Doxorubicin impairs cognitive function by upregulating AMPAR and NMDAR subunit expression and increasing neuroinflammation, oxidative stress, and apoptosis in the brain.

Introduction: The anticancer drug doxorubicin (DOX) is used for various malignancies. However, it also causes cognitive impairment in cancer survivors. In order to determine the mechanisms underlying the acute effects of DOX, we assessed the mRNA and protein expression of glutamate receptors and proteins involved in cognitive function and apoptosis. Methods: Fear-conditioning memory tests were performed in rats after a single intraperitoneal injection of DOX (25 mg/kg) to evaluate short-term memory function. Rat brain samples were collected, and GluA1 mRNA and protein expression; NR2A and NR2B mRNA expression; and COX-2, NF-kB, TNF-α, and MDA, Bax, and caspase-3 levels were assessed via reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays. Results: We observed a decreased number of entries in Y-maze, decreased exploration time to the novel object in the novel object recognition (NOR), and decreased freezing time in the fear-conditioning memory tests in DOX-treated rats relative to those in control rats, demonstrating cognitive impairment. GluA1, NR2B, and NR2A expression and MDA, NF-κB, Bax, COX-2, TNF-α, and caspase-3 levels in the brain were significantly elevated in DOX-treated rats. Conclusion: DOX induced cognitive impairment in the rats via neuronal toxicity by upregulating AMPAR and NMDAR expression and increasing neuroinflammation, oxidative stress, and apoptosis in the brain.

Phenyl-2-aminoethyl selenide ameliorates hippocampal long-term potentiation and cognitive deficits following doxorubicin treatment.

Chemotherapy-induced memory loss ("chemobrain") can occur following treatment with the widely used chemotherapeutic agent doxorubicin (DOX). However, the mechanisms through which DOX induces cognitive dysfunction are not clear, and there are no commercially available therapies for its treatment or prevention. Therefore, the aim of this study was to determine the therapeutic potential of phenyl-2-aminoethyl selenide (PAESe), an antioxidant drug previously demonstrated to reduce cardiotoxicity associated with DOX treatment, against DOX-induced chemobrain. Four groups of male athymic NCr nude (nu/nu) mice received five weekly tail-vein injections of saline (Control group), 5 mg/kg of DOX (DOX group), 10 mg/kg PAESe (PAESe group), or 5 mg/kg DOX and 10 mg/kg PAESe (DOX+PAESe group). Spatial memory was evaluated using Y-maze and novel object location tasks, while synaptic plasticity was assessed through the measurement of field excitatory postsynaptic potentials from the Schaffer collateral circuit. Western blot analyses were performed to assess hippocampal protein and phosphorylation levels. In this model, DOX impaired synaptic plasticity and memory, and increased phosphorylation of protein kinase B (Akt) and extracellular-regulated kinase (ERK). Co-administration of PAESe reduced Akt and ERK phosphorylation and ameliorated the synaptic and memory deficits associated with DOX treatment.

Health status outcome among cannabis addicts after treatment of addiction.

The abuse of Cannabis is a widespread issue in the Asir region. It has a lot of legal and occupational repercussions. The purpose of this study was to evaluate the health status of cannabis addicts at admission and after treatment using body mass index, glycemic status, liver function, renal function, and oxidative stress. A cross-sectional study was conducted with 120 participants. The study was conducted at Al Amal Hospital for Mental Health in Asir region of Saudi Arabia, with 100 hospitalized patients receiving addiction treatment and 20 healthy volunteers. The participants were divided into two groups: group I, the control group, and group II, the cannabis addicts. The socio-demographic data were gathered. The level of cannabis in the urine and the CWAS [Cannabis Withdrawal Assessment Scale] were determined. In addition, the Body Mass Index [BMI], vital signs [temperature, heart rate, systolic blood pressure, diastolic blood pressure, and respiratory rate], serum levels of albumin, total bilirubin, direct bilirubin, AST, ALT, and ALP, urea, creatinine, Thiobarbituric acid-reactive substances [TBARS], superoxide dismutase [SOD], reduced glutathione [GSH], and catalase [CAT] were analyzed on the first day of admission and after treatment. According to the results, there was no significant change in the body mass index. The vital signs in the cannabis user group were significantly lower than the corresponding admission values. Regarding renal function tests such as urea and creatinine, we found that after treatment, the mean urea and creatinine values in the cannabis user group did not differ significantly from the corresponding admission values. However, after treatment, the mean values of fasting blood glucose levels in the cannabis user group were significantly lower than at admission. Also, the mean values of liver function tests such as albumin, total bilirubin, direct bilirubin, AST, ALT, and ALP in the cannabis user group were significantly lower than the corresponding admission values after treatment. In assessing the antioxidant system, we found that the mean values of TBARS, SOD, GSH, and CAT in the cannabis user group did not differ significantly from the corresponding admission values after treatment. The current findings have revealed that cannabis addiction harms the various body systems and has significant implications for the addict's state of health. The values of oxidative stress biomarkers did not change in this study, but other measured parameters improved after treatment.

The Impact of Metformin on the Development of Hypothyroidism and Cardiotoxicity Induced by Cyclophosphamide, Methotrexate, and Fluorouracil in Rats.

Cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) are extensively utilized in the therapeutic management of various malignancies. It is noteworthy, however, that potential chemotherapy-related complications include the occurrence of hypothyroidism and cardiotoxicity. Metformin (MET) is a pharmacological agent for managing type 2 diabetes. It has been reported to mitigate certain toxic manifestations associated with chemotherapy. This study's primary objective is to investigate MET's protective effects against hypothyroidism and cardiotoxicity induced by CMF treatment. A total of forty male rats were allocated into four distinct groups, each consisting of ten rats per group. These groups were categorized as follows: saline, MET, CMF, and CMF + MET. The experimental group of rats were administered CMF via intraperitoneal injection, receiving two doses of CMF, and fed MET in their daily drinking water, with a 2.5 mg/mL concentration. Blood samples were collected into EDTA tubes for assessment of TSH, free and total (T4 and T3), troponin I, CK, and CK-MB levels utilizing Electrochemiluminescence Immunoassays (ECI). The saline and MET groups did not exhibit significant alterations in thyroid hormones or cardiotoxic biomarkers. In contrast, in the CMF group, there was a notable reduction in T4, FT4, T3, and FT3 levels but no significant changes in TSH levels; however, troponin I, CK, and CK-MB levels were notably elevated. MET co-treatment with CMF did not ameliorate these effects caused by CMF. In conclusion, CMF treatment induced hypothyroidism and cardiotoxicity in rats, but MET co-treatment did not rescue the reduction of thyroid hormones or the elevation of cardiotoxic biomarkers.

Evaluation of Cisplatin-Induced Acute Renal Failure Amelioration Using Fondaparinux and Alteplase.

Acute renal failure (ARF) is a deleterious condition with increased mortality or healthcare costs or dialysis-dependent end-stage renal disease. The study aims to compare prophylaxis with fondaparinux (Fund) vs. treatment with alteplase (Alt) in ameliorating cisplatin (Cis)-induced ARF. Sixty male mice were equally divided randomly into six groups of control, Cis, Alt, and Cis + Alt groups receiving normal saline for 10 days. All four groups except for the control received Cis (30 mg/kg, i.p.) on day 7, and 6 h later, both the Alt groups received Alt (0.9 mg/kg, i.v.). The animal groups Fund and Fund + Cis received Fund (5 mg/kg, i.p.) for 10 days, and the Fund + Cis group on day 7 received Cis. All the animal groups were euthanized 72 h after the Cis dose. The Fund + Cis group showed significantly increased expression levels of platelet count, retinoid X receptor alpha (RXR-α) and phosphorylated Akt (p-Akt) in addition to decreased levels of urea, blood urea nitrogen (BUN), uric acid, white blood cells (WBCs), red blood cells (RBCs), relative kidney body weight, kidney injury score, glucose, prothrombin (PT), A Disintegrin And Metalloproteinases-10 (ADAM10), extracellular matrix deposition, protease-activated receptor 2 (PAR-2), and fibrinogen expression when compared to the Cis-only group. Meanwhile, the Cis + Alt group showed increased caspase-3 expression in addition to decreased levels of urea, BUN, uric acid, WBCs, RBCs, glucose, platelet count and PT expression with a marked decrease in PAR-2 protein expression compared to the Cis group. The creatinine levels for both the Fund + Cis and Cis + Alt groups were found to be comparable to those of the Cis-only group. The results demonstrate that the coagulation system's activation through the stimulation of PAR-2 and fibrinogen due to Cis-induced ADAM10 protein expression mediated the apoptotic pathway, as indicated by caspase-3 expression through the p-Akt pathway. This is normally accompanied by the loss of RXR-α distal and proximal tubules as lipid droplets. When the animals were pre-treated with the anticoagulant, Fund, the previous deleterious effect was halted while the fibrinolytic agent, Alt, most of the time failed to treat Cis-induced toxicity.

Comparative evaluation of doxorubicin, cyclophosphamide, 5-fluorouracil, and cisplatin on cognitive dysfunction in rats: Delineating the role of inflammation of hippocampal neurons and hypothyroidism.

Chemotherapeutic agents such as doxorubicin, cyclophosphamide, fluorouracil, and cisplatin are commonly used to treat a variety of cancers and often result in chemobrain, which manifests as difficulties in learning and memory processes that can persist in the years following treatment. The current study aims to evaluate the cognitive function following treatment with these agents and the underlying mechanisms using a rat model of neuroinflammation and possible implication of thyroid toxicity in chemotherapy induced cognitive dysfunction. Wistar female rats were treated with a single dose of doxorubicin (DOX, 25 mg/kg), 5-fluorouracil (5-FU, 100 mg/kg), cisplatin (8 mg/kg), and cyclophosphamide (CYP, 200 mg/kg) by intraperitoneal injection. The cognitive performance of rats was then evaluated in spatial memory tasks using the Y-maze, novel object recognition (NOR), and elevated plus maze (EPM) tests. Serum levels of thyroid hormones (T3, T4, FT3, and FT4) and thyroid stimulating hormone (TSH) were measured, followed by estimation of TNFα, IL-6, and IL-1ß in the hippocampal tissue. Results revealed that all the chemotherapeutic agents produced impairment of cognitive function, and significant increase of pro-inflammatory cytokines such as TNFα, IL-6 and IL-1ß in the hippocampal tissues. There was a significant reduction in thyroid hormones (T3, FT3, and T4) and an increase in thyroid stimulating hormone (TSH) in serum, which may also have contributed to the decline in cognitive function. In conclusion, DOX, 5-FU, CYP, and cisplatin produces impairment of spatial memory possibly by inflammation of hippocampal neurons and endocrine disruption (hypothyroidism) in rats.

Protective Effect of Galantamine against Doxorubicin-Induced Neurotoxicity.

BACKGROUND AND AIMS: Doxorubicin (DOX) causes cognitive impairment (chemobrain) in patients with cancer. While DOX damages the cholinergic system, few studies have focused on the protective effects of cholinergic function on chemobrain. The acetylcholinesterase inhibitor galantamine (GAL) demonstrates neuroprotective properties. We investigated the mechanisms associated with DOX-induced cognitive impairments and the potential protective role of GAL in preventing chemobrain. MAIN METHODS: Female Wistar rats were divided into control, DOX, GAL, and DOX + GAL groups. The rats in the DOX group were administered DOX (5 mg/kg intraperitoneally twice weekly for two weeks), while those in the GAL group were orally administered GAL (2.5 mg/kg) via oral gavage once daily for 15 days. The combination group (DOX + GAL) received GAL (once daily) and DOX (two times per week) concurrently. The body weights and survival rates were monitored daily. The animals were subjected to behavioral tests to assess the memory function followed by the biochemical estimation of inflammatory markers, including tumor necrosis factor-α (TNF-α), interleukine-1ß (IL-1ß), and interleukine-6 (IL-6) in rat brain tissue and RT-qPCR. KEY FINDINGS: DOX caused a reduction in the body weight and survival rate, which was alleviated by GAL concomitant treatment with DOX (DOX + GAL). These groups had reduced body weights and survival rates. DOX-treated animals exhibited an impairment of short-term spatial working memory, manifested as a behavioral alteration in the Y-maze test, the novel object recognition (NOR) test, and the elevated plus-maze (EPM) test. Concurrent treatment with GAL (DOX + GAL) showed improved memory function, as evidenced by an increase in the number of entries and time spent in the novel arm, the time spent exploring the novel object, and the transfer latency in the Y-maze, NOR test, and EPM test, respectively. These findings were also supported by biochemical observations showing the reversal of DOX-induced changes in IL-1ß, IL-6, and TNF-α, as well as their relative expression of mRNA in brain tissue following concurrent GAL treatment. CONCLUSION: GAL appeared to be a neuroprotective agent against neuroinflammation caused by DOX by reducing inflammatory markers in the brain.

The Ameliorative Effect of Pioglitazone against Neuroinflammation Caused by Doxorubicin in Rats.

Doxorubicin (DOX) is a chemotherapeutic agent that is linked with complications such as cardiotoxicity and cognitive dysfunction, known as chemobrain. Chemobrain affects up to 75% of cancer survivors, and there are no known therapeutic options for its treatment. This study aimed to determine the protective effect of pioglitazone (PIO) against DOX-induced cognitive impairment. Forty Wistar female rats were equally divided into four groups: control, DOX-treated, PIO-treated, and DOX + PIO-treated. DOX was administered at a dose of 5 mg/kg, i.p., twice a week for two weeks (cumulative dose, 20 mg/kg). PIO was dissolved in drinking water at a concentration of 2 mg/kg in the PIO and DOX-PIO groups. The survival rates, change in body weight, and behavioral assessment were performed using Y-maze, novel object recognition (NOR), and elevated plus maze (EPM), followed by estimation of neuroinflammatory cytokines IL-6, IL-1ß, and TNF-α in brain homogenate and RT-PCR of a brain sample. Our results showed a survival rate of 40% and 65% in the DOX and DOX + PIO groups, respectively, compared with a 100% survival rate in the control and PIO treatment groups at the end of day 14. There was an insignificant increase in body weight in the PIO group and a significant reduction in the DOX and DOX + PIO groups as compared with the control groups. DOX-treated animals exhibited impairment of cognitive function, and the combination PIO showed reversal of DOX-induced cognitive impairment. This was evidenced by changes in IL-1ß, TNF-α, and IL-6 levels and also by mRNA expression of TNF- α, and IL-6. In conclusion, PIO treatment produced a reversal of DOX-induced memory impairment by alleviating neuronal inflammation by modulating the expression of inflammatory cytokines.

Development of Diphenyl carbonate-Crosslinked Cyclodextrin Based Nanosponges for Oral Delivery of Baricitinib: Formulation, Characterization and Pharmacokinetic Studies.

Background: The aim of the present investigation is to prepare baricitinib (BAR)-loaded diphenyl carbonate (DPC) ß-cyclodextrin (ßCD) based nanosponges (NSs) to improve the oral bioavailability. Methods: BAR-loaded DPC-crosslinked ßCD NSs (B-DCNs) were prepared prepared by varying the molar ratio of ßCD: DPC (1:1.5 to 1:6). The developed B-DCNs loaded with BAR were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), % yield and percent entrapment efficiency (%EE). Results: Based on the above evaluations, BAR-loaded DPC ßCD NSs (B-CDN3) was optimized with mean size (345.8±4.7 nm), PDI (0.335±0.005), Yield (91.46±7.4%) and EE (79.1±1.6%). The optimized NSs (B-CDN3) was further confirmed by SEM, spectral analysis, BET analysis, in vitro release and pharmacokinetic studies. The optimized NSs (B-CDN3) showed 2.13 times enhancement in bioavailability in comparison to pure BAR suspension. Conclusion: It could be anticipated that NSs loaded with BAR as a promising tool for release and bioavailability for the treatment of rheumatic arthritis and Covid-19.

Factors Affecting the Incidence, Progression, and Severity of COVID-19 in Type 1 Diabetes Mellitus.

OBJECTIVES: This study screened for factors affecting coronavirus disease 2019 (COVID-19) incidence in type 1 diabetes mellitus (T1DM) patients, appraised vitamin D's efficacy in preventing COVID-19, and assessed the effects of clinical characteristics, glycemic status, vitamin D, and hydroxychloroquine administration on COVID-19's progression and severity in T1DM patients. METHODS: This retrospective research on 150 adults was conducted at Security Forces Hospital, Riyadh, KSA. Participants were allocated to three groups (50/group): control, T1DM, and T1DM with COVID-19. Participants' fasting blood glucose (FBG), glycated hemoglobin (HbA1c), complete blood count, vitamin D, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin, lactate dehydrogenase (LDH), prothrombin time, activated partial thromboplastin time, D-dimer, liver and kidney function, and hydroxychloroquine treatment were retrieved and analyzed. RESULTS: The percentages of comorbidities and not taking hydroxychloroquine were significantly higher among T1DM patients with COVID-19 than patients with T1DM only. Mean vitamin D level was significantly lower in T1DM with COVID-19 patients than in the other two groups. Vitamin D showed a significant negative correlation with LDH, CRP, ESR, ferritin, and D-dimer, which was the most reliable predictor of COVID-19 severity in T1DM patients. CONCLUSION: Comorbidities and vitamin D deficiency are risk factors for COVID-19 in patients with T1DM. Patients who do not take hydroxychloroquine and have higher FBG and HbA1c levels are vulnerable to COVID-19. Vitamin D may be useful for preventing COVID-19 in T1DM patients. Comorbidities, higher FBG and HbA1c levels, not taking hydroxychloroquine, and vitamin D inadequacy elevate COVID-19 progression and severity in patients with T1DM.

Doxorubicin induces dysregulation of AMPA receptor and impairs hippocampal synaptic plasticity leading to learning and memory deficits.

Doxorubicin (Dox) is a chemotherapeutic agent used widely to treat a variety of malignant cancers. However, Dox chemotherapy is associated with several adverse effects, including "chemobrain," the observation that cancer patients exhibit through learning and memory difficulties extending even beyond treatment. This study investigated the effect of Dox treatment on learning and memory as well as hippocampal synaptic plasticity. Dox-treated mice (5 mg/kg weekly x 5) demonstrated impaired performance in the Y-maze spatial memory task and a significant reduction in hippocampal long-term potentiation. The deficit in synaptic plasticity was mirrored by deficits in the functionality of synaptic `α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) channels, including reduced probability of opening, decreased dwell open time, and increased closed times. Furthermore, a reduction in the AMPAR subunit GluA1 level, its downstream signaling molecule Ca2+/calmodulin-dependent protein kinase (CaMKII), and brain-derived neurotrophic factor (BDNF) were observed. This was also accompanied by an increase in extracellular signal regulated kinase (ERK) and protein kinase B (AKT) activation. Together these data suggest that Dox-induced cognitive impairments are at least partially due to alterations in the expression and functionality of the glutamatergic AMPAR system.

Phytochemical Analysis, Pharmacological and Safety Evaluations of Halophytic Plant, Salsola cyclophylla.

Salsola cyclophylla, an edible halophyte, is traditionally used for inflammation and pain. To confirm the claimed anti-inflammatory and analgesic properties, a detailed study on respective pharmacological actions was undertaken. The activities are contemplated to arise from its phytoconstituents. The LC-MS analysis of S. cyclophylla 95% aqueous-ethanolic extract revealed the presence of 52 compounds belonging to phenols, flavonoids, coumarins, and aliphatics class. A high concentration of Mn, Fe, and Zn was detected by atomic absorption spectroscopic analysis. The ethyl acetate extract showed the highest flavonoid contents (5.94 ± 0.04 mg/g, Quercetin Equivalents) and Fe2+-chelation (52%) potential with DPPH radicals-quenching IC50 at 1.35 ± 0.16 mg/mL, while the aqueous ethanolic extract exhibited maximum phenolics contents (136.08 ± 0.12 mg/g, gallic acid equivalents) with DPPH scavenging potential at IC50 0.615 ± 0.06 mg/mL. Aqueous ethanolic extract and standard quercetin DPPH radicals scavenging's were equal potent at 10 mg/mL concentrations. The aqueous ethanolic extract showed highest analgesic effect with pain reduction rates 89.86% (p = 0.03), 87.50% (p < 0.01), and 99.66% (p = 0.0004) after 60, 90, and 120 min, respectively. Additionally, aqueous ethanolic extract exhibited the highest anti-inflammation capacity at 41.07% (p < 0.0001), 34.51% (p < 0.0001), and 24.82% (p < 0.0001) after 2, 3, and 6 h of extract's administration, respectively. The phytochemical constituents, significant anti-oxidant potential, remarkable analgesic, and anti-inflammatory bioactivities of extracts supported the traditionally claimed anti-inflammatory and analgesic plant activities.

The impact of chicory (Cichoriumintybus L.) on hemodynamic functions and oxidative stress in cardiac toxicity induced by lead oxide nanoparticles in male rats.

BACKGROUND: A common environmental pollutant, lead can induce toxicity in several organ systems. A range of industrial and/or household materials and products contain lead, and food/liquid ingestion and inhalation are the mechanisms through which lead is introduced into the human body. OBJECTIVE: Since knowledge about the cardiac toxicity of acute lead nanoparticles is limited, this work sought to shed more light on the issue by investigating the therapeutic effects of chicory extract based on rat models to elevate cardiac functions and oxidative stress. METHODS: Four research groups were used, each consisting of ten albino rats of male sex and adult age. The groups were: control group, chicory group, lead oxide nanoparticle group, and lead oxide nanoparticle + chicory group. RESULTS: Compared to the control and chicory groups, the lead oxide nanoparticle group displayed a notable increase in heart functions and oxidative stress markers as well as alterations in cardiac histological structure. On the other hand, cardiac function modifications were counteracted through four-week administration of lead oxide nanoparticles alongside chicory. CONCLUSION: Heart damage caused by lead oxide nanoparticles may be attenuated by chicory through scavenging of free radicals.

Anthocyanins rich pomegranate cream as a topical formulation with anti-aging activity.

BACKGROUND: Anthocyanins are antioxidant compounds constitute the primary dyes of the pomegranate arils. Anthocyanins could protect the aged skin induced by oxidant exposure as a major role in aging processing and skin degeneration. PURPOSE: The study aimed to evaluate the anti-aging activity of anthocyanins rich pomegranate (Punica granatum) after formulated into a topical cream. Also, its effect on human dermal fibroblast function and epidermal keratinocyte were evaluated. METHOD: Anthocyanins were extracted from fresh pomegranate arils using acidified methanol and were purified by Sephadex LH-20 gel-column chromatography. Further, the fusion method was used to prepare cold cream containing pomegranate anthocyanins. The formulated cream was evaluated for their compatibility study, irritation, homogeneity, drug content, drug release, and stability tests. Furthermore, permeation study through abdominal rabbits, as well as Human application was performed. RESULTS: Compatibility study showed the absence of any interaction between anthocyanins and the used polymers. The formulated cream was nonirritant, homogenous and potentially reduced skin aging when applied to Human volunteers' skin. Furthermore, the skin permeation displayed a good permeation of 43.16% after 210 min. CONCLUSION: Pomegranate anthocyanins could be used as a safe, stable, homogeneous, nonirritant and effective topical anti-aging drug formulation for aged human people.

Vitamin B17 Ameliorates Methotrexate-Induced Reproductive Toxicity, Oxidative Stress, and Testicular Injury in Male Rats.

Methotrexate (MTX; 4-amino-10-methylfolic acid) is a folic acid reductase inhibitor used to treat autoimmune diseases and certain types of cancer. Testicular toxicity resulting from MTX is a significant side effect that may cause subsequent infertility. The present study was conducted to examine the ameliorating effects of vitamin B17 (VitB17) against testicular toxicity induced by MTX in male rats. A total of 50 male albino rats were equally divided into five groups [control group; vitamin B17 group (VitB17) administered VitB17 only; methotrexate group administered MTX only; cotreated group, (VitB17+MTX) and posttreated group (MTX+VitB17)]. In methotrexate group (MTX), a significant decrease was observed in body weight and the testicular weight, as well as the levels of plasma testosterone, luteinizing hormone and follicle-stimulating hormone compared with control. The sperm count, viability, morphology index, total motility, and progressive motility also decreased in MTX rats compared with control. Furthermore, the levels of reduced glutathione, catalase, and superoxide dismutase, as well as proliferating cell nuclear antigen protein expression, in the testicular tissue decreased in MTX compared with control. In addition, MTX caused a significant increase in DNA and tissue damage compared with control. However, VitB17 ameliorated these effects, indicating that it has a preventative and curative effect against MTX-induced reproductive toxicity in male rats. The protective effect of VitB17 may be associated to its antioxidant properties as it possibly acts as a free-radical scavenger and lipid peroxidation inhibitor, as well as its protective effect on the levels of GSH, SOD, and CAT.

Silver Citrate Nanoparticles Inhibit PMA-Induced TNFα Expression via Deactivation of NF-κB Activity in Human Cancer Cell-Lines, MCF-7.

BACKGROUND: The nuclear factor kappa-B (NF-κB) is a major transcription factor responsible for the production of numerous inflammatory mediators, including the tumor necrosis factor (TNFα), which has a lethal association with cancer's onset. The silver nanoparticles (AgNPs) are widely used in cancer treatment and several other biomedical applications. OBJECTIVE: The study aimed to determine the effects of silver citrate nanoparticles (AgNPs-CIT) on NF-κB activation together with TNFα mRNA/protein expressions in the phorbol myristate acetate (PMA)-stimulated MCF-7 human breast cancer cell-lines. METHODS: The AgNPs-CIT were synthesized by the reduction method, and the prepared AgNPs-CIT were characterized for their shape, absorption in UV-VIS electromagnetic radiations, size distribution, ζ-potential, and antioxidant activity. The MCF-7 cell-lines were pretreated with AgNPs-CIT and stimulated with PMA. The TNFα mRNA expressions were determined by real-time PCR, whereas the protein production was determined by the ELISA. The NF-κB activity was distinctly observed by highly-specific DNA-based ELISA, and by NF-κB-specific inhibitor, Bay 11-7082. RESULTS: The prepared AgNPs-CIT were spherical and have an absorption wavelength range of 381-452 nm wherein the particles size ranged between 19.2±0.1 to 220.77±0.12 nm with the charge range -9.99±0.8 to -34.63±0.1 mV. The prepared AgNPs-CIT showed comparative antioxidant activity at >40% inhibitions level of the DPPH radicals. The AgNPs-CIT were found to be non-toxic to MCF-7 cell-lines and inhibited PMA-induced activation of the NF-κBp65, and also the mRNA/protein expression of TNFα. CONCLUSION: This is the first report that showed AgNPs-CIT inhibited TNFα expression via deactivation of the NF-κB signaling event in stimulated breast cancer cells. The results have important implications for the development of novel therapeutic strategies for the prevention/treatment of cancers and/or inflammatory disorders.

Formulation of Ethyl Cellulose Microparticles Incorporated Pheophytin A Isolated from Suaeda vermiculata for Antioxidant and Cytotoxic Activities.

BACKGROUND: This study is designed to discover a method for delivering an efficient potent pheophytin a (pheo-a) into more absorbed and small polymeric ethyl cellulose (EC) microparticles. METHODS: Silica gel and Sephadex LH-20 columns were used to isolate pheo-a from the chloroform extract of the edible plant, Suaeda vermiculata. Pheo-a was incorporated into EC microparticles using emulsion-solvent techniques. The antioxidant activity of pheo-a microparticles was confirmed by the level of superoxide radical (SOD), nitric oxide (NO), and reducing power (RP) methods. Meanwhile, the cytotoxic effect of the product was investigated on MCF-7 cells using MTT assay. RESULTS: Pheo-a was isolated from S. vermiculata in a 12% concentration of the total chloroform extract. The structures were confirmed by NMR and IR spectroscopic analysis. The formulated microparticles were uniform, completely dispersed in the aqueous media, compatible as ingredients, and had a mean diameter of 139 ± 1.56 µm as measured by a particle size analyzer. Pheo-a demonstrated a valuable antioxidant activity when compared with ascorbic acid. The IC50 values of pheo-a microparticles were 200.5 and 137.7 µg/mL for SOD, and NO respectively. The reducing power of pheo-a microparticles was more potent than ascorbic acid and had a 4.2 µg/mL for IC50 value. Pheo-a microparticles did not show notable cytotoxicity on the MCF-7 cell line (IC50 = 35.9 µg/mL) compared with doxorubicin (IC50 = 3.2 µg/mL). CONCLUSIONS: the results showed that water-soluble pheo-a microparticles were prepared with a valuable antioxidant activity in a wide range of concentrations with a noteworthy cytotoxic effect.

Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation.

Cognitive deficits are commonly reported by patients following treatment with chemotherapeutic agents. Anthracycline-containing chemotherapy regimens are associated with cognitive impairment and reductions in neuronal connectivity in cancer survivors, and doxorubicin (Dox) is a commonly used anthracycline. Although it has been reported that Dox distribution to the central nervous system (CNS) is limited, considerable Dox concentrations are observed in the brain with co-administration of certain medications. Additionally, pro-inflammatory cytokines, which are overproduced in cancer or in response to chemotherapy, can reduce the integrity of the blood-brain barrier (BBB). Therefore, the aim of this study was to evaluate the acute neurotoxic effects of Dox on hippocampal neurons. In this study, we utilized a hippocampal cell line (H19-7/IGF-IR) along with rodent hippocampal slices to evaluate the acute neurotoxic effects of Dox. Hippocampal slices were used to measure long-term potentiation (LTP), and expression of proteins was determined by immunoblotting. Cellular assays for mitochondrial complex activity and lipid peroxidation were also utilized. We observed reduction in LTP in hippocampal slices with Dox. In addition, lipid peroxidation was increased as measured by thiobarbituric acid reactive substances content indicating oxidative stress. Caspase-3 expression was increased indicating an increased propensity for cell death. Finally, the phosphorylation of signaling molecules which modulate LTP including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, and Akt were increased. This data indicates that acute Dox exposure dose-dependently impairs synaptic processes associated with hippocampal neurotransmission, induces apoptosis, and increases lipid peroxidation leading to neurotoxicity.