ABSTRACT
Platelets play a role not only in hemostasis and thrombosis, but also in inflammation and innate immunity. We previously reported that an activated form of tyrosyl-tRNA synthetase (YRSACT) has an extratranslational activity that enhances megakaryopoiesis and platelet production in mice. Here, we report that YRSACT mimics inflammatory stress inducing a unique megakaryocyte (MK) population with stem cell (Sca1) and myeloid (F4/80) markers through a mechanism dependent on Toll-like receptor (TLR) activation and type I interferon (IFN-I) signaling. This mimicry of inflammatory stress by YRSACT was studied in mice infected by lymphocytic choriomeningitis virus (LCMV). Using Sca1/EGFP transgenic mice, we demonstrated that IFN-I induced by YRSACT or LCMV infection suppressed normal hematopoiesis while activating an alternative pathway of thrombopoiesis. Platelets of inflammatory origin (Sca1/EGFP+) were a relevant proportion of those circulating during recovery from thrombocytopenia. Analysis of these "inflammatory" MKs and platelets suggested their origin in myeloid/MK-biased hematopoietic stem cells (HSCs) that bypassed the classical MK-erythroid progenitor (MEP) pathway to replenish platelets and promote recovery from thrombocytopenia. Notably, inflammatory platelets displayed enhanced agonist-induced activation and procoagulant activities. Moreover, myeloid/MK-biased progenitors and MKs were mobilized from the bone marrow, as evidenced by their presence in the lung microvasculature within fibrin-containing microthrombi. Our results define the function of YRSACT in platelet generation and contribute to elucidate platelet alterations in number and function during viral infection.
Subject(s)
Spinocerebellar Ataxias , Thrombocytopenia , Thrombosis , Tyrosine-tRNA Ligase , Virus Diseases , Mice , Animals , Thrombopoiesis , Mice, TransgenicABSTRACT
Vincristine (VCR), a vinca alkaloid with anti-tumor and anti-oxidant properties, is acclaimed to possess cardioprotective action. However, the molecular mechanism underlying this protective effect remains unknown. This study investigated the effects of VCR on isoprenaline (ISO), a beta-adrenergic receptor agonist, induced cardiac hypertrophy in male Wistar rats. Animals were pre-treated with ISO (1 mg/kg) intraperitoneally for 14 days before VCR (25 µg/kg) intraperitoneal injection from days 1 to 28. Thereafter, mechanical, and electrical activities of the hearts of the rats were measured using a non-invasive blood pressure monitor and an electrocardiograph, respectively. After which, the heart was homogenized, and supernatants were assayed for contractile proteins: endothelin-1, cardiac troponin-1, angiotensin-II, and creatine kinase-MB, with markers of oxidative/nitrergic stress (SOD, CAT, MDA, GSH, and NO), inflammation (TNF-a and IL-6, NF-kB), and caspase-3 indicative of VCR reduced elevated blood pressure and reversed the abnormal electrocardiogram. ISO-induced increased endothelin-1, cardiac troponin-1, angiotensin-II, and creatine phosphokinase-MB, which were reversed by VCR. ISO also increased TNF-α, IL-6, NF-kB expression with increased caspase-3-mediated apoptosis in the heart. However, VCR reduced ISO-induced inflammation and apoptosis, with improved endogenous antioxidant agents (GSH, SOD, CAT) relative to ISO controls. Moreso, VCR, protected against ISO-induced histoarchitectural degeneration of cardiac myofibre. The result of this study revealed that VCR treatment significantly reverses ISO-induced cardiac hypertrophic phenotypes, via mechanisms connected to improved levels of proteins involved in excitation-contraction, and suppression of oxido-inflammatory and apoptotic pathways.
Subject(s)
Antioxidants , Apoptosis , Disease Models, Animal , Isoproterenol , NF-kappa B , Nitric Oxide , Oxidative Stress , Rats, Wistar , Reactive Oxygen Species , Signal Transduction , Vincristine , Animals , Male , Signal Transduction/drug effects , NF-kappa B/metabolism , Oxidative Stress/drug effects , Apoptosis/drug effects , Vincristine/pharmacology , Reactive Oxygen Species/metabolism , Antioxidants/pharmacology , Nitric Oxide/metabolism , Inflammation Mediators/metabolism , Cardiomegaly/chemically induced , Cardiomegaly/pathology , Cardiomegaly/metabolism , Cardiomegaly/drug therapy , Cardiomegaly/prevention & control , Rats , Anti-Inflammatory Agents/pharmacology , Myocardium/pathology , Myocardium/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Myocytes, Cardiac/metabolism , Ventricular Remodeling/drug effectsABSTRACT
The broad contemporary applications of silver nanoparticles (AgNPs) have been associated with various toxicities including reproductive toxicity. Taurine is well acknowledged for its potent pharmacological role in numerous disease models and chemically-mediated toxicity. We investigated the effect of taurine on AgNPs-induced reproductive toxicity in male rats. The animals were intraperitoneally injected with AgNPs (200 µg/kg) alone or co-administered with taurine at 50 and 100 mg/kg for 21 successive days. Exogenous taurine administration significantly abated AgNPs-induced oxidative injury by decreasing the levels of oxidative stress indices while boosting antioxidant enzymes activities and glutathione level in the hypothalamus, testes and epididymis of exposed animals. Taurine administration alleviated AgNPs-induced inflammatory response and caspase-3 activity, an apoptotic biomarker. Moreover, taurine significantly improved spermiogram, reproductive hormones and the marker enzymes of testicular function in AgNPs-treated animals. The ameliorative effect of taurine on pathological lesions induced by AgNPs in the exposed animals was substantiated by histopathological data. This study provides the first mechanistic evidence that taurine supplementation affords therapeutic effect against reproductive dysfunction associated with AgNPs exposure in male rats.
Subject(s)
Metal Nanoparticles , Silver , Rats , Male , Animals , Silver/toxicity , Rats, Wistar , Metal Nanoparticles/toxicity , Taurine/pharmacology , Taurine/metabolism , Testis , Antioxidants/pharmacology , Antioxidants/metabolism , Oxidative StressABSTRACT
Metabolic disorders (MDs), including dyslipidemia, non-alcoholic fatty liver disease, diabetes mellitus, obesity and cardiovascular diseases are a significant threat to human health, despite the many therapies developed for their treatment. Different classes of bioactive compounds, such as polyphenols, flavonoids, alkaloids, and triterpenes have shown therapeutic potential in ameliorating various disorders. Most of these compounds present low bioavailability when administered orally, being rapidly metabolized in the digestive tract and liver which makes their metabolites less effective. Moreover, some of the bioactive compounds cannot fully exert their beneficial properties due to the low solubility and complex chemical structure which impede the passive diffusion through the intestinal cell membranes. To overcome these limitations, an innovative delivery system of phytosomes was developed. This review aims to highlight the scientific evidence proving the enhanced therapeutic benefits of the bioactive compounds formulated in phytosomes compared to the free compounds. The existing knowledge concerning the phytosomes' preparation, their characterization and bioavailability as well as the commercially available phytosomes with therapeutic potential to alleviate MDs are concisely depicted. This review brings arguments to encourage the use of phytosome formulation to diminish risk factors inducing MDs, or to treat the already installed diseases as complementary therapy to allopathic medication.
Subject(s)
Metabolic Diseases , Phytochemicals , Animals , Humans , Biological Availability , Complementary Therapies/methods , Metabolic Diseases/drug therapy , Phytochemicals/administration & dosage , Phytochemicals/chemistry , Phytochemicals/pharmacology , Phytosomes , Polyphenols/chemistry , Polyphenols/pharmacology , Polyphenols/administration & dosageABSTRACT
This study investigated the modulatory effect of Ginkgo biloba extract on lead acetate-induced endothelial dysfunction. Animals were administered GBE (50 mg/kg and 100 mg/kg orally) after exposures to lead acetate (25 mg/kg orally) for 14 days. Aorta was harvested after euthanasia, the tissue was homogenised, and supernatants were decanted after centrifuging. Oxidative, nitrergic, inflammatory, and anti-apoptotic markers were assayed using standard biochemical procedure, ELISA, and immunohistochemistry, respectively. GBE reduced lead-induced oxidative stress by increasing SOD, GSH, and CAT as well as reducing MDA levels in endothelium. Pro-inflammatory cytokines (TNF-α and IL-6) were reduced while increasing Bcl-2 protein expression. GBE lowered endothelin-I and raised nitrite levels. Histological changes caused by lead acetate were normalised by GBE. Our findings suggest that Ginkgo biloba extract restored endothelin-I and nitric oxide functions by increasing Bcl-2 protein expression and reducing oxido-inflammatory stress in endothelium.
Subject(s)
Ginkgo Extract , Ginkgo biloba , Lead , Rats , Animals , Plant Extracts/pharmacology , Endothelins , Proto-Oncogene Proteins c-bcl-2 , AcetatesABSTRACT
Rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), and celiac disease (CD), are strongly associated with susceptible HLA class II haplotypes. The peptide-binding pockets of these molecules are polymorphic, thus each HLA class II protein presents a distinct set of peptides to CD4+ T cells. Peptide diversity is increased through post-translational modifications, generating non-templated sequences that enhance HLA binding and/or T cell recognition. The high-risk HLA-DR alleles that confer susceptibility to RA are notable for their ability to accommodate citrulline, promoting responses to citrullinated self-antigens. Likewise, HLA-DQ alleles associated with T1D and CD favor the binding of deamidated peptides. In this review, we discuss structural features that promote modified self-epitope presentation, provide evidence supporting the relevance of T cell recognition of such antigens in disease processes, and make a case that interrupting the pathways that generate such epitopes and reprogramming neoepitope-specific T cells are key strategies for effective therapeutic intervention.
Subject(s)
Arthritis, Rheumatoid , Diabetes Mellitus, Type 1 , Humans , T-Lymphocytes , HLA-DR Antigens , Peptides , EpitopesABSTRACT
BACKGROUND: The intestinal epithelial barrier is the interface for interaction between gut microbiota and host metabolic systems. Akkermansia muciniphila (A. muciniphila) is a key player in the colonic microbiota that resides in the mucus layer, whose abundance is selectively decreased in the faecal microbiota of inflammatory bowel disease (IBD) patients. This study aims to investigate the regulatory mechanism among A. muciniphila, a transcription factor cAMP-responsive element-binding protein H (CREBH), and microRNA-143/145 (miR-143/145) in intestinal inflammatory stress, gut barrier integrity and epithelial regeneration. METHODS: A novel mouse model with increased colonization of A muciniphila in the intestine of CREBH knockout mice, an epithelial wound healing assay and several molecular biological techniques were applied in this study. Results were analysed using a homoscedastic 2-tailed t-test. RESULTS: Increased colonization of A. muciniphila in mouse gut enhanced expression of intestinal CREBH, which was associated with the mitigation of intestinal endoplasmic reticulum (ER) stress, gut barrier leakage and blood endotoxemia induced by dextran sulfate sodium (DSS). Genetic depletion of CREBH (CREBH-KO) significantly inhibited the expression of tight junction proteins that are associated with gut barrier integrity, including Claudin5 and Claudin8, but upregulated Claudin2, a tight junction protein that enhances gut permeability, resulting in intestinal hyperpermeability and inflammation. Upregulation of CREBH by A. muciniphila further coupled with miR-143/145 promoted intestinal epithelial cell (IEC) regeneration and wound repair via insulin-like growth factor (IGF) and IGFBP5 signalling. Moreover, the gene expressing an outer membrane protein of A. muciniphila, Amuc_1100, was cloned into a mammalian cell-expression vector and successfully expressed in porcine and human IECs. Expression of Amuc_1100 in IECs could recapitulate the health beneficial effect of A. muciniphila on the gut by activating CREBH, inhibiting ER stress and enhancing the expression of genes involved in gut barrier integrity and IEC's regeneration. CONCLUSIONS: This study uncovers a novel mechanism that links A. muciniphila and its membrane protein with host CREBH, IGF signalling and miRNAs in mitigating intestinal inflammatory stress-gut barrier permeability and promoting intestinal wound healing. This novel finding may lend support to the development of therapeutic approaches for IBD by manipulating the interaction between host genes, gut bacteria and its bioactive components.
Subject(s)
Inflammatory Bowel Diseases , MicroRNAs , Humans , Animals , Mice , Swine , Membrane Proteins/metabolism , Verrucomicrobia/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , MammalsABSTRACT
Interaction of advanced glycation end products (AGE) with their receptor i.e. receptor for advanced glycation end products (RAGE), better understood as AGE-RAGE axis, generates oxidative and inflammatory stress. The generated stress extent, in turn aggravates the AGE and RAGE levels through a vicious self propagation cycle. The associated oxidation and inflammation culminates in modifications and subsequent detrimental state of cellular macromolecules, including nucleic acids and proteins, manifesting multiple diseased conditions. Under normal physiological state, fewer carbonyl group(s) and glutathione, a tripeptide antioxidant may be added to proteins during post-translational modifications, recognized as carbonylation and glutathionylation, respectively. However, under oxidative and inflammatory stress conditions, protein carbonylation and glutathionylation are caused to considerably greater extents, leading to numerous diseased complications. Thereby, increased protein carbonylation and glutathionylation could be used as predictive markers of oxidative and inflammatory stress. The AGE-RAGE axis generated oxidatively modified proteins can be screened via assessing the protein carbonylation and glutathionylation. The present article focuses on most widely used protein carbonylation and glutathionylation based assays for quantifying the AGE-RAGE axis mediated oxidative and inflammatory stress.
Subject(s)
Glycation End Products, Advanced , Oxidative Stress , Biomarkers/metabolism , Glycation End Products, Advanced/metabolism , Humans , Inflammation , Proteins/metabolism , Receptor for Advanced Glycation End Products/genetics , Receptor for Advanced Glycation End Products/metabolismABSTRACT
Compared to the general population, patients with arthritis have a higher risk of fertility abnormalities, which have deleterious effects on both reproductive function and pregnancy outcomes, especially in patients wishing to conceive. These may be due to the disease itself or those of drug therapies. Despite the increasing use of rituximab in arthritis, limited data are available on its potential to induce aneuploidy in germ cells. Therefore, the aim of the current investigation was to determine if repeated treatment with rituximab affects the incidence of aneuploidy and redox imbalance in arthritic mouse sperm. Mice were treated with 250 mg/kg rituximab once weakly for 3 weeks, and then sperm were sampled 22 days after the last dose of rituximab. Fluorescence in situ hybridization assay with chromosome-specific DNA probes was used to evaluate the disomic/diploid sperm. Our results showed that rituximab had no aneuploidogenic effect on the meiotic stage of spermatogenesis. Conversely, arthritis induced a significantly high frequency of disomy, and treatment of arthritic mice with rituximab reduced the increased levels of disomic sperm. The occurrence of total diploidy was not significantly different in all groups. Reduced glutathione and8-hydroxydeoxyguanosine, markers of oxidative stress were significantly altered in arthritic animals, while rituximab treatment restored these changes. Additionally, arthritis severity was reduced after rituximab treatment. We conclude that rituximab may efficiently alleviate the arthritis-induced effects on male meiosis and avert the higher risk of abnormal reproductive outcomes. Therefore, treating arthritic patients with rituximab may efficiently inhibit the transmission of genetic anomalies induced by arthritis to future generations.
Subject(s)
Arthritis, Rheumatoid , Semen , Humans , Male , Mice , Animals , Rituximab/pharmacology , Rituximab/therapeutic use , In Situ Hybridization, Fluorescence/methods , Mice, Inbred DBA , Spermatozoa , Aneuploidy , Arthritis, Rheumatoid/drug therapyABSTRACT
Flavonoid consumption has beneficial effects on human health, however, clinical evidence remains often inconclusive due to high interindividual variability. Although this high interindividual variability has been consistently observed in flavonoid research, the potential underlying reasons are still poorly studied. Especially the knowledge on the impact of health status on flavonoid responsiveness is limited and merits more investigation. Here, we aim to highlight the bidirectional interplay between flavonoids and cellular stress. First, the state-of-the-art concerning inflammatory stress and mitochondrial dysfunction is reviewed and a comprehensive overview of recent in vitro studies investigating the impact of flavonoids on cellular stress, induced by tumor necrosis factor α, lipopolysaccharide and mitochondrial stressors, is given. Second, we critically discuss the influence of cellular stress on flavonoid uptake, accumulation, metabolism and cell responses, which has, to our knowledge, never been extensively reviewed before. Next, we advocate the innovative insight that stratification of the general population based on health status can reveal subpopulations that benefit more from flavonoid consumption. Finally, suggestions are given for the development of future cell models that simulate the physiological micro-environment, including interindividual variability, since more mechanistic research is needed to establish scientific-based personalized food recommendations for specific subpopulations.
Subject(s)
Flavonoids , Food , Humans , Flavonoids/pharmacology , Flavonoids/metabolism , Lipopolysaccharides , Tumor Necrosis Factor-alphaABSTRACT
Doxorubicin (DOX) is a chemotherapeutic drug used in the treatment of various cancer types. DOX toxic side effects include neuronopathy and memory deficits. We investigated the effect of the antioxidant luteolin (LUT: 50 or 100 mg/kg; per os) on DOX (2 mg/kg; intraperitoneal)-induced oxidative stress (OS), inflammation, and apoptosis in the brain of Wistar rats for 14 days. We observed that LUT reduced DOX-mediated increase in OS biomarkers-catalase, superoxide dismutase, glutathione-S-transferase, and glutathione peroxidase. LUT increased glutathione and total sulphydryl levels and alleviated DOX-induced increases in the levels of reactive oxygen and nitrogen species, lipid peroxidation, myeloperoxidase, nitric oxide, tumor necrosis factor-α, and interleukin-1ß (IL-1ß). Additionally, LUT suppressed caspase-3 activity, increased anti-inflammatory cytokine-IL-10 level, and reduced pathological lesions in the examined organs of rats cotreated with LUT and DOX. Collectively, cotreatment with LUT lessened DOX-induced neurotoxicity. Supplementation of LUT as a chemopreventive agent might be useful in patients undergoing DOX chemotherapy.
Subject(s)
Doxorubicin/adverse effects , Luteolin/pharmacology , Neurotoxicity Syndromes , Animals , Doxorubicin/pharmacology , Male , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/prevention & control , Rats , Rats, WistarABSTRACT
Furan formed in processed food is hepatotoxic and likely carcinogenic in humans. We investigated protocatechuic acid (PCA) protective role in rats' hepatorenal function treated with furan. Rats were grouped and treated as follows: Control, PCA (50 mg/kg), furan alone (8 mg/kg), furan + PCA1 (25 + 8 mg/kg), and furan + PCA2 (50 + 8 mg/kg). Upon sacrifice, evaluation of hepatorenal function, oxidative stress status, reactive oxygen and nitrogen species (RONS), lipid peroxidation (LPO), myeloperoxidase (MPO) activity, among nitric oxide (NO) levels were performed. Cytokine levels (IL-10, IL-1ß, TNF-alpha), Caspase 3 and 9 activities, and histopathological examination were also assessed. We found that the final body and relative liver weights changed significantly (p < 0.05) in treated groups. Hepatic transaminases, urea, and creatinine increased (p < 0.05) in furan only treated group, and reduced in PCA co-treated groups. The furan-induced decrease in antioxidant status increased RONS, and LPO levels were alleviated (p < 0.05) by PCA co-treatment. Furthermore, furan-mediated increase in NO, IL-1ß, TNF-alpha levels, MPO, Cas-3, and 9 activities and suppressed IL-10 levels was reversed accordingly in rats' kidney and liver co-treated with PCA. The extent of furan-mediated hepatorenal lesions was lessened in PCA co-treated rats. Our findings suggest that PCA protects against oxido-inflammatory pathways, enhanced caspases 3 and 9 activations induced by furan in rat hepatorenal system.
Subject(s)
Furans , Hydroxybenzoates , Kidney , Liver , Tumor Necrosis Factor-alpha , Animals , Antioxidants/metabolism , Furans/toxicity , Hydroxybenzoates/pharmacology , Interleukin-10/metabolism , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Oxidative Stress , Rats , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
This study aimed to investigate the effect of cell surface CD47 downregulation on ischaemia-reperfusion injury (IRI) during pig liver transplantation. Blood samples were collected from healthy miniature Bama pigs randomly and equally divided into CD47 antagonism (group A), without CD47 antagonism (group B) and a sham group (group C). Blood samples were collected from groups A and B at 0, 8 and 48 hours after establishment of the new liver through an indwelling tube in the right internal jugular vein. Blood samples were collected at the same time points after liver dissociation from group C. The expression of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) was detected by enzyme-linked immunosorbent assay (ELISA); CD47 expression was detected by Western blot; and liver function indices, including alanine aminotransferase (ALT) and aspartic transaminase (AST), were directly read by an automatic biochemical analyzer. The concentrations of both receptors in group A were significantly lower than groups B and C, at 8 and 48 hours after establishment of blood flow. At 8 and 48 hours in the new liver stage, the values of CD47 levels, ALT and AST in group A were significantly reduced compared to groups B and C (P < 0.05). The levels of CD47 in the three groups were consistent with the trends of the aforementioned observation indicators. The liver functions of the recipients were significantly improved by reducing the release of the inflammatory mediators. This study provides new ideas and intervention approaches for the treatment of IRI in liver transplantation.
Subject(s)
CD47 Antigen/antagonists & inhibitors , Liver Transplantation/adverse effects , Liver Transplantation/methods , Reperfusion Injury/prevention & control , Animals , Down-Regulation , Reperfusion Injury/metabolism , SwineABSTRACT
Herbal and dietary supplements (HDS)-induced liver injury has been a great concern all over the world. Polygonum multiflorum Thunb., a well-known Chinese herbal medicine, is recently drawn increasing attention because of its hepatotoxicity. According to the clinical and experimental studies, P. multiflorum-induced liver injury (PM-DILI) is considered to be immune-mediated idiosyncratic liver injury, but the role of immune response and the underlying mechanisms are not completely elucidated. Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury (DILI). However, most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury. The aim of this review is to assess current epidemiological, clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P. multiflorum. The potential effects of factors associated with immune tolerance, including immune checkpoint molecules and regulatory immune cells on the individual's susceptibility to PM-DILI are also discussed. We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.
Subject(s)
Adaptive Immunity/drug effects , Chemical and Drug Induced Liver Injury/physiopathology , Drugs, Chinese Herbal/adverse effects , Fallopia multiflora/adverse effects , Immunity, Innate/drug effects , Liver/drug effects , Adaptive Immunity/genetics , Animals , Asian People , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/toxicity , Fallopia multiflora/toxicity , HLA-B35 Antigen/genetics , Humans , Immune Tolerance/physiology , Lipopolysaccharides/toxicityABSTRACT
The therapeutic and pharmacological management of Alzheimer's disease (AD) is generally considered a major concern in ethnomedicine. Moreover, plant-based foods containing flavonoids were previously reported to show neuroprotective effects by modulating self-aggregation of amyloid-ß (Aß)/or tau peptide into oligomers and fibrils, associated with the pathogenesis of AD. This study investigated the impact of Moringa oleifera-supplemented diet (MO-SD) in scopolamine-induced spatial memory deficit in mice. Mice were partitioned into two phases with five groups each (n=6) and pretreated intraperitoneally with scopolamine (1 mg/kg) prior the daily oral administration of MO-SD (1 %, 5 % and 10 %) for 7 and 14 days. Spatial memory function was assessed using the Morris water maze (MWM) test. Thereafter, markers of cholinergic system inhibition (Acetylcholinesterase; AChE) and oxido-inflammatory stress (Malonaldehyde, MDA; Nitrite; Superoxide Dismutase, SOD; Tumor necrosis factor-alpha, TNF-α) and histo-morphology of the cortico-hippocampal neuron were measured. The scopolamine treatment led to loss of spatial memory function in mice spatial exploration of the escape platform in the MWM test. Meanwhile, treatment with MO-SD attenuated loss of spatial memory function via significant decrease in escape latency, significant increase in the frequency of cross with time spent in the platform quadrant. Furthermore, scopolamine treatment altered the endogenous antioxidants and pro-inflammatory mediators, elevated acetylcholinesterase activity and promoted chromatolysis of the cortico-hippocampal neuron. However, MO-SD significantly ameliorated oxido-inflammatory stress, restored cholinergic transmission via acetylcholinesterase inhibition and maintains neuronal integrity in the mice brain at both phases. These results suggest that Moringa oleifera-supplemented diet may serve a potential therapeutic and possible pharmacological macromolecule for preventing loss of neuronal cells and management of Alzheimer's disease.
Subject(s)
Moringa oleifera , Scopolamine , Acetylcholinesterase/metabolism , Animals , Cholinergic Agents/pharmacology , Diet , Hippocampus/metabolism , Maze Learning , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Memory Disorders/prevention & control , Mice , Moringa oleifera/metabolism , Oxidative Stress , Scopolamine/pharmacology , Spatial Memory , Synaptic TransmissionABSTRACT
BACKGROUND: Robot-assisted surgery is increasingly implemented for the resection of colorectal cancer, although the scientific evidence for adopting this technique is still limited. This study's main objective was to compare short-term complication rates, oncological outcomes, and the inflammatory stress response after colorectal resection for cancer performed laparoscopic or robot-assisted. METHODS: We conducted a retrospective cohort study comparing the robot-assisted approach to laparoscopic surgery for elective malignant colorectal neoplasm. Certified colorectal and da Vinci ® robotic surgeons performed resections at a Danish tertiary colorectal high volume center from May 2017 to March 2019. We analyzed the two surgical groups using uni- and multivariate regression analyses to detect differences in intra- and postoperative clinical outcomes and the inflammatory stress response. RESULTS: Two hundred and ninety-eight patients were enrolled in the study. Significant differences favoring robot-assisted surgery was demonstrated for; length of hospital stay (4 days, interquartile range (4, 5) versus 5 days, interquartile range (4-7), p < 0.001), and intraoperative blood loss (50 mL, interquartile range (20-100) versus 100 mL, interquartile range (50-150), p < 0.001) compared to laparoscopic surgery. The inflammatory stress response was significantly higher after laparoscopic compared to robot-assisted surgery reflected by an increase in C-reactive protein concentration (exponentiated coefficient = 1.23, 95% confidence interval (1.06-1.46), p = 0.008). No differences between the two groups were found concerning mortality, microradical resection rate, conversion to open surgery, and surgical or medical short-term complication rates. CONCLUSION: Robot-assisted surgery is feasible and can be safely implemented for colorectal resections. The robot-assisted approach, when compared to laparoscopic surgery, was associated with improved intra- and postoperative outcomes. Extensive prospective studies are needed to determine the short- and long-term outcomes of robotic surgery for colorectal cancer.
Subject(s)
Colorectal Neoplasms , Laparoscopy , Robotic Surgical Procedures , Robotics , Colorectal Neoplasms/surgery , Humans , Postoperative Complications , Prognosis , Prospective Studies , Retrospective Studies , Robotic Surgical Procedures/adverse effects , Treatment OutcomeABSTRACT
Perfluorooctanoic acid is a synthetic perfluoroalkyl-persistent in the environment and toxic to humans. N-acetylcysteine is a pro-drug of both amino acid l-cysteine and glutathione-a non-enzymatic antioxidant. N-acetylcysteine serves as an antidote for paracetamol poisoning and alleviates cellular oxidative and inflammatory stressors. We investigated N-acetylcysteine role against reproductive toxicity in male Wistar rats (weight: 140-220 g; 10 weeks old) posed by perfluorooctanoic acid exposure. Randomised rat cohorts were dosed both with perfluorooctanoic acid (5 mg/kg; p.o) or co-dosed with N-acetylcysteine (25 and 50 mg/kg p.o) for 28 days. Sperm physiognomies, biomarkers of testicular function and reproductive hormones, oxidative stress and inflammation were evaluated. Co-treatment with N-acetylcysteine significantly (p < .05) reversed perfluorooctanoic acid-mediated decreases in reproductive enzyme activities, and adverse effect on testosterone, luteinising and follicle-stimulating hormone concentrations. N-acetylcysteine treatment alone, improved sperm motility, count and viability, and reduced total sperm abnormalities. Co-treatment with N-acetylcysteine mitigated perfluorooctanoic acid-induced alterations in sperm function parameters. N-acetylcysteine abated (p < .05) perfluorooctanoic acid-induced oxidative stress in experimental rats testes and epididymis, and generally improved antioxidant enzyme activities and cellular thiol levels. Furthermore, N-acetylcysteine suppressed inflammatory responses and remedied perfluorooctanoic acid-mediated histological injuries in rat. Cooperatively, N-acetylcysteine enhanced reproductive function in perfluorooctanoic acid dosed rats, by lessening oxidative and nitrative stressors and mitigated inflammatory responses in the examined organ.
Subject(s)
Acetylcysteine , Fluorocarbons , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Caprylates , Fluorocarbons/metabolism , Fluorocarbons/toxicity , Humans , Male , Oxidative Stress , Rats , Rats, Wistar , Sperm Motility , Spermatozoa/metabolism , Testis/metabolism , Testosterone/metabolismABSTRACT
BACKGROUND: Apolipoprotein L1, APOL1, is a trypanosome lytic factor present in human and certain other primates. APOL1 gene variants, present in individuals of recent sub-Saharan African descent, increase risk for glomerular disease and associate with the disease progression, but the molecular mechanisms have not been defined. OBJECTIVES: We focus on the mechanism how APOL1 variant proteins enhance podocyte injury in the stressed kidney. METHODS: First, we investigated the expression of APOL1 protein isoform and the localization of APOL1 protein in the kidney. Next, we examined the role of APOL1 in the podocyte stress and the inflammatory signaling in the kidney after hemi-nephrectomy. RESULTS: We identified a novel RNA variant that lacks a secretory pathway signal sequence and we found that the predicted APOL1-B3 protein isoform was expressed in human podocytes in vivo and by BAC-APOL1 transgenic mice. APOL1-B3-G2 transgenic mice, carrying a renal risk variant, manifested podocyte injury and increased pro-IL-1ß mRNA in isolated glomeruli and increased IL-1ß production in the remnant kidney after uninephrectomy. APOL1-B3 interacted with NLRP12, a key regulator of Toll-like receptor signaling. CONCLUSIONS: These results suggest a possible mechanism for podocyte injury by which one of the APOL1 protein isoforms, APOL1-B3 and its renal risk variants, enhances inflammatory signaling.
Subject(s)
Apolipoprotein L1/genetics , Inflammation/genetics , Kidney Glomerulus/metabolism , Nephrectomy , Podocytes/metabolism , RNA, Messenger/metabolism , Stress, Physiological/genetics , Animals , Apolipoprotein L1/metabolism , Humans , In Vitro Techniques , Inflammation/metabolism , Interleukin-1beta/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Kidney Glomerulus/pathology , Mice , Mice, Transgenic , Podocytes/pathology , Protein IsoformsABSTRACT
Loranthus micranthus (African mistletoe)-Loranthaceae family, is used in Nigerian traditional medicine for treating male infertility and lowering diabetic blood sugar levels. We investigated possible mechanism(s) involved in mitigation of L. micranthus leaves nanoparticles (LMLNPs) on streptozotocin (STZ)-induced testicular alterations. Type two diabetes mellitus (T2DM) was induced in male rats following 2 weeks feeding with fructose and single intraperitoneal injection of STZ. Control (nondiabetic) and (diabetic) rats received buffer only. Diabetic rats were treated with metformin or LMLNPs (two different doses) for 28 days. Hormonal profile, oxido-inflammatory stress parameters, glucose metabolism and steroidogenic enzymes/regulatory protein (StAR) and Nuclear factor erythroid 2-related factor 2 (Nrf2) protein in testes and sperm parameters were evaluated. Metformin and LMLNPs treatment significantly reduced blood glucose level in diabetic rats. Furthermore, LMLNPs enhanced glucose metabolism and testicular steroidogenic enzymes/protein, increased reproductive hormone levels and sperm functional parameters in diabetic rats. Additionally, LMLNPs suppressed testicular oxido-inflammatory stress biomarkers and inhibited lipid peroxidation in diabetic rats while augmenting Nrf2 pathway. Conclusively, LMLNPs potently reversed adverse effects of T2DM testicular dysfunction of rats. Use of LMLNPs in abating diabetic consequences proves an acceptable alternative to traditional crude extract preparations, as a result of better packaging and preservation.
Subject(s)
Diabetes Mellitus, Experimental , Loranthaceae , Nanoparticles , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Glucose/metabolism , Humans , Male , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Rats , Rats, Wistar , Streptozocin , Testis/metabolismABSTRACT
Twisting of the spermatic cord is considered a popular problem in the urological field, which may lead to testicular necrosis and male infertility. Sitagliptin, a glucose-lowering agent, proved to have a vindicatory function in myocardial and renal ischaemia/reperfusion (I/R), but its role in testicular I/R has not yet been studied. The current work investigates its capability to recover the testicular I/R injury with shedding more light on the mechanism of its action. Four groups were used: sham, sham pretreated with sitagliptin, I/R and sitagliptin/I/R-pretreated groups. The outcomes proved that I/R significantly decreased the serum testosterone, with a major increase in oxidative, inflammatory and nitrosative stress, along with a reduction in testicular vascular endothelial growth factor-A level with marked germinal cell apoptosis. However, pretreatment with sitagliptin significantly reversed the profound testicular I/R damaging effects, on the basis of its antioxidant, anti-inflammatory and anti-apoptotic activities with the ability of recuperation of the testicular vascularity.