGRP release in mice.


Subject(s)
Capsaicin , Transient Receptor Potential Channels , Analgesics/pharmacology , Animals , Calcitonin Gene-Related Peptide/metabolism , Capsaicin/pharmacology , Cytokines/pharmacology , Docosahexaenoic Acids , Hyperalgesia , Lipopolysaccharides/pharmacology , Mice , Monocytes/metabolism , Neurons , Neutrophils , Nociceptors/metabolism , Pain , TRPA1 Cation Channel , TRPV Cation Channels
13.
Antioxidants (Basel) ; 11(7)2022 Jun 27.
Article in English | MEDLINE | ID: mdl-35883752

ABSTRACT

Hesperidin is derived from citrus fruits among other plants. Hesperidin was methylated to increase its solubility, generating hesperidin methyl chalcone (HMC), an emerging flavonoid that possess anti-inflammatory and antioxidant properties. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a powerful regulator of cellular resistance to oxidant products. Previous data evidenced HMC can activate Nrf2 signaling, providing antioxidant protection against diverse pathological conditions. However, its effects on kidney damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) have not been evaluated so far. Mice received a nephrotoxic dose of diclofenac (200 mg/kg) orally followed by intra-peritoneal (i.p.) administration of HMC (0.03-3 mg/kg) or vehicle. Plasmatic levels of urea, creatinine, oxidative stress, and cytokines were assessed. Regarding the kidneys, oxidative parameters, cytokine production, kidney swelling, urine NGAL, histopathology, and Nrf2 mRNA expression and downstream targets were evaluated. HMC dose-dependently targeted diclofenac systemic alterations by decreasing urea and creatinine levels, and lipid peroxidation, as well as IL-6, IFN-γ, and IL-33 production, and restored antioxidant properties in plasma samples. In kidney samples, HMC re-established antioxidant defenses, inhibited lipid peroxidation and pro-inflammatory cytokines and upregulated IL-10, reduced kidney swelling, urine NGAL, and histopathological alterations. Additionally, HMC induced mRNA expression of Nrf2 and its downstream effectors HO-1 and Nqo1, as well as reduced the levels of Keap1 protein detected in renal tissue. The present data demonstrate HMC is a potential compound for the treatment of acute renal damage caused by diclofenac, a routinely prescribed non-steroidal anti-inflammatory drug.

14.
Br J Pharmacol ; 179(18): 4500-4515, 2022 09.
Article in English | MEDLINE | ID: mdl-35716378

ABSTRACT

BACKGROUND AND PURPOSE: Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain. Current therapies are often ineffective in reducing gout-related pain. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic proprieties. In this study, we evaluated the effects and mechanisms of action of RvD1 in an experimental mouse model of gouty arthritis, an aim that was not pursued previously in the literature. EXPERIMENTAL APPROACH: Male mice were treated with RvD1 (intrathecally or intraperitoneally) before or after intraarticular stimulation with MSU. Mechanical hyperalgesia was assessed using an electronic von Frey aesthesiometer. Leukocyte recruitment was determined by knee joint wash cell counting and immunofluorescence. IL-1ß production was measured by ELISA. Phosphorylated NF-kB and apoptosis-associated speck-like protein containing CARD (ASC) were detected by immunofluorescence, and mRNA expression was determined by RT-qPCR. CGRP release was determined by EIA and immunofluorescence. MSU crystal phagocytosis was evaluated by confocal microscopy. KEY RESULTS: RvD1 inhibited MSU-induced mechanical hyperalgesia in a dose- and time-dependent manner by reducing leukocyte recruitment and IL-1ß production in the knee joint. Intrathecal RvD1 reduced the activation of peptidergic neurons and macrophages as well as silenced nociceptor to macrophage communication and macrophage function. CGRP stimulated MSU phagocytosis and IL-1ß production by macrophages. RvD1 downmodulated this phenomenon directly by acting on macrophages, and indirectly by inhibiting CGRP release and CGRP-dependent activation of macrophages. CONCLUSIONS AND IMPLICATIONS: This study reveals a hitherto unknown neuro-immune axis in gouty arthritis that is targeted by RvD1.


Subject(s)
Arthritis, Gouty , Animals , Arthritis, Gouty/chemically induced , Arthritis, Gouty/drug therapy , Calcitonin Gene-Related Peptide , Docosahexaenoic Acids , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Inflammation/metabolism , Macrophage Activation , Male , Mice , Neuroimmunomodulation , Neurons , Nociceptors/metabolism , Pain , Uric Acid/chemistry , Uric Acid/pharmacology
15.
Pain ; 163(12): 2326-2336, 2022 12 01.
Article in English | MEDLINE | ID: mdl-35543646

ABSTRACT

ABSTRACT: The lack of sensitive and robust behavioral assessments of pain in preclinical models has been a major limitation for both pain research and the development of novel analgesics. Here, we demonstrate a novel data acquisition and analysis platform that provides automated, quantitative, and objective measures of naturalistic rodent behavior in an observer-independent and unbiased fashion. The technology records freely behaving mice, in the dark, over extended periods for continuous acquisition of 2 parallel video data streams: (1) near-infrared frustrated total internal reflection for detecting the degree, force, and timing of surface contact and (2) simultaneous ongoing video graphing of whole-body pose. Using machine vision and machine learning, we automatically extract and quantify behavioral features from these data to reveal moment-by-moment changes that capture the internal pain state of rodents in multiple pain models. We show that these voluntary pain-related behaviors are reversible by analgesics and that analgesia can be automatically and objectively differentiated from sedation. Finally, we used this approach to generate a paw luminance ratio measure that is sensitive in capturing dynamic mechanical hypersensitivity over a period and scalable for high-throughput preclinical analgesic efficacy assessment.


Subject(s)
Analgesia , Pain , Mice , Animals , Pain/diagnosis , Pain/drug therapy , Pain Management , Analgesics/pharmacology , Analgesics/therapeutic use , Pain Measurement
16.
Chem Biol Interact ; 361: 109969, 2022 Jul 01.
Article in English | MEDLINE | ID: mdl-35526601

ABSTRACT

Leishmaniasis is a group of chronic parasitic diseases in humans caused by species of the Leishmania genus. Current treatments have high toxicity, cost, duration, limited effectiveness, significantly complex administration, and drug-resistant strains. These factors highlight the importance of research into new therapies that use drugs without toxic effects. Solidagenone (SOL), the main labdane diterpene isolated from the plant Solidago chilensis, has anti-inflammatory, gastroprotective, antioxidant, tissue repair-inducing effects, suggesting a role in novel drug development. This study investigates in vivo mechanism action of SOL treatment in L. amazonensis-infected BALB/c mice. SOL was isolated from the roots of S. chilensis, and L. amazonensis-infected mice were treated daily with SOL (10, 50, 100 mg/kg) by gavage for 30 days. Gastric (NAG, MPO), hepatic (AST, ALT), systemic (body weight, NO) toxicity, leishmanicidal activity (lesion size, parasite burden), cell profile (macrophage, neutrophil infiltration), antioxidant (ABTS, NBT, NO), oxidant parameters (FRAP, ABTS), Th1, Th2, Th17 cytokines (CBA), collagen deposition (picrosirius), arginase, iNOS, NF-kB, and NRF2 (immunofluorescence) were evaluated. In vivo results showed SOL-treatment did not induce gastric, hepatic, or systemic toxicity in L. amazonensis-infected mice. SOL was able to reduce the lesion size and parasite load at the site of infection, increasing macrophage infiltration and neutrophil migration, exerting a balance in antioxidant (increased ABTS, NBT reduction, and NO), oxidative (increased FRAP and ABTS), and anti-inflammatory responses (reduced TNF-α, IFN-γ and increased IL-6, IL-17 production), and inducing arginase, iNOS, NF-kB, NRF2 and collagen deposition (type III), favoring wound healing and accelerating tissue repair at the site injury.


Subject(s)
Furans , Leishmaniasis, Cutaneous , Naphthalenes , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Arginase/metabolism , Furans/pharmacology , Leishmania , Leishmaniasis, Cutaneous/drug therapy , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Naphthalenes/pharmacology , Wound Healing
17.
Food Technol Biotechnol ; 60(1): 21-28, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35440885

ABSTRACT

Research background: Extracts from grape pomace, including the wine, show many biological effects such as antioxidant and anti-inflammatory activities. Unfortunately, winemakers discard the bagasse, so the waste is not exploited, although it contains bioactive compounds with antioxidant and anti-inflammatory properties. The work aims to analyze the hydroethanolic extract of peels from Vitis labrusca agro-industrial waste and to evaluate its antinociceptive and anti-inflammatory properties. This study is relevant for reusing a residue and adding value to the grape economic chain. Experimental approach: A representative sample of pomace was obtained and the peels were used to produce the extract. The phenolic compounds were determined by mass spectrometry in multiple reaction monitoring mode and Folin-Ciocalteu colorimetric method, using gallic acid as standard. The biological analyses were carried out using mice orally treated with crude extract at doses of 30, 100 and 300 mg/kg. We evaluated mechanical hyperalgesia by the von Frey method, thermal heat hyperalgesia using a hot plate at 55 °C, paw edema using a pachymeter, and neutrophil recruitment by measurement of myeloperoxidase activity. The nephrotoxicity and hepatotoxicity were evaluated by biochemical analyses using blood samples that were collected after the Vitis labrusca administration. Results and conclusions: In all wet winemaking residues peel mass fraction was 75%, and in dry residues 59%. We identified nine anthocyanins (3-O-glucosides: peonidin, delphinidin, petunidin and malvidin; 3-p-coumaroyl-glucosides: cyanidin, peonidin, petunidin and malvidin, and malvidin-3,5-diglucoside), five flavonoids (apigenin-7-glucoside, luteolin-7-glucoside, quercetin-3-galactoside, isorhamnetin-3-glucoside and myricetin-3-rutinoside), and mass fraction of phenolic compounds, expressed as gallic acid equivalents, was 26.62 mg/g. In vivo assays showed that Vitis labrusca extract at mass fractions 100 and 300 mg/kg reduced carrageenan-induced mechanical and thermal hyperalgesia, 50% of the paw edema, and neutrophil recruitment. In addition, there were no indications of nephrotoxicity and hepatotoxicity. Our extract obtained from winemaking residue has analgesic and anti-inflammatory properties, related at least in part to the presence of phenolic compounds, and it is not toxic to renal and hepatic tissues. Novelty and scientific contribution: This bio-product can be used as an alternative to synthetic anti-inflammatory agents with the same pharmacological potential and fewer side effects. We demonstrated that Vitis labrusca winemaking waste can be used for the production of antinociceptive and anti-inflammatory products (nutraceutical, pharmaceutical and cosmetics) without toxicity, contributing to the environmental economy.

18.
Life Sci ; 295: 120405, 2022 Apr 15.
Article in English | MEDLINE | ID: mdl-35181311

ABSTRACT

AIMS: The rostral ventrolateral medulla (RVLM) is the main sympathetic output of the central nervous system to control blood pressure. Reportedly, reactive oxygen species (ROS) can increase arterial pressure, leading to hypertension. As ROS increase the sympathetic tone in RVLM and obese animals present grater oxidative stress, it would be important to note this relationship. MAIN METHODS: Therefore, we evaluated the systemic and central effects (in the RVLM) of vitamin C (vit C, an antioxidant) on the redox balance and cardiovascular and autonomic profiles in hyperadipose male rats. We also evaluated the neurotransmission by L-glutamate (L-glu) and vit C in the RVLM of awake hyperadipose rats. KEY FINDINGS: Our study confirmed that hyperadipose rats were hypertensive and tachycardic, presented increased sympathetic and decreased parasympathetic modulation of the heart, and had increased plasma lipoperoxidation compared with the control rats (CTR). Oral vitamin C treatment reverted cardiovascular, autonomic, and plasma redox dysfunction. Hyperadipose rats presented a higher blood pressure increase after L-glu microinjection and a lower response to vit C in the RVLM compared with the CTR group. Biochemical analysis of redox balance in RVLM punches showed that hyperadipose rats have increased NBT and T-BARS, and after treatment with vit C, the oxidative profile decreased. The antioxidative activity of vit C reduced the amount of ROS in the RVLM area that might have resulted in lowered blood pressure and sympathetic modulation. SIGNIFICANCE: Our data suggest central and peripheral benefits of vit C treatment on cardiovascular, autonomic, and oxidative dysfunctions in hyperadipose animals.


Subject(s)
Ascorbic Acid/pharmacology , Hypertension/drug therapy , Medulla Oblongata/metabolism , Animals , Antioxidants/pharmacology , Autonomic Nervous System/physiopathology , Blood Pressure/drug effects , Cardiovascular System/physiopathology , Heart Rate/drug effects , Hypertension/physiopathology , Male , Medulla Oblongata/drug effects , Oxidative Stress/drug effects , Oxidative Stress/physiology , Rats , Rats, Wistar , Reactive Oxygen Species/pharmacology , Superoxide Dismutase/metabolism , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/metabolism
19.
Acta Histochem ; 124(1): 151843, 2022 Jan.
Article in English | MEDLINE | ID: mdl-35021147

ABSTRACT

Aluminium (Al) is an important metal, but it can be toxic including for prostate tissue. This study aimed to evaluate whether exposure to aluminium chloride (AlCl3) during the peripubertal period affects ventral prostate development in rats. Male Wistar rats (30 days old) were distributed into three experimental groups: control (sterile 0.9% saline solution), AL7 (7 mg AlCl3/kg) and AL34 (34 mg AlCl3/kg). Animals were treated intraperitoneally from postnatal day (PND) 36-66 (peripubertal period). At PND67, the animals were anaesthetized and euthanized. Blood was collected for testosterone levels. The ventral prostate (VP) was removed, weighed and processed for histochemistry and immunohistochemistry to detect androgen (AR) and Ki67. Stereological and histopathological analyses, mast cell counts, and determinations of myeloperoxidase (MPO) and N-acetyl glycosidase (NAG) activity and IL-6 levels were performed. The AL34 group presented a reduction in body weight and increase in MPO activity compared to the other groups. In both the AL7 and AL34 groups, there was reorganization of the prostatic tissue compartments. There was no significant difference in prostate weight, number of granulated or degranulated mast cells, or testosterone levels. In conclusion, the exposure to aluminium chloride during the peripubertal period impairs the prostatic development.


Subject(s)
Androgens , Prostate , Aluminum Chloride , Animals , Immunohistochemistry , Male , Prostate/pathology , Rats , Rats, Wistar
20.
Mediators Inflamm ; 2021: 9330596, 2021.
Article in English | MEDLINE | ID: mdl-34764817

ABSTRACT

UVB radiation is certainly one of the most important environmental threats to which we are subjected to. This fact highlights the crucial protective role of the skin. However, the skin itself may not be capable of protecting against UVB depending on irradiation intensity and time of exposition. Sun blockers are used to protect our skin, but they fail to fully protect it against oxidative and inflammatory injuries initiated by UVB. To solve this issue, topical administration of active molecules is an option. 15-Deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2) is an arachidonic acid-derived lipid with proresolution and anti-inflammatory actions. However, as far as we are aware, there is no evidence of its therapeutic use in a topical formulation to treat the deleterious events initiated by UVB, which was the aim of the present study. We used a nonionic cream to vehiculate 15d-PGJ2 (30, 90, and 300 ng/mouse) (TFcPGJ2) in the skin of hairless mice. UVB increased skin edema, myeloperoxidase activity, metalloproteinase-9 activity, lipid peroxidation, superoxide anion production, gp91phox and COX-2 mRNA expression, cytokine production, sunburn and mast cells, thickening of the epidermis, and collagen degradation. UVB also diminished skin ability to reduce iron and scavenge free radicals, reduced glutathione (GSH), sulfhydryl proteins, and catalase activity. TFcPGJ2 inhibited all these pathological alterations in the skin caused by UVB. No activity was observed with the unloaded topical formulation. The protective outcome of TFcPGJ2 indicates it is a promising therapeutic approach against cutaneous inflammatory and oxidative pathological alterations.


Subject(s)
Oxidative Stress , Prostaglandins , Administration, Topical , Animals , Mice , Mice, Hairless , Prostaglandins/metabolism , Skin/metabolism , Ultraviolet Rays
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