Journal of Exercise & Organ Cross Talk

Abstract This study aimed to investigate the effects of high-intensity interval training (HIIT) on Adiponectin receptor 1 (AdipR1) gene expression in breast tumor tissue and serum levels of glutathione peroxidase (GPX) and glutathione reductase (GR) in a murine model of breast cancer. Sixteen female BALB/c mice were inoculated subcutaneously with 4T1 murine mammary carcinoma cells (5 × 10⁵ cells/mouse). One week post-inoculation, mice were randomly assigned to either a tumor-bearing control group (Tumor, n=8) or a tumor-bearing group subjected to HIIT (Tumor+HIIT, n=8). The HIIT protocol was performed on a motor-driven treadmill five days/week for four weeks, consisting of six 2-minute high-intensity intervals (18–25 m/min, 80–90% VO₂max) interspersed with 3-minute active recovery periods (5–9 m/min). Twenty-four hours after the final session, tumor tissues were excised for AdipR1 gene expression analysis via quantitative real-time PCR (2^-ΔΔCT method), and serum samples were collected for assessment of GPX and GR levels using ELISA. Statistical comparisons were performed using independent samples t-tests (p<0.05). HIIT significantly upregulated AdipR1 gene expression in breast tumor tissue compared to the control group (p<0.0001). Serum GPX levels were significantly decreased in the Tumor+HIIT group compared to the Tumor control group (p<0.0001). However, no significant difference was observed in serum GR levels between the two groups (p=0.7499). These findings suggest that HIIT may influence breast cancer progression through adiponectin-mediated pathways and oxidative stress regulation, providing a potential non-pharmacological adjunctive strategy for breast cancer management. Further studies are warranted to elucidate the underlying molecular mechanisms and clinical implications.

Abstract This study investigated the effects of high intensity interval training (HIIT), Nano-selenium supplementation, and their combination on the expression of LDHA, LDHB, and the LDHA/LDHB ratio in mice breast tumor tissue. Female mice (n=32) were inoculated with mammary adenocarcinoma cells (4T1) and randomly assigned to four groups (n=8 each): tumor control (Tu), tumor+HIIT (Tu+Ex), tumor + Nano-selenium (Tu+Nsel, 2 mg/kg/day orally), and tumor+HIIT+Nano-selenium (Tu+Ex+Nsel). HIIT was performed on a treadmill (30 min/day, 5 days/week) for four weeks. One-way ANOVA revealed significant differences among groups for LDHA expression (F=38.66, p<0.0001). Compared to the Tu group, all intervention groups (Tu+Ex,Tu+Nsel, and Tu+Ex+Nsel) showed a significant increase in LDHA expression (p<0.05). The greatest increase was observed in the combined treatment group (Tu+Ex+Nsel), which was significantly higher than both Tu+Ex and Tu+Nsel (p<0.001). For the LDHA/LDHB ratio, a significant overall effect was found (F=163.87, p<0.0001). The Tu+Nsel group exhibited a significant increase in the ratio compared to the Tu group (p<0.05), whereas both Tu+Ex and Tu+Ex+Nsel showed a significant decrease in the ratio (p<0.05). The ratio in the Tu+Nsel group was also significantly higher than in the two exercise containing groups (p<0.05). HIIT and Nano-selenium independently upregulate LDHA expression in breast tumor tissue, with an additive effect when combined. However, only Nano-selenium alone increased the LDHA/LDHB ratio, while exercise-based interventions (with or without Nano-selenium) decreased this ratio. These findings suggest that exercise and Nano-selenium differentially shift the balance between LDHA and LDHB, potentially influencing tumor lactate metabolism and the tumor microenvironment.

Abstract To investigate the individual and combined effects of six weeks of aerobic exercise and hydroalcoholic extract of Urtica dioica (nettle) on tumor volume, body weight, and interleukin-10 (IL-10) levels in both serum and tumor tissue in male C57BL/6 mice bearing B16F10 melanoma tumors. Thirty-two male C57BL/6 mice (6–8 weeks old, 12–14 g) were randomly assigned to four equal groups (n=8): Control, Aerobic Exercise (AE), Nettle Extract (NE), and Combined (AE+NE). Melanoma was induced via surgical implantation of B16F10 tumor fragments. The AE protocol consisted of treadmill running for 6 weeks (5 days/week, progressing from 20 to 30 minutes/session at 6–16 m/min). The NE group received intraperitoneal injections of hydroalcoholic nettle extract (200 mg/kg body weight). The combined group received both interventions. The combined AE+NE group showing a significant reduction in tumor volume compared to the control group (p=0.0186). One-way ANOVA revealed significant differences in serum IL-10 across groups (F=9.811, p=0.0001), with significant increases observed in the AE (p=0.0003) and AE+NE (p = 0.0005) groups compared to controls. For tumor IL-10, a significant difference was also found across groups (F=3.047, p= 0.0451), with the combined AE+NE group showing a significant decrease (p =0.0435) compared to the control group. No significant correlation was found between serum and tumor IL-10 levels in any group (p>0.05). The combined intervention significantly suppressed tumor growth compared to controls and was associated with increased serum IL-10 levels but decreased IL-10 levels within the tumor microenvironment, suggesting a complex, compartment-specific immunomodulatory effect.

Abstract Melanoma is an aggressive malignancy with a high propensity for metastasis, particularly to the liver. This study investigated the individual and combined effects of resistance training (RT) and pineapple extract (PE) supplementation on primary melanoma tumor growth and the expression of hepatic apoptotic markers (Bax, Bcl-2) in a murine model. C57BL/6 mice bearing subcutaneous B16F10 melanoma tumors were allocated to four groups: Tumor Control (TC), RT, PE, and Combined (RT+PE). The six-week intervention consisted of ladder-climbing RT and/or oral PE supplementation. Tumor volume was measured throughout the study. Upon completion, hepatic Bax and Bcl-2 gene expression was analyzed via qPCR. While RT and PE alone did not significantly affect tumor volume, the Combined (RT+PE) group showed a significant reduction compared to the TC group (p<0.05). In the liver, all intervention groups (RT, PE, and Combined) significantly decreased pro-apoptotic Bax expression and increased anti-apoptotic Bcl-2 expression relative to the TC group (p<0.05). The combination of resistance training and pineapple extract exhibits a synergistic effect in reducing primary melanoma tumor growth. Furthermore, both interventions independently and collectively modulate systemic apoptotic markers in the liver, suggesting a potential role in influencing the hepatic microenvironment. This non-invasive combinatorial approach may represent a promising complementary strategy for managing melanoma progression and its systemic effects.

Abstract This study aimed to evaluate the individual and combined effects of aerobic training (AT) and pineapple supplementation (extract) on programmed cell death protein 1 (PD-1) gene expression within the tumor microenvironment and on systemic interleukin-10 (IL-10) levels in a murine melanoma model. Twenty C57BL/6 mice were randomly assigned into four groups (n=5 per group) following melanoma tumor induction: Tumor control, AT, Pineapple Supplement (PS), and AT+PS. The AT group underwent a structured aerobic training program, while the PS group received pineapple extract (300 mg/kg/day) via oral gavage for six weeks. Serum IL-10 concentrations were quantified by ELISA, and PD-1 mRNA expression in tumor tissue was analyzed using quantitative RT-PCR. All intervention groups—AT, PS, and their combination—resulted in a significant downregulation of PD-1 gene expression within the tumor compared to the control group (p < 0.05). In contrast, neither AT nor PS alone significantly altered systemic IL-10 levels. The combination therapy (AT+PS) produced the most pronounced suppression of PD-1 and was the only intervention to elicit a significant, though modest, reduction in serum IL-10. These findings indicate that the primary immunomodulatory effect of these interventions is localized to the tumor microenvironment and is largely independent of systemic IL-10 signaling. The synergistic combination of aerobic training and pineapple supplementation potently suppresses PD-1 gene expression, suggesting a promising, non-pharmacological strategy for enhancing anti-tumor immunity. Further investigation is required to confirm these effects at the protein level and to elucidate the underlying mechanisms.

Abstract This study investigated the combined efficacy of interval training and thyme honey in attenuating the expression of inflammatory genes (TNF-α and TGF-β) in renal tissue and improving insulin resistance in diabetic rats. In this experimental study, 32 young male Wistar rats were divided into 4 groups: diabetes mellitus control (DM), diabetes and interval training (DM+HIIT), diabetes and thyme honey (DM+TH), and diabetes and interval training-thyme honey (DM+HIIT+TH). Animals in the training group underwent 40 sessions of training over two months with a gradual increase in the number of intense intervals from 2 to 8 intervals and an intensity of 80 to 95% of maximum running speed. At the same time, the samples in the TH groups received thyme honey at a rate of g/kg 3 and 5 days per week. Insulin resistance index (HOMA-IR) was performed using the formula. TNF- α  and TGF-β gene expression in kidney tissue was evaluated using Real-Time PCR. Based on the results of the present study, DM+HIIT significantly reduced HOMA-IR compared to the diabetes group (p<0.05). However, the DM+HIIT+TH group did not yield a greater improvement in HOMA-IR than the DM+HIIT group alone. Also, TNF-α and TGF-β genes in the DM+HIIT, DM+TH and DM+HIIT+TH groups showed a significant decrease compared to the diabetes group (p<0.05). In conclusion, our findings provide strong evidence that both interval training and thyme honey supplementation independently ameliorate diabetic nephropathy by downregulating key pro-fibrotic and inflammatory mediators. While the combination therapy was highly effective at suppressing inflammatory genes, it did not provide a synergistic benefit for insulin sensitivity compared to exercise alone. These results suggest that interval exercise is the primary driver of improved insulin sensitivity in this model.

Abstract Epidemiological evidence indicates that obesity is associated with accelerated prostate cancer progression and elevated mortality rates. However, the underlying physiological mechanisms linking obesity to prostate cancer pathogenesis remain unclear. This study aimed to examine the effects of six weeks of moderate-intensity aerobic training combined with cannabidiol (CBD) supplementation on prostate protein kinase B (Akt) gene expression in high-fat diet (HFD)-induced obese male rats. Forty male Wistar rats (240 ± 20 g) were randomly assigned to five experimental groups: healthy control, HFD, HFD+exercise, HFD+CBD, HFD+exercise and CBD (n=8 per group). CBD was administered via oral gavage at 100 mg/kg, five days per week for six weeks. The aerobic exercise protocol consisted of treadmill running at progressive intensities, ranging from 15 m/min for 30 min to 27 m/min for 60 min, five days per week for six weeks. Following the intervention, prostate tissue was extracted for quantitative analysis of Akt gene expression. Statistical analysis revealed that aerobic exercise significantly modulated Akt gene expression (P=0.015). Similarly, CBD administration exerted a significant effect on Akt expression (P=0.004). However, no significant interactive effect was observed between aerobic exercise and CBD (P=0.068). These findings suggest that both aerobic exercise and CBD independently influence Akt signaling pathways, potentially through anti-inflammatory mechanisms, which may contribute to prostate cancer prevention. Further research is warranted to elucidate the precise molecular interactions involved.

Abstract The aim of the present study is to investigate the effect of aerobic exercise and nano-curcumin supplementation on cardiac TGF-β1/TRAF6 and CTGF pathways in rat with brain tumors. Forty male Wistar rats were divided into 5 groups (n=8 in each) of healthy control, brain tumor, tumor + aerobic exercise (AE), tumor + nanocurcumin (N-CUR) and tumor+AE+N-CUR. Glioblastoma was injected into the rats in the frontal cortex. Nano curcumin supplement at the dose of 80 mg/kg was gavage for 4 weeks, 5 days a week. The training groups performed aerobic exercises on the treadmill for 4 weeks, 3 days a week at a speed of 18 meters per minute, for 25-40 minutes. At the end, the rats were sacrificed and TGF-β1, TRAF6, CTGF were analyzed from the myocardium by Real-time PCR method. Compared to the healthy control group, Tumor group significantly increased TGF-β1 mRNA and TRAF6 mRNA in the myocardium (p<0.05). Also, compared to the healthy control group, all tumor groups showed a significant increase in CTGF mRNA expression (p<0.05). In contrast to the Tumor group, the Tumor+AE and Tumor+AE+N-CUR groups showed a significant decrease in TGF-β1 mRNA at myocardium (p=0.0010 and p=0.0002, respectively). It seems that aerobic exercise or exercise with nano-curcumin supplement has better protective effects on the heart of tumor rats with downregulation of TGF-β1. It is suggested that different doses and various exercise modalities should be investigated to control cardiac fibrosis from the TGF-β1/TRAF6 and CTGF pathways.

Abstract Unmanaged Type 2 Diabetes (DM2) is a known risk factor for cognitive decline, dementia, and Alzheimer's disease (DM3). This study explores the combined effects of high-intensity interval training (HIIT) and thyme honey on the expression of genes involved in memory-related signaling pathways (BDNF-TrkB-CREB), which are compromised in both DM2 and DM3. This experimental study involved 36 young male Wistar rats, divided into four groups: control (C), HIIT (T), thyme honey (H), and HIIT-thyme honey (TH). The T and TH groups underwent 40 training sessions over two months, with progressively increasing intervals (from 2 to 8) and intensity (from 80% to 95% of maximum running speed). Concurrently, the H and TH groups were administered 3 g/kg of thyme honey 5 days a week. Changes in BDNF, TrkB, and CREB gene expression were assessed using RT-PCR. The data were analyzed through one-way ANOVA, Bonferroni post hoc test, and Univariate analysis using SPSS-22 software. A significant increase in BDNF and CREB expression in the interactive intervention group and the expression of the TrkB gene in honey intervention groups were observed compared to diabetic control (P≥0.001). The interactive intervention with HIIT exercises and thyme honey has a synergistic effect on increasing gene expression in memory-related pathways. The highest effect size was observed for HIIT training on BDNF (EF=0.667) and CREB (EF=0.540), while the honey intervention showed a significant effect size on TrkB (EF=0.666).

Abstract Resistance exercises and nutritional strategy are the best ways to prevent with age- related muscle atrophy (sarcopenia) by improving the physiological function of skeletal muscle. This study investigated the effect of 8 weeks of Water resistance training with consumption of dark chocolate on the changes and correlation of IGF-1 and FOXO3 in elderly women. In this study, 40 sedentary elderly women with an age range of 60-73 years were randomly divided into four groups: 1. water resistance training, 2. water resistance training + dark chocolate, 3. dark chocolate, 4. control. The subjects of the training groups did water resistance training for eight weeks. During these 8 weeks, the dark chocolate groups consumed 30 grams of 83% dark chocolate every day, and the control group received neither exercise nor Dark chocolate. Blood sampling was done 48 hours before the study and after the end of the last training session. Expressions of IGF-1 and FOXO3 were measured by real time-PCR method. After 8 weeks of water resistance training and consumption of dark chocolate, the expression of insulin-like growth factor 1 (IGF-1) gene increased significantly compared to the pretest (p<0.05). However, FOXO3 did not change significantly (p>0.05). These findings underscore the potential of targeted exercise and dietary interventions in enhancing muscle health among the elderly, although further research is needed to understand the implications of unchanged FOXO3 in this context.

Abstract We investigate the effect of 6 weeks of aerobic training and probiotic supplementation on glycemic index and the correlation between glutathione peroxidase (GPX) and interleukin 15 (IL-15) in rats fed a high-fat diet. 40 male Wistar rats were divided into 5 groups (8 each): healthy control, high-fat diet (HFD), HFD+ aerobic exercise (Tr), HFD+ probiotic supplement (Sup) and HFD+Tr+Sup. Rats in the HFD group received a special high-fat diet for 2 months before the main protocol. The rats in the training groups ran on a rodent treadmill for 6 weeks, 5 days a week. Lactobacillus bifidus supplement was gavage to the rats of the supplemented groups in the amount of 10⁹ CFU/ml after each round of training. The results of the statistical test showed that the HFD groups had a significant decrease in GPX compared to the healthy control group (p<0.05). However, only the HFD+Tr+Sup group showed a significant increase in GPX compared to the HFD and HFD+Tr groups (p<0.05). In contrast, HFD+Sup showed a significant increase in IL-15 gene expression compared to the healthy control group. Compared to the HFD group, the HFD+Tr and HFD+Tr+Sup groups showed a decrease and the HFD+Sup group showed a significant increase in IL-15 gene expression (p<0.05). The correlation between GPX and IL-15 was not confirmed (p<0.05). It seems that exercise training and lactobacillus supplementation are effective in regulating glucose, GPX and IL-15 indices after HFD. However, more studies should be done for the relationship and cross talk between antioxidant indices and IL-15.

Abstract The present study will investigate the changes and correlation between the antioxidant enzyme superoxide dismutase (SOD) and the expression of interleukin 10 (IL-10) in rats fed a high-fat diet (HFD) after 6 weeks of aerobic exercise supplemented with the probiotic Lactobacillus bifidus. 40 male Wistar rats were divided into 5 groups (8 each): healthy control, high-fat diet (HFD), HFD+aerobic exercise (Tr), HFD+probiotic supplementation (Sup), and HFD+Tr+Sup. The rats in the HFD group received a special high-fat diet for 2 months prior to the main protocol. The rats in the exercise groups ran on a rodent treadmill for 6 weeks, 5 days a week. Lactobacillus bifidus supplementation was gavaged at a dose of 1 cc to the rats in the supplementation groups after each exercise session. Finally, the rats were sacrificed, and the IL-10 variable was measured using the Real-Time PCR method. The results of the present study indicated that the high-fat diet increased cholesterol and triglyceride levels (p<0.05). The HFD and HFD+Sup groups showed a significant decrease in SOD compared to the healthy control group (p<0.05). All treatment groups demonstrated a significant increase in SOD compared to the HFD group (p<0.05). The HFD+Tr and HFD+Tr+Sup groups showed a significant increase in IL-10 compared to the HFD group (p<0.05). However, the correlation between SOD and IL-10 was not confirmed (p>0.05). There was no correlation between the antioxidant enzyme and IL-10. Nevertheless, exercise and Lactobacillus bifidus were able to regulate the lipid profile, SOD, and IL-10 after a high-fat diet.

Abstract Performing aerobic exercise in different disease conditions can regulate cardiac homeostasis and reduce cardiac apoptosis caused by the disease. In brain cancer, other tissues, including cardiac tissue, can also be affected. Since exercise training causes organ crosstalk, in this study, the effects of aerobic exercise training (AET) on cardiac apoptosis in Glioblastoma multiforme (GBM) rats are evaluated. Twenty-four male Wistar rats were divided into 3 groups (n=8 in each) of healthy control, GBM, and GBM+AET. Glioblastoma was injected into the frontal cortex of rats. The training group (AET) performed aerobic exercises on the treadmill for 4 weeks, 3 days a week at a speed of 18 meters per minute, for 25-40 minutes. In the end, the rats were sacrificed and caspase-3 and caspase-7 were analyzed from the myocardium by Real-time PCR method. Considering H&E image, the GBM group showed necrosis and apoptosis in cardiac tissue compared to the healthy group. Compared to the healthy control group, GBM significantly increased caspase-3 and caspase-7 mRNA in the myocardium (p<0.05). However, in contrast to the GBM group, the GBM+AET showed a significant decrease in caspase-3 and caspase-7 mRNA at the myocardium (p<0.05). Since tumor formation in the body can affect other distant tissues in an endocrine manner, it is suggested to prioritize aerobic exercise to control the damage caused by GBM on heart tissue. However, more studies are needed, especially on human samples.