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Topic:Inflammation

Inflammation is a biological response of the horse's body to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a complex process that involves the activation of immune cells, the release of inflammatory mediators, and changes in blood flow. In horses, inflammation can manifest in various forms, affecting different tissues and organs, including the joints, respiratory system, and skin. The inflammatory response is an essential component of the horse's immune system, aiming to eliminate the initial cause of cell injury, clear out damaged cells and tissues, and establish tissue repair. This topic page gathers peer-reviewed research studies and scholarly articles that explore the mechanisms, effects, and management of inflammation in equine health.
Ultrasound biomicroscopic imaging parameters associated with outcome in equine infectious ulcerative keratitis and stromal abscesses.
Journal of the American Veterinary Medical Association    June 6, 2024   Volume 262, Issue S2 S57-S64 doi: 10.2460/javma.24.02.0097
Collins EN, Barr EM, Westermeyer H, Gilger BC, Oh A.To determine the predictive value of corneal ultrasound biomicroscopy (UBM) findings for the outcome of equine corneal disease. Methods: 46 horses with a clinical diagnosis of either infectious ulcerative keratitis or stromal abscess. Methods: Corneal UBM (VevoMD; UHF70; VisualSonics) of horses with infectious corneal disease presenting to the North Carolina State University Equine Ophthalmology Service from 2019 to 2023 were evaluated. Size and depth of lesion, presence of Descemet membrane disruption (DMD), corneal thickness, and aqueous humor cell counts (AHCC) were assessed. Comparisons of...
Use of recombinant tissue plasminogen activator (rTPA) for treatment of fibrin in the anterior chamber of the horse.
Veterinary medicine and science    May 31, 2024   Volume 10, Issue 4 e1448 doi: 10.1002/vms3.1448
Pereira R, Bowen M, Rapezzano G, Redpath A, Pratt S, Hallowell G.Recombinant intracameral tissue plasminogen activator (rTPA) administration can aid clearance of fibrin from the anterior chamber. In this retrospective multicentre case series, the effect of intracameral rTPA administration to treat fibrin in the anterior chamber resulting from trauma or inflammatory ocular disease was evaluated. Clinical data from 30 treatments in 29 horses were obtained from medical records from 2003 to 2022. Association between time from onset of clinical signs and time for rTPA treatment to effect was studied with regression analysis. Twenty-seven horses (93.1%) had no pr...
Changes in plasma metabolite concentrations and enzyme activities in aging riding horses.
Frontiers in veterinary science    May 31, 2024   Volume 11 1345548 doi: 10.3389/fvets.2024.1345548
Asahi Y, Arai T, Tanaka Y.In older horses, basal metabolic rate decreases, and plasma metabolite and hormone concentrations related to energy metabolism change. The occurrence of age-related diseases, which increases in old animals, may enhance inflammatory reactivity (inflammaging). Finding the appropriate treatment for inflammaging at an early stage may prevent various age-related diseases. Changes in metabolite and hormone concentrations and enzyme activities involved in energy metabolism in the plasma of clinically healthy riding horses of various ages were measured to identify biomarkers of inflammaging (persisten...
Autoimmune Dermatopathies of Horses.
The Veterinary clinics of North America. Equine practice    May 30, 2024   S0749-0739(24)00027-0 doi: 10.1016/j.cveq.2024.04.001
Marsella R.Autoimmune dermatopathies are not common in horses. These autoimmune diseases can be idiopathic or triggered by an antigen such as drugs, vaccines, or neoplasia. The most common one is pemphigus foliaceus, which manifests as a pustular, crusting eruption. Other more common pustular diseases should be ruled out before considering pemphigus. Vasculitis is relatively common in horses and can be triggered by a variety of antigenic stimulations. Systemic lupus and true idiopathic autoimmune vasculitis are very rare in horses. Every effort should be made to reach a final diagnosis, as the prognosis ...
Findings and Prognosis in 149 Horses with Histological Changes Compatible with Inflammatory Bowel Disease.
Animals : an open access journal from MDPI    May 30, 2024   Volume 14, Issue 11 doi: 10.3390/ani14111638
Kranenburg LC, Bouwmeester BF, van den Boom R.Inflammatory bowel disease (IBD) is a chronic disease characterized by different cell infiltrates in the intestine. The aims of this study were to report the clinical and clinicopathological findings in horses with histological changes compatible with IBD in the duodenum. Further, the clinical progression of IBD and survival were investigated. Patient records were reviewed for horses in which histological evidence of IBD was found in duodenal biopsies collected during endoscopy. The histological changes were classified as mild, moderate or severe and the predominant infiltrating cell type was ...
Approach to Immune-mediated Ocular Diseases.
The Veterinary clinics of North America. Equine practice    May 27, 2024   Volume 40, Issue 2 275-286 doi: 10.1016/j.cveq.2024.04.003
Knickelbein KE, Lassaline ME.Immune-mediated ocular inflammation is a common clinical diagnosis reached for horses with keratitis and uveitis. This diagnosis is made as a diagnosis of exclusion following a thorough effort to rule out an underlying cause for the inflammation, most importantly infectious and neoplastic disease. Practically, response to ophthalmic and systemic anti-inflammatory or immunomodulatory medications is used to support a diagnosis of immune-mediated ocular inflammation; however, such medications are often contraindicated in the face of infection or neoplasia. This article will summarize our current ...
Evaluation of stem-cell therapies in companion animal disease models: a concise review (2015-2023).
Stem cells (Dayton, Ohio)    May 25, 2024   Volume 42, Issue 8 677-705 doi: 10.1093/stmcls/sxae034
Williams ZJ, Pezzanite LM, Chow L, Rockow M, Dow SW.Companion animals in veterinary medicine develop multiple naturally occurring diseases analogous to human conditions. We previously reported a comprehensive review on the feasibility, safety, and biologic activity of using novel stem cell therapies to treat a variety of inflammatory conditions in dogs and cats (2008-2015) [Hoffman AM, Dow SW. Concise review: stem cell trials using companion animal disease models. Stem Cells. 2016;34(7):1709-1729. https://doi.org/10.1002/stem.2377]. The purpose of this review is to provide an updated summary of current studies in companion animal disease models...
What is your diagnosis? Cerebrospinal fluid from a horse.
Veterinary clinical pathology    May 24, 2024   Volume 53 Suppl 2 152-154 doi: 10.1111/vcp.13216
Larosche SA, Weyna AAW, Stanton JB, Hart K, Meichner K.No abstract available
Monitoring of inflammatory blood biomarkers in foals with Rhodococcus Equi pneumonia during antimicrobial treatment.
Journal of equine veterinary science    May 24, 2024   Volume 138 105103 doi: 10.1016/j.jevs.2024.105103
Deniz Ö, Ekinci G, Onmaz AC, Derelli FM, Fazio F, Aragona F, Hoven RVD.Rhodococcus equi (R. equi), a gram-positive facultative intracellular pathogen, is a common cause of pneumonia in foals and represents a major cause of disease and death. The aim of the present study was to investigate the time-depended changes in White Blood Cells (WBC), basophils (Baso), neutrophils (Neu), lymphocytes (Lymf), monocytes (Mon), eosinophils (Eos), platelet (PLT) counts, fibrinogen (Fbg) concentration, interferon (IFN-α, IFN-γ) and interleukins (IL-2 and IL-10) in foals with clinical R. equi pneumonia. The main treatment was with azithromycin-rifampicin for 14 days. Blood was ...
Bilateral bronchoalveolar lavage cytology profiles in a warmblood horse population during a 1-year period.
Journal of veterinary internal medicine    May 23, 2024   doi: 10.1111/jvim.17118
Rasmussen N, Karlsen P, Otten ND, Fjeldborg J, Hansen S.Bronchoalveolar lavage (BAL) cytology results from 1 lung might not be representative of both lungs. Objective: To determine whether the lung site sampled would influence the horse's BAL cytology profile, and if a pooled BAL sample would be superior with regard to BAL cytology diagnosis in a cohort of healthy and subclinical asthmatic warmblood horses. Methods: Fifty-nine horses in 2021 and 70 horses in 2022, the follow-up included 53 of the same in each year. Methods: A cross-sectional study with follow-up included BAL cytology samples from individual lungs and from pooled BAL samples. The BA...
Immune-mediated Equine Vasculopathies.
The Veterinary clinics of North America. Equine practice    May 23, 2024   Volume 40, Issue 2 253-261 doi: 10.1016/j.cveq.2024.04.002
Bozorgmanesh R.Immune-mediated vasculopathies occur secondary to infection or another noninfectious stimulus. Potential triggers include heterologous antigens including viruses, injected proteins and drugs; or auto-antigens including immunoglobulins or other endogenous proteins. Although these conditions are rare in horses, immune-mediated vasculopathies can cause considerable morbidity, with variable clinical signs depending on severity and organ system affected. Examples include purpura hemorrhagica, systemic lupus erythematosus, drug-induced vasculitis, paraneoplastic vasculitis, and idiopathic immune-med...
Approach to Inflammatory Bowel Disease.
The Veterinary clinics of North America. Equine practice    May 23, 2024   Volume 40, Issue 2 287-306 doi: 10.1016/j.cveq.2024.04.004
Timko K.Inflammatory bowel disease (IBD) in the horse encompasses a group of infiltrative gastrointestinal disorders resulting in malabsorption, maldigestion, weight loss, colic, and sometimes diarrhea. The type of IBD can be classified as granulomatous, lymphocytic-plasmacytic, or eosinophilic enterocolitis. The diagnosis of IBD in equids is based on consistent clinical signs and clinicopathologic findings in conjunction with confirmatory histopathology from a gastrointestinal biopsy. Treatment usually consists of a combination of immunosuppressive medications, anthelmintics, and dietary modification...
The balance of n-6 and n-3 fatty acids in canine, feline, and equine nutrition: exploring sources and the significance of alpha-linolenic acid.
Journal of animal science    May 22, 2024   Volume 102 doi: 10.1093/jas/skae143
Burron S, Richards T, Krebs G, Trevizan L, Rankovic A, Hartwig S, Pearson W, Ma DWL, Shoveller AK.Both n-6 and n-3 fatty acids (FA) have numerous significant physiological roles for mammals. The interplay between these families of FA is of interest in companion animal nutrition due to the influence of the n-6:n-3 FA ratio on the modulation of the inflammatory response in disease management and treatment. As both human and animal diets have shifted to greater consumption of vegetable oils rich in n-6 FA, the supplementation of n-3 FA to canine, feline, and equine diets has been advocated for. Although fish oils are commonly added to supply the long-chain n-3 FA eicosapentaenoic acid (EPA), ...
Case report: Equine metacarpophalangeal joint partial and full thickness defects treated with allogenic equine synovial membrane mesenchymal stem/stromal cell combined with umbilical cord mesenchymal stem/stromal cell conditioned medium.
Frontiers in veterinary science    May 22, 2024   Volume 11 1403174 doi: 10.3389/fvets.2024.1403174
Reis IL, Lopes B, Sousa P, Sousa AC, Rêma A, Caseiro AR, Briote I, Rocha AM, Pereira JP, Mendonça CM, Santos JM, Lamas L, Atayde LM, Alvites RD....Here, we describe a case of a 5-year-old show-jumping stallion presented with severe lameness, swelling, and pain on palpation of the left metacarpophalangeal joint (MCj). Diagnostic imaging revealed full and partial-thickness articular defects over the lateral condyle of the third metacarpus (MC3) and the dorsolateral aspect of the first phalanx (P1). After the lesion's arthroscopic curettage, the patient was subjected to an innovative regenerative treatment consisting of two intra-articular injections of equine synovial membrane mesenchymal stem/stromal cells (eSM-MSCs) combined with umbilic...
Evaluation of gastrointestinal tract lesions and serum malondialdehyde levels after repeated oral administration of phenylbutazone in horses.
Veterinary research communications    May 21, 2024   Volume 48, Issue 4 2343-2355 doi: 10.1007/s11259-024-10415-y
Tesena P, Vinijkumthorn R, Preuksathaporn T, Piyakul P, Chotikaprakal T, Sirireugwipas R, Wong-Aree K, Prapaiwan N.Phenylbutazone (PBZ) is a widely used nonsteroidal anti-inflammatory drug for horses. However, because of its gastrointestinal side effects, its administration requires careful attention in veterinary practice. Malondialdehyde (MDA) is a serum biomarker associated with increased damage to the equine gastrointestinal system. This study investigated the hematological effects and alterations in the gastrointestinal tract and assessed serum MDA concentrations following repeated oral PBZ administration at clinical doses. Fourteen horses were randomly divided into control and treatment groups. All h...
Eosinophils Play a Surprising Leading Role in Recurrent Urticaria in Horses.
Vaccines    May 21, 2024   Volume 12, Issue 6 doi: 10.3390/vaccines12060562
Birkmann K, Jebbawi F, Waldern N, Hug S, Inversini V, Keller G, Holm A, Grest P, Canonica F, Schmid-Grendelmeier P, Fettelschoss-Gabriel A.Urticaria, independent of or associated with allergies, is commonly seen in horses and often shows a high reoccurrence rate. Managing these horses is discouraging, and efficient treatment options are lacking. Due to an incidental finding in a study on horses affected by insect bite hypersensitivity using the eosinophil-targeting eIL-5-CuMV-TT vaccine, we observed the prevention of reoccurring seasonal urticaria in four subsequent years with re-vaccination. In an exploratory case series of horses affected with non-seasonal urticaria, we aimed to investigate the role of eosinophils in urticaria....
The Best Protocol to Treat Equine Skin Wounds by Second Intention Healing: A Scoping Review of the Literature.
Animals : an open access journal from MDPI    May 18, 2024   Volume 14, Issue 10 doi: 10.3390/ani14101500
Ribeiro G, Carvalho L, Borges J, Prazeres J.Equine skin wound treatment continues to be a challenge for veterinarians. Despite being a frequent practice, it remains difficult to choose an evidence-based treatment protocol. This study aimed to comprehensively explore the literature and provide a scoping review of therapeutic strategies for equine skin wounds and identify knowledge gaps and opportunities for future research. This review was conducted using specific criteria to select literature that described methods to manage second intention wound healing. After removing duplicates and screening papers for suitability, 81 manuscripts we...
Dexmedetomidine preconditioning reduces ischaemia-reperfusion injury in equine model of large colon volvulus.
Equine veterinary journal    May 15, 2024   Volume 56, Issue 6 1251-1258 doi: 10.1111/evj.14099
Watkins A, Engiles J, Long A, Brandly J, Hopster K.Large colon volvulus is a cause of colic in horses with high morbidity and mortality when not promptly treated. More treatment options are needed to improve the outcome of these cases by protecting against the damage caused by ischaemia and reperfusion injury. Objective: To determine the effect of preconditioning with dexmedetomidine prior to induction of ischaemia-reperfusion (IR) injury in a large colon volvulus model in the horse. Methods: Randomised blinded in vivo experiments. Methods: Horses received either a dexmedetomidine (DEX) or saline (CON) constant rate infusion (CRI) immediately ...
Feasibility of hemoperfusion using extracorporeal therapy in the horse.
Frontiers in veterinary science    May 14, 2024   Volume 11 1414426 doi: 10.3389/fvets.2024.1414426
Hobbs KJ, Le Sueur ANV, Burke MJ, Cooper BL, Sheats MK, Ueda Y.Develop, implement, and monitor for adverse effects of, a novel hemoperfusion therapy in adult horses. Unassigned: A prospective, observational feasibility study using three healthy adult horses from the North Carolina State University teaching herd. Health status was determined by physical exam, complete blood count, coagulation panel, and serum biochemistry. Each horse was instrumented with a 14 Fr × 25 cm double-lumen temporary hemodialysis catheter and underwent a 240 min polymer-based hemoperfusion session. Horses were administered unfractionated heparin to maintain anti-coagulation ...
Microbiota characterization throughout the digestive tract of horses fed a high-fiber vs. a high-starch diet.
Frontiers in veterinary science    May 14, 2024   Volume 11 1386135 doi: 10.3389/fvets.2024.1386135
Raspa F, Chessa S, Bergero D, Sacchi P, Ferrocino I, Cocolin L, Corvaglia MR, Moretti R, Cavallini D, Valle E.Diet is one of the main factors influencing the intestinal microbiota in horses, yet a systematic characterization of the microbiota along the length of the digestive tract in clinically healthy horses, homogenous for age and breed and receiving a specific diet is lacking. Unassigned: The study used 16S rRNA amplicon sequencing to characterize the microbiota of the intestinal tracts of 19 healthy Bardigiano horses of 14.3  ±  0.7  months of age fed one of two diets. Nine horses received a high-starch diet (HS), and ten horses received a high-fiber diet (HF). After 129  days, the horse...
Expression of IL-10 and TGF-β1 in horses experimentally infected with T. equi merozoites is associated with antibody production but not modulation of pro-inflammatory responses.
Frontiers in immunology    May 13, 2024   Volume 15 1370255 doi: 10.3389/fimmu.2024.1370255
Onzere CK, Bastos RG, Bishop RP, Suarez CE, Fry LM. () is an apicomplexan parasite that causes severe hemolytic anemia in equids. Presently, there is inadequate knowledge of the immune responses induced by in equid hosts impeding understanding of the host parasite relationship and development of potent vaccines for control of infections. The objective of this study was to evaluate the host-parasite dynamics between merozoites and infected horses by assessing cytokine expression during primary and secondary parasite exposure, and to determine whether the pattern of expression correlated with clinical indicators of disease. Our findings showe...
Immunology of Physical Exercise: Is Equus caballus an Appropriate Animal Model for Human Athletes?
International journal of molecular sciences    May 10, 2024   Volume 25, Issue 10 5210 doi: 10.3390/ijms25105210
Witkowska-Piłaszewicz O, Malin K, Dąbrowska I, Grzędzicka J, Ostaszewski P, Carter C.Domestic horses routinely participate in vigorous and various athletic activities. This enables the horse to serve as a model for studying athletic physiology and immunology in other species, including humans. For instance, as a model of physical efforts, such as endurance rides (long-distance running/aerobic exercise) and races (anaerobic exercise), the horse can be useful in evaluating post-exercise response. Currently, there has been significant interest in finding biomarkers, which characterize the advancement of training and adaptation to physical exercise in the horse. The parallels in c...
Towards personalized medicine for the treatment of equine asthma.
Veterinary journal (London, England : 1997)    May 2, 2024   106125 doi: 10.1016/j.tvjl.2024.106125
Leduc L, Leclère M, Lavoie JP.Although horses with asthma share similar clinical signs, the heterogeneity of the disease in terms of severity, triggering factors, inflammatory profile, and pathological features has hindered our ability to define biologically distinct subgroups. The recognition of phenotypes and endotypes could enable the development of precision medicine, including personalized, targeted therapy, to benefit affected horses. While in its infancy in horses, this review outlines the phenotypes of equine asthma and discusses how knowledge gained from targeted therapy in human medicine can be applied to evaluat...
Neonatal and maternal upregulation of antileukoproteinase in horses.
Frontiers in immunology    April 26, 2024   Volume 15 1395030 doi: 10.3389/fimmu.2024.1395030
Holmes CM, Babasyan S, Wagner B.The end of gestation, ensuing parturition, and the neonatal period represent highly dynamic phases for immunological changes in both mother and offspring. The regulation of innate immune cells at the maternal-fetal interface during late term pregnancy, after birth, and during microbial colonization of the neonatal gut and other mucosal surfaces, is crucial for controlling inflammation and maintaining homeostasis. Innate immune cells and mucosal epithelial cells express antileukoproteinase (SLPI), which has anti-inflammatory and anti-protease activity that can regulate cellular activation. Unas...
Equine Musculoskeletal Pathologies: Clinical Approaches and Therapeutical Perspectives-A Review.
Veterinary sciences    April 26, 2024   Volume 11, Issue 5 doi: 10.3390/vetsci11050190
Reis IL, Lopes B, Sousa P, Sousa AC, Caseiro AR, Mendonça CM, Santos JM, Atayde LM, Alvites RD, Maurício AC.Musculoskeletal injuries such as equine osteoarthritis, osteoarticular defects, tendonitis/desmitis, and muscular disorders are prevalent among sport horses, with a fair prognosis for returning to exercise or previous performance levels. The field of equine medicine has witnessed rapid and fruitful development, resulting in a diverse range of therapeutic options for musculoskeletal problems. Staying abreast of these advancements can be challenging, prompting the need for a comprehensive review of commonly used and recent treatments. The aim is to compile current therapeutic options for managin...
Rutin prevents EqHV-8 induced infection and oxidative stress via Nrf2/HO-1 signaling pathway.
Frontiers in cellular and infection microbiology    April 25, 2024   Volume 14 1386462 doi: 10.3389/fcimb.2024.1386462
Chen L, Li S, Li W, Yu Y, Sun Q, Chen W, Zhou H, Wang C, Li L, Xu M, Khan MZ, Li Y, Wang T.The Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway has been extensively studied for its role in regulating antioxidant and antiviral responses. The Equid herpesvirus type 8 (EqHV-8) poses a significant threat to the equine industry, primarily manifesting as respiratory disease, abortions, and neurological disorders in horses and donkeys. Oxidative stress is considered a key factor associated with pathogenesis of EqHV-8 infection. Unfortunately, there is currently a dearth of therapeutic interventions available for the effective control of EqHV-8. R...
Carbonate buffer mixture and fecal microbiota transplantation hold promising therapeutic effects on oligofructose-induced diarrhea in horses.
Frontiers in veterinary science    April 22, 2024   Volume 11 1388227 doi: 10.3389/fvets.2024.1388227
Tuniyazi M, Tang R, Hu X, Fu Y, Zhang N.Diarrhea is a common gastrointestinal disorder in horses, with diet-induced diarrhea being an emerging challenge. This study aimed to investigate the gut microbiota differences in healthy and diet-induced diarrheic horses and evaluate the effectiveness of fecal microbiota transplantation (FMT) and carbonate buffer mixture (CBM) as potential therapeutic approaches. Twenty healthy horses were included in the study, with four groups: Control, Diarrhea, CBM, and FMT. Diarrhea was induced using oligofructose, and fecal samples were collected for microbiota analysis. FMT and CBM treatments were admi...
Differences in bone turnover markers and injury risks between local and international horses: A Victorian Spring Racing Carnival study.
Equine veterinary journal    April 18, 2024   Volume 57, Issue 2 333-346 doi: 10.1111/evj.14098
Ayodele BA, Pagel CN, Mackie EJ, Armour F, Yamada S, Zahra P, Courtman N, Whitton RC, Hitchens PL.Musculoskeletal injuries (MSI) are common in racehorses and have been of increasing concern in horses travelling internationally to compete. Understanding the differences in bone turnover between local horses and international horses following long-distance air transportation may inform MSI prevention strategies. Objective: To understand the differences in bone turnover markers and risk of MSI between local horses and international horses following long-distance air transportation. Methods: Prospective cohort. Methods: The concentrations of bone turnover markers (OCN and CTXI), markers of stre...
Local and systemic responses to repeated gluteal muscle microbiopsies in mature sedentary horses.
Journal of equine veterinary science    April 18, 2024   105070 doi: 10.1016/j.jevs.2024.105070
Artman JL, Wesolowski LT, Semanchik PL, Isles JK, Norton SA, White-Springer SH.We aimed to test the hypothesis that repeated muscle collections would impact mitochondrial function, antioxidant status, and markers of inflammation and muscle damage. Twenty-six horses (8 geldings, 18 mares; mean±SD 9.5±3.5 y) had gluteus medius muscle biopsy samples collected at: 0 and 24h (n=7); 0 and 6h (n=6); 0, 6, and 12h (n=7); or 0, 6, 12, and 24h (n=6). Blood was collected from all horses every 6h for 72h, starting 24h prior to the 0h muscle collection. Data were analyzed using mixed linear models. Muscle integrative (per mg tissue) electron transfer capacity of complex II decrease...
Arthrospira platensis enriched with Cr(III), Mg(II), and Mn(II) ions improves insulin sensitivity and reduces systemic inflammation in equine metabolic affected horses.
Frontiers in endocrinology    April 16, 2024   Volume 15 1382844 doi: 10.3389/fendo.2024.1382844
Tomal A, Szłapka-Kosarzewska J, Mironiuk M, Michalak I, Marycz K.Equine metabolic syndrome (EMS) is a critical endocrine condition in horses, characterized by hyperinsulinemia, hyperlipidemia, and insulin resistance, posing a significant threat to their health. This study investigates the efficacy of supplementing EMS-affected horses with Arthrospira platensis enriched with Cr(III), Mg(II), and Mn(II) ions using biosorption process in improving insulin sensitivity and glucose tolerance, reducing inflammation, and mitigating obesity-related fat accumulation. Our results demonstrate that Arthrospira supplementation reduces baseline insulin and glucose levels,...
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