Involvement of Nrf2-PPAR-γ signaling in Coenzyme Q10 protecting effect against methotrexate-induced testicular oxidative damage.

Studies have identified Coenzyme Q10 (CoQ10) as a promising agent in improving idiopathic male infertility; however, its role in chemically or environmentally induced testicular dysfunction is not well-established. We investigated the potential of CoQ10 to attenuate methotrexate (MTX)-induced testicular damage and to identify molecular targets of CoQ10 effects. Wistar rats received a single intraperitoneal dose of 20 mg/kg MTX on the fifth day of the 10-day experimental protocol. 100 mg/kg CoQ10 was given orally daily for ten days, alone or combined with MTX. The testes of MTX-treated animals showed thickened tunica albuginea, distortion of seminiferous tubules with a marked reduction of germinal lining, a few primary spermatocytes with no spermatozoa, apoptotic cells, congested sub-capsular and interstitial blood vessels, and interstitial edema. Reduction of reproductive hormones and increased oxidative, inflammatory, and apoptotic biomarkers levels were also seen in the MTX-treated rats. CoQ10 + MTX-treated rats were protected against MTX-induced testicular histological changes and showed improvement in testosterone, luteinizing-, and follicle-stimulating hormone serum levels compared to the MTX group. The testes of the CoQ10 + MTX-treated rats showed reduced malondialdehyde, myloperoxidase, tumor necrosis factor -α, interleukin-6 and -1ß and Bax: Bcl2 ratio and enhanced glutathione, and catalase compared to MTX alone. CoQ10 enhanced MTX-induced downregulation of Nrf2 and PPAR-γ signaling and modulated its downstream targets, the inducible nitric oxide synthase, NF-κB, Bax, and Bcl2. In conclusion, CoQ10 targeted the Nrf2-PPAR-γ signaling loop and its downstream pathways, mitigating MTX-induced oxidative stress-related damages and alleviating the testicular dysfunction MTX caused. Our data suggest Nrf2-PPAR-γ signaling as a potential therapeutic target in testicular toxicity, where oxidative stress, inflammation, and apoptosis trigger damage.

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.

Zinc's protective role against hydroxychloroquine-induced cardiac effects in adult male albino rats.

Background: Long exposure to Hydroxychloroquine (HCQ) has been complicated by some dangerous though infrequent cardiotoxicity. Methods: A total of 40 normal adult male albino rats dispersed into 4 groups were used. Group 1 (Control group), Group II (HCQ treated group), Group III (zinc [Zn]-treated group), and Group IV (HCQ and Zn treated group). Once the experimentation ended, rats were sacrificed and cardiac soft tissue sections were processed twenty-four hours at the end of the experiment for histological study. Results: Cardiac-stained sections revealed that HCQ induced widespread necrosis, dilatation, and vacuolar degeneration. However, the combination of HCQ with Zn ameliorated these damaging effects. Cardiac enzyme parameters were also studied in the 4 groups and revealed CK-MB and troponin were considerably elevated in groups II associated to the control group. Conclusion: It was concluded that Zn revealed a protective role against HCQ cardiomyopathy in adult male albino rats. This might signify an appreciated means for Zn-based treatment in the upcoming subsequent clinical records to adjust doses and guarantee patient safeguard.

The impact of oral ciprofloxacin on the structure and functions of rat gastric mucosa.

Ciprofloxacin (CPX), is a fluoroquinolone antibiotic used to treat a number of gram-negative and gram-positive bacterial infections. Ciprofloxacin can cause severe side effects, ranging from tendon problems, nerve damage, to serious mood or behavior changes. The purpose of this study was to investigate how ciprofloxacin affects gastric cell lines in rats with a distinctive emphasis on physiological, histopathological, and bacteriological changes. Male albino rats (n = 21) were distributed into three groups; control, CPX, and CPX-withdrawal groups. The treated rats were given CPX tablets (12.5 mg/kg) dissolved in carboxymethyl cellulose (CMC) 0.5% orally once daily via gavage for sixty consecutive days. Control rats received only the vehicle. The withdrawal group was treated for 60 days and the drug was withdrawn for another sixty days. After completion of the experiment, all rats were sacrificed and gastric tissues were treated for light, immunohistochemical, and scanning electron microscopic examination. Image J software was used to measure immune-labeled gastric epithelial cells. Blood samples were also collected for H. Pylori immunoglobulins IgM, IgA, and IgG. Results showed that treated rats acquired significantly strongly positive tumor necrosis factor (TNFα) and significant reduction of serum level of H. pylori IgM, IgA, and IgG in all the study groups. It could be concluded that prolonged oral CPX administration to albino rats changes the gastric mucosal architecture and bacteriology.

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.

Therapeutic Implications of a Polymethoxylated Flavone, Tangeretin, in the Management of Cancer via Modulation of Different Molecular Pathways.

Chemotherapeutics can induce oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, and abnormalities in neurotransmitter metabolism leading to toxicity. Because there have been no therapeutic strategies developed to target inflammation and oxidative stress, there is a continuing need for new and improved therapy. As a result, there has been increasing interest in complementary and alternative medicine with anticancer potential. Studies have shown that the antioxidant activities and anti-inflammatory effects of citrus fruits are promising natural phytochemicals in the development of new anticancer agents. Tangeretin is a naturally polymethoxylated flavone compound extracted from the citrus peel that has shown significant intestinal absorption and adequate bioavailability, with the added benefit of promoting longevity. In addition, tangeretin is known to exhibit considerable selective toxicity to many types of cancer cell proliferation such as ovarian, brain, blood, and skin cancer. Evidence indicates that tangeretin acts through several mechanisms including growth inhibition, induction of apoptosis, autophagy, antiangiogenesis, and estrogenic-like effects. Furthermore, tangeretin works through mitigating levels of inflammatory mediators in the immune system. Using tangeretin in combination with clinically applied anticancer drugs could be a good strategy for increasing the efficiency of these agents and protecting noncancerous cells from damage caused by chemotherapy. The purpose of this review is to highlight the protective effects of a novel natural product, tangeretin against chemotherapeutic-induced toxicity. The development of chemoprevention strategies can lead to significant health care improvement in cancer survivors. Thus, study outcomes may attract more investigators to conduct tangeretin-related research and find out potentially significant impacts on health care of cancer patients and decreased health problems associated with chemotherapeutics-induced toxicity.

Protective Effects of Cocos Nucifera Oil in Paraphenylene Diamine Toxicity.

BACKGROUND: Paraphenylenediamine (PPD) is a highly toxic compound used for hair-dyeing worldwide. PPD self-poisoning had significantly increased in recent times with increased mortality rates. OBJECTIVE: This study aims to evaluate the toxic effects of PPD and the protective potential of its prospective antidote Virgin Coconut Oil (Cocos nucifera). METHODS: PPD was identified and validated by FT-IR and UV mass spectrometer. PPD toxicity was induced in-vivo by single intraperitoneal injection (40 mg/kg and 60 mg/kg). Single-injection of Virgin Coconut Oil (VCO) was administered in the presence of PPD at doses of 5 mg/kg and 10 mg/kg. Blood was analyzed for renal, hepatic and cardiac biomarkers. Relevant organs were collected, weighed and preserved for histopathological examination. Statistical analysis was carried out to note mortality rate, survival duration and serum biochemical parameter. Molecular docking studies were performed to assess attachment of PPD with histaminergic receptors. RESULTS: PPD injection achieved 100% mortality rate with short survival span, and disturbed hepatic, renal, and cardiac serum markers with marked histopathological changes. VCO notably decreased mortality rate, raised treatment time window with marked adjustment in hepatic, renal, and cardiac markers. Docking studies proved that PPD attaches robustly with histaminergic receptors. CONCLUSION: The study concludes that VCO possesses lifesaving protection against PPD toxicity and can be a suitable antidote.

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.

Anti-oxidative and DNA protecting effects of flavonoids-rich Scutellaria lateriflora.

Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Americans and Europeans as a nerve tonic for more than 200 years. In vivo studies have shown anxiolytic activity ofS. lateriflora in animals and humans. However, the neuroprotective mechanisms ofS. lateriflora are not fully understood. Oxidative stress plays a vital role in the neurodegenerative and neuropsychiatric diseases such as anxiety, Alzheimer's disease, depression, and Parkinson's disease. Bioactive compounds present in various medicinal plants neutralize or scavenge toxic free radicals and thus suppress oxidative stress. Therefore, the objective of this study was to investigate the antioxidant effects of S. lateriflora. The antioxidant potential of aqueous or ethanolic extracts of S. lateriflora was determined in mouse brain tissue using various biochemical assays. Protective effects of S. lateriflora against oxidative stress induced DNA fragmentation was determined using plasmid DNA. The ethanolic and aqueous extracts scavenged the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. The ethanolic extract reduced tert-butyl peroxide-induced reactive oxygen species (ROS) and lipid peroxides in the mouse brain homogenates. Furthermore, the ethanolic extract of S. lateriflora protected hydrogen peroxide-UV induced cleavage of supercoiled plasmid DNA. In conclusion, S. lateriflora exhibited significant antioxidant effects. The current findings posit S. lateriflora as one of the potential experimental herbal drugs that should be screened for its therapeutic potential against various oxidative stress associated mental disorders.

Long term alterations in synaptic physiology, expression of ß2 nicotinic receptors and ERK1/2 signaling in the hippocampus of rats with prenatal nicotine exposure.

Smoking during pregnancy is associated with long lasting, hippocampus dependent, cognitive deficits in children. The current study was performed to investigate the effect of prenatal nicotine exposure on excitatory synaptic physiology and cellular signaling in the hippocampus using a rodent model. Excitatory synaptic physiology was analyzed using electrophysiological methods to detect changes in synaptic plasticity, excitatory synaptic transmission and synaptic currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the hippocampus. Additionally, western blot experiments were performed to quantify alterations in protein expression levels in the hippocampus. Prenatal nicotine exposure resulted in a decrease in long term potentiation (LTP) and an increase in long term depression (LTD). Basal synaptic transmission was also reduced with a concomitant decline in AMPAR mediated synaptic currents at the cellular and single channel levels. Presynaptic pool of vesicles docked close to release sites were also diminished in nicotine exposed rats. Moreover, reduced levels of ß2 subunit containing nicotinic receptors and extracellular signal regulated kinase1/2 (ERK1/2) were observed in nicotine exposed rats. These results suggest that long lasting alterations in excitatory synaptic physiology, AMPAR synaptic currents and ERK1/2 signaling may serve as the molecular mechanisms for cognitive deficits associated with prenatal nicotine exposure.

Developmental nicotine exposure induced alterations in behavior and glutamate receptor function in hippocampus.

In the developing brain, nicotinic acetylcholine receptors (nAChRs) are involved in cell survival, targeting, formation of neural and sensory circuits, and development and maturation of other neurotransmitter systems. This regulatory role is disrupted when the developing brain is exposed to nicotine, which occurs with tobacco use during pregnancy. Prenatal nicotine exposure has been shown to be a strong risk factor for memory deficits and other behavioral aberrations in the offspring. The molecular mechanisms underlying these neurobehavioral outcomes are not clearly elucidated. We used a rodent model to assess behavioral, neurophysiological, and neurochemical consequences of prenatal nicotine exposure in rat offspring with specific emphasis on the hippocampal glutamatergic system. Pregnant dams were infused with nicotine (6 mg/kg/day) subcutaneously from the third day of pregnancy until birth. Results indicate that prenatal nicotine exposure leads to increased anxiety and depressive-like effects and impaired spatial memory. Synaptic plasticity in the form of long-term potentiation (LTP), basal synaptic transmission, and AMPA receptor-mediated synaptic currents were reduced. The deficit in synaptic plasticity was paralleled by declines in protein levels of vesicular glutamate transporter 1 (VGLUT1), synaptophysin, AMPA receptor subunit GluR1, phospho(Ser845) GluR1, and postsynaptic density 95 (PSD-95). These results suggest that prenatal nicotine exposure by maternal smoking could result in alterations in the glutamatergic system in the hippocampus contributing to the abnormal neurobehavioral outcomes.