Physiology and Pharmacology
Volume:28 Issue: 2, Jul 2024

Acute kidney injury (AKI) is a severe complication of rhabdomyolysis (RM), where skeletal muscle injury leads to the release of cell contents into the bloodstream, ultimately obstructing renal tubules. This results in renal dysfunction due to increased oxidative stress, inflammation, and apoptosis. Glycerol (10 mL/kg) injection is one of the most common methods to induce experimental AKI; but 10 mL/kg dosage seems to be harmful to rats because we have observed some side effects. This study was designed to evaluate the effects of isoflurane pretreatment in the glycerol model of acute kidney injury, but at first we tried to find a better dosage of glycerol to induce AKI less harmful.

28 male Wistar rats were used in our investigation. We first studied to find the most effective dosage of glycerol for AKI induction in three groups (5, 6.25, and 10 mL/kg), and accordingly 6.25 mL/kg was selected. Secondly, we investigated isoflurane (1.5%, 20 minutes) pretreatment effects on glycerol-induced AKI by estimating blood urea nitrogen (BUN), creatinine (Cr), Bax/Bcl-2 proteins ratio (Bcl-2-associated X/B-cell lymphoma 2), malondialdehyde (MDA), superoxide dismutase (SOD), and histological changes in renal tissues.

The results showed that isoflurane pretreatment suppressed oxidative stress and apoptosis, and therefore was able to improve renal function.

Isoflurane pretreatment might be protective against rhabdomyolysis-induced AKI because of its anti-oxidant and anti-apoptotic activities.

The genus Cinnamomum (cinnamon) is one of the well-known aromatic spices throughout the world with numerous medicinal applications. Several beneficial pharmacological properties of cinnamon have been evaluated, including antioxidant, antiinflammatory, anti-diabetic, anticancer, cardiovascular-disease-lowering, and neurological disorder-improving effects. This review critically evaluates studies regarding the molecular mechanisms underlying the antioxidant and anti-inflammatory properties of cinnamon species.

Using three online literature databases (PubMed, Scopus, Science Direct), we identified studies describing the antioxidant and anti-inflammatory properties of cinnamon species. A literature search was carried out using a combination of keywords such as (“Cinnamomum,”) AND (“antioxidant” OR “anti-inflammatory”) or other related words. In this review, we evaluated new findings regarding the molecular mechanisms of antioxidant and anti-inflammatory effects of Cinnamomum species published from 2005 until December 2022. A total of 38 papers were selected to describe the antioxidant and anti-inflammatory properties of cinnamon species.

Cinnamon species possess antioxidant effects by reducing ROS, MDA, and NO levels, and depleting GSH, decreasing MPO activity, and enhancing the growth of SOD and CAT. Additionally, the suppression of caspase-3 and caspase-9 activity and the upregulation of bcl-2 expression determine the anti-apoptotic effects of cinnamon. Their anti-inflammatory effects are mainly related to the reduction of TNF-α, IL-1β, IL-6, IL-18, IL-10, iNOS, MCP-1, and COX-2, and the inhibition of NF-κB, ERK1/2, p38, and JNK activation.

This review highlighted the antioxidant and anti-inflammatory effects of genus cinnamon and can provide a suitable basis for further pharmacologic surveys and efficient clinical research on cinnamon to obtain new evidence on its benefits for human health.

While the involvement of neuropeptide Y (NPY) in learning and memory, as well as the role of the Y1 receptor, are well established, the function of the Y2 receptor remains a topic of debate. While the involvement of neuropeptide Y (NPY) in learning and memory, as well as the role of the Y1 receptor, are well established, the function of the Y2 receptor remains a topic of debate. Some studies suggest that NPY may also play a role in autophagy. In our investigation, we aimed to explore whether NPY and its Y2 receptor inhibitor could influence memory modulation or affect Beclin-1 expression in a rat model of Alzheimer’s disease (AD). NPY may also have a role in autophagy, according to some studies.

Intracerebroventricular (i.c.v) injections of amyloid-beta (Aβ1-42, 2µg/µl/ side) were used to establish an animal model of AD. NPY (10 ng/µl, 10 µl, i.c.v) was administered 30 minutes before the retrieval. Y2 antagonist BIIE-0246 was injected 15 minutes before NPY administration in the targeted groups. BIIE-0246 was used at three different concentrations (20 nM, 200 nM, and 2 µM). Passive avoidance memory and novel object recognition were both evaluated. Subsequently, Beclin-1 protein expression in the hippocampus was determined using western blot analysis.

It was found that NPY administration improved passive avoidance and cognitive memory in animals treated with Aβ. Injecting BIIE-0246 before NPY did not reverse the improving effect of NPY on passive avoidance and Novel Object Recognition memories. Furthermore, compared to sham-operated animals, Aβ treatment significantly reduced the hippocampal expression of Beclin-1 protein (P≤0.05), and neither NPY nor NPY Y2 receptor inhibitors affected Beclin-1.

In Aβ-induced memory impairment, it is thought that NPY can improve both aversive and cognitive memory. Blocking NPY Y2 receptors with BIIE-0246 did not alter NPY’s memory-enhancing effect

Toll-like receptor (TLR) 4 is involved in neuroinflammatory processes in peripheral tissues and central nervous system. Pro-inflammatory cytokines production, due to over activation of TLR4, interfere with insulin signaling elements lead to insulin resistance. Regarding the critical roles of TLR4 and insulin in the pathogenesis of Parkinson’s disease (PD), in the present study the TLR4/insulin receptor interaction was assessed in a neuroinflammation model of PD.

LPS was injected into the right striatum of male Wistar rats (20µg/rat). Insulin (2.5IU/ day), insulin receptor antagonist (S961; 6.5nM/kg), or TLR4 antibody (Resatorvid (TAK242); 0.01µg/rat) were administered intracerebroventricularly (ICV) for 14 days. Insulin and TAK242 were also simultaneously injected in a distinct group. Behavioral assessments were performed using rotarod, apomorphine-induced rotation, and cylinder tests. The levels of α-synuclein, TLR4, and elements of the insulin signaling pathway were measured in the striatum.

LPS impaired motor performance of the animals and increased the levels of α-synuclein and TLR4. Furthermore, it reduced mRNA levels of IRS1 and IRS2 and enhanced GSK3β mRNA and protein levels, indicating the development of insulin resistance. Treatment with insulin and TAK 242 improved motor deficits, restored insulin signaling pathway, and reduced α-synuclein and TLR4 levels.

The findings indicate that LPS impaired motor function, at least in part, via α-synuclein and TLR4 overexpression, leading to insulin resistance. Suppression of TLR4 and activation of insulin receptors attenuated motor deficits, suggesting that TLR4 and insulin receptors are promising therapeutic targets for PD modification.

Improper glycemic control is associated with diabetic cognitive dysfunction. Several studies have confirmed the neuroprotective effects of metformin and insulin. This study aimed to investigate the effects of metformin and/or insulin therapy on neurocognitive functions in a type 2 diabetes mellitus (T2DM) rat model.

Fifty adult male Wistar rats were used in this study and had free access to water and a normal chow diet. After an acclimatization period, 10 rats were kept on a normal chow diet and considered as the control group. T2DM was induced in the other 40 rats by a high-fat diet and low-dose streptozotocin method. Then, diabetic rats were randomly allocated into 4 equal groups: Non-treated diabetic group; Metformin-treated diabetic group (treated with metformin 250 mg/kg/day for 6 weeks); Insulin-treated diabetic group (treated with NPH insulin 40 U/kg for 6 weeks); and Metformin and insulin-treated diabetic group. Neurocognitive functions were assessed by footprint assay, Y-maze, open field test, and Morris water maze. Glycaemic profile, serum levels of amyloid A, interleukin-18, and nuclear factor-kappa B were analyzed. Brain malondialdehyde and total antioxidant capacity were measured. A histopathological examination of the frontal lobe was performed.

Treatment with metformin and/or insulin significantly improved the impaired neurocognitive dysfunction, brain oxidative stress, changes in biochemical parameters, and the associated histopathological changes in the frontal cortex of diabetic rats. The combined therapy showed a better effect than either monotherapy alone.

Metformin and insulin therapy may be valuable for the prevention of neurocognitive dysfunction in T2DM.

Sports activity increases PGC1α and Nrf2, the regulatory factors of mitochondrial biogenesis. This paper aims to study the impact of two-month sodium citrate supplementation with Moderate-Intensity Continuous Training (MICT) on PGC-1α and Nrf2 expression in diabetic rats.

Forty-five three-month-old male Wistar rats were haphazardly assigned to one of five equal groups (N=9): (1) healthy; (2) diabetic; (3) diabetes + exercise (DE); (4) diabetes+ supplementation (DS); and (5) diabetic + exercise + supplementation (DSE), matched according to their weights. After induction, exercises began on a treadmill for 8 weeks, five days a week. The MICT protocol ran at 70% of their maximum speed for 36 minutes. The rats supplemented with sodium-citrate- at 15 mmol/L in drinking water for two months. PGC-1α and Nrf2 expression were measured through Western blotting in the soleus muscle. Data were analyzed using univariate analysis of variance (ANOVA) and the Tukey post-hoc test. Cohen’s D effect size (ES) was calculated to compare the groups.

The results showed that induction of diabetes significantly reduced the expression of PGC-1α (P< 0.001; ES=1.36) and Nrf2 (P<0.088; ES=0.24), while exercise increased PGC-1α expression (P<0.001; ES=0.68). Sodium citrate supplementation, either alone or in combination with MICT activity, did not show a clear advantage for Nrf2 expression.

MICT activity and sodium citrate supplementation, by increasing PGC-1α expression, can be considered therapeutic strategies for diabetic patients. However, to increase Nrf2 expression, further studies with different exercise intensities and doses of sodium citrate supplementation are needed.

Intestinal colitis, also known as ulcerative colitis, is an inflammatory bowel disease characterized by long-term inflammation and ulcers in the gastrointestinal tract. It has been suggested that the mucosal expression of angiotensin II (AT-II) is increased in colitis. This study aimed to examine the potential therapeutic effects of combination therapy with Enalapril, an angiotensin-converting enzyme inhibitor, and sulfasalazine (SSZ) in a murine colitis model.

Male C57BL/6 mice were divided into five groups: control group (distilled water), dextran sulphate sodium (DSS) group (colitis group) (1% DSS), SSZ group (positive control group) with 100 mg/kg/day, Enalapril alone group with 4 mg/kg/day, and Enalapril (4 mg/kg/day) + SSZ (100 mg/kg/day) group.

There was a significant reduction in the disease activity index among the mice receiving the combination of Enalapril and SSZ compared to the colitis group. Enalapril and SSZ treatment was associated with a lower reduction in colon length, decreased colon weight, spleen weight, and spleen-to-body weight in mice with colitis. Following DSS administration, Enalapril and SSZ also significantly decreased MDA levels, an oxidant marker, and increased total thiol, SOD, and CAT levels, as antioxidants. Additionally, mucosal damage, crypt loss, pathological changes, and inflammation scores decreased after treatment with Enalapril and SSZ in comparison with the colitis group. The combination of Enalapril and SSZ reduced colon collagen content and caused a decrease in fibrosis compared to the colitis group.

The results of this study indicated that Enalapril alone and in combination with SSZ decreased inflammation and clinical symptoms of colitis induced by DSS.

The anti-inflammatory and immunomodulatory properties of tarragon have been noted. Here, we examined the effects of an aqueous extract of the tarragon plant in a rat model of ulcerative colitis.

Ulcerative colitis was induced in Wistar rats using a 2 ml acetic acid (4%) intrarectal enema. Experimental groups received sulfasalazine (2 mg/kg) or tarragon aqueous extract (100 mg/kg) orally for ten consecutive days. After ten days, the animals were euthanized and evaluated for disease activity index (DAI), production of inflammatory and pro-inflammatory mediators in the intestinal tissue.

Both the tarragon aqueous extract and sulfasalazine treatments were effective in reducing the disease severity index in experimental ulcerative colitis. Malondialdehyde intensity, nitric oxide level, and myeloperoxidase activity regressed in the colon of animals treated with the tarragon aqueous extract more than in the group treated with sulfasalazine. However, sulfasalazine significantly reduced TNF-α and IL-1 levels compared to the tarragon aqueous extract. There was no statistical difference in IL-6 and PGE2 reduction between the two groups.

These findings suggested that the aqueous extract of tarragon may be applied as a natural resource to control ulcerative colitis.

The sympathetic nervous system and the renin-angiotensin system (RAS) are the most pivotal vasoactive systems in regulating renal hemodynamics. The main objective of this study was to determine the role of the angiotensin II (Ang II) type 1 receptor (AT1R) antagonist on renal hemodynamic responses to Ang 1-7 infusion in innervated and denervated male and female rats.

Male and female Wistar rats underwent unilateral nephrectomy. Four weeks later, they were divided into two groups: innervated and acutely denervated groups. Subsequently, the anesthetized and catheterized rats in both groups were treated with saline as a vehicle and losartan infusion. Mean arterial pressure (MAP), renal blood flow (RBF), renal perfusion pressure (RPP), and renal vascular resistance (RVR) responses to Ang 1-7 (100, 300, and 1000 ng kg−1 min−1 ) were then measured at controlled RPP.

Basal MAP, RPP, RBF, and RVR did not show significant differences between the intact and denervated groups. Losartan significantly decreased MAP, RPP, and RVR in both innervated and denervated male and female rats (P<0.001), while RBF increased only in innervated and denervated female rats (P<0.004). However, following Ang 1-7 administration, the RBF response to Ang 1-7 infusion differed significantly between intact and denervated male rats treated with losartan (P<0.04). This response was not observed in female rats.

These data suggest a synergistic effect of losartan and Ang 1-7 on increased RBF in the presence of renal sympathetic nerves in male rats.

Although exogenous nitric oxide (NO) is used as medicine, in the previous we showed its inhibitory effect on the proliferation ability of rat bone marrow mesenchymal stem cells (BMSCs). In the present investigation, the inhibitory role of exogenous NO on BMSCs cell cycle was studied.

BMSCs after the third passage were treated for one hour every 48 hours with 100μM of sodium nitroprusside as an NO donor. Then, after 5,10,15, and 20 days of treatment, the viability, proliferation, and cell cycle of the BMSCs was investigated. In addition, the expression of the Raf1, CDK2, CDK4, P53, and GAPDH genes was studied.

Cell treatment caused a significant reduction in viability and proliferation at 5,10,15, and 20 days. Also, the treatment caused cell cycle arrest at G1 after 20 days. In addition, it was found that the CDK2 and CDK4 expression were down-regulated whereas the P53 expression was up-regulated, but the expression of Raf1 as well as GAPDH remained the same.

This study showed that prolonged treatment with a NO donor arrest the BMSCs cell cycle due to overexpression of P53, which inhibits the expression of Cdk2 and Cdk4.