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Journal of Neuroimmune Pharmacology :... Dec 2023Reduced uterine perfusion pressure (RUPP) is a well-established model which mimics many clinical features of preeclampsia (PE). Edaravone is a free radical scavenger...
Reduced uterine perfusion pressure (RUPP) is a well-established model which mimics many clinical features of preeclampsia (PE). Edaravone is a free radical scavenger with neuroprotective, antioxidant and anti-inflammatory effects against different models of cerebral ischemia. Therefore, we aimed to elucidate the different potential mechanisms through which PE affects fetal brain development using our previously established RUPP-placental ischemia mouse model. In addition, we investigated the neuroprotective effect of edaravone against the RUPP-induced fetal brain development alterations. On gestation day (GD) 13, pregnant mice were divided into four groups; sham (SV), edaravone (SE), RUPP (RV), and RUPP+edaravone (RE). SV and SE groups underwent sham surgeries, however, RV and RE groups were subjected to RUPP surgery via bilateral uterine ligation. Edaravone (3mg/kg) was injected via tail i.v. injection from GD 14-18. The fetal brains from different groups were collected on GD 18 and subjected to further investigations. The results showed that RUPP altered the structure of fetal brain cortex, induced neurodegeneration, increased the expression of the investigated pro-inflammatory markers; TNF-α, IL-6, IL-1β, and MMP-9. RUPP resulted in microglial and astrocyte activation in the fetal brains, in addition to upregulation of Hif-1α and iNOS. Edaravone conferred a neuroprotective effect via alleviating the inflammatory response, restoring the neuronal structure and decreasing oxidative stress in the developing fetal brain. In conclusion, RUPP-placental ischemia mouse model could be a useful tool to further understand the underlying mechanisms of PE-induced child neuronal alterations. Edaravone could be a potential adjuvant therapy during PE to protect the developing fetal brain. The current study investigated the effects of a placenta-induced ischemia mouse model using reduced uterine perfusion pressure (RUPP) surgery on the fetal brain development and the potential neuroprotective effects of the drug edaravone. The study found that the RUPP model caused neurodegeneration and a pro-inflammatory response in the developing fetal brain, as well as hypoxia and oxidative stress. However, maternal injection of edaravone showed a strong ability to protect against these detrimental effects and target multiple pathways associated with neuronal damage. The current study suggests that the RUPP model could be useful for further study of the impact of preeclampsia on fetal brain development and that edaravone may have potential as a therapy for protecting against this damage.
Topics: Humans; Rats; Child; Pregnancy; Female; Mice; Animals; Placenta; Antioxidants; Pre-Eclampsia; Edaravone; Neuroprotective Agents; Rats, Sprague-Dawley; Brain; Ischemia; Anti-Inflammatory Agents; Disease Models, Animal
PubMed: 37924374
DOI: 10.1007/s11481-023-10095-6 -
Tissue & Cell Aug 2023One of the biggest factors that negatively affect the cancer treatment plan is the toxic effects of chemotherapeutics on non-target cells and tissues. This information...
One of the biggest factors that negatively affect the cancer treatment plan is the toxic effects of chemotherapeutics on non-target cells and tissues. This information prompted us to investigate the protective effects of silymarin (SL), a hepatoprotective agent, against the hepatotoxic effects of the anticancer drug paclitaxel (PAC). Four groups were formed from 28 rats as control, PAC (2 mg/kg), SL (100 mg/kg) and PAC + SL (combination of PAC with SL). After completing the experimental procedures, the tissues collected after anesthesia were analyzed by Western blot, qRT-PCR, biochemical, stereological, immunohistochemical, and histopathological techniques. Administration of PAC significantly increased the expression of tumor necrosis factor-alpha (TNF-α), Bax, cytochrome-c (cyt-c), and active caspase-3, as well as malondialdehyde (MDA) levels in liver tissue and decreased glutathione (GSH) levels compared with the control group. PAC also resulted in a significant increase in serum triglyceride (TG), cholesterol (CH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the control group. Pathological changes such as microvesicular steatosis, the formation of Councilman bodies, an increase in total sinusoidal volume, and a decrease in the total number of hepatocytes were observed in the liver tissue of the PAC group. Almost all analysis results in the PAC + SL group were similar to those in the control group, and no significant pathological alterations were observed in this group. The data obtained show that SL protects the liver from the harmful effects of PAC, especially thanks to its TNF-α suppressor, anti-inflammatory, anti-apoptotic and antioxidant effects. Based on this result, in cases where PAC is used in cancer treatment, it can be recommended to be used together with SL to prevent harmful effects on healthy liver tissue and to continue treatment uninterruptedly and effectively.
Topics: Rats; Animals; Antioxidants; Silymarin; Tumor Necrosis Factor-alpha; Paclitaxel; Liver; Chemical and Drug Induced Liver Injury; Antineoplastic Agents; Alanine Transaminase; Aspartate Aminotransferases; Oxidative Stress
PubMed: 37459721
DOI: 10.1016/j.tice.2023.102158 -
Bioorganic Chemistry Dec 2023Oxidative stress and a series of excessive inflammatory responses are major obstacles to neurological functional recovery after ischemic stroke. In this study, we...
Oxidative stress and a series of excessive inflammatory responses are major obstacles to neurological functional recovery after ischemic stroke. In this study, we synthesized several novel 9-phenanthranilamide derivatives and evaluated their anti-inflammatory and antioxidant activities. Among the initially screened compounds, most could strongly inhibi lipopolysaccharide (LPS)-stimulated production of IL-1β, IL-6 and TNF-α in microglial cells. Additionally, compounds 8b, 8q, 8r and 8s significantly inhibited the production of NO, and they also had dose-dependent protective effects on PC12 neuronal cells induced by HO. The antineuroinflammatory effects of 8r and 8s were associated with the downregulation of LPS-induced inflammatory mediators of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and both compounds inhibited the NF-κB signaling pathway. Further examinations showed that 8s had a significant neuroprotective effect on rats with middle cerebral artery occlusion (MCAO). It decreased the infarct volume and the neurological deficit score. Overall, our results suggested that compound 8s might be a promising agent for stroke treatment.
Topics: Rats; Animals; Antioxidants; Lipopolysaccharides; Hydrogen Peroxide; Anti-Inflammatory Agents; Signal Transduction; Neuroprotective Agents; Cyclooxygenase 2; Nitric Oxide; Nitric Oxide Synthase Type II
PubMed: 37778192
DOI: 10.1016/j.bioorg.2023.106861 -
Cellular and Molecular Neurobiology Aug 2023Elabela (ELA), which is the second endogenous peptide ligand of the apelin receptor (APJ) to be discovered, has been widely studied for potential use as a therapeutic...
Elabela (ELA), which is the second endogenous peptide ligand of the apelin receptor (APJ) to be discovered, has been widely studied for potential use as a therapeutic peptide. However, its role in ischemic stroke (IS), which is a leading cause of disability and death worldwide and has limited therapeutic options, is uncertain. The aim of the present study was to investigate the beneficial effects of ELA on neuron survival after ischemia and the underlying molecular mechanisms. Primary cortical neurons were isolated from the cerebral cortex of pregnant C57BL/6J mice. Flow cytometry and immunofluorescence showed that ELA inhibited oxygen-glucose deprivation (OGD) -induced apoptosis and axonal damage in vitro. Additionally, analysis of the Gene Expression Omnibus database revealed that the expression of microRNA-124-3p (miR-124-3p) was decreased in blood samples from patients with IS, while the expression of C-terminal domain small phosphatase 1 (CTDSP1) was increased. These results indicated that miR-124-3p and CTDSP1 were related to ischemic stroke, and there might be a negative regulatory relationship between them. Then, we found that ELA significantly elevated miR-124-3p expression, suppressed CTDSP1 expression, and increased p-AKT expression by binding to the APJ receptor under OGD in vitro. A dual-luciferase reporter assay confirmed that CTDSP1 was a direct target of miR-124-3p. Furthermore, adenovirus-mediated overexpression of CTDSP1 exacerbated neuronal apoptosis and axonal damage and suppressed AKT phosphorylation, while treatment with ELA or miR-124-3p mimics reversed these effects. In conclusion, these results indicated that ELA could alleviate neuronal apoptosis and axonal damage by upregulating miR-124-3p and activating the CTDSP1/AKT signaling pathway. This study, for the first time, verified the protective effect of ELA against neuronal injury after ischemia and revealed the underlying mechanisms. We demonstrated the potential for the use of ELA as a therapeutic agent in the treatment of ischemic stroke.
Topics: Mice; Animals; Neuroprotective Agents; Ischemic Stroke; Proto-Oncogene Proteins c-akt; Phosphoric Monoester Hydrolases; Mice, Inbred C57BL; MicroRNAs; Peptides; Apoptosis; Glucose
PubMed: 37106272
DOI: 10.1007/s10571-023-01352-6 -
Life Sciences Jun 2024Sepsis is a life-threatening condition manifested by organ dysfunction caused by a dysregulated host response to infection. Lung, brain, liver, kidney, and heart are... (Review)
Review
Sepsis is a life-threatening condition manifested by organ dysfunction caused by a dysregulated host response to infection. Lung, brain, liver, kidney, and heart are among the affected organs. Sepsis-induced cardiomyopathy is a common cause of death among septic patients. Sepsis-induced cardiomyopathy is characterized by an acute and reversible significant decline in biventricular both systolic and diastolic function. This is accompanied by left ventricular dilatation. The pathogenesis underlying sepsis-induced cardiomyopathy is multifactorial. Hence, targeting an individual pathway may not be effective in halting the extensive dysregulated immune response. Despite major advances in sepsis management strategies, no effective pharmacological strategies have been shown to treat or even reverse sepsis-induced cardiomyopathy. Melatonin, namely, N-acetyl-5-methoxytryptamine, is synthesized in the pineal gland of mammals and can also be produced in many cells and tissues. Melatonin has cardioprotective, neuroprotective, and anti-tumor activity. Several literature reviews have explored the role of melatonin in preventing sepsis-induced organ failure. Melatonin was found to act on different pathways that are involved in the pathogenesis of sepsis-induced cardiomyopathy. Through its antimicrobial, anti-inflammatory, and antioxidant activity, it offers a potential role in sepsis-induced cardiomyopathy. Its antioxidant activity is through free radical scavenging against reactive oxygen and nitrogen species and modulating the expression and activity of antioxidant enzymes. Melatonin anti-inflammatory activities control the overactive immune system and mitigate cytokine storm. Also, it mitigates mitochondrial dysfunction, a major mechanism involved in sepsis-induced cardiomyopathy, and thus controls apoptosis. Therefore, this review discusses melatonin as a promising drug for the management of sepsis-induced cardiomyopathy.
Topics: Melatonin; Sepsis; Humans; Cardiomyopathies; Animals; Antioxidants; Cardiotonic Agents
PubMed: 38580195
DOI: 10.1016/j.lfs.2024.122611 -
European Review For Medical and... Nov 2023The present research aimed to study the possible protective effects of Silymarin on testicular I/R injury in a rat model evaluated through histopathology and biochemical...
OBJECTIVE
The present research aimed to study the possible protective effects of Silymarin on testicular I/R injury in a rat model evaluated through histopathology and biochemical parameters.
MATERIALS AND METHODS
This research investigated the impact of Silymarin on IR damage in male Wistar albino rats. Animals were divided into three groups: group 1 (sham), group 2 (IR), and group 3 (IR+Silymarin).
RESULTS
There were no notable differences in the levels of malondialdehyde (MDA), myeloperoxidase (MPO), and glutathione (GSH) across the three groups (p=0.260, p=0.486 and p=0.803, respectively). Contrarily, the total antioxidant status (TAS) levels exhibited significant variations between groups (p=0.001). The total oxidant status (TOS) levels also differed significantly between groups (p=0.004). The tissue evaluations uncovered substantial differences in the Johnson score, which is used to gauge testicular damage. A distinct contrast was seen between Group 1 and Group 2, and also between Group 2 and Group 3, with an all-encompassing p-value lower than 0.01. The same significant disparities were found for the percentages of Bax and Annexin V immunostaining (p<0.01 for each), reflecting the inflammation and apoptosis brought about by ischemia-reperfusion and the protective effects of the treatment.
CONCLUSIONS
The outcomes of the current investigation showed that Silymarin could be a valuable agent for reducing testicular tissue damage following I/R injury.
Topics: Humans; Rats; Male; Animals; Spermatic Cord Torsion; Rats, Wistar; Silymarin; Oxidative Stress; Reperfusion Injury; Testis; Antioxidants; Glutathione; Malondialdehyde
PubMed: 37975368
DOI: 10.26355/eurrev_202311_34319 -
Radiotherapy and Oncology : Journal of... May 2024High precision, image-guided radiotherapy (RT) has increased the therapeutic ratio, enabling higher tumor and lower normal tissue doses, leading to improved patient... (Review)
Review
High precision, image-guided radiotherapy (RT) has increased the therapeutic ratio, enabling higher tumor and lower normal tissue doses, leading to improved patient outcomes. Nevertheless, some patients remain at risk of developing serious side effects.In many clinical situations, the radiation tolerance of normal tissues close to the target volume limits the dose that can safely be delivered and thus the potential for tumor control and cure. This is particularly so in patients being re-treated for tumor progression or a second primary tumor within a previous irradiated volume, scenarios that are becoming more frequent in clinical practice.Various normal tissue 'radioprotective' drugs with the potential to reduce side effects have been studied previously. Unfortunately, most have failed to impact clinical practice because of lack of therapeutic efficacy, concern about concurrent tumor protection or excessive drug-related toxicity. This review highlights the evidence indicating that targeting the CXCL12/CXCR4 pathway can mitigate acute and late RT-induced injury and reduce treatment side effects in a manner that overcomes these previous translational challenges. Pre-clinical studies involving a broad range of normal tissues commonly affected in clinical practice, including skin, lung, the gastrointestinal tract and brain, have shown that CXCL12 signalling is upregulated by RT and attracts CXCR4-expressing inflammatory cells that exacerbate acute tissue injury and late fibrosis. These studies also provide convincing evidence that inhibition of CXCL12/CXCR4 signalling during or after RT can reduce or prevent RT side effects, warranting further evaluation in clinical studies. Greater dialogue with the pharmaceutical industry is needed to prioritize the development and availability of CXCL12/CXCR4 inhibitors for future RT studies.
Topics: Animals; Humans; Chemokine CXCL12; Neoplasms; Radiation Injuries; Radiation Tolerance; Radiation-Protective Agents; Radiotherapy, Image-Guided; Receptors, CXCR4; Signal Transduction; Chemokines, CXC
PubMed: 38447871
DOI: 10.1016/j.radonc.2024.110194 -
British Dental Journal May 2024
Topics: Humans; Fluorides; Cariostatic Agents; Dental Caries; United Kingdom; Fluoridation; Child
PubMed: 38789782
DOI: 10.1038/s41415-024-7494-5 -
British Dental Journal Jun 2024
Topics: Humans; Fluorides; Cariostatic Agents; Dental Caries; United Kingdom; Fluoridation; Child
PubMed: 38877272
DOI: 10.1038/s41415-024-7547-9 -
Journal of Ethnopharmacology Mar 2024Naoxinqing (NXQ) tablets are derived from persimmon leaves and are widely used in China for promoting blood circulation and removing blood stasis in China. We aimed to...
AIM OF THE STUDY
Naoxinqing (NXQ) tablets are derived from persimmon leaves and are widely used in China for promoting blood circulation and removing blood stasis in China. We aimed to explore whether NXQ has the therapeutic effect on ischemic stroke and explored its possible mechanism.
MATERIALS AND METHODS
The cerebral artery occlusion/reperfusion (MCAO/R) surgery was used to establish the cerebral ischemic/reperfusion rat model. NXQ (60 mg/kg and 120 mg/kg) were administered orally. The TTC staining, whole brain water content, histopathology staining, immunofluorescent staining, enzyme-linked immunosorbent assay (ELISA) and Western blot analyses were performed to determine the therapeutical effect of NXQ on MCAO/R rats.
RESULTS
The study demonstrated that NXQ reduced the cerebral infarction volumes and neurologic deficits in MCAO/R rats. The neuroprotective effects of NXQ were accompanied by inhibited oxidative stress and inflammation. The nerve regeneration effects of NXQ were related to regulating the AMPKα/NAMPT/SIRT1/PGC-1α pathway.
CONCLUSION
In summary, our results revealed that NXQ had a significant protective effect on cerebral ischemia-reperfusion injury in rats. This study broadens the therapeutic scope of NXQ tablets and provides new neuroprotective mechanisms of NXQ as an anti-stroke therapeutic agent.
Topics: Rats; Animals; Sirtuin 1; Stroke; Brain; Brain Ischemia; Metabolic Diseases; Reperfusion Injury; Infarction, Middle Cerebral Artery; Neuroprotective Agents
PubMed: 38159826
DOI: 10.1016/j.jep.2023.117672