Cinnamic Acid Ameliorates Acetic Acid-induced Inflammatory Response through Inhibition of TLR-4 in Colitis Rat Model.

BACKGROUND: Cinnamic acid, an active compound in cinnamon spp., has anti-inflamatory and antioxidant characteristics and is favorable in managing inflammatory bowel diseases. OBJECTIVE: Evaluate cinnamic acid's effects on colitis in rats. METHODS: To induce colitis in experimental rats, excluding the sham group, a 4% intrarectal solution of acetic acid was administered. The rats were then given oral doses of cinnamic acid at 30, 45, and 90 mg/kg for two days. The animals were assessed for macroscopic and microscopic changes, and the levels of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and myeloperoxidase (MPO) were measured using Eliza kits. Additionally, real-time PCR was performed to examine the gene level of toll-like receptor 4 (TLR-4) in the colon. RESULTS: Effective reduction of inflammation in acetic acid-induced colitis was achieved through cinnamic acid at doses of 45 and 90 mg/kg. The decrease was achieved by inhibiting the activities of TNF-α, IL-6, and MPO while downregulating the expression of TLR-4. It is important to note that macroscopic and microscopic evaluations were significant in determining the effectiveness of cinnamic acid in reducing inflammation. CONCLUSION: Downregulation of inflammatory cytokines and TLR-4 expression may contribute to cinnamic acid's anti-inflammatory effect.

Polysaccharide-based hydrogel enriched by epidermal growth factor peptide fragment for improving the wound healing process.

Wounds represent a "silent epidemic" in the global population that impact significantly people's quality of life and the economy of societies. Owing to the numerous therapies, the pursuit of a perfect wound dressing with superior performance for treating all sorts of wounds is still underway. Several studies have shown the potential of integrating restorative peptides into the scaffolds as potential therapeutic candidates for wound healing. So far, there is little information about the wound-healing effect of S-acetamidomethyl Cys 20-31-EGF peptide, a main fragment of epidermal growth factor. In this regard, the effectiveness of this peptide in the alginate-gum arabic polysaccharide hydrogel was evaluated as a wound dressing (AG-P). Physicochemical evaluation of the hydrogels demonstrated that the incorporation of the peptide compressed the hydrogel network due to the presence of hydrogen and electrostatic bonds without significant effect on the mechanical, viscoelastic properties, swelling and degradation rate of the hydrogel. The hydrogel could continuously release the peptide and prevent rapid attenuation of its concentration. Cellular assessment of AG-P by scratch test and CFSE cytoplasmic dye/flow cytometry technique encouraged the migration and proliferation of human fibroblast cells, respectively. The effect of the AG-P on the expression of IL-6, TNF-α, NF-kB1 and VEGF genes indicated that this hydrogel reduced inflammation, and significantly increased angiogenesis compared to the control group based on the Real-time PCR results. In vitro assessment indicated that this structure can promote efficient and faster wound regeneration by altering the microenvironment of the wound. The hydrogel showed interesting features to be more equipped with other therapeutic agents making it as suitable dressing for various type of the wounds.

Alginate/gum arabic-based biomimetic hydrogel enriched with immobilized nerve growth factor and carnosine improves diabetic wound regeneration.

Diabetic foot ulcers (DFUs) often remain untreated because they are difficult to heal, caused by reduced skin sensitivity and impaired blood vessel formation. In this study, we propose a novel approach to manage DFUs using a multifunctional hydrogel made from a combination of alginate and gum arabic. To enhance the healing properties of the hydrogel, we immobilized nerve growth factor (NGF), within specially designed mesoporous silica nanoparticles (MSN). The MSNs were then incorporated into the hydrogel along with carnosine (Car), which further improves the hydrogel's therapeutic properties. The hydrogel containing the immobilized NGF (SiNGF) could control the sustain release of NGF for >21 days, indicating that the target hydrogel (AG-Car/SiNGF) can serve as a suitable reservoir managing diabetic wound regeneration. In addition, Car was able to effectively reduce inflammation and significantly increase angiogenesis compared to the control group. Based on the histological results obtained from diabetic rats, the target hydrogel (AG-Car/SiNGF) reduced inflammation and improved re-epithelialization, angiogenesis, and collagen deposition. Specific staining also confirmed that AG-Car/SiNGF exhibited improved tissue neovascularization, transforming growth factor-beta (TGFß) expression, and nerve neurofilament. Overall, our research suggests that this newly developed composite system holds promise as a potential treatment for non-healing diabetic wounds.

Metformin ameliorates cardiopulmonary toxicity induced by chlorpyrifos.

Chlorpyrifos (CPF) is a widely used pesticide that can impair body organs. Nonetheless, metformin is known for its protective role against dysfunction at cellular and molecular levels led by inflammatory and oxidative stress. This study aimed to investigate the modulatory impacts of metformin on CPF-induced heart and lung damage. Following the treatment of Wistar rats with different combinations of metformin and CPF, plasma, as well as heart and lung tissues, were isolated to examine the level of oxidative stress biomarkers like reactive oxygen species (ROS) and malondialdehyde (MDA), inflammatory cytokines such as tumor necrosis alpha (TNF-α), high mobility group box 1 (HMGB1) gene, deoxyribonucleic acid (DNA) damage, lactate, ADP/ATP ratio, expression of relevant genes (TRADD, TERT, KL), and along with histological analysis. Based on the findings, metformin significantly modulates the impairments in heart and lung tissues induced by CPF.

Comparison of the safety and efficacy of fingolimod and tofacitinib in the zebrafish model of colitis.

BACKGROUND: Oral targeted small molecules, including sphingosine 1 phosphate receptor (S1PR) modulators and tyrosine kinase inhibitors (TKIs), seem to revolutionize the management of inflammatory bowel disease (IBD). To select the most effective treatment, there is an unmet need to comparatively study their mechanism of action, efficacy, and toxicity in the preclinical stage and further translate it into clinical practice. METHODS: Using 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced adult zebrafish colitis model, LC50 of fingolimod and tofacitinib were determined based on the acute toxicity test to compare aquatic toxicity potential. Subsequently, the efficacy of different concentrations of tofacitinib and fingolimod was compared using flow cytometry, qPCR, and histopathology analyses. RESULTS: TNBS significantly reduced the length of villi, and the number of goblet cells increased the level of TNF-α, MyD88, and NF-κB2, the thickness of villi and necrosis, and induced histopathological changes. All of these parameters were reversed almost dose-dependently with both medications, with the highest concentration of fingolimod being superior to other groups. Additionally, results from qPCR analysis suggested that these medications might suppress canonical and non-canonical NF-κB pathways by targeting toll-like receptors and MyD88. LC50 of tofacitinib and fingolimod was 0.9014 and 0.36 mg/L, respectively. Hence, both are in the cory 1 of the Global Harmonization System (GHS) aquatic toxicity and are toxic to adult zebrafish life. CONCLUSION: Given the better efficacy of fingolimod, it is worth translating the effectiveness and safety of S1PR modulators into IBD patients and comparing them with TKIs in head-to-head studies; albeit, their toxicity should not be overlooked.

The electrocardiographic, hemodynamic, echocardiographic, and biochemical evaluation of treatment with edaravone on acute cardiac toxicity of aluminum phosphide.

Aluminum phosphide (AlP) poisoning can be highly fatal due to its severe toxicity to the heart. Based on the evidence, edaravone (EDA) has protective effects on various pathological conditions of the heart. This research aimed to examine the potential protective effects of EDA on AlP-induced cardiotoxicity in rats. The rats were divided into six groups, including almond oil (control), normal saline, AlP (LD50), and AlP + EDA (20, 30, and 45 mg/kg). Thirty minutes following AlP poisoning, the electrocardiographic (ECG), blood pressure (BP), and heart rate (HR) parameters were examined for 180 min. The EDA was injected 60 min following the AlP poisoning intraperitoneally. Also, 24 h after poisoning, echocardiography was carried out to evaluate the ejection fraction (EF), stroke volume (SV), and cardiac output (CO). The biochemical and molecular parameters, such as the activities of the mitochondrial complexes, reactive oxygen species (ROS), apoptosis and necrosis, and troponin I and lactate levels, were also examined after 12 and 24 h in the heart tissue. According to the results, AlP-induced ECG abnormalities, decrease in blood pressure, heart rate, SV, EF%, and CO were significantly improved with EDA at doses of 30 and 45 mg/kg. Likewise, EDA significantly improved complex I and IV activity, apoptosis and necrosis, ROS, troponin I, and lactate levels following AlP-poisoning (p < 0.05). Also, the mean survival time was increased following EDA treatment, which can be attributed to the EDA's protective effects against diverse underlying mechanisms of phosphine-induced cardiac toxicity. These findings suggest that EDA, by ameliorating heart function and modulating mitochondrial activity, might relieve AlP-induced cardiotoxicity. Nonetheless, additional investigations are required to examine any potential clinical advantages of EDA in this toxicity.

The neuroprotective effects of melatonin against diabetic neuropathy: A systematic review of non-clinical studies.

Backgrounds: Diabetes can cause diabetic neuropathy (DN), a nerve injury. High blood sugar (glucose) levels can harm nerves all over your body. The nerves in your legs and feet are the most commonly affected by DN. The purpose of this study was to conduct a review of melatonin's potential neuroprotective properties against DN. Method: A full systematic search was conducted in several electronic databases (Scopus, PubMed, and Web of Science) up to March 2022 under the PRISMA guidelines. Forty-seven studies were screened using predefined inclusion and exclusion criteria. Finally, the current systematic review included nine publications that met the inclusion criteria. Result: According to in vivo findings, melatonin treatment reduces DN via inhibition of oxidative stress and inflammatory pathways. However, compared to the diabetes groups alone, melatonin treatment exhibited an anti-oxidant trend. According to other research, DN also significantly produces biochemical alterations in neuron cells/tissues. Additionally, histological alterations in neuron tissue following DN were detected. Conclusion: Nonetheless, in the majority of cases, these diabetes-induced biochemical and histological alterations were reversed when melatonin was administered. It is worth noting that the administration of melatonin ameliorates the neuropathy caused by diabetes. Melatonin exerts these neuroprotective effects via various anti-oxidant, anti-inflammatory, and other mechanisms.

Antiproliferative activity of new derivatives of pyrazino[1,2-a]benzimidazole: Integrated cell-based assay and computational studies with divalent magnesium, iron, and copper ions.

Magnesium, iron, and copper are three vital metals that play essential roles in cancer cell proliferation. This study aimed to evaluate the metal chelation of new derivatives of pyrazino[1,2-a]benzimidazole and investigate their antiproliferative properties. The density functional theory method has been employed to evaluate the complexation properties of new synthetic pyrazino[1,2-a]benzimidazole derivatives possessing the 4-OMe, 2,4-dimethyl, and 3,4,5-trimethoxy substitution on N-2 phenyl ring with divalent magnesium, iron, and copper. The free energies for the water-ligand exchange reactions were employed to investigate the thermodynamic stability, water exchange properties, and electronic properties in the gas phase. Natural population analysis was employed to estimate atomic partial charges, second-order interactions between the filled and vacant orbitals, and the occupancies of the metals' valence s, p, and d orbitals. Among pyrazino[1,2-a]benzimidazole derivatives, the 3,4,5-trimethoxy substituted pyrazino[1,2-a]benzimidazole shows better electron donor ability. This compound also reduced proliferation and increased the apoptosis of human glioblastoma cancer cells.

Lead inhibits the odontogenic differentiation potential of dental pulp stem cells by affecting WNT1/ß-catenin signaling and related miRNAs expression.

Lead (Pb) is ubiquitous in environment that accumulates in teeth and calcified tissues from where it releases gradually with aging and adversely affects dental health. This study aimed to determine the effect of Pb exposure on odontogenic differentiation potential of isolated human dental pulp stem cells and investigate the possible underlying epigenetic factors. In the absence of Pb exposure, stem cells displayed significant odontogenic markers including elevated Alkaline Phosphatase (ALP) activity, Alizarin red staining intensity, and increased expression of odontogenic DMP1 and DSPP genes. Exposure to 60 µM Pb resulted in reduced ALP activity and calcium deposition. Also, diminished expression of RUNX2, DMP1, and DSPP, as well as Wnt signaling mediators including WNT1, and ß-catenin were detected. The expression of Wnt signaling related microRNAs, miRNA-139-5p and miRNA-142-3p, on the other hand, were shown to have a significant increase. We concluded that Pb could adversely affect the odontogenic differentiation potential of dental pulp stem cell. The underlying mechanism might related to Pb-induced epigenetic dysregulation of WNT1/ß-catenin pathway-related miRNAs leading to down-regulation of Wnt/ß-catenin related odontogenic genes and eventually impaired odontogenic differentiation process.

Molecular Evidence on the Inhibitory Potential of Metformin against Chlorpyrifos-Induced Neurotoxicity.

Chlorpyrifos (CPF) is an organophosphorus (OP) pesticide, resulting in various health complications as the result of ingestion, inhalation, or skin absorption, and leads to DNA damage and increased oxidative stress. Metformin, derived from Galega officinalis, is reported to have anti-inflammatory and anti-apoptotic properties; thus, this study aimed to investigate the beneficial role of metformin in neurotoxicity induced by sub-acute exposure to CPF in Wistar rats. In this study, animals were divided into nine groups and were treated with different combinations of metformin and CPF. Following the 28 days of CPF and metformin administration, brain tissues were separated. The levels of inflammatory biomarkers such as tumor necrosis factor alpha (TNFα) and interleukin 1ß (IL-1ß), as well as the expression of 5HT1 and 5HT2 genes, were analyzed. Moreover, the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and the ADP/ATP ratio, in addition to the activity of acetylcholinesterase (AChE) and superoxide dismutase (SOD), were tested through in vitro experiments. This study demonstrated the potential role of metformin in alleviating the mentioned biomarkers, which can be altered negatively as a result of CPF toxicity. Moreover, metformin showed protective potential in modulating inflammation, as well as oxidative stress, the expression of genes, and histological analysis, in a concentration-dependent manner.

Investigation of anti-cancer effects of new pyrazino[1,2-a]benzimidazole derivatives on human glioblastoma cells through 2D in vitro model and 3D-printed microfluidic device.

AIMS: Recent studies show targeted therapy of new pyrazino[1,2-a]benzimidazole derivatives with COX-II inhibitory effects on different cancer cells. This study aimed to investigate 2D cell culture and 3D spheroid formation of glioblastoma multiforme (GBM) cells using a microfluidic device after exposure to these compounds. MAIN METHODS: After isolating astrocytes from human GBM samples, IC50 of 2,6-dimethyl pyrazino[1,2-a]benzimidazole (L1) and 3,4,5-trimethoxy pyrazino[1,2-a]benzimidazole (L2) were determined as 13 µM and 85 µM, respectively. Then, in all experiments, cells were exposed to subtoxic concentrations of L1 (6.5 µM) and L2 (42.5 µM), which were ½IC50. In the following, in two phases, cell cycle, migration, and gene expression through 2D cell culture and tumor spheroid formation ability using a 3D-printed microfluidic chip were assessed. KEY FINDINGS: The obtained results showed that both compounds have positive effects in reducing G2/M cell population and GBM cell migration. Furthermore, real-time gene expression data showed that L1 and L2 significantly impact the upregulation of P21 and P53 and down-regulation of cyclin D1, MMP2, and MMP9. On the other hand, GBM spheroids exposed to L1 and L2 become smaller with fewer live cells. SIGNIFICANCE: Our data on human isolated astrocyte cells in 2D and 3D cell culture conditions showed that L1 and L2 compounds could reduce GBM cells' invasion by controlling gene expressions associated with migration and proliferation. Moreover, designing microfluidic platform and related cell culture protocols facilitates the broad screening of 3D multicellular tumor spheroids derived from GBM tumor biopsies and provides effective drug development for brain gliomas.

Modification of the hemodynamic and molecular features of phosphine, a potent mitochondrial toxicant in the heart, by cannabidiol.

Aluminum phosphide (AlP) poisoning is common in many countries responsible for high mortality. The heart is the main target organ in AlP poisoning. Several studies have reported the beneficial effects of cannabidiol (CBD) in reducing heart injuries. This study aimed to investigate the possible protective effect of CBD on cardiac toxicity caused by AlP poisoning. Study groups included almond oil, normal saline, sole CBD (100 µg/kg), AlP (11.5 mg/kg), and four groups of AlP + CBD (following AlP gavage, CBD administrated at doses of 5, 25, 50, and 100 µg/kg via intravenous (iv) injection). Thirty minutes after AlP treatment, an electronic cardiovascular device (PowerLab) was used to record electrocardiographic (ECG) changes, heart rate (HR), and blood pressure (BP) for three hours. Cardiac tissue was examined for the activities of mitochondrial complexes, ADP/ATP ratio, the release of cytochrome C, mitochondrial membrane potential (MMP), apoptosis, oxidative stress parameter, and cardiac biomarkers at 12 and 24 hours time points. AlP administration caused abnormal ECG, decreased HR, and BP. AlP also significantly reduced mitochondrial complex I and IV activity and ADP/ATP ratio. The level of cytochrome C release, apoptosis, oxidative stress, and cardiac biomarkers was considerably increased by AlP, which was compensated following CBD administration. CBD was able to improve hemodynamic function to some extent in AlP poisoned rats. CBD restored ATP levels and mitochondrial function and decreased oxidative damage and thus, prevented the heart cells from entering the apoptotic stage. Further clinical trials are needed to explore any possible benefits of CBD in AlP-poisoned patients.

The Effect of Levosimendan on Phosphine-Induced Nephrotoxicity: Biochemical and Histopathological Assessment.

BACKGROUND: Aluminum phosphide (AlP) toxicity is associated with a high risk of death due to heart, liver, and kidney failure as the target organs. Phosphine gas released due to the ingestion is the main factor involved in the multi-organ failure with various mechanisms. Levosimendan (LEV) is a calcium sensitizer with a pleiotropic effect on multiple organs. This study aimed to investigate whether LEV can alleviate AlP-induced nephrotoxicity in the rat model. METHOD: Six groups included control group (almond oil only), sole LEV group (48 µg/kg), AlP group (LD50=10 µg/kg), and the poisoned groups treated with LEV at doses of 12, 24, and 48 µg/kg 30 min after AlP gavage. After 24 hours of treatment, serum and kidney samples were taken for biochemical and histopathological analyses. RESULT: Biochemical analysis of the AlP group showed that the activity of complexes I, II, and IV was significantly reduced, while the levels of lipid peroxidation (LPO) and reactive oxygen species (ROS), lactate, and myeloperoxidase (MPO) activity significantly increased. Also, AlP reduced live renal cells and elevated necrosis. However, the levels of serum creatinine and blood urea nitrogen were not affected by the poisoning. LEV co-treatment could increase mitochondrial complex activity and reduce MPO activity, LPO, ROS, and lactate levels. Additionally, the histopathological analysis showed the detrimental effects of AlP on kidney tissue, which was mitigated by LEV administration. CONCLUSION: Our findings showed that LEV can potentially improve oxidative stress, imbalance in the redox status, necrosis, and pathological injuries in kidney tissue following AlP-poisoning.

Combination therapy of cisplatin and resveratrol to induce cellular aging in gastric cancer cells: Focusing on oxidative stress, and cell cycle arrest.

Background: As a medical dilemma, gastric cancer will have 7.3 million new cases in 2040. Despite the disease's high economic and global burden, conventional chemotherapy regimens containing cisplatin have insufficient effectiveness and act non-specifically, leading to several adverse drug reactions To address these issues, the biological efficacy of the cisplatin-resveratrol combination was tested. Methods: To find IC50, gastric adenocarcinoma cells (AGS) were exposed to different concentrations of resveratrol and cisplatin. Anti-cancer and anti-metastatic effects of 100 M resveratrol with concentrations of cisplatin (25, 50, and 100 g/ml) were studied by assessing ß-galactosidase and telomerase activities, senescence and migration gene expression, reactive oxygen species (ROS) level, and cell cycle arrest. Results: Co-administration of cisplatin and resveratrol increased ß-galactosidase activity, ROS level as a key marker of oxidative stress, p53, p38, p16, p21, and MMP-2 gene expression, and induced G0/G1 cell cycle arrest. Additionally, telomerase activity, pro-inflammatory gene expression, and cell invasion were suppressed. The best results were achieved with 100 g/ml cisplatin co-administered with resveratrol. Conclusion: The current study proved the synergistic effect of the cisplatin-resveratrol combination on suppressing metastasis and inducing apoptosis and cell senescence through targeting P38/P53 and P16/P21 pathways. Such promising results warrant translation to animal models and the clinic. This may lead to cost-effective, available, and accessible treatment regimens with targeted action and the fewest ADRs.

Molecular Evidence of the Inhibitory Potential of Melatonin against NaAsO2-Induced Aging in Male Rats.

Arsenic (As) poisoning is widespread due to exposure to pollution. The toxic level of (As) causes oxidative stress-induced aging and tissue damage. Since melatonin (MLT) has anti-oxidant and anti-aging properties, we aimed to evaluate the protective effect of MLT against the toxicity of sodium arsenite (NaAsO2). Healthy male NMRI mice were divided into eight different groups. The control group received a standard regular diet. Other groups were treated with varying diets, including MLT alone, NaAsO2, and NaAsO2 plus MLT. After one month of treatment, biochemical and pathological tests were performed on blood, heart, and lung tissue samples. NaAsO2 increased the levels of TNF-α, 8-hydroxy-2-deoxy guanosine (8OHdG), malondialdehyde (MDA), reactive oxygen species (ROS), and high mobility group box 1 (HMGB1), increased the expression of TNF receptor type 1-associated death domain (TRADD) mRNA and telomerase reverse transcriptase, and decreased the expression of Klotho (KL) mRNA in both plasma and tissues. In contrast, MLT reduced MDA, ROS, HMGB1, lactate, and TNF-α enhanced the mRNA expression of KL, and suppressed the mRNA expression of the TERT and TRADD genes. Thus, MLT confers potent protection against NaAsO2- induced tissue injury and oxidative stress.

Assessment of cytotoxic effects of new derivatives of pyrazino[1,2-a] benzimidazole on isolated human glioblastoma cells and mitochondria.

AIMS: Glioblastoma multiforme (GBM) is a highly devastating malignant brain tumor with poor pharmacotherapy. Based on COX-2 inhibitory effects in preventing cancer progression, new pyrazino[1,2-a]benzimidazole derivatives were assessed on isolated human GBM cells. MAIN METHODS: In this study, firstly, primary culture of astrocytes from human GBM samples was prepared and exposed to 2,6-dimethyl pyrazino[1,2-a]benzimidazole (L1) and 3,4,5-trimethoxy pyrazino[1,2-a]benzimidazole (L2) for finding their half-maximal inhibitory concentration (IC50). In the following, in two phases, cell apoptosis pathway and mitochondrial markers were investigated on GBM and also HEK293 cells (as non-cancerous normal cells). KEY FINDINGS: The MTT results represented a remarkable selective cytotoxic effect of both L1 and L2 on GBM cells, and interestingly not on normal cells. After 48 h, IC50 of L1 and L2 were calculated as 13 µM and 85 µM, respectively. Annexin/PI staining showed that L1 and L2 induce apoptosis in GBM cells, and caspase measurement showed that apoptosis occurs through mitochondrial signaling. In the clonogenic assay, GBM cells formed more paraclones and fewer holoclones after treating with L1 and L2. L1 and L2 also selectively enhanced mitochondrial damaged markers, including reactive oxygen species (ROS) formation, and mitochondrial swelling, decreased mitochondrial membrane potential (MMP) and cytochrome c release in isolated cancerous GBM mitochondria. SIGNIFICANCE: Our findings on human primary astrocyte cells illustrated that L1 and L2 compounds, with COX-2 inhibitory effect, through the intrinsic pathway of apoptosis concerning mitochondrial damage enhancement have therapeutic potentials on GBM.

Electrocardiographic, hemodynamic, and biochemical evidence on the protective effects of exenatide against phosphine-induced cardiotoxicity in rat model.

Aluminum phosphide (AlP) poisoning can be deadly in most cases targeting the heart. To overcome AlP toxicity, exenatide has been studied in the present study due to its pleiotropic effects on cardiac damages. In this study, the rats were exposed to LD50 of AlP (10 mg/kg) by gavage, and exenatide at doses (0.05, 0.1, and 0.2 mg/kg) injected intraperitoneally 30 min after poisoning. The cardiac parameters including heart rate (HR), blood pressure (BP), QRS, corrected QT (QTc), and ST were monitored for 180 min. Blood glucose level was measured in the study groups 30 min after exenatide injection. Evaluation of biochemical parameters including mitochondrial complexes I, II, and IV activities, adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio, malondialdehyde (MDA), apoptosis, lactate, troponin I, and brain natriuretic peptide (BNP) was done on heart tissues after 12 and 24 h. Additionally, the tissues were analyzed for any pathological damages including necrosis, hemorrhage, or hyperemia 24 h post-treatment. Our results showed that AlP-induced HR, BP, and electrocardiographic changes were improved by exenatide at all doses. The blood glucose levels of poisoned animals reached control levels after exenatide treatment. Besides, treatment with exenatide at all doses improved complexes I and IV activity, ADP/ATP ratio, and apoptosis. Malondialdehyde, lactate, troponin I, and BNP levels were also diminished after exenatide co-treatment in poisoned animals. On the other hand, administration of exenatide doses improved the histopathology of AlP-induced tissues. Based on our findings, exenatide has a protective effect against phosphine-induced cardiotoxicity in an almost dose-dependent way. However, further investigations are needed on the potential clinical use of exenatide in this poisoning.

Toxic potential of botulinum toxin type A on senescence in a Drosophila melanogaster model.

Botulinum toxin type-A (BoNT/A) application, especially neurological disorders, has been spread nowadays while it may cause side effects. The current study aimed to assess the BoNT/A dose-dependent effect on induction of aging in the Drosophila melanogaster model. The third instar larvae of Drosophila melanogaster were exposed to » LC50, ½ LC50, and LC50 of BoNT/A in the Drosophila diet for 48 h while H2O2 1% was used as a positive control. After the exposure time, some larvae were collected for molecular study, including gene expression analysis, comet assay, oxidative stress markers, and the phenotype changes. BoNT/A induced dose-dependent cytotoxicity, elevated reactive oxygen species (ROS) levels, and superoxide dismutase (SOD) enzyme activity. In addition, it caused DNA damage and activated caspase-3 and -9, and reduced the body size of the fly, especially in high doses. In line with the purpose of the study, aging markers, including ß-galactosidase (ß-gal), p16, p21, p38, and p53, were up-regulated by BoNT/A low dose. BoNT/A activates the aging pathway in the low dose, and increasing the dose induces toxicity, including oxidative stress, DNA damage, and apoptosis.

Vinpocetine Effect on the Juncture of Diabetes and Aging: An in-vitro study.

BACKGROUND: The rapid-growing population of diabetic patients and the elderly are among the direst challenges that the science of medicine is facing today. Targeting these two challenges can shed light on new means to control and ideally reverse this trend. In this experiment, Vinpocetine's effect on aged pancreatic beta-cell functions in correlation with oxidative stress was studied. METHODS: Islet cells were isolated from the pancreas of aged rats and exposed to Vinpocetine, dissolved in acetone and RPMI, for 48 h. Then, senescence-associated molecular parameters, including P16 and P38 gene expressions and ß-galactosidase activity, were investigated along with diabetic and inflammation markers. RESULTS: Experimental results showed that Vinpocetine could significantly increase aged islets insulin secretion and also make a meaningful reduction in oxidative stress markers. This drug can also decrease expression levels of P16 and P38, the primary genes responsible for the aging pathway. TNF-α, IL-6, and NF-κB expressions were also reduced noticeably after treatment with Vinpocetine. CONCLUSION: The current study showed that Vinpocetine, a derivative of the secondary plant metabolite called Vincamine, could break this vicious cycle of oxidative stress and aging by reducing oxidative stress and inflammation, thus inhibiting cellular aging.

The role of levosimendan in phosphine-induced cardiotoxicity: evaluation of electrocardiographic, echocardiographic, and biochemical parameters.

Aluminum phosphide (AlP) causes serious poisoning in which severe cardiac suppression is the significant lethal consequence. According to evidence, levosimendan can exert outstanding cardiac support and protection in different pathological conditions. This study aimed to investigate the mechanisms by which levosimendan may alleviate cardiovascular toxicity due to AlP intoxication in the rat model. The groups included control group (normal saline only), sole levosimendan groups (12, 24, 48 µg/kg), AlP group (10 mg/kg), and AlP + levosimendan groups receiving 12, 24, 48 µg/kg levosimendan intraperitoneally 30 min after AlP administration. Electrocardiographic (ECG) parameters (QRS and PR duration and ST height), heart rate, and blood pressure were monitored for 180 minutes. Also, after 24 h of poisoning, echocardiography was applied to assess left ventricle function. Evaluation of the biochemical parameters in heart tissue, including mitochondrial complexes I, II, IV activity, ADP/ATP ratio, the rate of apoptosis, malondialdehyde (MDA), lactate, and troponin I levels, were done after 12 and 24 h. AlP-induced ECG abnormalities (PR duration and ST height), reduction in heart rate, blood pressure, cardiac output, ejection fraction, and stroke volume were improved by levosimendan administration. Besides, levosimendan significantly improved complex IV activity, the ADP/ATP ratio, apoptosis, MDA, lactate, and troponin I level following AlP-poisoning. Our results suggest that levosimendan might alleviate AlP-induced cardiotoxicity by modulating mitochondrial activity and improving cardiac function. However, the potential clinical use of levosimendan in this toxicity needs more investigations.