Protective potential of naringenin and its nanoformulations in redox mechanisms of injury and disease

Increasing evidence suggests that elevated intracellular levels of reactive oxygen species (ROS) play a significant role in the pathogenesis of many diseases. Increased intracellular levels of ROS can lead to the oxidation of lipids, DNA, and proteins, contributing to cellular damage. Hence, the maintenance of redox hemostasis is essential. Naringenin (NAR) is a flavonoid included in the flavanones subcategory. Various pharmacological actions have been ascribable to this phytochemical composition, including antioxidant, anti-inflammatory, antibacterial, antiviral, antitumor, antiadipogenic, neuro-, and cardio-protective activities. This review focused on the underlying mechanism responsible for the antioxidative stress properties of NAR and its' nanoformulations. Several lines of in vitro and in vivo investigations suggest the effects of NAR and its nanoformulation on their target cells via modulating signaling pathways. These nanoformulations include nanoemulsion, nanocarriers, solid lipid nanoparticles (SLN), and nanomicelle. This review also highlights several beneficial health effects of NAR nanoformulations on human diseases including brain disorders, cancer, rheumatoid arthritis, and small intestine injuries. Employing nanoformulation can improve the pharmacokinetic properties of NAR and consequently efficiency by reducing its limitations, such as low bioavailability. The protective effects of NAR and its’ nanoformulations against oxidative stress may be linked to the modulation of Nrf2-heme oxygenase-1, NO/cGMP/potassium channel, COX-2, NF-κB, AMPK/SIRT3, PI3K/Akt/mTOR, BDNF, NOX, and LOX-1 pathways. Understanding the mechanism behind the protective effects of NAR can facilitate drug development for the treatment of oxidative stress-related disorders

Vitamin C protects against chronic social isolation stress-induced weight gain and depressive-like behavior in adult male rats

Objective. Considering the importance of ghrelin in stress-induced hyperphagia and a role of antioxidants in decreasing body weight, in the present study, the effect of vitamin C (VitC) on ghrelin secretion and food intake following chronic social isolation (CIS) was evaluated in rats

Motor dysfunction of gastric antral smooth muscle in diabetic rats: Contribution of ATP-dependent potassium channels

Background: The goal of the current research was to further elucidate the role of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in the motility and contractility force of gastric smooth muscle of diabetic rats. Materials and Methods: Male Wistar rats (190–230 g) were grouped into control and streptozotocin (STZ)-induced diabetes (55 mg/kg) rats. Thirty days later, gastric muscle contractility was measured using a myograph and a force transducer of antral segments immersed in a tissue bath. Gastric emptying response was measured through feeding of standard pellet. Furthermore, the expression of KATP channel subunits in antral smooth muscle was determined by western blot technique. Results: The amplitude of KCl-evoked twitch contractions of diabetic antral strips was about 25% more than control (P < 0.05). Application of minoxidil, a KATP channel opener, dose dependently decreased the force of twitch contractions in both normal and diabetic antral strips. Application of 10 μM glibenclamide, a KATP channel blocker, did not antagonize the minoxidil-induced relaxation of antral strips. Diabetic gastric emptying was faster than normal, although not significant. Despite the relaxant effect of minoxidil on gastric emptying rate in normal rats (P < 0.05), this effect was not observed in diabetic rats. Also, glibenclamide increased gastric emptying and antagonized minoxidil-induced relaxation in normal rats (P < 0.05). Furthermore, the expression of KATP Kir6.1 and SUR2B subunits was substantially reduced in antral smooth muscle in diabetic condition (P < 0.01). Conclusion: These results propose that KATP channels may contribute to the development of gastric motility disorders in diabetes

Preventing effect of L-type calcium channel blockade on electrophysiological alterations in dentate gyrus granule cells induced by entorhinal amyloid pathology.

The entorhinal cortex (EC) is one of the earliest affected brain regions in Alzheimer's disease (AD). EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG) with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were investigated. The amyloid beta (Aβ) 1-42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin) accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days), almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer's disease

Changes in Protease-Activated Receptor and Trypsin-1 Expression Are Involved in the Therapeutic Effect of Mg2+ Supplementation in Type 2 Diabetes-Induced Gastric Injury in Male Adult Rats

Purpose. Gastric inflammation is common and usually severe in patients with type 2 diabetes mellitus (T2DM). Evidence suggests protease-activated receptors (PARs) are a link between inflammation and gastrointestinal dysfunction. Given that magnesium (Mg2+) deficiency is a highly prevalent condition in T2DM patients, we assessed the therapeutic role of Mg2+ on the factors involved in gastric inflammation in T2DM. Methods. A rat model of T2DM gastropathy was established using a long-term high-fat diet + a low dose of streptozocin. Twenty-four rats were divided into control, T2DM , T2DM + insulin (positive control), and T2DM + Mg2+ groups. At the end of 2-month therapies, changes in the expression of gastric trypsin-1, PAR1, PAR2, PAR3, PI3K/Akt, and COX-2 proteins were measured by western blot. Hematoxylin and eosin and Masson’s trichrome staining were used to detect gastric mucosal injury and fibrosis. Results. The expression of trypsin-1, PAR1, PAR2, PAR3, and COX-2 increased in diabetes, and Mg2+/insulin treatment strongly decreased their expression. The PI3K/p-Akt significantly decreased in T2DM, and treatment with Mg2+/insulin improved PI3K in T2DM rats. Staining of the gastric antrum tissue of the insulin/Mg2+-treated T2DM rats showed a significantly minimal mucosal and fibrotic injury compared with those of rats from the T2DM group. Conclusion. Mg2+ supplement, comparable to insulin, via decreasing PARs expression, mitigating COX-2 activity, and decreasing collagen deposition could exert a potent gastroprotective effect against inflammation, ulcer, and fibrotic development in T2DM patients

Summary of membrane properties of DG granule cells in different groups.

<p>Values are mean ± SEM. One way ANOVA showed no significant difference between different groups.</p><p>Summary of membrane properties of DG granule cells in different groups.</p

Changes of excitability of granule cells following treatment with Aβ and the protective effect of CCBs.

<p>A, a small current injection was sufficient to evoke an AP in the control granule cells, but not in the EC-Aβ cells. B, the current required to evoke minimal AP firing in EC-Aβ granule cells (right panel) evoked strong AP firing in the control cells (left panel). C, the minimal current to evoke one AP during one second (rheobase current) is increased in the EC-Aβ granule cells compared to the control group. Treatment with calcium channel blockers, isradipine and nimodipine, preserved rheobase current in the EC-Aβ granule cells. D and E, the rheobase related to the R_in in the control and granule cells from Aβ treated rats, respectively. Note different y and x axis scales in these panels. Values are mean ± SEM. ***p < 0.001 compared to the control group and ^##p < 0.01 compared to the EC-Aβ group. Control group, n = 15 cells/ 6 rats; EC-Aβ group, n = 15 cells/ 8 rats; EC-Aβ + ISR, n = 10 cells/ 6 rats; EC-Aβ + NIM, n = 7 cells/ 5 rats.</p

Firing properties of dentate gyrus granule cells in response to ramp currents.

<p>A, representative spike firings of DG granule cells in response to ramp current clamp. Aβ microinjection into the EC induced: a significant increase in latency of the first AP (B), a significant increase of current required to evoke the first AP (C), and a significant decrease in AP numbers (D). Treatment by isradipine and nimodipine preserved granule cells from these changes. *p < 0.05 and **p < 0.01 compared with the control cells. ^#p < 0.05 and ^##p < 0.01 compared to the EC-Aβ group. Control and EC-Aβ groups, n = 6 cells/ 4 rats; EC-Aβ + ISR, n = 5 cells/ 4 rats; EC-Aβ + NIM, n = 6 cells/ 4 rats.</p

Firing properties of DG granule cells evoked by current injections.

<p>A, Aβ pathogenesis in the EC produced changes in firing pattern and decreased firing rate of DG granule cells at different current injections. Co-treatment with calcium channel blockers, isradipine or nimodipine, almost restored the normal firing pattern. B, Number of action potentials evoked at different current steps from 50 to 300 pA with intact synaptic transmission. C, Number of action potentials evoked at different current injections after synaptic transmission blockade in the presence of CNQX; 10 μM, APV; 50 μM and bicuculline; 20 μM, the difference of AP numbers still remained between the control and EC-Aβ cells. Values are mean ± SEM. *p < 0.05, **p < 0.01 and ***p < 0.001 contrasted to control cells, ^##p < 0.01 and ^###p < 0.001 compared to EC-Aβ group. Control group, n = 12 cells/ 6 rats; EC-Aβ group, n = 12 cells/ 8 rats; EC-Aβ + ISR, n = 10 cells/ 6 rats; EC-Aβ + NIM, n = 7 cells/ 5 rats.</p

CCBs preserve normal R_in against EC-Aβ in the granule cells.

<p>A, R_in was significantly decreased in the granule cells from Aβ treated rats compared to the control group. Treatment by istradipine and nimodipine preserved R_in against Aβ. B, R_in of granule cells in presence of synaptic blockers (CNQX; 10 μM, APV; 50 μM and bicuculline; 20 μM) in different groups. Values are mean ± SEM. *p < 0.05 and ***p < 0.001 compared to the control group, ^#p < 0.05, ^###p < 0.001 contrasted to the EC-Aβ group. Control group, n = 15 cells/ 6 rats; EC-Aβ group, n = 15 cells/ 8 rats; EC-Aβ + ISR, n = 10 cells/ 6 rats; EC-Aβ + NIM, n = 7 cells/ 5 rats.</p