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Doxorubicin (DOX) is an effective chemotherapeutic agent used for the treatment of various types of cancer. However, its poor solubility, undesirable side effects, and short half-life have remained a challenge. We used a formulation based on graphene oxide as an anticancer drug delivery system for DOX in MCF-7 breast cancer cells, to address these issues. In vitro release studies confirmed that the synthesized formulation has an improved release profile in acidic conditions (similar to the tumor microenvironment). Further in vitro studies, including MTT, uptake, and apoptosis assays were performed. The toxic effects of the nanocarrier on the kidney, heart and liver of healthy rats were also evaluated. We observed that the DOX-loaded carrier improved the cytotoxic effect of DOX on the breast cell line compared to free DOX. In summary, our results introduce the DOX-loaded carrier as a potential platform for in vitro targeting of cancer cells and suggest further studies are necessary to investigate its in vivo anti-cancer potential.

This study aimed to investigate the underlying mechanisms in anti-tumorigenesis effects of exercise through evaluation of inflammation and apoptosis. Twenty-four Wistar rats were divided into control, exercise, 1,2-dimethylhydrazine (DMH), and DMH + exercise. After a week, rats in the DMH group were given DMH twice a week for 2 weeks. Animals in the exercise groups performed exercise on a treadmill 5 days/week for 8 weeks. After 8 weeks of training, levels of COX-2, PCNA, Bax, Bcl-2, and procaspase-3/cleaved caspase-3 were assessed. Histological changes, number of aberrant crypt foci (ACF), and serum levels of TNF-[alpha] and IL-6 were also analyzed. ACF number was significantly decreased following the exercise program. Protein levels of COX-2 and PCNA and serum levels of IL-6 and TNF-[alpha] were significantly elevated in the rats receiving DMH and downregulated after performing the exercise program (P < 0.05). Exercise upregulated apoptosis, which was evident from the increased Bax/Bcl2 ratio, and enhanced the expression levels of activated caspase-3 as compared to the DMH group. The colonic architecture was improved in DMH + exercise. Exercise can effectively attenuate DMH-induced increase of inflammatory markers. Exercise induces apoptosis at the downstream of the inflammatory response. Therefore, exercise may play a role as a moderator of inflammation to exert protective effects against colon cancer. Key words: exercise, colorectal cancer, dimethylhydrazine, ACF, PCNA, COX-2, apoptosis. Cette etude portait sur les modes d'action sous-jacents des effets anti-tumorigenes de l'exercice physique par l'intermediaire de l'inflammation et de l'apoptose. Nous avons reparti 24 rats Wistar dans les groupes suivants: temoin, exercice physique, 1,2-dimethylhydrazine (DMH) et DMH + exercice physique. Apres une semaine, nous avons administre aux rats DMH du DMH 2 fois par semaine pendant 2 semaines. Les animaux des groupes exercice physique ont couru sur un tapis roulant 5 jours par semaine pendant 8 semaines. Apres 8 semaines d'entrainement, nous avons evalue les taux de COX-2, de PCNA, de Bax, de Bcl-2 et de caspase 3 scindee par la procaspase 3. Nous avons aussi evalue les variations histologiques, le nombre de foyers de cryptes aberrantes, ainsi que les taux seriques de TNF-[alpha] et d'IL-6. Le nombre de foyers de cryptes aberrantes etait nettement moins eleve a la suite du programme d'exercice physique. Les taux de COX-2 et de PCNA en proteines et les taux seriques d'IL-6 et de TNF-[alpha] etaient nettement plus eleves chez les rats recevant du DMH, avec une regulation a la baisse apres le programme d'exercice physique (P < 0,05). L'exercice physique entrainait une regulation a la hausse de l'apoptose, ce dont temoignait une augmentation du ratio Bax/Bcl2 avec une augmentation des taux d'expression de la caspase 3 activee par rapport au groupe DMH. Nous avons observe une amelioration de l'architecture du colon dans le groupe DMH + exercice physique. L'exercice physique peut attenuer efficacement la hausse des marqueurs de l'inflammation engendree par le DMH. L'exercice physique engendre de l'apoptose en aval de la reaction inflammatoire. Par consequent, l'exercice physique pourrait jouer un role en tant que moderateur de l'inflammation pour exercer des effets protecteurs contre le cancer du colon. [Traduit par la Redaction] Mots-cles: exercice physique, cancer colorectal, dimethylhydrazine, foyers de cryptes aberrantes, PCNA, COX-2, apoptose., Introduction Colorectal cancer with an increasing rate of morbidity and mortality is considered as one of the major causes of death worldwide (Haggar and Boushey 2009; Roncucci and Mariani 2015). [...]

A significant increase in the worldwide incidence and prevalence of type 2 diabetic mellitus (T2DM) has elevated the need for studies on novel and effective therapeutic strategies. Sirtuin 1 (SIRT1) is an NAD + dependent protein deacetylase with a critical function in the regulation of glucose/lipid metabolism, insulin resistance, inflammation, oxidative stress, and mitochondrial function. SIRT1 is also involved in the regulation of insulin secretion from pancreatic β-cells and protecting these cells from inflammation and oxidative stress-mediated tissue damages. In this regard, major SIRT1 activators have been demonstrated to exert a beneficial impact in reversing T2DM-related complications including cardiomyopathy, nephropathy, retinopathy, and neuropathy, hence treating T2DM. Therefore, an accumulating number of recent studies have investigated the efficacy of targeting SIRT1 as a therapeutic strategy in T2DM. In this review we aimed to discuss the current understanding of the physiological and biological roles of SIRT1, then its implication in the pathogenesis of T2DM, and the therapeutic potential of SIRT1 in combating T2DM. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most common cancers among the elderly, which is also seen in the forms of hereditary syndromes occurring in younger individuals. Numerous studies have been conducted to understand the molecular and cellular pathobiology underlying colorectal cancer. These studies have found that cellular signaling pathways are at the core of colorectal cancer pathology. Because of this, new agents have been proposed as possible candidates to accompany routine therapy regimens. One of these agents is melatonin, a neuro‐hormone known best for its essential role in upholding the circadian rhythm and orchestrating the many physiologic changes it accompanies. Melatonin is shown to be able to modulate many signaling pathways involved in many essential cell functions, which if deregulated cause an accelerated pace towards cancer. More so, melatonin is involved in the regulation of immune function, tumor microenvironment, and acts as an antioxidant agent. Many studies have focused on the beneficial effects of melatonin in colorectal cancers, such as induction of apoptosis, increased sensitivity to chemotherapy agents and radiotherapy, limiting cellular proliferation, migration, and invasion. The present review aims to illustrate the known significance of melatonin in colorectal cancer and to address possible clinical use. [ABSTRACT FROM AUTHOR]

Introduction: Antidepressants can modulate brain monoamines by acting on pre-synaptic and postsynaptic receptors. Autoreceptors can reduce the monoamines effect on the somatodendritic or pre-synaptic regions despite its postsynaptic counter effects. The direct effect of some antidepressants is related to its temporal and spatial bioavailability in the vicinity of these receptors (still a matter of controversies). This research evaluated the direct effect of acute bupropion on the Ventral Tegmental Area (VTA) dopaminergic neuronal firing rate. Methods: Male Wistar rats were divided into intracerebroventricular and microiontophoretic groups with 14 subgroups (n=5 in each subgroup). Amounts of 1, 0.5, 0.1, 0.01, 0.001, and 0.0001 mol of bupropion (5 μL/3 min) were microinfused to the first group and then the ejected amounts of bupropion at -500, -300, -150, -50 nA of electrical currents (1 mol, pH=4.5, 5 min) were applied to the second group. The control and sham subgroups were studied in each group, too. The units with stable firing rates were extracted, and the effect of bupropion was evaluated statistically with a P value less than 0.05 as the level of significance. Results: The highest amount of bupropion in the intracerebroventricular application could excite 42% of the neurons and inhibit 56% of them, but the highest amount of microiontophoretic application of bupropion could inhibit 97.5% of the neurons. The neuronal response to bupropion was dose-dependent in all treated groups. Conclusion: The dual effects of intracerebroventricular bupropion on the VTA dopaminergic neurons but solo inhibitory effect of its microiontophoretic application reflect the intra-VTA and extra-VTA heterogenic cellular and molecular control over the dopaminergic outflow that can be mediated by different receptors. The dopamine autoreceptors on the VTA dopaminergic neurons have complex modulatory effects on the dopaminergic response. [ABSTRACT FROM AUTHOR]

Recent studies have indicated that downregulation of insulin-like growth factor (IGF)-1 and its downstream targets are the main mechanisms underlying the anti-cancer impact of exercise. Therefore, we examined the impact of exercise on chemically induced-aberrant crypt foci (ACF), the earliest step of colorectal carcinogenesis, in rats and involvement of the IGF-1/IGF binding protein (IGFBP)-3/Erk axis. Twenty-four male Wistar rats were assigned into two groups (n=12): the control and exercise group. After eight weeks of training intervention, 6 rats were randomly selected from each group and received four injections of 1,2-dimethylhydrazine (DMH; 40 mg/kg), for two weeks. 0.2% methylene blue staining was used to evaluate the number of ACF in the colon. IGF-1 and IGFBP-3 protein levels in the serum were measured using commercially available ELISA kits for rat. The expression levels of proliferating cell nuclear antigen (PCNA), Erk1/2 and p-Erk1/2 were evaluated in colon tissue. Histological assessments were also performed in all groups. We found that the total number of ACF was significantly lowered after eight-week exercise (P<0.05). Moreover, the exercise program downregulated the IGF-1, PCNA, and p-Erk1/2 expressions and upregulated IGFBP-3 expression. Exercise was also found to increase the goblet cell number and improved colon architecture. Our finding demonstrated reduced ACF number in rat colons following exercise training, and this function may be associated with the inhibition of IGF-1/IGFBP-3/Erk1/2 signaling. Therefore, exercise appears to result in a lower number of ACF for preventing colon cancer., Competing Interests: None., (IJCEP Copyright © 2021.)

Introduction: Colorectal cancer (CRC) is one of the most lethal human malignancies with a global alarming rate of incidence. The development of resistance against common chemotherapeutics such as 5-fluorouracil (5-FU) remains a big burden for CRC therapy. Therefore, we investigated the effects of melatonin on the increasing 5-FU- mediated apoptosis and its underlying mechanism in SW-480 CRC cell line. Methods: The effects of melatonin and 5- FU, alone or in combination, on cell proliferation were evaluated using an MTT assay. Further, Annexin-V Flow cytometry was used for determining the effects of melatonin and 5-FU on the apoptosis of SW-480 cell lines. The expression levels of Bax, Bcl-2, pro-caspase-3/activated caspase 3, X-linked inhibitor of apoptosis proteins (XIAP), and survivin were measured after 48 hours incubation with drugs. Cellular levels of reactive oxygen species (ROS), catalase, superoxide dismutase and glutathione peroxidase were also evaluated. Results: Melatonin and 5-FU significantly decreased the cell proliferation of SW-480 cells. Combination of 5-FU with melatonin significantly decreased the IC50 value of 5-FU from 100 μM to 50 μM. Moreover, combination therapy increased intracellular levels of ROS and suppressed antioxidant enzymatic activities ( P < 0.05). Treatment with either melatonin or 5-FU resulted in the induction of apoptosis in comparison to control ( P > 0.05). XIAP and survivin expression levels potently decreased after combination treatment with melatonin and 5-FU ( P  < 0.05). Conclusion: We demonstrated that melatonin exerts a reversing effect on the resistance to apoptosis by targeting oxidative stress, XIAP and survivin in CRC cells. Therefore, more studies need for better understanding of underlying mechanisms for beneficial effects of combination of melatonin and 5-FU., (© 2021 The Author(s).)