Introduction
The body's homeostatic response of the body is tremendously affected by rigorous exercise and is negatively influenced by high ambient temperatures and relative humidity [1].
Although several sources of IL-6 have been identified such as (e.g., T cells, B cells, macrophages, neutrophils, monocytes, keratinocytes, fibroblasts, endothelial cells, epithelial cells, osteoblasts, chondrocytes, adipocytes, and mesangial cells), the majority of the IL-6 that is produced during exercise and is seenfound in the peripheral blood comes from contracting muscles [2]. Exercise intensity and duration determine how much of the IL-6 response is produced [3]. Muscle contractions and IL-6 synthesis may be connected by several mechanisms and theories;: transcriptional factors that control the production of IL-6 can be activated by alterations in the homeostasis of calcium, decreased availability of glucose, and enhanced free radicals generation [4 -6]. Leukocytes, the hepatic tissue, fatty tissue, and the interaction of the hypothalamus, pituitary, and adrenal glands, are all modulated by IL-6 and may all affect how the body responds to exercise in terms of metabolism and immunity. However, for a marked systemic IL-6 response to occur, a significant amount of muscle tissue must be exercised [7]. Intrleukin-6The IL-6, also known as a myokine, possesses a significant anti-inflammatory prpertyability in its effects as a myokine. It significantly increases rises during exercise and is present in the blood before other cytokines. It is believed that it acts as a hormone to increase extracellular substrates during exercise [8].
Animals cannot synthesize ergothioneine (ERG), an extremely stable, naturally occurring nutraceutical that can only be obtained through their food. It is produced by Actinomycetales bacteria and non-yeast fungi. The greatest amounts of L-ergothioneine are found in mushrooms, especially in species like such as Boletus edulis and Pleurotus ostreatus. L-ergothioneine being a potent antioxidant may enhance the synthesis of IL-6 thereby quickly promoting the repair of damaged tissues. It is eliminated from the bloodstream and accumulates in cells and tissues following damage and oxidative stress [9]. It is swiftly absorbed by tissues by an exceptional transporter known as organic cation transporter new type 1 (OCTN-1), which plays distinct and significant functions in cellular processes [10-11]. The rate at which cells collect it suggests that ERG serves a critical physiological role [12]. Ergothioneine has two major functions: it regulates energy and shields tissue from oxidative and inflammatory harm. Ergothioneine It does not oxidize at the usual body pH, making it a highly stable antioxidant. Moreover, it prevents the generation of hydroxyl radicals from ferrous (Fe2+) ions and hydrogen peroxide [13]. Ergothioneine combats reactive oxygen species produced during physical activity, such as O2−, H2O2, OH-, and O2, functioning both as an selfless antioxidant and as a modulator of the cellular antioxidant defense and also modulating cytokine such as IL-6, thereby influencing cellular responses and functions [11].
The diseases rheumatoid arthritis and Crohn's disease are two long-standing inflammatory disorders that have been linked to changes in the gene coding for ergothioneine ERG transporter (OCTN1) [14-15]. Higher erythrocyte and monocyte concentrations of EGT ERG were discovered in individuals with less inflammation, and these levels were strongly linked with the expression of ergothioneine ERG transporter mRNA in specific body cells [16 ].
Consequently, this experiment aimeds to ascertain the effect of ergothioneine ERG on the myokine, interleukinIL-6, after an exercise of 2000 m at the highest possible speed (60 Km/h) in Arabian stallions.
Results
The meteorological indices of the site of the study in the hot-dry season are shown in
1. The dry-bulb temperature (DBT) rose (p < 0.05) from 22.6 ˚C±1.23 ˚C at 6 a.m. in the morning to 38.6 ˚C ± 6.53 ˚C at mid-day. The humidity index rose (p < 0.05) from 64.4% ± 2.34 % at 6 a.m. to 74.3% ± 6.73 % at mid-day (12.00 h). The temperature-humidity index increased from 76.41± 0.56 at 06.00 h a.m. in the morning tto 83.36 ± 4.53 at mid-day (12.00 h).
The findings of hematological indices are shown in Table 2. A higher leukcocyte count (8.73 ± 0.94 × 109/μl)) was obtained in the EXEC group compared to the count of 4.03 ± 0.14 × 109 /μl recorded in the EXEE group. The neutrophil count of 4.04 ± 3.09 × 109 /μl recorded in the EXEE group was higher (p < 0.05) than the value (2.14 ± 0.63 × 109/μl)) obtained in the EXEE stallions after the race.
.....
| Time of Day | Dry-Bulb Temperature (ºC) | Relative Humidity (%) | Temperature-Humidity Index |
| 06.00 | 22.6 ± 1.23a(22 - 24) | 64.4 ± 2.34a(63 – 68) | 76.41 ± 0.56a(68.71 - 83.65) |
| 12.00 | 38.6 ± 6.53b(37-39) | 74.3± 6.73b(72 - 78) | 83.36 ± 4.53b(81.32 - 89.01) |
| 18.00 | 36.5 ± 0.17(36-37) | 78.8 ± 5.98(76 - 81) | 83.24 ± 3.49(83.21 - 84.95) |
| Overall Mean ± SEM | 37.22 ± 4.17(36.11 - 37.33) | 75.19 ± 5.98(73.65 – 81.11) | 81.45 ± 5.18(78.11-84.76) |
a,bMeans for the same column having different superscript letters are significantly (P < 0.05) different .Values in Parentheses are Minimum - Maximum.
| Parameters | Time | NEXE | EXEC | EXEE |
| Leucocytes (×10 9 /L) | Pre-exercise | 3.21 ± 0.13 | 4.41 ± 0.18 | 4.82 ± 0.86 |
| null | Post-exercise | 3.33 ± 0.24 | 8.73 ± 0.94a | 4.03 ± 0.14b |
| Neutrophil (×10 9 /L) | Pre-exercise | 2.53 ± 0.11 | 2.83 ± 0.46 | 2.62 ± 0.76 |
| null | Post-exercise | 2.42 ± 0.13 | 4.04 ± 3.09a | 2.14 ± 0.63b |
| Lymphocytes (×10 9 /L) | Pre-exercise | 1.32 ± 0.21 | 1.72 ± 0.21 | 1.80 ± 0.19 |
| null | Post-exercise | 1.48 ± 0.42 | 1.69 ± 0.42 | 1.63 ± 0.57 |
| Monocytes (×10 9 /L) | Pre-exercise | 0.11 ± 0.05 | 0.17 ± 0.02 | 0.17 ± 0.03 |
| null | Post-exercise | 0.17 ± 0.03 | 0.18 ± 0.04 | 0.21 ± 0.02 |
| Erythrocytes (×10 12 /L) | Pre-exercise | 6.12 ± 0.13 | 7.42 ± 0.23 | 6.82 ± 0.37 |
| null | Post-exercise | 15.22 ± 3.74 | 11.63 ± 1.54 | 12.22 ± 0.68 |
| Total Protein (g/dl) | Pre-exercise | 4.4 ± 0.13 | 3.9 ± 0.16 | 4.35 ± 0.21 |
| null | Post-exercise | 5.1 ± 0.17 | 6.77 ± 0.56 | 7.11 ± 0.58 |
| Packed Cell Volume (%) | Pre-exercise | 32.13 ± 7.25 | 29.07 ± 0.26 | 29.15 ± 1.21 |
| null | Post-exercise | 35.42 ± 0.14 | 45.42 ± 0.24a | 54.42 ± 3.87b |
| Haemoglobin (g/dl) | Pre-exercisePost-exercise | 9.71 ± 0.369.95 ± 3.11 | 8.71 ± 0.3610.27 ± 2.77 | 7.65 ± 0.318.93 ± 2.83 |
| Neutrophil/Lymphocyte ratio | Pre-exercisePost-exercise | 1.91 ± 0.882.02 ± 0.03 | 1.65 ± 0.324.17 ± 0.69a | 1.46 ± 0.642.97 ± 0.23b |
a,bMeans for the same row having different superscript letters are significantly (P < 0.05) different. Key:NEXE = Not administered with ergothioneine, not exercised.EXEC = Not administered with ergothioneine but exercise. EXEE = Administered with ergothioneine before exercise
The value of stress index recorded in the EXEC group (4.17 ± 0.69) was higher than the value of 2.97 ± 0.13 recorded in the EXEE horses.
The IL-6 concentrations recorded in this study are shown in Figure 1. Concentrations of IL-6 obtained post-exercise were significantly higher in the EXEE stallions than in the EXEC stallions.
Discussion
The environmental temperature, humidity index, and temperature-humidity index of the experimental site in the hot-dry season were all found to be relatively high. The study's overall mean DBT of 37.22˚C ± 4.17 ˚C was higher than the 20˚C–25 ˚C range considered to beas the thermoneutral range zone for horses [17-19]. Horses experience heat stress when the ambient temperature is higher than the thermoneutral zone because of increased metabolism, enhanced heat losses via skin evaporation, and lowered thermal insulation. The RH value (75.19% ± 5.98%) recorded was also higher than the 70% level recommended for horses [20]. Elevated DBT and RH values in this the current experiment suggest that the horses experienced thermal stress. High DBT and RH make it challenging for sweat to evaporate from the skin's surface because the air is already moist. The horse is therefore put under heat stress by this occurrence. According to dos Santos et al. [21], the THI, a measure of heat load, was extremely high in this study, indicating that the stallions were under stress due to the hot temperatures in the study area. Elevated THI levels found in this study indicated the need for interventions, including the installation of fans in the stallions' stables and the administration of supplements to the horses, to lessen the deleterious effects of heat stress. Exercise causes a horse to gradually lose heat from its muscles and internal organs into the blood, which worsens the effects of heat stress on the stallions' locomotor system and lowers performance [22].
According to Faria et al. [23], the stress index (neutrophil-lymphocyte ratio), which is an indicator of inflammation and stress, was higher in the EXEC stallions than in the EXEE stallions, suggesting that the treatment with ergothioneine ERG before exercise reduced the stress of exercise and lowered inflammatory response. Better stress management and a lowered inflammatory response are indicated by a lower stress index (neutrophil-lymphocyte ratio).
It is unclear how the skeletal muscle responds to exercise-induced inflammation and injury by coordinating an adaptation mechanism that protects the muscle from future harm, known as the repeated bout effect (RBE) [24]. although IL-6, which has both pro- and anti-inflammatory actions, plays a crucial role. IL-6It is a myokine and is produced and expressed by the muscles more than other cytokines, such as TNFα and IL1β. It sends out an alert signal when there is tissue damage due to exercise [8]. The anti-inflammatory impact typically occurs after a brief but intense exercise, as demonstrated in this study [25]. IL6'sThe anti-inflammatory effects of IL-6 are brought on by the classical signaling mechanism [8]. More than any other cytokine, the blood concentration of IL-6 rises after intense exercise [25]. It has been proven that IL-6 has a role in regulating the early inflammatory response brought on by exercise in horses [26]. After exercise, interleukin-6 (IL-6) is released from the contracting skeletal muscles into the blood stream and metabolism is characterizsed by a rapid increases in plasma levels, with a peak few hours after exercise, and a gradual return to basal levels within 48 hours. IL-6 plays a role in regulating energy intake during exercise, acting as a "smart meter" to signal the release of energy substrates from liver and fatty tissue [25]. Although having a low affinity for IL-6, soluble glycoprotein 130 (sgp130) possesses a marked affinity for the IL-6/sIL-6 complex, inhibiting the inflammatory action of IL-6 after brief, intense exercise as observed in this study (21). According to a study, myocytes and macrophages have quite different signaling pathways for interleukinIL-6 in the exercising skeletal muscle after a period of intensive exercise [27]. It appears that muscular interleukinIL-6 expression is controlled by a connection of signaling events, including the Ca²+/NFAT and glycogen/p38 MAPK pathways, in contrast to macrophages IL-6 signaling, which depends on eliciting the nuclear factor kappa (BNF-B) signaling pathway [28]. Hence, IL-6 signaling in macrophages or monocytes results in inflammation, whereas the activation of IL-6 and its signaling in skeletal muscle after exercise is completely different from an earlier TNF response or NF-B activation and reduces inflammation [29]. Muscles are known to produce and release IL-6, which has been linked to the regulation of metabolism and the acceleration of satellite cell regeneration and proliferative activities [30]. InterleukinIL-6 is a short-term energy allocator that is also released from muscles as a result of reduced energy content. Interleukin-6 improves muscular energy uptake during exercise and releases cellular energy content through lipolysis [31]. We concluded that the greater levels of IL-6 after intense exercise may inhibit the excessive production of type 1 pro-inflammatory cytokines, hence lowering inflammation. An important enzyme involved in inflammation called myeloperoxidase (MPO) has been demonstrated to be inhibited by ergothioneine ERG. Moreover, it is widely known for terminating MPO-based reactive substances more quickly than glutathione and vitamin C. This includes HOCl [9 ].
Many investigations on this special molecule have revealed that it may lessen underlying disorders and tissue damage in various tissues, including the skeletal muscles [9]. Divalent metal ions, such as like Fe2+ and Cu2+ , can be bounnd to ergothioneine ERG with high stability constants [12]. By creating redox-inactive compounds with ergothioneineERG, this metal ion chelation stops the deterioration of biomolecules. Ergothioneine ERG could prevent future oxidative stress, which would reduce harm to muscles as well as, other tissues, and organs (especially the brain) [32]. While the expression of proinflammatory cytokines' expression is influenced by ergothioneineERG, it is possible that this compound could help break the cycle of hyperinflammation that is caused by macrophage activation and hyperferritinemia [33-34]. The findings of this study agree are in line with the study of Steensberg et al. [35] who reported that exercise can cause an increaseraise in interleukinIL-6, which can be explained by the synthesis of interleukinIL-6 in contracting human skeletal muscles. Ergothioneine ERG effectively targeted reactive oxygen species produced during the exercise, such as O2−, H2O, hydroxyl ion, and oxygen, functioning both as a self-sacrificing antioxidant and as a modulator of the cellular antioxidant defense and immune systems, thereby influencing the cellular redox state. Once the cellular redox state was established, it enhanced the optimal activity of S-Adenosyl-methionine (SAM) synthase. SAM plays a crucial role in maintaining normal cellular function and survival, being involved in three essential metabolic pathways: transmethylation, trans-sulfuration, and polyamine synthesis, all of which are vital for normal cellular function and stability.
Conclusion
It can Therefore, it can be concluded that ergothioneine ERG administration to stallions before exercise will enhance some hematological parameters and the synthesis of IL-6.
Experimental Animals
We used 24 untrained, clinically healthy Arabian stallions aged 5.7 ± 0.54 (range: 5-6 years) years, with an average weight of 401 ± 32.11 kilograms (range: 395 to -404 kg). The stallions were obtained from a royal stable and were only used for pleasure riding. The stallions were divided into three groups of eight each. Group I (NEXE), did was not engaged in exercise and was not administered ergothioneineERG, the second group (EXEC), was engaged in exercise but was not administered ergothioneineERG, and the third group (EXEE), received ergothioneine ERG before exercise.
The housing for the stallions was constructed using cement bricks, a concrete floor, corrugated iron roofing sheets, and a wooden ceiling. The horses underwent two weeks of preconditioning. The horses were fed with hay and their meal was augmented with groundnut bran. They had unlimited access to water. The stallions were checked for intestinal helminths, and all the infected ones were treated using albendazole (5 mg/kg body weight; Jubaili Agrotec, Kano, Nigeria).
Determination of Thermal Environmental Parameters
The relative humidity (RH) and dry-bulb temperature (DBT) values were ascertained by deploying a dry and wet-bulb thermometer manufactured by Mark, England. The formula postulated by Hartmann et al. [17], stated below was used to calculate the Temperature Humidity Index (THI).
THI = (DBT × 0.8) + {(RH/100 × (DBT-14.4) + 46.4}
Blood Sampling
Before the experiment, the site of the sample collection was cleaned with a clean piece of cotton dipped in an alcohol solution. Samples of blood (10 mL) were obtained from each stallion 15 minutes after the exercise and 2 hours after the exercise using 18-gauge needles. Jugular venipuncture was used to get the blood samples, and they were subsequently dispensed into both plain vacuum containers and vacuum containers with the anticoagulant potassium ethylenediaminetetraacetic acid (EDTA). The hematological parameters and IL-6 levels of the samples of blood were determined in the physiological research laboratory after the samples were conveyed to the laboratory using a box packed with ice. The stallions were fasted for about three 3 hours and were fed only after the experiment.
Administration of Ergothioneine to Stallions
Ergothioneine The ERG manufactured by Oxis International, (Los Angeles, California, USA) was given orally to each horse in the EXEE group four weeks before the experiment at a dose of 0.2 mg/kg. In the morning, ergothioneine ERG was given administered before eating. Ergothioneine The ERG was placed in warm water and aspirated using a correct-sized syringe. The solution was given orally to the restrained horse by putting the syringe into the mouth's corner and depressing the plunger to dispense the medication into the animal's mouth. The head of the horse's head was then slightly raised to ensure that the entire solution had been swallowed.
Exercise Protocol
Following the treatment of the stallions in the EXEE group, each of them was mounted by an appropriately kitted and trained rider with an average weight of 70.56 ± 4.23 kg and exercised at 2000 m at the highest possible speed using a standard race track.
Determination of Haematological Parameters
Using a standardized automatic analyzer for veterinary use (KT-6610 VET) manufactured in Jiangsu, China,) the following parameters were determined: count of erythrocytes, count of leukcocytes, haematocrit, and concentration of haemoglobin.
Determination of Serum Interleukin-6 Concentration
The Cloud-Clone Corporation (Houston, USA) horse IL-6 ELISA kit, a highly sensitive kit that shows detectable values in serum, was deployed to evaluate the serum content of IL-6. To obtain the serum, the whole blood was drawn, permitted to clot, and subsequently centrifuged to isolate the serum from blood cells and other elements. The clear, yellowish liquid that remains is the serum. An anti-interleukinIL-6 antibody which has been coated on the microplate was enclosed with this kit. The antibody conjugated with biotin unique for IL-6 was then placed in the appropriate microplate wells with the standards. ThenNext, each microplate well was added with horseradish peroxidase conjugated with avidin and placed in an incubator. Only wells that had interleukinIL-6, antibody conjugated with biotin, and Avidin- conjugated enzyme had altered its colour after the inclusion of Tetramethylbenzidine (TMB) solution subtrate. A solution of sulphuric acid was used to terminate the substrate-enzyme reaction, and the alteration in colour was evaluated spectrophotometrically at 450 nm wavelength. The optical density of the samples was then compared to the standard plot to ascertain the IL-6 content of the samples.
Data Analyses
The data obtained from this experiment was were expressed as mean ± standard error of the mean. The statistical test Shapiro-Wilk was used to determine whether the data was were normally distributed. The data was found to be normally distributed. The statistical test of one-way analysis of variance (ANOVA) was deployed applied to analyze the data after which it was subjected to Tukey’s post- hoc test. Only values of p ≤ 0.05 were considered significant. The Graph Pad Prism (version 5.3) manufactured by (GraphPad Software, Inc.) was used.
Authors' Contributions
ASA and JOA designed the experiment. ASA, JOA, PIR, and TA developed and edited the manuscript. DAA and ASA performed the research and analysis of the data.
Acknowledgements
he authority of the University of Ilorin, Nigeria is appreciated for partially funding the study.
Conflict of interest
The authors hereby declare that they have no competing interests.
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