Therapeutic potential of Phycocyanin in gastrointestinal cancers and related disorders.

Gastrointestinal cancer is the most fatal cancer worldwide. The etiology of gastrointestinal cancer has yet to be fully characterized. Alcohol consumption, obesity, tobacco, Helicobacter pylori and gastrointestinal disorders, including gastroesophageal reflux disease, gastric ulcer, colon polyps and non-alcoholic fatty liver disease are among the several risks factors for gastrointestinal cancers. Phycocyanin which is abundant in Spirulina. Phycocyanin, a member of phycobiliprotein family with intense blue color, is an anti-diabetic, neuroprotective, anti-oxidative, anti-inflammatory, and anticancer compound. Evidence exists supporting that phycocyanin has antitumor effects, exerting its pharmacological effects by targeting a variety of cellular and molecular processes, i.e., apoptosis, cell-cycle arrest, migration and Wnt/ß-catenin signaling. Phycocyanin has also been applied in treatment of several gastrointestinal disorders such as, gastric ulcer, ulcerative colitis and fatty liver that is known as a risk factor for progression to cancer. Herein, we summarize various cellular and molecular pathways that are affected by phycocyanin, its efficacy upon combined drug treatment, and the potential for nanotechnology in its gastrointestinal cancer therapy.

Therapeutic Potential of Fingolimod on Psychological Symptoms and Cognitive Function in Neuropsychiatric and Neurological Disorders.

Neuropsychiatric and neurological disorders pose a significant global health burden, highlighting the need for innovative therapeutic approaches. Fingolimod (FTY720), a common drug to treat multiple sclerosis, has shown promising efficacy against various neuropsychiatric and neurological disorders. Fingolimod exerts its neuroprotective effects by targeting multiple cellular and molecular processes, such as apoptosis, oxidative stress, neuroinflammation, and autophagy. By modulating Sphingosine-1-Phosphate Receptor activity, a key regulator of immune cell trafficking and neuronal function, it also affects synaptic activity and strengthens memory formation. In the hippocampus, fingolimod decreases glutamate levels and increases GABA levels, suggesting a potential role in modulating synaptic transmission and neuronal excitability. Taken together, fingolimod has emerged as a promising neuroprotective agent for neuropsychiatric and neurological disorders. Its broad spectrum of cellular and molecular effects, including the modulation of apoptosis, oxidative stress, neuroinflammation, autophagy, and synaptic plasticity, provides a comprehensive therapeutic approach for these debilitating conditions. Further research is warranted to fully elucidate the mechanisms of action of fingolimod and optimize its use in the treatment of neuropsychiatric and neurological disorders.

The Potential of Targeting Autophagy-Related Non-coding RNAs in the Treatment of Alzheimer's and Parkinson's Diseases.

Clearance of accumulated protein aggregates is one of the functions of autophagy. Recently, a clearer understanding of non-coding RNAs (ncRNAs) functions documented that ncRNAs have important roles in several biological processes associated with the development and progression of neurodegenerative disorders. Subtypes of ncRNA, including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), are commonly dysregulated in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Dysregulation of these non-coding RNAs has been associated with inhibition or stimulation of autophagy. Decreased miR-124 led to decreased/increased autophagy in experimental model of Alzheimer and Parkinson diseases. Increased BACE1-AS showed enhanced autophagy in Alzheimer disease by targeting miR-214-3p, Beclin-1, LC3-I/LC3-II, p62, and ATG5. A significant increase in NEAT1led to stimulated autophagy in experimental model of PD by targeting PINK1, LC3-I, LC3-II, p62 and miR-374c-5p. In addition, increased BDNF-AS and SNHG1 decreased autophagy in MPTP-induced PD by targeting miR-125b-5p and miR-221/222, respectively. The upregulation of circNF1-419 and circSAMD4A resulted in an increased autophagy by regulating Dynamin-1 and miR-29c 3p, respectively. A detailed discussion of miRNAs, circRNAs, and lncRNAs in relation to their autophagy-related signaling pathways is presented in this study.

Non-coding RNAs and Aquaporin 4: Their Role in the Pathogenesis of Neurological Disorders.

Neurological disorders are a major group of non-communicable diseases affecting quality of life. Non-Coding RNAs (ncRNAs) have an important role in the etiology of neurological disorders. In studies on the genesis of neurological diseases, aquaporin 4 (AQP4) expression and activity have both been linked to ncRNAs. The upregulation or downregulation of several ncRNAs leads to neurological disorder progression by targeting AQP4. The role of ncRNAs and AQP4 in neurological disorders is discussed in this review.

Non-Coding RNAs and Neurodegenerative Diseases: Information of their Roles in Apoptosis.

Apoptosis can be known as a key factor in the pathogenesis of neurodegenerative disorders. In disease conditions, the rate of apoptosis expands and tissue damage may become apparent. Recently, the scientific studies of the non-coding RNAs (ncRNAs) has provided new information of the molecular mechanisms that contribute to neurodegenerative disorders. Numerous reports have documented that ncRNAs have important contributions to several biological processes associated with the increase of neurodegenerative disorders. In addition, microRNAs (miRNAs), circular RNAs (circRNAs), as well as, long ncRNAs (lncRNAs) represent ncRNAs subtypes with the usual dysregulation in neurodegenerative disorders. Dysregulating ncRNAs has been associated with inhibiting or stimulating apoptosis in neurodegenerative disorders. Therefore, this review highlighted several ncRNAs linked to apoptosis in neurodegenerative disorders. CircRNAs, lncRNAs, and miRNAs were also illustrated completely regarding the respective signaling pathways of apoptosis.

Protective effects of nanocurcumin against stress-induced deterioration in the intestine.

The therapeutic activities of curcumin have long been investigated in some chronic and inflammatory diseases. This study was designed to investigate the protective effects of nanocurcumin on intestinal barrier function, apoptosis, and oxidative stress in rats exposed to traffic noise. Forty rats were divided into four groups: two traffic noise-exposed groups of animals that received either vehicle (NOISE) or nanocurcumin (NCUR + NOISE) and two control groups that either remained intact (CON) or received nanocurcumin (NCUR). Nanocurcumin injection (15 mg/Kg/ip) and traffic noise exposure were administered daily for two weeks. The relative protein expression of intestinal tight junctions, occludin, and ZO-1 and Bax/Bcl-2 ratio was measured to evaluate barrier integrity and apoptosis in intestinal samples, respectively. Plasma D-lactate concentration was examined as a criterion of intestinal permeability. Corticosterone, superoxide dismutase (SOD) activity, glutathione (GSH), total antioxidant capacity (TAC), and nitrite were measured in serum. The noise exposure increased Bax/Bcl-2 ratio, corticosterone, and oxidative stress in the NOISE animals. Nanocurcumin treatment improved the Bax/Bcl-2 ratio and reduced corticosterone and oxidative stress in the NCUR + NOISE animals. The expression of tight junction proteins was decreased while the concentration of D-lactate was increased in the NOISE animals. Nanocurcumin did not efficiently impact the expression of tight junction proteins and the D-lactate level in the NCUR + NOISE group. Nanocurcumin administration displayed antioxidant and anti-apoptotic roles in the noise-exposed rats, however, it did not affect the intestinal barrier integrity. We concluded that reduced apoptosis in the intestine might be related to the antioxidant activity of nanocurcumin and its modulatory effects on the HPA axis in the nanocurcumin-treated animals.

Preconditioning exercise reduces hippocampal neuronal damage via increasing Klotho expression in ischemic rats.

Considerable amounts of oxidants are produced in cerebral ischemia, where oxidative stress plays a key role in neuronal damage after ischemia. Klotho, an anti-aging protein, alleviates oxidative stress by activating the transcription of an important antioxidant enzyme, manganese superoxide dismutase (MnSOD), in the nervous system. Thus, increased Klotho expression level could lead to a reduction in neuronal damages after brain ischemia via lowering oxidative stress. It is known that physical activity increases Klotho expressions. In this study, we assessed neuroprotective effects of preconditioning exercise in rats (treadmill running at a speed of 20 m/min,30 min/day, six days/week, for3 weeks) on hippocampal Klotho and MnSOD expression in the brain using an animal model of stroke, middle cerebral artery occlusion (MCAO). Our study revealed a reduction in hippocampal Klotho and MnSOD expression as well as CA1 neuronal activity in MCAO compared to the sham group. Exercise prevented the ischemia-induced decline in Klotho and MnSOD expression levels as well as CA1 neuronal activity in Exercise + MCAO compared to the MCAO group. Also, exercise significantly improved the neurological scores and reduced brain infarction area in Exercise + MCAO in comparison to MCAO group. There was a post-ischemia deficit in the working memory, as measured by spontaneous alternation percentage using Y-maze test, in MCAO compared to the sham group. The latter effect was not observed in the Exercise + MCAO group, which could be related to an increase in the antioxidant capacity as exhibited by Klotho and MnSOD up-regulation. The results were confirmed with a positive correlation between Klotho expression and MnSOD expression which allows proposing Klotho as a potential neuroprotective protein in ischemic stroke with respect to antioxidant defense. In general, the present study suggested that preconditioning exercise induced upregulation of Klotho and MnSOD, as well as attenuated the post-ischemic injuries. The upregulation of Klotho might be an underlying mechanism by which preconditioning exercise plays as a neuroprotective factor against post-ischemic neural injuries in ischemic rats.

Nanocurcumin substantially alleviates noise stress-induced anxiety-like behavior: The roles of tight junctions and NMDA receptors in the hippocampus.

Environmental noise stress affects non-auditory brain regions such as the hippocampus; an area of the brain implicated in cognition and emotion. Recent experimental data indicate that dysfunction of the blood-brain barrier (BBB) and overexpression of NMDA receptors may cause anxiety. In this experiment, we evaluated the effect of nanocurcumin on anxiety-like behavior and the expression of tight junctions and NMDA receptor subunits in the hippocampus of rats exposed to traffic noise. Forty rats were assigned to control (CON), stress (ST), nanocurcumin (NC), and nanocurcumin+stress (NC+ST) groups. Anxiety-like behavior was evaluated through an elevated zero maze apparatus. The gene expression of tight junctions and NMDA receptor subunits was examined by real-time PCR in the hippocampus. Statistical analysis showed that noise exposure developed anxiety-like behavior and elevated the corticosterone level in the ST group compared to the CON group. The nanocurcumin administration decreased the stress and anxiety in the NC+ST group compared to the ST animals. While the noise stress reduced the gene expression of tight junctions occludin, claudin-5, and ZO-1, the nanocurcumin administration increased them in the NC+ST animals. Furthermore, the noise stress elevated the gene expression of the NMDA receptor subunits GRIN1 and GRIN2B. The NC+ST animals showed a modification of these subunits compared to the ST animals. Our findings showed that noise exposure promotes stress and anxiety and impairs the NMDA receptor structure and BBB integrity. The nanocurcumin treatment partly restores the destructive effects of noise exposure.

Effects of nano-curcumin on noise stress-induced hippocampus-dependent memory impairment: behavioral and electrophysiological aspects.

BACKGROUND: Noise pollution is one of the fundamental factors in the etiology of many disorders. Noise stress adversely affects cognitive behaviors and long-term potentiation (LTP), the candidate mechanism of learning and memory. In the present study, we examined the neuroprotective effects of nano-curcumin on behavioral and electrophysiological aspects of hippocampus-dependent memory in noise-exposed animals. METHODS: The stressed animals received either vehicle (ST) or nano-curcumin (NANO + ST) for 2 weeks. The control groups remained either intact (CON) or received nano-curcumin (NANO + CON). The ST and NANO + ST groups were exposed to daily noise for 2 weeks. The spatial memory was assessed in the Morris water maze. The LTP was investigated through field potential recording in the CA3-CA1 pathway of the hippocampus. Serum corticosterone level was measured at the end of the experiments. RESULTS: The ST group showed a lower cognitive function and suppressed LTP compared to the CON group. The nano-curcumin treatment improved the maze navigation and LTP induction compared to the ST group. While the stress exposure elevated the serum level of corticosterone in the ST animals, nano-curcumin treatment reduced it. CONCLUSIONS: The nano-curcumin treatment restores impaired behavioral and electrophysiological aspects of learning and memory in the noise-exposed animals. The plasma corticosterone levels may be associated with changes in cognitive behavior and synaptic plasticity.

Dimethyl fumarate protects the aged brain following chronic cerebral hypoperfusion-related ischemia in rats in Nrf2-dependent manner.

It has been stated that chronic cerebral hypoperfusion (CCH) markedly prompts neuronal damage and affects cognition. Dimethyl fumarate (DMF), a nuclear erythroid 2-related factor 2 (Nrf2) activator, represents a class of molecules exhibiting neuroprotection. We explored the effect of DMF on CCH using a model of permanent left common carotid occlusion. The left common carotid artery was occluded and then DMF (100mg.kg-1) was orally administrated three times per week for four consecutive weeks. Behavioral rests, PET imaging and Hematoxylin and Eosin staining, were examined and also, the hippocampal level of inflammatory, Nrf2 antioxidant, neuronal plasticity and apoptotic factors were determined using Western blot analysis and related ELISA kits. The neurological deficit scores were significantly reduced in the treatment group compared with the CCH group (P<0.001). DMF decreased the novel object recognition index (NOR) compared with the CCH group, while CCH + DMF increased the NOR compared with the CCH group (P<0.001). CCH + DMF reduces the ratio of Bax/Bcl2 and capase-3 activity in comparison to the CCH group (P<0.001). Treatment with DMF increased Nrf2, NAD(P)H dehydrogenase-1 and Heme oxygenase-1 and decreased Tumor necrosis factor α and Nuclear factor-κB density compared with the CCH group (P<0.001). A significant increase in brain-derived neurotrophic factor and c-fos was found in DMF-treated rats compared with the CCH group (P<0.001). Also, retinoic acid inhibits Nrf2 activation via DMF and increases inflammatory factors in hypoperfused rats' hippocampus compared with the CCH group (P<0.001). Long-term DMF treatment induces the Nrf2 pathway and has beneficial effects on memory and motility in CCH.

Lactobacillus rhamnosus R0011 Treatment Enhanced Efficacy of Capecitabine against Colon Cancer in Male Balb/c Mice.

The microbiome of the intestinal system is well-known as a modulatory factor. Having a balanced status of microbiota could help to prevent diseases, especially cancers related to the gastrointestinal system. We investigated the effects of Lactobacillus rhamnosus (Lr) and capecitabine on tumor size and physiologic features, such as bodyweight, liver enzymes, and blood profile, in a subcutaneously induced cancer model using CT-26 murine colon carcinoma cells. We divided 48 male Balb/c inbred mice into six groups. Lr had been orally pre-inoculated to the mice for 14 day consecutively. CT-26 cells were implanted subcutaneously into the mice's flank. Following the injection of cancer cells, Lr was inoculated to the mice three times per week for four weeks. Capecitabine was inoculated in the third week after the induction of cancer. The tumor size was significantly decreased in treated groups in comparison to the cancer group (1174.5 ± 63.8, 1119.2 ± 86.3, and 985.6 ± 48 mm3 vs. 1674.2 ± 66 mm3, P < 0.0001). Data showed that Lr and capecitabine enhanced Bax/Bcl-2 ratio and caspase-3 level compared to cancer group (p < 0.0001). White blood cells (WBCs) were significantly decreased in the capecitabine group compared to probiotic group (P < 0.05). Measurement of bodyweight, liver enzymes, and interleukin-6 (IL-6) level showed that Lr, in addition to preventive and therapeutic effects, might have protective effects against chemotherapy side effects. Preventing WBCs' reduction, protecting mice from losing weight, induction of apoptosis, and enhancing the serum level of IL-6 indicated that Lr might be associated with better management of colorectal cancer and chemotherapy side effects.

Dietary Approaches to Stop Hypertension via Indo-Mediterranean Foods, May Be Superior to DASH Diet Intervention.

Western-type diet with high salt and sugar, sedentary behavior, obesity, tobacco and alcoholism are important risk factors for hypertension. This review aims to highlight the role of western diet-induced oxidative stress and inflammation in the pathogenesis of hypertension and the role of various types of diets in its prevention with reference to dietary approaches to stop hypertension (DASH) diet. It seems that it is crucial to alter the western type of diet because such diets can also predispose all CVDs. Western diet-induced oxidative stress is characterized by excessive production of reactive oxygen species (ROS) with an altered oxidation-reduction (redox) state, leading to a marked increase in inflammation and vascular dysfunction. Apart from genetic and environmental factors, one important cause for differences in the prevalence of hypertension in various countries may be diet quality, deficiency in functional foods, and salt consumption. The role of the DASH diet has been established. However, there are gaps in knowledge about the role of some Indo-Mediterranean foods and Japanese foods, which have been found to decrease blood pressure (BP) by improving vascular function. The notable Indo-Mediterranean foods are pulses, porridge, spices, and millets; fruits such as guava and blackberry and vegetables, which may also decrease BPs. The Japanese diet consists of soya tofu, whole rice, in particular medical rice, vegetables and plenty of fish rich in fish oil, fish peptides and taurine that are known to decrease BPs. Epidemiological studies and randomized, controlled trials have demonstrated the role of these diets in the prevention of hypertension and metabolic diseases. Such evidence is still meager from Japan, although the prevalence of hypertension is lower (15-21%) compared to other developed countries, which may be due to the high quality of the Japanese diet. Interestingly, some foods, such as berries, guava, pumpkin seeds, carrots, soya beans, and spices, have been found to cause a decrease in BPs. Omega-3 fatty acids, fish peptide, taurine, dietary vitamin D, vitamin C, potassium, magnesium, flavonoids, nitrate and l-arginine are potential nutrients that can also decrease BPs. Larger cohort studies and controlled trials are necessary to confirm our views.

Tannic acid protects aged brain against cerebral hypoperfusion via modulation of Nrf2 and inflammatory pathways.

Current study purposed to investigate the neuroprotective effects of Tannic Acid (TA) on mild chronic cerebral hypoperfusion model in rats. Male Wistar rats were subjected to permanent Unilateral Common Carotid Artery Occlusion (UCCAO), followed by TA treatment (0.05% w/v) in drinking water for one month. Nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO-1), heme oxygenase-1 (HO-1), factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, blood triglyceride, blood glucose, and liver enzymes' activity were detected after the experimental period. Also, behavioral tests, hematoxylin and eosin (H&E) staining, and PET scan were performed after treatment. Post-treatment of TA improved locomotion and memory function (P < 0.001), and reduced neural cell death (P < 0.001) in the treatment group compared to UCCAO rats. Furthermore, long-term TA treatment significantly increased the levels of Nrf2 (P < 0.001), NQO-1 (P < 0.001), and HO-1 (P < 0.001) in the hippocampus of the treatment group compared to the UCCAO group. TA consumption in the treatment group applied its anti-inflammatory effects via reducing the activity of NF-κB and TNF-α in comparison with the UCCAO group (P < 0.001 for both). Blood triglyceride, blood glucose, and liver enzymes did not change considerably in the groups (P > 0.05). The current results indicate that long-term post-treatment of TA exhibits protective effects against memory deficit and motor dysfunction. The cellular mechanism of TA in hypoperfused rats might be associated with the activation of antioxidant pathways, especially the Nrf2 pathway, and suppressing inflammatory factors like NF-κB and TNF-α.

Probiotic Lactobacillus rhamnosus Supplementation Improved Capecitabine Protective Effect against Gastric Cancer Growth in Male BALB/c Mice.

The gastric cancer (GC) is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Herein, we studied the effects of probiotics (Lactobacillus rhamnosus) on subcutaneous implantation of xenograft GC. Moreover, the effect of probiotics (L. rhamnosus) was compared with the capecitabine drug as known used drug against GC. Human GC tissue was obtained from patients with gastric adenocarcinoma and grafted into mice armpit. Probiotic (L. rhamnosus) was given to animals by gavage 2 weeks prior to GC and 4 weeks after GC induction. Also, capecitabine was orally added through feeding tube at the last week of treatment procedure. All grafted animals received cyclosporine a day before the surgery and during the study period to prevent graft rejection. Capecitabine-probiotic complex reduced the size of the axillary implanted GC when compared with control group. Furthermore, combination of capecitabine and probiotic increased apoptotic and necrotic responses in the grafted tumor, blood cells (red blood cells, white blood cells, and platelet counts) in comparison with capecitabine. Probiotic (L. rhamnosus) administration effectively improved the therapeutic index and outcomes, and also, improved the therapeutic effects of the capecitabine.

High-protein and low-calorie diets improved the anti-aging Klotho protein in the rats' brain: the toxic role of high-fat diet.

BACKGROUND: In the current study, our specific aim was to characterize the Klotho protein and expression levels in the hippocampus and prefrontal cortex of old rats treated with different diets (high-fat, high-protein, low-calorie, high-protein and low-calorie). METHODS: Rats were treated with high-fat, high-protein, low-calorie, low-calorie high-protein diets for 10 weeks and then behavioral and molecular assessments were evaluated. RESULTS: Statistical analysis showed the percentage of open arm time was increased in the high-protein, low-calorie and low-calorie high-protein groups compared with old control (old-C) rats. The percentage of open arm entries was increased in the low-calorie and low-calorie high-protein group compared with old-C rats. The body weight and serum triglyceride were decreased in the low-calorie and low-calorie high-protein groups in comparison to control old rats. Low-calorie and low-calorie high-protein treatments statistically enhanced caspase-3 level compared with old-C rats in the hippocampus and prefrontal cortex. Treatment of old rats with high-protein, low-calorie and low-calorie high-protein could increase Klotho-α level compared with control old rats. The levels of Klotho-α, c-fos and brain-derived neurotrophic factors were decreased in the low-calorie high-protein group in Klotho inhibitor's presence compared with the low-calorie high-protein group. CONCLUSION: According to our findings, Klotho-α level was reduced in old rats. Low-calorie, high-protein and particularly low-calorie high-protein diets increased this protein level and consequently increased neuronal plasticity and improved memory function.

Exogenous Ghrelin Could Not Ameliorate 3,4-methylenedioxymethamphetamine-induced Acute Liver Injury in The Rat: Involved Mechanisms.

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is often abused by youth as a recreational drug. MDMA abuse is a growing problem in different parts of the world. An important adverse consequence of the drug consumption is hepatotoxicity of different intensities. However, the underlying mechanism of this toxicity has not been completely understood. Ghrelin is a gut hormone with growth hormone stimulatory effect. It expresses in liver, albeit at a much lower level than in stomach, and exerts a hepatoprotective effect. In this study, we investigated hepatotoxicity effect of MDMA alone and its combination with ghrelin as a hepatoprotective agent. MDMA and MDMA+ ghrelin could transiently increase serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) followed by tissue necrosis. However, they could significantly decrease liver tumor necrosis factor-a (TNF-±) in both treatment groups. Unexpectedly, in MDMA treated rats, Bax, Bcl-xl, Bcl-2, Fas, Fas ligand (Fas-L), caspase 8, cytochrome c, caspase 3 gene expression, and DNA fragmentation were nearly unchanged. In addition, apoptosis in MDMA+ ghrelin group was significantly reduced when compared with MDMA treated animals. In all, MDMA could transiently increase serum transaminases and induce tissue necrosis and liver toxicity. Ghrelin, however, could not stop liver enzyme rise and MDMA hepatotoxicity. MDMA hepatotoxicity seems to be mediated via tissue necrosis than apoptotic and inflammatory pathways. Conceivably, ghrelin as an anti-inflammatory and anti-apoptotic agent may not protect hepatocytes against MDMA liver toxicity.

Age-related difference in protective effect of early post-conditioning on ischemic brain injury: possible involvement of MAP-2/Synaptophysin role.

Brain Ischemia/Reperfusion (I/R) injury leads to the failure of the microtubules function and neuronal death. Ischemic post-conditioning is defined as a series of rapid alternating interruptions of blood flow in the first seconds of reperfusion. In the present study, the caspase-3, Microtubule-Associated Protein-2 (MAP-2), Protein Kinase C α (PKCα), c-fos, and synaptophysin were evaluated in the hippocampus of focal I/R post-conditioning model in a time -dependent study in aged and young rats. Adult and aged rats were subjected to right MCAO for 30 min and post-conditioned (10 s) for 3 cycles. Sensory-motor tests were performed, and locomotion and anxiety-like behavior were evaluated. Molecular tests were done by detection kit, RT-PCR, and Western blotting techniques. Ninety-six hours after I/R post-conditioning, neurological signs, locomotion, anxiety-like behavior, and ischemic area were improved in young rats compared to 6 h after I/R post-conditioning (P < 0.001). Caspase-3 activity declined in the hippocampus and cortex of I/R post-conditioned young rats in 96 h after I/R post-conditioning compared with 6 h after I/R post-conditioning (P < 0.001). Also, MAP-2 mRNA, MAP-2 protein level, PKCα, c-fos and synaptophysin protein levels were enhanced during post-conditioning in young rats in 96 h after I/R post-conditioning compared with 6 h after induction of I/R post-conditioning. The results of the present study suggested that, early post-conditioning might be considered as a candidate for therapeutic methods against I/R in the adult animals not aged rats. Moreover, inhibition of cell death in post-conditioned ischemic rats was found to be regulated by some neuroprotective molecules as well as MAP-2 and c-fos in young rats. Graphical abstract Graphical abstract representing the post-conditioning (PC) treatment timeline in adult and old rats.

Sorafenib-loaded PAMAM dendrimer attenuates liver fibrosis and its complications in bile-duct-ligated rats.

We assessed the effect of sorafenib-loaded polyamidoamine (PAMAM) dendrimer on liver fibrosis induced by bile duct ligation (BDL). Male Wistar rats were divided into 9 groups: intact, sham, DMSO + BDL, BDL, sorafenib (30 mg/kg), sorafenib (60 mg/kg), PAMAM + BDL, sorafenib (30 mg/kg) + PAMAM + BDL, sorafenib (60 mg/kg) + PAMAM + BDL. BDL was induced and then rats were treated daily with sorafenib and (or) PAMAM for 4 weeks. Improvement of liver was detected via assessment of ascites formation, collagen deposition, liver blood flow, vascular endothelial growth factor level, and blood cells count. Sorafenib-loaded PAMAM dendrimer in both 30 and 60 mg/kg doses reduced ascites formation, reduced collagen deposition, and improved drug-induced hematological side effects of sorafenib alone in comparison with sorafenib-alone treatment. Sorafenib-loaded PAMAM dendrimer increased liver blood flow compared with sorafenib-received groups. Sorafenib-loaded PAMAM dendrimer reduced BDL-induced liver injury compared with sorafenib-received groups. Moreover, sorafenib-loaded PAMAM dendrimer decreased vascular endothelial growth factor level in serum and liver tissue in comparison with sorafenib-received groups. Sorafenib-loaded PAMAM dendrimer profoundly improved the therapeutic effects of sorafenib in BDL rats.

Effects of prenatal exposure to chrysotile asbestos on hippocampal neurogenesis and long-term behavioral changes in adult male rat offspring.

Prenatal development is a critical period of life that many environmental pollutants have been suggested to influence fetal growth. Nevertheless, there are still a few investigations into the prenatal exposure to chrysotile asbestos and its neurodevelopmental and behavioral outcome in offspring. In this study, twenty-eight pregnant Wistar rats were divided into four groups and received three-times repeated intraperitoneal injections of normal saline, chrysotile, ascorbic acid and the combination of chrysotile and ascorbic acid on gestational days 11, 14 and 17. The maternal serum levels of malondialdehyde (MDA) and prooxidant-antioxidant balance (PAB) and hippocampal MDA content in adult male offspring were measured. At postnatal day (PND) 60, elevated plus maze was performed to determine anxiety-like behavior, also depression-like behavior was examined using a forced swim test at PND 61- 62. Thereafter, the quantitative analysis of Ki-67, NeuN and GFAP positive cells in the hippocampal dentate gyrus were studied by immunostaining. Our data showed that prenatal exposure to chrysotile increased the maternal serum level of MDA and PAB as well as hippocampal MDA content in adult male offspring, also increased the depression- and anxiety-like behaviors of adult male offspring and decreased the hippocampal Ki-67+, NeuN+ and GFAP+ cells in dantate gyrus of adult male offspring. However, co-administration of ascorbic acid and chrysotile decreased hippocampal lipid peroxidation and increased the Ki-67+, NeuN+ and GFAP+ cells in adult male offspring. In summary, these results indicated that oxidative stress induced by prenatal exposure to chrysotile, lead to the long-lasting decrease of the hippocampal cell proliferation and neuronal differentiation as well as astrogliosis of adult male offspring that exhibit more depression- and anxiety-like behaviors in adulthood and co-treatment of ascorbic acid with chrysotile asbestos attenuated the changes.

Acute physical and psychological stress effects on visceral hypersensitivity in male rat: role of central nucleus of the amygdala / Efeitos agudos do estresse físico e psicológico na hipersensibilidade visceral em rato macho: papel do núcleo central da amídala

ABSTRACT Objective: The aim of this study was to investigate the effects of acute physical and psychological stress and temporary central nucleus of the amygdala (CeA) block on stress-induced visceral hypersensitivity. Methods: Forty two male Wistar rats were used in this study. Animals were divided into 7 groups (n = 6); 1 - Control, 2 - physical stress, 3 - psychological stress, 4 - sham, 5 - lidocaine, 6 - lidocaine + physical stress and 7 - lidocaine + psychological stress. Stress induction was done using a communication box. Results: Abdominal withdrawal reflex (AWR) score was monitored one hour after stress exposure. AWR score significantly heightened at 20, 40 and 60 mmHg in the psychological stress group compared with control (p < 0.05), while, it was almost unchanged in other groups. This score was strikingly decreased at 20, 40 and 60 mmHg in lidocaine + psychological stress group compared with psychological stress with no tangible response on physical stress. Total stool weight was significantly increased in psychological stress group compared with control (0.72 ± 0.15, 0.1 ± 0.06 g) (p < 0.05), but it did not change in physical stress compared to control group (0.16 ± 0.12, 0.1 ± 0.06 g) (p < 0.05). Concomitant use of lidocaine with stress followed the same results in psychological groups (0.18 ± 0.2, 0.72 ± 0.15 g) (p < 0.05), while it did not have any effect on physical stress group (0.25 ± 0.1, 0.16 ± 0.12 g) (p < 0.05). Conclusions: Psychological stress could strongly affect visceral hypersensitivity. This effect is statistically comparable with physical stress. Temporary CeA block could also reduce visceral hypersensitivity post-acute psychological stress.

RESUMEN Objetivo: O objetivo desse estudo foi investigar os efeitos do estresse físico e psicológico agudo e bloqueio temporário do núcleo central da amídala (CeA) na hipersensibilidade visceral induzida por estresse. Métodos: Quarenta e dois ratos Wistar machos foram empregados nesse estudo. Os animais foram divididos em 7 grupos (n = 6): 1 - Controle, 2 - estresse físico, 3 - estresse psicológico, 4 - simulacro, 5 - lidocaína, 6 - lidocaína + estresse físico e 7 - lidocaína + estresse psicológico. A indução do estresse foi feita com o uso de uma caixa de comunicação. Resultados: O escore do reflexo de retirada abdominal (RRA) foi monitorado uma hora depois da exposição ao estresse. O escore RRA aumentou significativamente a 20, 40 e 60 mmHg no grupo de estresse psicológico versus controle (p < 0,05), enquanto que praticamente permaneceu inalterado nos demais grupos. Esse escore diminuiu drasticamente a 20, 40 e 60 mmHg no grupo de lidocaína + estresse psicológico versus estresse psicológico, sem resposta tangível no estresse físico. O peso total das fezes aumentou significativamente no grupo de estresse psicológico versus controle (0,72 ± 0,15, 0,1 ± 0,06 g) (p < 0,05), mas não houve mudança no grupo de estresse físico versus controle (0,16 ± 0,12, 0,1 ± 0,06 g) (p < 0,05). O uso simultâneo da lidocaína com o estresse acompanhou os mesmos resultados nos grupos psicológicos (0,18 ± 0,2, 0,72 ± 0,15 g) (p < 0,05), enquanto que não foi observado qualquer efeito no grupo de estresse físico (0,25 ± 0,1, 0,16 ± 0,12 g) (p < 0,05). Conclusões: O estresse psicológico pode afetar fortemente a hipersensibilidade visceral. Esse efeito é estatisticamente comparável com o estresse físico. Um bloqueio temporário do CeA também pode reduzir a hipersensibilidade visceral pós-estresse psicológico agudo.