Rational design of an anti-cancer peptide inhibiting CD147 / Cyp A interaction.

The CD147 / Cyp A interaction is a critical pathway in cancer types and an essential factor in entering the COVID-19 virus into the host cell. Melittin acts as an inhibitory peptide in cancer types by blocking the CD147/ Cyp A interaction. The clinical application of Melittin is limited due to weak penetration into cancer cells. TAT is an arginine-rich peptide with high penetration ability into cells widely used in drug delivery systems. This study aimed to design a hybrid peptide derived from Melittin and TAT to inhibit CD147 /Cyp A interaction. An amino acid region with high anti-cancer activity in Melittin was selected based on the physicochemical properties. Based on the results, a truncated Melittin peptide with 15 amino acids by the GGGS linker was fused to a TAT peptide (nine amino acids) to increase the penetration rate into the cell. A new hybrid peptide analog(TM) was selected by replacing the glycine with serine based on random point mutation. Docking results indicated that the TM peptide acts as an inhibitory peptide with high binding energy when interacting with CD147 and the CypA proteins. RMSD and RMSF results confirmed the high stability of the TM peptide in interaction with CD147. Also, the coarse-grained simulation showed the penetration potential of TM peptide into the DOPS-DOPC model membrane. Our findings indicated that the designed multifunctional peptide could be an attractive therapeutic candidate to halter tumor types and COVID-19 infection.

Intraperitoneal injection of buprenorphine on anxiety-like behavior and alteration in expression of Gfap and Nrf2 in methamphetamine treated rats.

The effects of buprenorphine (BUP) on anxiety-like behavior and the expression of the glial fibrillary acidic protein (Gfap) and nuclear factor erythroid 2-related factor 2 (Nrf2) in methamphetamine (METH)-treated rats were investigated in this study. Twenty-eight male Wistar rats were randomly divided into four groups including control (saline), METH (10.00 mg kg-1), BUP (10.00 mg kg-1), and BUP+METH groups and treated for five days. On the final day of treatment, gene expression levels and anxiety were evaluated using elevated plus-maze (EPM). According to the results, five days of METH injection reduced open arm exploration in the EPM. In contrast, the open arm entries and the time spent in the open arms were increased in the BUP+METH group compared to the METH group. The expression levels of Gfap and Nrf2 were lower in METH-treated rats compared to controls, whereas Gfap and Nrf2 expression levels were higher in the METH+BUP-treated rats compared to the METH-treated rats, however, it was similar to the controls. These findings suggested that co-administration of BUP+METH could decrease anxiety-like behavior through increasing the activity of the antioxidant protection system and might have therapeutic potential for preventing anxiety in METH users.

Rapid treatments for depression: Endocannabinoid system as a therapeutic target.

Current first-line treatments for major depressive disorder (MDD), i.e., antidepressant drugs and psychotherapy, show delayed onset of therapeutic effect as late as 2-3 weeks or more. In the clinic, the speed of beginning of the actions of antidepressant drugs or other interventions is vital for many reasons. Late-onset means that depression, its related disability, and the potential danger of suicide remain a threat for some patients. There are some rapid-acting antidepressant interventions, such as sleep deprivation, ketamine, acute exercise, which induce a significant response, ranging from a few hours to maximally one week, and most of them share a common characteristic that is the activation of the endocannabinoid (eCB) system. Activation of this system, i.e., augmentation of eCB signaling, appears to have anti-depressant-like actions. This article puts the idea forward that the activation of eCB signaling represents a critical mechanism of rapid-acting therapeutic interventions in MDD, and this system might contribute to the development of novel rapid-acting treatments for MDD.

Effect of exercise intensity and duration on the levels of stress hormones and hypothalamic-pituitary-gonadal axis in adult male rats: an experimental study.

PURPOSE: The effect of exercise on stress has been demonstrated in several studies which have shown that exercise intensity and duration have various effects on the reproductive axis. This study evaluated the effect of different intensities and durations of exercise on the hormonal indices of stress, such as corticosterone (CORT), norepinephrine (NEP), and also reproductive performance indices, including gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and testosterone (T). METHODS: In this experimental study, 30 adult Wistar rats were randomly divided into five groups as follows: no-exercise, RME-1 (regular moderate exercise for 1 month), RME-6 (regular moderate exercise for 6 months), RIE-1 (regular intensive exercise for 1 month), and RIE-6 (regular intensive exercise for 6 months). At the end of the experiment, the serum levels of the abovementioned hormones and hypothalamic expression of the Gnrh gene were measured using the enzyme-linked immunosorbent assay and the real-time polymerase chain reaction method, respectively. RESULTS: The levels of stress hormones, including CORT and NEP, increased only in the RIE-1 group compared with the no-exercise group. In addition, an increase was observed in T hormone levels in the RME-1 group compared with those in the no-exercise group, whereas LH and T hormone levels showed a greater decrease in the RIE-6 group than in the no-exercise group. Gnrh expression levels showed an increase and a decrease in the RME-1 and RIE-6 groups compared with the no-exercise group, respectively. CONCLUSION: These results confirmed the effects of different intensities and durations of exercise on sex hormone levels.

Conjugated Linoleic Acid-Curcumin Attenuates Cognitive Deficits and Oxidative Stress Parameters in the Ethidium Bromide-Induced Model of Demyelination.

Oxidative stress has been shown to play an important role in the pathogenesis of multiple sclerosis (MS). Curcumin (CUR), an antioxidant compound, can be a potent treatment for neurodegenerative diseases, such as MS. CUR has poor bioavailability; therefore, it is used in nanoforms to increase its bioavailability. In the present study, the effects of CUR and conjugated linoleic acid-CUR (Lino-CUR) on spatial memory and oxidative stress in a putative animal model of MS were investigated. Forty-nine adult male Wistar rats (250 ± 50 g) were randomly divided into seven groups (n = 7): control, sham, ethidium bromide (EB), CUR (20 and 40 µg/kg) + EB, and Lino-CUR (20 and 40 µg/kg) + EB groups. Following MS induction, the groups were treated for 5 consecutive days. Finally, spatial memory and levels of oxidative stress parameters were assessed. Treatment with CUR and Lino-CUR at two doses significantly improved spatial memory and reduced oxidative stress parameters in the experimental models of MS. Furthermore, the effects of high dose (40 µg/kg) of Lino-CUR were more remarkable. These findings suggest that the microinjection of CUR in its synthetic form Lino-CUR significantly ameliorated spatial memory, through the reduction of oxidative stress markers in the brain of studied animals as a rat model of MS.

Synergistic effects of quercetin and regular exercise on the recovery of spatial memory and reduction of parameters of oxidative stress in animal model of Alzheimer's disease.

It has widely been reported that the brain in Alzheimer's disease (AD) is affected by increased oxidative stress, and this may have a role in the pathogenesis of this disorder. Quercetin, a polyphenol extensively found in nature, has recently been considered. Also, physical activities have a paradoxical effect on brain function in older adults. Therefore, this study aimed at investigating the synergic effects of quercetin (as chemical treatment) and exercise (as physical treatment) on AD-induced learning and memory impairment. Fifty-six adult male Wistar rats were randomly assigned into one of the following eight groups (n=7): The Control, Sham (saline), AD (intracerebroventricular administration of streptozotocin (STZ)), AD+80 mg/kg Quercetin (STZ+Q80), Quercetin vehicle (1 % Ethanol)+STZ, Exercise pretreatment (EX)+STZ, Off the treadmill+STZ, and EX+Q80+STZ. Quercetin administration was done intraperitoneally for 21 days after STZ injection. The rats ran on the treadmill for one hour a day for 60 days at a speed of 20-22 m/min. After the treatment, the spatial memory and levels of oxidative stress parameters were evaluated. The results showed that STZ caused spatial memory impairment and increased oxidative stress in the hippocampus. Exercise pretreatment or Quercetin injection improved the spatial memory impairment and oxidative stress caused by STZ injection. However, the combination of quercetin and exercise pretreatment was more effective. It can be concluded that the combined exercise pretreatment and Quercetin injection affected the antioxidant defense system and improved STZ-induced memory impairment.

One-month of high-intensity exercise did not change the food intake and the hypothalamic arcuate nucleus proopiomelanocortin and neuropeptide Y expression levels in male Wistar rats.

OBJECTIVE: The hypothalamic arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) circuitries are involved in the inhibition and stimulation of the appetite, respectively. The aim of this study was to investigate the effects of one-month lasting high-intensity exercise on the POMC mRNA and NPY mRNA expression in the above-mentioned brain structure and appetite and food intake levels. METHODS: Fourteen male Wistar rats (250±50 g) were used and kept in the well-controlled conditions (22±2 °C, 50±5% humidity, and 12 h dark/light cycle) with food and water ad libitum. The rats were divided into two groups (n=7): 1) control group (C, these rats served as controls) and 2) exercised group (RIE, these rats performed a high-intensity exercise for one month (5 days per week) 40 min daily with speed 35 m/min. The total exercise time was 60 min. The body weight and food intake were recorded continuously during the experiments. RESULTS: The results showed relative mRNA expression of POMC and NPY estimated in the hypothalamic arcuate nucleus. There were no significant differences in the NPY and POMC mRNAs expression levels and food intake between C and RIE groups. CONCLUSIONS: The present data indicate that one-month regular intensive exercise did not alter the levels of NPY and POMC mRNAs expression (as two important factors in the regulation of appetite) in the hypothalamic arcuate nucleus and food intake suggesting that this type of exercise itself is not an appropriate procedure for the body weight reduction.

Various responses of male pituitary-gonadal axis to different intensities of long-term exercise: Role of expression of KNDYrelated genes.

The essential role of regular physical activity has been emphasized for maintaining a healthy life. However, unfortunately, during the last few decades, the lifestyle of people has led to a decrease in physical activity. Research studies have shown that exercise of different intensities is applied on reproductive performance indices, luteinizing hormone (LH) and testosterone (T), with different effects. Nevertheless, the molecular and cellular mechanisms underlying its function are not completely understood. Therefore, this study aimed to evaluate the role of kisspeptin, neurokinin-B and pro-dynorphin (KNDY) gene-expression changes located in the upstream of GnRH neurons in transferring the effects of different long-term exercise intensities on male reproductive axis. Twenty-one adult Wistar rats were randomly divided into control, 6-month regular moderate exercise (RME-6) and 6-month regular intensive exercise (RIE-6). In moderate and intensive exercise groups, rats were treated 5 days a week for 60 min, at 22 and 35 m/min, respectively. Finally, the hypothalamic arcuate nucleus was isolated and the relative gene expression of kisspeptin (Kiss1), neurokinin-B (Nkb), pro-dynorphin (Pdyn) and gonadotropin-releasing hormone (Gnrh) genes were measured by realtime polymerase chain reaction method. The results showed that RIE-6 treatment decreased Gnrh and increased Pdyn mRNA levels in the arcuate nucleus. Furthermore, although RME-6 treatment decreased Nkb and increased Pdyn mRNA levels, the Gnrh mRNAwas not affected. Regarding the Gnrh mRNA levels and serum concentrations of reproductive indices (LH and T), moderate exercise did not impose harmful effects on the hypothalamic-pituitary-gonadal axis than intensive exercise. The different impacts of diverse long-term exercise intensities on the male pituitary-gonadal axis maybe relay by the various changes in hypothalamic Nkb and Pdyn gene expressions.

Effects of short- and long-term regular exercise on reproductive tissue in streptozotocin-induced diabetic male Wistar rats.

OBJECTIVE: Reproductive disorders are one of the complications of diabetes mellitus. Since conflicting results have been obtained from different studies, which examined serum levels of cytokines in patients with diabetes, and considering the fact that the origin of cytokines cannot be accurately determined from their serum changes, attempts were made in the present study to study histological changes and testicular tissue levels of TNF-α and IL-1 in rats treated with exercise. Considering the effects of exercise in reducing blood sugar level and its complications, two types of short-term and long-term regular exercises were also considered to evaluate their effects on male reproductive tissues. METHODS: In this study, 60 male rats with the weight range of 250±50 g were used and were randomly divided into six groups (10 rats each). Healthy groups included sedentary control group, and groups treated with two and eight weeks of exercise. Rats with type 1 diabetes (induced by streptozotocin) included sedentary control group, groups treated with two and eight weeks of exercise (six groups). All groups were evaluated in terms of testicular tissue levels of TNF-α and IL-1 using ELISA and the histometry of spermatogonia, primary spermatocytes, Sertoli cells, epithelial thickness, diameter of veins, and thickness of the seminiferous tubule. RESULTS: Histological changes resulting from diabetes, particularly in the diameter of testicular veins and a number of cells, including Sertoli, highlights the important fact that tissue perfusion in patients with diabetes is especially crucial, in a way that exercise proved useful for tissue structures by offsetting this complication. Measurement of the cytokines IL-1 and TNF-α in the current study showed that perfusion problems are more important in diabetic complications than inflammatory factors. CONCLUSIONS: The main result of this research is recommendation of investigating the tissue of interest for diagnosis of diabetes complications, measuring inflammatory mediators of tissue rather than evaluating their serum concentrations, and focusing on vascular complications as a major complication of diabetes. Furthermore, regular exercise could help improve the function of reproductive organs in healthy groups and prevent diabetes infertility complications to an acceptable degree in diabetic groups.

Attenuation of phosphorylated connexin-43 protein levels in diabetic rat heart by regular moderate exercise.

BACKGROUND: High blood glucose levels increase the ratio of phosphorylated to non-phosphorylated connexin-43 amounts, which leads to the decomposition of the hyperphosphorylated connexin-43. This can cause heart arrhythmia in diabetic patients. Considering the effective role of exercise in diabetic patients, and because there are few studies regarding the effect of exercise on phosphorylated connexin-43 protein levels, in the present study the impact of different periods of moderate regular exercise on phosphorylated Connexion-43 levels were examined. METHODS: Sixty (60) male Wistar rats (300 ± 50 g) were randomly divided into six groups (n = 10). A week after induction of diabetes by injection of streptozotocin, one hour treadmill exercise, 5 days a week with 22 (m/min) speeds was undertaken. Left ventricles of hearts were isolated and immediately frozen. Finally, phosphorylated connexin-43 protein levels were measured by ELISA method. RESULTS: The means of blood glucose levels were significantly decreased (P < 0/05) by increasing days of exercise. The means of blood glucose levels were significantly decreased (P < 0/05) by increasing days of exercise. Regular moderate exercise reduced the connexin-43 levels by increasing days of exercise (P < 0.01). CONCLUSION: It is concluded that regular moderate exercise reduces the amount of phosphorylated connexin-43 protein levels in the ventricular myocardium, by reducing blood glucose levels. This can result in partial inhibition of cardiac arrhythmia observed in diabetic patients. This research was done in Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.