Hamed Alizadeh Pahlavani

Background: Type 2 diabetes mellitus (T2DM) negatively affects metabolic and neurobiological processes, including increases in hepatic β ‐hydroxybutyrate (BHB) and reductions in hippocampal doublecortin (DCX). Both saffron extract and resistance training have shown independent benefits in improving glycemic and neuroplastic markers; however, their combined effects on DCX and BHB in diabetic conditions have not been fully examined. This study evaluated the independent and synergistic effects of saffron extract supplementation and resistance training on glucose, hippocampal DCX, and hepatic BHB levels in rats with T2DM. Methods: Thirty adult male rats were randomly assigned to five groups ( n = 6 each): control (C), diabetic (D), diabetic with resistance training (DT), diabetic with saffron extract (DS), and diabetic with resistance training plus saffron extract (DTS). Diabetes was induced using streptozotocin (60 mg/kg). Saffron extract (25 mg/kg/day) was administered orally in the DS and DTS groups, and resistance training was performed five sessions per week for 6 weeks. Blood glucose, hippocampal DCX, and hepatic BHB levels were measured. Data were analyzed using one‐way ANOVA with a significance threshold of p < 0.05. Results: Both saffron extract and resistance training independently reduced glucose levels compared with the diabetic group, whereas the combined intervention produced the greatest reduction. DCX levels were significantly higher in the DTS group than in the D, DT, and DS groups ( p < 0.05). BHB levels in the DT, DS, and DTS groups were significantly lower than in the D group, with the lowest levels observed in the DT and DTS groups ( p < 0.05). Conclusion: Saffron extract combined with resistance training more effectively improves glucose regulation, increases hippocampal DCX expression, and reduces hepatic BHB levels in T2DM rats compared with either intervention alone.

Exercise and fasting, by activating hypothalamic neurons, lead to appetite regulation, increased energy efficiency, increased brown fat cells, and weight loss. Additionally, fasting and exercise affect brain plasticity and cognitive function by reducing oxidative brain damage and increasing brain-derived neurotrophic factor (BDNF), potentially reducing the risk of neurological diseases. In humans, these lifestyle interventions can also modulate autophagy and apoptosis in lymphocytes, especially natural killer (NK) cells, T cells, and B cells, which play an important role in fighting cancer and virus-infected cells. Fasting and exercise increase the concentration of autophagic monocytes, enhance killer T lymphocytes, strengthen the immune system, and delay cancer progression. Fasting and exercise can improve metabolic and inflammatory parameters through immune-related molecules, reducing systemic inflammation. Furthermore, they are associated with changes in the composition and function of gastrointestinal microbes, including an increase in beneficial microbes and a decrease in pathogenic bacteria, along with intestinal epithelial integrity.

Objective: Androgenic steroids abuse among young athletes has long-term health consequences, causing profound damage to vital organs such as the heart, blood vessels, brain, liver, gonads, kidneys, and skin. Results: In the vessels, steroids cause plaque formation, vascular calcification, thrombosis, and coronary artery disease, and in the heart, they lead to pathological fibrosis, dilated cardiomyopathy, heart failure, fatal ventricular arrhythmias, acute myocardial infarction, and reduced ejection fraction. The brain also suffers from cognitive decline, memory impairment, and a constellation of neurotransmitter abnormalities that lead to depression. In the liver, the consequences are severe and manifest as increased oxidative stress, liver dysfunction, hepatotoxicity, cholestatic jaundice, liver tumours, cell death, and elevations in liver enzymes, bilirubin, and cholesterol. Male athletes experience testicular atrophy, temporary suppression of spermatogenesis, hypogonadism, reduced fertility, infertility, and hormonal imbalance. In contrast, women experience ovarian dysfunction and menstrual irregularities. In the kidney, steroids lead to increased inflammatory cytokines, fibrosis, renal tubular hypertrophy, glomerular changes, and structural damage, and show higher levels of serum creatinine, urinary protein, and cystatin C. In athletes, steroids can lead to various skin problems such as acne, gynecomastia, prostatitis, and alopecia.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in the elderly with dementia, memory loss, and severe cognitive impairment that imposes high medical costs on individuals. The causes of AD include increased deposition of amyloid beta (Aβ) and phosphorylated tau, age, mitochondrial defects, increased neuroinflammation, decreased synaptic connections, and decreased nerve growth factors (NGF). While in animals moderate-intensity exercise restores hippocampal and amygdala memory through increased levels of p-AKT, p-TrkB, and p-PKC and decreased levels of Aβ, tau phosphorylation, and amyloid precursor proteins (APP) in AD. Aerobic exercise (with an intensity of 50–75% of VO2 max) prevents hippocampal volume reduction, spatial memory reduction, and learning reduction through increasing synaptic flexibility. Exercise training induces the binding of brain-derived neurotrophic factor (BDNF) to TrkB and the binding of NGF to TrkA to induce cell survival and neuronal plasticity. After aerobic training and high-intensity interval training, the increase of VEGF, angiopoietin 1 and 2, NO, tPA, and HCAR1 in cerebral vessels causes increased blood flow and angiogenesis in the cerebellum, motor cortex, striatum, and hippocampus. In the hippocampus, exercise training decreases mitochondrial fragmentation, DRP1, and FIS1, improving OPA1, MFN1, MFN2, and mitochondrial morphology. In humans, acute exercise as an anti-inflammatory condition causes an acute increase in IL-6 and an increase in anti-inflammatory factors such as IL-1RA and IL-10. Moderate-intensity exercise also inhibits inflammatory markers such as IFN-γ, IL-1β, IL-6, CRP, TNF-α, sTNFR1, COX-2, and NF-κB. Aerobic exercise significantly increases plasma levels of BDNF, nerve growth factor, synaptic plasticity, motor activity, spatial memory, and exploratory behavior in AD subjects. Irisin is a myokine released from skeletal muscle during exercise and protects the hippocampus by suppressing Aβ accumulation and promoting hippocampal proliferation through STAT3 signaling. Therefore, combined exercise training such as aerobic training, strength training, balance and coordination training, and cognitive and social activities seems to provide important benefits for people with AD.

Sarcopenia is a severe loss of muscle mass and functional decline during aging that can lead to reduced quality of life, limited patient independence, and increased risk of falls. The causes of sarcopenia include inactivity, oxidant production, reduction of antioxidant defense, disruption of mitochondrial activity, disruption of mitophagy, and change in mitochondrial biogenesis. There is evidence that mitochondrial dysfunction is an important cause of sarcopenia. Oxidative stress and reduction of antioxidant defenses in mitochondria form a vicious cycle that leads to the intensification of mitochondrial separation, suppression of mitochondrial fusion/fission, inhibition of electron transport chain, reduction of ATP production, an increase of mitochondrial DNA damage, and mitochondrial biogenesis disorder. On the other hand, exercise adds to the healthy mitochondrial network by increasing markers of mitochondrial fusion and fission, and transforms defective mitochondria into efficient mitochondria. Sarcopenia also leads to a decrease in mitochondrial dynamics, mitophagy markers, and mitochondrial network efficiency by increasing the level of ROS and apoptosis. In contrast, exercise increases mitochondrial biogenesis by activating genes affected by PGC1-ɑ (such as CaMK, AMPK, MAPKs) and altering cellular calcium, ATP-AMP ratio, and cellular stress. Activation of PGC1-ɑ also regulates transcription factors (such as TFAM, MEFs, and NRFs) and leads to the formation of new mitochondrial networks. Hence, moderate-intensity exercise can be used as a non-invasive treatment for sarcopenia by activating pathways that regulate the mitochondrial network in skeletal muscle.

Introduction Autophagy, apoptosis, and atrophy pathways are responsible for controlling cardiac cell homeostasis. This study aims to investigate the effect of high-intensity interval training (HIIT) on the expression of proteins involved in autophagy, apoptosis, and atrophy pathways in the myocardium of type 2 diabetic rats. Methods In this experimental study, 18 male Sprague-Dawley rats (2 months old, weighing 280 ± 20 g) were selected. 12 rats were made diabetic through intraperitoneal injection of STZ and nicotinamide solutions. These rats were randomly divided into 2 groups, HIIT + diabetes (HIIT + D), and diabetic (6 rats in each group). A control group (6 rats) was also considered. The HIIT + D group did HIIT protocol 4 days a week for 8 weeks. To analyze the data, one-way ANOVA and Tukey's post hoc tests were used. Results It was shown that HIIT leads to a significant increase in AKT and mTOR protein content between the HIIT + D and diabetic groups in the left ventricle. But there is no significant change in the content of AMPK proteins. The content of FOXO3a, Beclin1, P53, myostatin, and SMAD2/3 proteins showed a significant decrease in the HIIT + D group. The protein content of caspase-3 in the activated form did not show a significant change, but there was a significant decrease in the content of the initial form (Pro). Conclusion HIIT along with increasing regulation of AKT and mTOR proteins can disable autophagy, apoptosis, and atrophy pathways. Therefore, the process of apoptosis and atrophy of heart cells is reduced in type 2 diabetic rats.

The prevalence of maternal obesity during pregnancy is associated with the risk of gestational diabetes, preeclampsia, and cardiomyopathy. Environmental factors such as active lifestyles and apelin may lead to beneficial changes. In rats, apelin and exercise (45 to 65% VO_2max for 6 to 9 weeks) during pregnancy increase brown adipose tissue (BAT) proteins such as Cidea, Elovl3, UCP1, PRDM16, and PGC-1α in males and females fetuses, while white adipose tissue (WAT) is reduced. In humans and animals, apelin and exercise stimulate the expression of the glucose transporters (GLUT1/2/4) in the muscle and adipose tissue through the PI3K/Akt and AMPK pathways. Hence, exercise and apelin may are known as regulators of energy metabolism and be anti-obesity and anti-diabetic properties. In mice, exercise also creates a short-term hypoxic environment in the pregnant mother, activating HIF-1, VEGF, and VEGFR, and increasing angiogenesis. Exercise and apelin also increase vasodilation, angiogenesis, and suppression of inflammation through the L-arginine/eNOS/NO pathway in humans. Exercise can stimulate the ACE2-Ang-(1-7)-Mas axis in parallel with inhibiting the ACE-Ang II-AT1 pathway. Exercise and apelin seem to prevent preeclampsia through these processes. In rats, moderate-intensity exercise (60 to 70% VO_2max for 8 weeks) and apelin/APJ also may prevent pathological hypertrophy in pregnancy by activating the PI3K/Akt/mTOR/p70S6K pathway, PI3k-Akt-ERK1/2-p70S6K pathway, and the anti-inflammatory cytokine IL-10. Since pre-clinical studies have been more on animal models, future research with scientific guidelines should pay more attention to human specimens. In future research, time factors such as the first, second, and third trimesters of pregnancy and the intensity and duration of exercise are important variables that should be considered to determine the optimal intensity and duration of exercise.