Mechanism of anticancer effect of ETP-45658, a PI3K/AKT/mTOR pathway inhibitor on HT-29 Cells.

The PI3K pathway plays a crucial role in tumor cell proliferation across various cancers, including colon cancer, making it a promising treatment target. This study aims to investigate the antiproliferative activity of ETP-45658, a PI3K/AKT/mTOR pathway inhibitor, on colon cancer and elucidate the underlying mechanisms. HT-29 colon cancer cells were treated with varying doses of ETP 45658 and its cytotoxic effect assessed using the XTT cell viability assay.ELISA was also used to measure TAS, TOS, Bax, BCL-2, cleaved caspase 3, cleaved PARP, and 8-oxo-dG levels. Flow cytometry was performed to investigate apoptosis, cell cycle, caspase 3/7 activity, and mitochondrial membrane potential. Additionally, following the administration of DAPI (4,6-diamidino-2-phenylindole) dye, the cells were visualized using an immunofluorescence microscope. It was observed that ETP-45658 exerted a dose-dependent and statistically significant antiproliferative effect on HT-29 colon cancer cells. Further investigations using the IC50 dose showed that ETP-45658 decreased TAS levels and increased TOS levels and revealed that it upregulated apoptotic proteins while downregulating anti-apoptotic proteins. Our findings also showed that it increased Annexin V binding, arrested the cell cycle at G0/G1 phase, induced caspase 3/7 activity, impaired mitochondrial membrane potential, and ultimately triggered apoptosis in HT-29 cells. ETP-45658 shows promise against colon cancer by inducing cell death, and oxidative stress, and arresting the cell cycle. Targeting the PI3K/AKT/mTOR pathway with ETP-45658 offers exciting potential for colon cancer treatment.

FGF-18 alleviates memory impairments and neuropathological changes in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial pathology marked by amyloid beta (Aß) accumulation, tau hyperphosphorylation, and progressive cognitive decline. Previous studies show that fibroblast growth factor 18 (FGF18) exerts a neuroprotective effect in experimental models of neurodegeneration; however, how it affects AD pathology remains unknown. This study aimed to ascertain the impact of FGF18 on the behavioral and neuropathological changes in the rat model of sporadic AD induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). The rats were treated with FGF18 (0.94 and 1.88 pmol, ICV) on the 15th day after STZ injection. Their cognitive function was assessed in the Morris water maze and passive avoidance tests for 5 days from the 16th to the 21st days. Aß levels and histological signs of neurotoxicity were detected using the enzyme-linked immunosorbent assay (ELISA) assay and histopathological analysis of the brain, respectively. FGF18 mildly ameliorated the STZ-induced cognitive impairment; the Aß accumulation was reduced; and the neuronal damage including pyknosis and apoptosis was alleviated in the rat brain. This study highlights the promising therapeutic potential for FGF18 in managing AD.

Galium aparine L. protects against acetaminophen-induced hepatotoxicity in rats.

The toxicity of acetaminophen (N-acetyl-para-aminophenol (APAP)) is the most frequent cause of drug-induced liver damage. Galium aparine L. (GA) is traditionally used to treat jaundice. We aimed to investigate the hepatoprotective potential of GA in the APAP-induced hepatic encephalopathy (HE) rat model. Qualitative phytochemical characterization of GA was performed by LC/Q-TOF/MS analysis. Wistar rats were pretreated with GA (250 and 500 mg/kg b.wt. per oral) for five days. On the 6th day, the rats were exposed to APAP (1500 mg/kg b.wt. oral gavage) and behavioral tests (open field and passive avoidance tests) were applied on the 7th and 8th days. The animals were killed, and biochemical and histopathological parameters were assessed in blood and hepatic specimens. GA pretreated rats exhibited a significant reduction in APAP-induced liver damage, evidenced by the reduction in liver necrosis and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin (BIL). GA demonstrated an anxiolytic effect, as seen in the acquisition trial and grooming behavior. The short-term memory performances of animals were not changed in all groups, suggesting that APAP intoxication did not affect hippocampal function. These results show that GA extract markedly exerts hepatoprotective activity, while its effect on hepatic encephalopathy was limited.

Thiamine alleviates cognitive impairment and epileptogenesis by relieving brain inflammation in PTZ-induced kindling rat model.

OBJECTIVE: Epileptogenesis, the process by which the brain becomes epileptic, is related to neuroinflammation, hyperexcitability cognitive deficits. Evidence suggests that improving brain inflammation can inhibit the epileptogenesis process and help the emergence of new drugs for the treatment of epilepsy. Therefore, the PTZ kindling model of epilepsy was utilized to assess the neuroprotective role of thiamine in epileptogenesis. METHODS: Male rats were exposed to PTZ-induced kindling and pretreated with low thiamine (25 mg/kg) or high thiamine (50 mg/kg). Cyclooxygenase (COX-1 and COX-2), interleukin 1-beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), and nuclear factor-κB (NF-κB) concentrations in the brain were analyzed using biochemical assays. Cognitive function was evaluated using the passive avoidance test. RESULTS: Thiamine ameliorated epileptogenesis and enhanced the rats' performance in the passive avoidance test. Also, thiamine significantly decreased the level of neuroinflammatory mediators in the brain induced by PTZ. CONCLUSION: These results provide evidence that thiamine alleviates PTZ-induced neuroinflammation and cognitive impairments.

Involvement of nitric oxide pathway in the acute anticonvulsant effect of salmon calcitonin in rats.

Epilepsy is a chronic neurological disease that is thought to affect up to 1% of the world's population. Evidence suggests that salmon calcitonin (sCT) has positive effects on epileptic seizures and epileptogenesis. However, it remains unknown that whether nitric oxide (NO) pathway contributed to this antiepileptic effect of sCT. We have used the pentylenetetrazole (PTZ)-induced seizure rat model to identify the effect of sCT on seizure score, seizure-induced cognitive deficit, and the NO pathway in the brain. We found that sCT increases the first myoclonic jerk (FMJ), decreased Racine's convulsion scale (RCS), and abates seizure-induced cognitive impairment. We further demonstrated that sCT attenuated the abnormal increase of NO in the brain. These results revealed that sCT exerts an antiepileptic effect by modulating the NO pathway in the brain.

Protective effects of lamotrigine and vitamin B12 on pentylenetetrazole-induced epileptogenesis in rats.

Epileptogenesis is a process that includes molecular and cellular events that foster the establishment of hyperexcitable neuronal networks in the brain. Pentylenetetrazole (PTZ)-induced kindling model in rodents has added new information to the knowledge about the pathogenesis of epilepsy and potential targets of novel antiepileptic agents. Evidence from animal and human studies suggests that oxidative and inflammatory events may play important roles in the initiation and maintaining seizure activities. Vitamin B12 has beneficial effects on the nervous system and presents pleiotropic effects with antioxidant and anti-inflammatory aspects. In the present study, we aimed to test the hypothesis that vitamin B12 and their combination with lamotrigine prevents behavioral deficits, hippocampal damage, oxidation, and proinflammatory state during epileptogenesis. Male rats were subjected to PTZ-induced epileptogenesis and pretreated with vitamin B12 (50 µg/kg) or Lamotrigine (LTG) (25 mg/kg) or B12 (50 µg/kg) + LTG (25 mg/kg). Vitamin B12 and its combination with LTG suppressed epileptogenesis and improved the performance of rats in the passive avoidance test. In addition, Vitamin B12 and its combination with LTG decreased levels of total oxidative status (TOS), oxidative stress index (OSI), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and increased total antioxidant status (TAS) levels in the hippocampus and cerebral cortex. Furthermore, it reduced hippocampal neuronal damage. Current findings support the beneficial actions of vitamin B12 due to its antioxidative and anti-inflammatory properties during the course of disease.

Ghrelin receptor agonist hexarelin attenuates antinociceptive tolerance to morphine in rats.

Ghrelin, a peptide hormone released from the gastric endocrine glands, shows analgesic activity apart from its various physiological effects. Nevertheless, the effects of ghrelin receptor (GHS-R) agonists on morphine analgesia and tolerance have not yet been elucidated. The purpose of this study was to evaluate the effects of the ghrelin receptor agonist hexarelin and antagonist [d-Lys3]-GHRP-6 on morphine antinociception and tolerance in rats. A total of 104 Wistar albino male adult rats (weighing approximately 220-240 g) were used in the experiments. To induce morphine tolerance, a three-day cumulative dose regimen was used in the rats. Then, randomly selected rats were evaluated for morphine tolerance on day 4. The analgesic effects of hexarelin (0.2 mg·kg-1), [d-Lys3]-GHRP-6 (10 mg·kg-1), and morphine (5 mg·kg-1) were measured at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. The findings suggest that hexarelin in combination with morphine attenuates analgesic tolerance to morphine. On the other hand, ghrelin receptor antagonist [d-Lys3]-GHRP-6 has no significant analgesic activity on the morphine tolerance in analgesia tests. Furthermore, co-administration of hexarelin and morphine increases the analgesic effect. In conclusion, these data indicate that administration of GHS-R agonist hexarelin with morphine enhances the antinociception and attenuates morphine tolerance.