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1.
Int J Mol Sci ; 25(4)2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38396978

ABSTRACT

The core symptoms of attention deficit hyperactivity disorder (ADHD) are due to the hypofunction of the brain's adrenergic (NE) and dopamine (DA) systems. Drugs that enhance DA and NE neurotransmission in the brain by blocking their transporters or receptors are the current therapeutic strategies. Of late, the emerging results point out the serotonergic (5-HT) system, which indirectly modulates the DA activity in reducing the core symptoms of ADHD. On this basis, second-generation antipsychotics, which utilize 5-HT receptors, were prescribed to children with ADHD. However, it is not clear how serotonergic receptors modulate the DA activity to minimize the symptoms of ADHD. The present study investigates the efficacy of serotonergic and alpha-2 adrenergic receptor manipulation in tackling the core symptoms of ADHD and how it affects the DA neuroreceptors in the brain regions involved in ADHD. Fifteen-day-old male spontaneously hypertensive rats (SHRs) received 5-HT1A agonist (ipsapirone) or 5-HT2A antagonist (MDL 100907) (i.p.) or alpha-2 agonist (GFC) from postnatal days 15 to 42 along with age-matched Wistar Kyoto rats (WKY) (n = 8 in each group). ADHD-like behaviors were assessed using a battery of behavioral tests during postnatal days 44 to 65. After the behavioral tests, rat brains were processed to estimate the density of 5-HT1A, 5-HT2A, DA-D1, and DA-D2 neuroreceptors in the prefrontal cortex, the striatum, and the substantia nigra. All three neuroreceptor manipulations were able to minimize the core symptoms of ADHD in SHRs. The positive effect was mainly associated with the upregulation of 5-HT2A receptors in all three areas investigated, while 5-HT1A was in the prefrontal cortex and the substantia nigra. Further, the DA-D1 receptor expression was downregulated by all three neuroreceptor manipulations except for alpha-2 adrenergic receptor agonists in the striatum and 5-HT2A antagonists in the substantia nigra. The DA-D2 expression was upregulated in the striatum while downregulated in the prefrontal cortex and the substantia nigra. In this animal model study, the 5-HT1A agonist or 5-HT2A antagonist monotherapies were able to curtail the ADHD symptoms by differential expression of DA receptors in different regions of the brain.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Humans , Rats , Animals , Child , Male , Rats, Inbred SHR , Adrenergic Agents/therapeutic use , Serotonin 5-HT2 Receptor Antagonists/therapeutic use , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Dopamine/metabolism , Rats, Inbred WKY
2.
Int J Mol Sci ; 24(23)2023 Nov 23.
Article in English | MEDLINE | ID: mdl-38068971

ABSTRACT

Diabetic neuropathy is an important long-term complication of diabetes. This study explored the hypothesis that hydrogen sulfide (H2S) ameliorates neuropathic pain by controlling antiapoptotic and pro-apoptotic processes. The effects of a slow-releasing H2S donor, GYY4137, on the expression of antiapoptotic and pro-apoptotic genes and proteins, such as B-cell lymphoma 2 (Bcl2) and Bcl-2-like protein 4 (Bax), as well as caspases, cyclooxygenase (COX)-1 and COX-2, monocytes/macrophages, and endothelial cells, in the spinal cord of male Sprague-Dawley rats with streptozotocin-induced peripheral diabetic neuropathy, were investigated using reverse transcription-PCR, western blot and immunohistochemistry. The antihypoalgesic activities of GYY4137 on diabetic rats were evaluated using the tail flick test. Treatment of diabetic rats with GYY4137 attenuated thermal hypoalgesia and prevented both the diabetes-induced increase in Bax mRNA expression (p = 0.0032) and the diabetes-induced decrease in Bcl2 mRNA expression (p = 0.028). The GYY4137-treated diabetic group had increased COX-1 (p = 0.015), decreased COX-2 (p = 0.002), reduced caspase-7 and caspase-9 protein expression (p < 0.05), and lower numbers of endothelial and monocyte/macrophage cells (p < 0.05) compared to the non-treated diabetic group. In summary, the current study demonstrated the protective properties of H2S, which prevented the development of neuropathy related behavior, and suppressed apoptosis activation pathways and inflammation in the spinal cord. H2S-releasing drugs could be considered as possible treatment options of diabetic peripheral neuropathy.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Neuropathies , Hydrogen Sulfide , Neuroprotective Agents , Rats , Animals , Male , Hydrogen Sulfide/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Streptozocin , Diabetic Neuropathies/etiology , Diabetic Neuropathies/complications , Rats, Wistar , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism , Diabetes Mellitus, Experimental/metabolism , Endothelial Cells/metabolism , Cyclooxygenase 2 , Rats, Sprague-Dawley , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger
3.
Cureus ; 15(1): e34360, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36874729

ABSTRACT

Injuries of the hand's flexor tendons carry a poor prognosis, mainly if they are in zone II (also called 'the critical zone' or 'no man's land'). The superficial tendon in this zone ends by bifurcating and attaching to the sides of the middle phalanx, exposing the deep tendon that attaches to the distal phalanx. Thus, trauma to this zone may result in a complete cut to the deep tendon while the superficial one remains intact. The lacerated tendon, in turn, would be retracted proximally to the palm making it difficult to be found during wound exploration. The complex anatomy of the hand, particularly that of the flexor zones, may contribute to the misdiagnosis of a tendon injury. We report five cases of an isolated cut of the flexor digitorum profundus (FDP) tendon after traumatic injury to the flexor zone II of the hand. The mechanism of injury of each case is reported together with a clinical approach that guides ED physicians toward diagnosing flexor tendon injuries in hand. In cut wounds involving the flexor zone II of the hand, it should be not surprising to find that the deep tendon (FDP) is completely lacerated without an injury to the superficial one (FDS). Therefore, we conclude that a systematic examination approach for traumatic hand injuries is essential to ensure the proper assessment. Understanding the mechanism of injury, performing a systemic examination approach, and having basic anatomical knowledge of flexor tendons of the hand are essential to identifying tendon injuries, anticipating complications, and providing adequate healthcare.

4.
Front Pharmacol ; 14: 1085314, 2023.
Article in English | MEDLINE | ID: mdl-36726586

ABSTRACT

Introduction: Crush injuries occur from acute traumatic nerve compression resulting in different degrees of neural damage leading to permanent functional deficits. Recently, we have shown that administration of Fraction B (FB) derived from catfish epidermal secretions accelerates healing of damaged nerve in a sciatic nerve crush injury, as it ameliorates the neurobehavioral deficits and enhances axonal regeneration, as well as protects spinal neurons and increases astrocytic activity and decreasing GAP-43 expression. The present study aimed to investigate the role of FB treatment on the apoptotic pathway in the neuroregeneration of the sciatic nerve crush injury. Methods: Male Wistar rats were randomly assigned into five groups: (I) SHAM, (II) CRUSH, (III) CRUSH + (1.5 mg/kg) FB, (IV) CRUSH + (3 mg/kg) FB, and (V) CRUSH + (4.5 mg/kg) FB. Rats underwent sciatic nerve crush surgery, followed by treatment with FB administered intraperitoneally (IP) daily for two weeks and then sacrificed at the end of the fourth week. Results: FB improved the recovery of neurobehavioral functions with a concomitant increase in axonal regeneration and neuroprotective effects on spinal cord neurons following crush injury. Further, FB enhanced Schwann cells (SCs) proliferation with a significant increase in myelin basic protein expression. FB-treated animals demonstrated higher numbers of neurons in the spinal cord, possibly through ameliorating oxidative DNA damage and alleviating the mitochondrial-dependent apoptotic pathway by inhibiting the release of cytochrome c and the activation of caspase-3 in the spinal cord neurons. Conclusion: FB alleviates the neurodegenerative changes in the lumbar spinal cord neurons and recovers the decrease in the neuronal count through its anti-apoptotic and DNA antioxidative properties.

5.
Front Physiol ; 13: 1039588, 2022.
Article in English | MEDLINE | ID: mdl-36685197

ABSTRACT

Introduction: Diabetes Mellitus (DM) is the most common metabolic disease worldwide and is associated with many systemic complications. Muscle atrophy is one of the significant complications in DM patients, making routine tasks laborious as atrophy continues. It is known that heat stress stimulates heat shock proteins and other proteins that maintain muscle mass; however, it is not thoroughly studied in diabetic conditions. This study addressed whether heat therapy can attenuate muscle atrophy in STZ-induced diabetic rats and explored its mechanism of action on specific muscle proteins. Methods: Male Sprague Dawley rats were randomly divided into short-term (3 weeks) and long-term (6 weeks) experiments. In each experiment rats were divided into control, heat therapy, diabetic and diabetic + heat therapy groups. Rats in heat therapy groups were exposed to heat therapy for 30 min daily for three or six weeks in a temperature-controlled (42°C) chamber. Results: The attenuation of neuromuscular functions assessed by Rotarod, Kondziella's inverted screen, and extensor postural thrust tests showed that diabetic rats exposed to heat therapy performed significantly better than diabetic controls. Muscle cross sectional area data established that heat therapy reduced muscle atrophy by 34.3% within 3 weeks and 44.1% within 6 weeks in the diabetic groups. Further, heat therapy significantly decreased muscle atrophy markers (CD68, KLF, and MAFbx) and significantly elevated muscle hypertrophy markers (AKT, mTOR, and HSP70). Conclusions: This study shows the relevance and clinical significance of utilizing heat therapy as a viable treatment to attenuate muscle atrophy in diabetic patients.

6.
Front Pharmacol ; 12: 632028, 2021.
Article in English | MEDLINE | ID: mdl-33986668

ABSTRACT

Preliminary investigations showed that preparations from Arabian Gulf catfish (Arius bilineatus, Val) epidermal gel secretion (PCEGS) exhibit potent anti-inflammatory and healing properties as shown in our previous clinical trials for the healing of non-healing diabetic foot ulcers, chronic back pain, and some other neurological disorders. Here, we report for the first time a unique preparation containing only proteins and lipids (soluble protein fraction B, SPF-FB), derived from the PCEGS accelerated the healing and recovery of sensory-motor functions of experimental sciatic nerve crush injury in rats with its unique neuroprotective and neuroregenerative properties on the spinal neurons and peripheral nerve fibers. Male rats were randomly assigned to five groups: (I) NAÏVE, (II) SHAM, (III) CRUSH treated with saline, (IV) CRUSH + SPF-FB treated with 3 mg/kg intraperitoneally (IP) and (V) CRUSH + SPF-FB treated with 6 mg/kg subcutaneously (SC) groups. The crush groups III, IV and V underwent sciatic nerve crush injury, followed by treatment daily for 14 days with saline, SPF-FB IP and SPF-FB SC. All animals were tested for the neurobehavioral parameters throughout the 6 weeks of the study. Sciatic nerve and spinal cord tissues were processed for light and electron histological examinations, stereological analysis, immunohistochemical and biochemical examinations at Week 4 and Week 6 post-injury. Administration of SPF-FB IP or SC significantly enhanced the neurobehavioral sensory and motor performance and histomorphological neuroregeneration of the sciatic nerve-injured rats. The stereological evaluation of the axon area, average axon perimeters, and myelin thickness revealed significant histomorphological evidence of neuroregeneration in the FB-treated sciatic nerve crush injured groups compared to controls at 4 and 6 weeks. SPF-FB treatment significantly prevented the increased in NeuN-immunoreactive neurons, increased GFAP immunoreactive astrocytes, and decreased GAP-43. We conclude that SPF-FB treatment lessens neurobehavioral deficits, enhances axonal regeneration following nerve injury. We conclude that SPF-FB treatment lessens neurobehavioral deficits and enhances axonal regeneration following nerve injury, as well as protects spinal neurons and enhances subcellular recovery by increasing astrocytic activity and decreasing GAP-43 expression.

7.
J Neuropathol Exp Neurol ; 79(12): 1320-1343, 2020 12 04.
Article in English | MEDLINE | ID: mdl-33271602

ABSTRACT

Long-term diabetic patients suffer immensely from diabetic neuropathy. This study was designed to investigate the effects of hydrogen sulfide (H2S) on peripheral neuropathy, activation of microglia, astrocytes, and the cascade secretion of proinflammatory cytokines in the streptozotocin (STZ)-induced peripheral diabetic neuropathy rat model. STZ-induced diabetic rats were treated with the water-soluble, slow-releasing H2S donor GYY4137 (50 mg/kg; i.p.) daily for 4 weeks. Antiallodynic/antihyperalgesic activities were evaluated using different tests and histopathological changes and the expression of proinflammatory cytokines in the spinal cord were examined. GYY4137 treatment produced neuroprotective effects in the spinal cord of diabetic animals and modulated their sensory deficits. The treatment decreased allodynia (p < 0.05) and mechanical hyperalgesia (p < 0.01) and restored thermal hyperalgesia (p < 0.001) compared with diabetic rats. The treatment decreased the microglial response and increased astrocyte counts in spinal cord gray and white matter compared with untreated diabetic rats. Proinflammatory cytokines were reduced in the treated group compared with diabetic rats. These results suggest that H2S has a potentially ameliorative effect on the neuropathic pain through the control of astrocyte activation and microglia-mediated inflammation, which may be considered as a possible treatment of peripheral nerve hypersensitivity in diabetic patients.


Subject(s)
Astrocytes/drug effects , Diabetes Mellitus, Experimental/metabolism , Diabetic Neuropathies/drug therapy , Microglia/drug effects , Morpholines/pharmacology , Neuroprotective Agents/pharmacology , Organothiophosphorus Compounds/pharmacology , Spinal Cord/drug effects , Animals , Astrocytes/metabolism , Cytokines/metabolism , Diabetic Neuropathies/metabolism , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Inflammation Mediators/metabolism , Male , Microglia/metabolism , Morpholines/therapeutic use , Neuroprotective Agents/therapeutic use , Organothiophosphorus Compounds/therapeutic use , Rats , Rats, Sprague-Dawley , Spinal Cord/metabolism , Treatment Outcome
8.
Front Pharmacol ; 11: 899, 2020.
Article in English | MEDLINE | ID: mdl-32625093

ABSTRACT

Preparations from Arabian Gulf catfish (Arius bilineatus, Val) epidermal gel secretion (PCEGS) effectively heal chronic wounds in diabetic patients. However, specific lipid components of PCEGS that are responsible for various aspects of wound healing are unknown. Here, we report for the first time that, i) a unique preparation containing only proteins and lipids (Fraction B, FB), derived from the PCEGS accelerated the healing of experimental dermal wounds in female rats (transdermal punch biopsy) in vivo. Histological analyses showed that topical treatment of these wounds with FB promoted the migration of fibroblasts, facilitated the production of extracellular matrix (collagen, fibronectin), induced capillary formation and recruitment of immune cells, and accelerated overall wound healing by day 4 (tested at 1, 2, 3, 4, and 10 days; n=15 for vehicle; n=15 for FB treatment), ii) the lipids responsible for different stages of wound healing were separated into a protein-free bioactive lipid fraction, Ft, which contained a few common long-chain fatty acids, a unique furan fatty acid (F6) and a cholesterol metabolite, cholesta-3,5-diene (S5). Ft (the partially purified lipid fraction of PCEGS), and F6 and S5 present in Ft, proved to be bioactive for wound healing in human dermal fibroblasts. Ft increased the production and extracellular deposition of collagen and fibronectin, ex vivo, iii) Ft and its subcomponents, pure F6 and S5, also promoted human dermal fibroblast migration into the scratch wound gaps, ex vivo, iv) Ft, F6, and S5 promoted the recruitment of neutrophils (Green fluorescence protein labeled) to the site of injury in the transected tailfins of transgenic zebrafish, in vivo, v) Ft, but not F6 or S5, promoted the regeneration of tissues at the wound site in the transgenic zebrafish tailfin, in vivo. Therefore, we conclude that lipid fraction Ft from PCEGS contains the components necessary to promote complete wound healing, and F6 and S5 are responsible for promoting fibroblast and neutrophil recruitment to the site of wounds.

9.
PLoS One ; 14(12): e0226626, 2019.
Article in English | MEDLINE | ID: mdl-31877172

ABSTRACT

Ginkgo biloba leaves extract (GBE) was subjected to neuroprotective-guided fractionation to produce eleven fractions with different polarities and constituents. The intermediate polar fraction was shown to be terpene trilactones-enriched fraction (TEGBE). Out of this fraction, pure ginkgolide B (G-B) was further purified and identified based on its spectral data. The effects of GBE and TEGBE were evaluated in comparison to that of G-B in the crush sciatic nerve injury rat model. To evaluate the neuroprotective effects, sixty Wistar male rats were randomly allocated into 6 groups: naive, sham, crush + normal saline, and three treatment groups; crush + GBE, crush + TEGBE, and crush + G-B. Treatments were given one hour following injury, and once daily for 14 days. Neurobehavioral tests, histomorphological examinations, and immunohistochemical analysis of the sciatic nerve and the spinal cord were performed at weeks 3 and 6 post-injury. GBE, TEGBE and G-B were shown to enhance the functional and sensory behavioral parameters and to protect the histological and the ultrastructural elements in the sciatic nerve. Additionally, all treatments prevented spinal cord neurons from further deterioration. It was shown that G-B has the most significant potential effects among all treatments with values that were nearly comparable to those of sham and naive groups.


Subject(s)
Crush Injuries/drug therapy , Ginkgolides/therapeutic use , Lactones/therapeutic use , Neuroprotective Agents/therapeutic use , Peripheral Nerve Injuries/drug therapy , Plant Extracts/therapeutic use , Sciatic Nerve/injuries , Animals , Crush Injuries/pathology , Ginkgo biloba , Male , Peripheral Nerve Injuries/pathology , Rats, Wistar , Sciatic Nerve/drug effects , Sciatic Nerve/pathology
10.
PLoS One ; 14(11): e0224163, 2019.
Article in English | MEDLINE | ID: mdl-31675376

ABSTRACT

The angiotensin-(1-7) [Ang-(1-7)]/MAS1 receptor signaling axis is a key endogenous anti-inflammatory signaling pathway. However, the mechanisms by which its mediates the anti-inflammatory effects are not completely understood. Using an allergic murine model of asthma, we investigated whether Ang-1(1-7)/MAS1 receptor axis a): inhibits allergic inflammation via modulation of Src-dependent transactivation of the epidermal growth factor receptor (EGFR) and downstream signaling effectors such as ERK1/2, and b): directly inhibits neutrophil and/or eosinophil chemotaxis ex vivo. Ovalbumin (OVA)-induced allergic inflammation resulted in increased phosphorylation of Src kinase, EGFR, and ERK1/2. In addition, OVA challenge increased airway cellular influx, perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyperresponsiveness (AHR). Treatment with Ang-(1-7) inhibited phosphorylation of Src kinase, EGFR, ERK1/2, the cellular and histopathological changes and AHR. Ang-(1-7) treatment also inhibited neutrophil and eosinophil chemotaxis ex vivo. These changes were reversed following pre-treatment with A779. These data show that the anti-inflammatory actions of Ang-(1-7)/ MAS1 receptor axis are mediated, at least in part, via inhibition of Src-dependent transactivation of EGFR and downstream signaling molecules such as ERK1/2. This study therefore shows that inhibition of the Src/EGRF/ERK1/2 dependent signaling pathway is one of the mechanisms by which the Ang-(1-7)/ MAS1 receptor axis mediates it anti-inflammatory effects in diseases such as asthma.


Subject(s)
Angiotensin I/metabolism , Asthma/metabolism , ErbB Receptors/metabolism , Peptide Fragments/metabolism , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Respiratory Hypersensitivity/metabolism , Signal Transduction , src-Family Kinases/metabolism , Animals , Blotting, Western , Bronchoalveolar Lavage Fluid/cytology , Chemotaxis, Leukocyte , Disease Models, Animal , Fluorescent Antibody Technique , Lung/pathology , Male , Mice , Mice, Inbred BALB C , Proto-Oncogene Mas , Respiratory Hypersensitivity/pathology
11.
Toxicol Ind Health ; 34(10): 665-678, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30003842

ABSTRACT

Lead (Pb) is a neurotoxic heavy metal that largely affects the developing nervous system. The present study examined the temporal effect of perinatal Pb exposure on neurogenesis and cortical neuronal morphology. Wistar pregnant rats were exposed to 0.5% lead acetate throughout pregnancy and to postnatal day (PD) 28. Offspring were grouped as gestational day (GD) 18 and 21 and PD 7, 14, 21, and 28 in both control and experimental groups. Brain sections were processed for immunohistological staining with anti-proliferating cell nuclear antigen (PCNA) or glial fibrillary acidic protein (GFAP). Brains from 14, 21, and 28 PDs pups were processed for Golgi-Cox stain. Pb exposure significantly increased PCNA-positive nuclei in the ventricular and subventricular zones of the lateral ventricle at 18 and 21 GDs. Postnatally, the Pb-treated groups showed a significant decrease in PCNA-positivity and neuron density compared to control. This reduction was associated with an increase in damaged or apoptotic cell profiles in the experimental groups. At PD 21, there was a significant increase in GFAP immunoreactivity in Pb-exposed groups compared with control. Furthermore, the total apical and basal dendritic length of pyramidal neurons in layer 2-3 of the Golgi-Cox stained sensorimotor cortex was comparable in both control and Pb-exposed groups. Spine density per 10 µm was significantly increased at PD 14 and 21 on the apical dendrites but not basal dendrites of Pb-treated groups. In conclusion, developmental Pb exposure in rats induces a toxic effect on neurogenesis and on cortical neurons, which may be related to cognitive disabilities observed in children exposed to lead.


Subject(s)
Cerebral Cortex/drug effects , Lead/toxicity , Neurogenesis/drug effects , Prenatal Exposure Delayed Effects/pathology , Animals , Cerebral Cortex/pathology , Female , Glial Fibrillary Acidic Protein/metabolism , Pregnancy , Proliferating Cell Nuclear Antigen/metabolism , Rats , Rats, Wistar , Sensorimotor Cortex/drug effects , Sensorimotor Cortex/pathology
12.
Neuropharmacology ; 128: 231-243, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29054367

ABSTRACT

Monoamine oxidase-B (MAOB), a flavin adenine dinucleotide (FAD), is an enzyme which catalyzes the oxidation of amines. MAOB is proposed to play a major role in the pathogenesis of neurodegeneration through the production of reactive oxygen species (ROS) and neurotoxins. The present study was designed to outline the effects of the MAOB inhibitor (MAOB-I) on neuroprotection of spinal neurons, regeneration of sciatic nerve fibers, and recovery of sensory-motor functions in the sciatic nerve crush injury model. Male Wistar rats (4-months-old) were assigned to i) Naïve (N), ii) Sham (S), iii) Sciatic nerve crush and treated with saline (CRUSH + SALINE) and iv) Sciatic nerve crush and treated with MAOB inhibitor (CRUSH + MAOB-I) groups (n = 10/group). In groups iii and iv, the crush injury was produced by crushing the sciatic nerve followed by treatment with saline or MAOB-I (Selegiline® 2.5 mg/kg) intraperitoneally for 10 days. Behavioral tests were conducted from week 1 to week 6. At the end of the study, sciatic nerve and lumbar spinal cord were examined by immunohistochemistry, light and electron microscopy. MAOB-I treatment showed significant improvement in sensory and motor functions compared to saline treatment (p < 0.05-0.001) in injured nerves. The morphological study showed a significantly increased number of nerve fibers in sciatic nerve distal to the site of injury (p < 0.05), with better myelination pattern in CRUSH + MAOB-I treated group compared to CRUSH + SALINE group. Spinal cord ventral horns showed a significant increase in the number of NeuN-immunoreactive neurons in the MAOB-I treated group compared to Saline treated group (p < 0.01). MAOB-I has a significant potential for protecting the degenerating spinal cord neurons and enhancing the regeneration of injured sciatic nerve fibers following crush injury.


Subject(s)
Monoamine Oxidase Inhibitors/therapeutic use , Nerve Degeneration/prevention & control , Nerve Regeneration/drug effects , Recovery of Function/drug effects , Sciatic Neuropathy/complications , Spinal Cord/pathology , Animals , Anterior Horn Cells/drug effects , Anterior Horn Cells/pathology , Disease Models, Animal , Gene Expression Regulation/drug effects , Male , Movement/drug effects , Myelin Basic Protein/metabolism , Nerve Fibers, Myelinated/drug effects , Nerve Fibers, Myelinated/pathology , Nerve Fibers, Myelinated/ultrastructure , Pain Threshold/drug effects , Phosphopyruvate Hydratase/metabolism , Rats , Rats, Wistar , Sciatic Neuropathy/drug therapy , Sciatic Neuropathy/pathology , Selegiline/pharmacology , Selegiline/therapeutic use , Weight-Bearing/physiology
13.
Sci Rep ; 7(1): 9919, 2017 08 30.
Article in English | MEDLINE | ID: mdl-28855674

ABSTRACT

The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kδ/Akt and NF-κB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IκB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice. Treatment with inhibitors of Src (SU6656) or EGFR (AG1478) reduced EGFR phosphorylation and downstream signaling which resulted in the inhibition of the OVA-induced inflammatory cell influx in bronchoalveolar lavage fluid (BALF), perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyper-responsiveness. Treatment with pathway-selective inhibitors for ERK1/2 (PD89059) and PI3Kδ/Akt (IC-87114) respectively, or an inhibitor of NF-κB (BAY11-7085) also reduced the OVA-induced asthmatic phenotype but to a lesser extent compared to Src/EGFR inhibition. Thus, Src via EGFR transactivation and subsequent downstream activation of multiple pathways regulates the allergic airway inflammatory response. Furthermore, a broader upstream inhibition of Src/EGFR offers an attractive therapeutic alternative in the treatment of asthma relative to selectively targeting the individual downstream signaling effectors.


Subject(s)
Asthma/genetics , NF-kappa B/metabolism , Ovalbumin/adverse effects , Proto-Oncogene Proteins pp60(c-src)/metabolism , Transcriptional Activation , Animals , Asthma/chemically induced , Asthma/drug therapy , Asthma/metabolism , Bronchoalveolar Lavage Fluid/immunology , Down-Regulation , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Indoles/administration & dosage , Indoles/pharmacology , MAP Kinase Signaling System , Male , Mice , Mice, Inbred BALB C , Phosphorylation/drug effects , Quinazolines/administration & dosage , Quinazolines/pharmacology , Signal Transduction , Sulfonamides/administration & dosage , Sulfonamides/pharmacology , Tyrphostins/administration & dosage , Tyrphostins/pharmacology
14.
J Neurosurg Spine ; 27(5): 593-613, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28777065

ABSTRACT

OBJECTIVE This study examined the capacity of the major polyphenolic green tea extract (-)-epigallocatechin-3-gallate (EGCG) to suppress oxidative stress and stimulate the recovery and prompt the regeneration of sciatic nerve after crush injury. METHODS Adult male Wistar rats were randomly assigned to one of 4 groups: 1) Naïve, 2) Sham (sham injury, surgical control group), 3) Crush (sciatic nerve crush injury treated with saline), and 4) Crush+EGCG (sciatic nerve crush injury treated with intraperitoneally administered EGCG, 50 mg/kg). All animals were tested for motor and sensory neurobehavioral parameters throughout the study. Sciatic nerve and spinal cord tissues were harvested and processed for morphometric and stereological analysis. For the biochemical assays, the time points were Day 1, Day 7, Day 14, and Day 28 after nerve injury. RESULTS After sciatic nerve crush injury, the EGCG-treated animals (Crush+EGCG group) showed significantly better recovery of foot position and toe spread and 50% greater improvement in motor recovery than the saline-treated animals (Crush group). The Crush+EGCG group displayed an early hopping response at the beginning of the 3rd week postinjury. Animals in the Crush+EGCG group also showed a significant reduction in mechanical allodynia and hyperalgesia latencies and significant improvement in recovery from nociception deficits in both heat withdrawal and tail flick withdrawal latencies compared with the Crush group. In both the Crush+EGCG and Crush groups, quantitative evaluation revealed significant morphological evidence of neuroregeneration according to the following parameters: mean cross-sectional area of axons, myelin thickness in the sciatic nerve (from Week 4 to Week 8), increase of myelin basic protein concentration and gene expression in both the injured sciatic nerve and spinal cord, and fiber diameter to axon diameter ratio and myelin thickness to axon diameter ratio at Week 2 after sciatic nerve injury. However, the axon area remained much smaller in both the Crush+EGCG and Crush groups compared with the Sham and Naïve groups. The number of axons per unit area was significantly decreased in the Crush+EGCG and Crush groups compared with controls. Sciatic nerve injury produced generalized oxidative stress manifested as a significant increase of isoprostanes in the urine and decrease of the total antioxidant capacity (TAC) of the blood from Day 7 until Day 14. EGCG-treated rats showed significantly less increase of isoprostanes than saline-treated animals and also showed full recovery of TAC levels by Day 14 after nerve injury. In spinal cord tissue analysis, EGCG-treated animals showed induced glutathione reductase and suppressed induction of heme oxygenase 1 gene expression compared with nontreated animals. CONCLUSIONS EGCG treatment suppressed the crush-induced production of isoprostanes and stimulated the recovery of the TAC and was associated with remarkable alleviation of motor and sensory impairment and significant histomorphological evidence of neuronal regeneration following sciatic nerve crush injury in rats. The findings of this study suggest that EGCG can be used as an adjunctive therapeutic remedy for nerve injury. However, further investigations are needed to establish the antioxidative mechanism involved in the regenerative process after nerve injury. Only upregulation of glutathione reductase supports the idea that EGCG is acting indirectly via induction of enzymes or transcription factors.


Subject(s)
Antioxidants/pharmacology , Catechin/analogs & derivatives , Crush Injuries/drug therapy , Peripheral Nerve Injuries/drug therapy , Sciatic Nerve/drug effects , Sciatic Nerve/injuries , Animals , Axons/drug effects , Axons/pathology , Catechin/pharmacology , Crush Injuries/pathology , Crush Injuries/physiopathology , Disease Models, Animal , Hyperalgesia/drug therapy , Hyperalgesia/pathology , Hyperalgesia/physiopathology , Male , Motor Activity/drug effects , Motor Activity/physiology , Nerve Regeneration/drug effects , Nerve Regeneration/physiology , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/physiology , Peripheral Nerve Injuries/pathology , Peripheral Nerve Injuries/physiopathology , RNA, Messenger/metabolism , Random Allocation , Rats, Wistar , Recovery of Function/drug effects , Sciatic Nerve/pathology , Sciatic Nerve/physiopathology , Sciatic Neuropathy/drug therapy , Sciatic Neuropathy/pathology , Sciatic Neuropathy/physiopathology , Spinal Cord/drug effects , Spinal Cord/pathology , Spinal Cord/physiopathology
15.
Obes Surg ; 27(5): 1271-1276, 2017 05.
Article in English | MEDLINE | ID: mdl-27889885

ABSTRACT

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has gained popularity as the leading bariatric procedure for the treatment of morbid obesity. Due to the rising numbers of bariatric surgeries, neurologic complications have become increasingly recognized. Our aim was to examine biochemical and hormonal factors that are associated with neuropathy post-LSG. METHODS: Thirty-two patients were included: 16 patients with neuropathy in the neuropathic group (NG) and 16 patients without neuropathy in the control group (CG). Diagnosis was made by a consultant neurologist, and blood samples were taken to examine vitamin deficiencies and hormones involved in neuropathy. RESULTS: There was no significant difference between the BMI (p = 0.1) in both groups as well as excess weight loss percentages post-LSG at 12 months (p = 0.6). B12 levels were within normal range, but higher in NG (p = 0.005). Vitamin B1 and B2 levels were significantly lower in NG; p values are 0.000 and 0.031, respectively. Vitamin B6 levels were significantly higher in NG (p = 0.02) and copper levels were lower in NG (p = 0.009). There was no significant difference in GLP-1 response in both groups. CONCLUSION: Our data showed post-LSG neuropathy is associated with lower levels of vitamin B1, B2, and copper, plus patients who are older in age. Vitamin B6 was significantly higher in the NG, which is, at toxic levels, associated with neuropathy. No difference in preoperative BMI, excess weight loss percent at 1 year, and GLP-1 levels was found. Larger data is required to validate our results.


Subject(s)
Copper/deficiency , Gastrectomy/adverse effects , Glucagon-Like Peptide 1/deficiency , Obesity, Morbid/surgery , Vitamin B Deficiency/blood , Adult , Copper/blood , Female , Glucagon-Like Peptide 1/blood , Humans , Laparoscopy , Male , Middle Aged , Treatment Outcome , Vitamin B Deficiency/etiology , Weight Loss
16.
PeerJ ; 4: e2195, 2016.
Article in English | MEDLINE | ID: mdl-27441124

ABSTRACT

Background. Testicular ischemia reperfusion injury (tIRI) is considered the mechanism underlying the pathology of testicular torsion and detorsion. Left untreated, tIRI can induce testis dysfunction, damage to spermatogenesis and possible infertility. In this study, we aimed to assess the activities and expression of glycolytic enzymes (GEs) in the testis and their possible modulation during tIRI. The effect of fructose 1,6-diphosphate (FDP), a glycolytic intermediate, on tIRI was also investigated. Methods. Male Sprague-Dawley rats were divided into three groups: sham, unilateral tIRI, and tIRI + FDP (2 mg/kg). tIRI was induced by occlusion of the testicular artery for 1 h followed by 4 h of reperfusion. FDP was injected peritoneally 30 min prior to reperfusion. Histological and biochemical analyses were used to assess damage to spermatogenesis, activities of major GEs, and energy and oxidative stress markers. The relative mRNA expression of GEs was evaluated by real-time PCR. ELISA and immunohistochemistry were used to evaluate the expression of p53 and TP53-induced glycolysis and apoptosis regulator (TIGAR). Results. Histological analysis revealed tIRI-induced spermatogenic damage as represented by a significant decrease in the Johnsen biopsy score. In addition, tIRI reduced the activities of hexokinase 1, phosphofructokinase-1, glyceraldehyde 3-phosphate dehydrogenase, and lactate dehydrogenase C. However, mRNA expression downregulation was detected only for hexokinase 1, phosphoglycerate kinase 2, and lactate dehydrogenase C. ATP and NADPH depletion was also induced by tIRI and was accompanied by an increased Malondialdehyde concentration, reduced glutathione level, and reduced superoxide dismutase and catalase enzyme activities. The immunoexpression of p53 and TIGAR was markedly increased after tIRI. The above tIRI-induced alterations were attenuated by FDP treatment. Discussion. Our findings indicate that tIRI-induced spermatogenic damage is associated with dysregulation of GE activity and gene expression, which were associated with activation of the TIGAR/p53 pathway. FDP treatment had a beneficial effect on alleviating the damaging effects of tIRI. This study further emphasizes the importance of metabolic regulation for proper spermatogenesis.

17.
Interface Focus ; 6(3): 20160008, 2016 Jun 06.
Article in English | MEDLINE | ID: mdl-27274807

ABSTRACT

A mammalian tooth is abraded when a sliding contact between a particle and the tooth surface leads to an immediate loss of tooth tissue. Over time, these contacts can lead to wear serious enough to impair the oral processing of food. Both anatomical and physiological mechanisms have evolved in mammals to try to prevent wear, indicating its evolutionary importance, but it is still an established survival threat. Here we consider that many wear marks result from a cutting action whereby the contacting tip(s) of such wear particles acts akin to a tool tip. Recent theoretical developments show that it is possible to estimate the toughness of abraded materials via cutting tests. Here, we report experiments intended to establish the wear resistance of enamel in terms of its toughness and how friction varies. Imaging via atomic force microscopy (AFM) was used to assess the damage involved. Damage ranged from pure plastic deformation to fracture with and without lateral microcracks. Grooves cut with a Berkovich diamond were the most consistent, suggesting that the toughness of enamel in cutting is 244 J m(-2), which is very high. Friction was higher in the presence of a polyphenolic compound, indicating that this could increase wear potential.

18.
Urology ; 94: 312.e1-8, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27125877

ABSTRACT

OBJECTIVE: To investigate whether exogenous angiotensin (Ang)-(1-7) administration can protect against the damaging consequences of testicular ischemia reperfusion (tIR) injury. MATERIALS AND METHODS: Eighteen male Sprague-Dawley rats were divided equally among the following 3 groups: sham, unilateral tIR injury (1 hour of ischemic treatment and 4 hours of reperfusion), and tIR + Ang-(1-7) (0.3 mg/kg). Testicular tissues obtained from the rats were evaluated for the expression of testicular angiotensin-converting enzyme (tACE), Ang-(1-7), and the Ang-(1-7)-specific receptor Mas by immunohistochemistry and enzyme-linked immunosorbent assay. Reduced spermatogenesis, induction of the caspase-8 pathway, and nitric oxide (NO) generation were assessed. The effects of tIR and Ang-(1-7) treatment on the PI3K/Akt antiapoptosis pathway were also investigated. RESULTS: Testicular morphological changes and reduced spermatogenesis associated with decreased expression of the tACE/Ang-(1-7)/Mas axis were observed during tIR. These effects were also accompanied by increased activity of caspase-3 and -8, downregulation of the survivin and BAD transcripts, and decreased NO formation. During tIR, PTEN expression was increased, leading to inactivation of the PI3K/Akt pathway. Acute treatment with Ang-(1-7) prior to reperfusion attenuated the tIR-induced damage described above. CONCLUSION: Expression of the tACE/Ang-(1-7)/Mas axis was downregulated during tIR. Administration of exogenous Ang-(1-7) prior to reperfusion rescued tACE and Mas expression and protected against germ cell apoptosis and oxidative stress. Increased NO generation and activation of the PI3K/Akt signaling pathway may have partially contributed to these effects. The tACE/Ang-(1-7)/Mas axis likely plays a role in the maintenance of normal testis physiology and spermatogenesis.


Subject(s)
Angiotensin I/physiology , Angiotensin I/therapeutic use , Peptide Fragments/physiology , Peptide Fragments/therapeutic use , Peptidyl-Dipeptidase A/biosynthesis , Reperfusion Injury/prevention & control , Testis/blood supply , Testis/metabolism , Animals , Male , Peptidyl-Dipeptidase A/physiology , Proto-Oncogene Mas , Proto-Oncogene Proteins/physiology , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/physiology , Reperfusion Injury/etiology
19.
Naunyn Schmiedebergs Arch Pharmacol ; 389(5): 539-51, 2016 May.
Article in English | MEDLINE | ID: mdl-26915501

ABSTRACT

Testicular ischemia reperfusion injury (tIRI) is considered as the underlying mechanism of testicular torsion, which can cause male infertility. tIRI-induced damage was investigated by assessing the gene expression of spermatogenesis master transcription factors (TFs) and that of major adhesion molecules of the blood-testis barrier. The effect of lutein, a hydroxyl carotenoid, in alleviating tIRI-induced damage was also studied. Male Sprague-Dawley rats were divided into three groups: sham, unilateral tIRI, and tIRI + lutein (0.2 mg/kg). tIRI was induced by occlusion of the testicular artery for 1 h, followed by 4 h of reperfusion. Lutein was injected 15 min after the start of ischemia. Histological analysis and real-time polymerase chain reaction revealed significant decreases in tissue biopsy scores, reduced seminiferous tubule diameters, and downregulated the mRNA expression of the TFs cAMP-responsive element modulator (CREM), TATA box-binding protein-related factor 2 (TRF2), and regulatory factor X 2 (RFX2) compared with the sham group. Lutein treatment reversed these effects. The mRNA expression of the adhesion molecules N-cadherin, nectin-2, claudin-11, occludin, and connexin-43 was significantly downregulated during tIRI, but this change was prevented by lutein treatment. In addition, lutein normalized the tIRI-induced increase in total antioxidant capacity, increased malondialdehyde (MDA) levels, augmented number of TdT-mediated dUTP-X nick-end labeling (TUNEL)-positive nuclei, and activated caspase-8 pathway. The components of survivor activating factor enhancement (SAFE) were also activated during tIRI. Increased tissue expression of TNF-α and its receptor, TNFR1, was accompanied by increased phosphorylation of Janus kinase (JAK) and STAT3, which was prevented by lutein treatment. Our findings suggested that tIRI-induced spermatogenic damage may involve modulation of the SAFE pathway and could benefit from lutein treatment.


Subject(s)
Lutein/pharmacology , Reperfusion Injury/metabolism , Testis/drug effects , Animals , Apoptosis/drug effects , Caspase 3/metabolism , Caspase 8/metabolism , In Situ Nick-End Labeling , Janus Kinase 1/metabolism , Male , Malondialdehyde/metabolism , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Receptors, Tumor Necrosis Factor, Type I/metabolism , STAT3 Transcription Factor/metabolism , Spermatogenesis/drug effects , Testis/metabolism , Transcription Factors/genetics , Transcription, Genetic/drug effects , Tumor Necrosis Factor-alpha/metabolism
20.
Neuropharmacology ; 102: 1-20, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26514400

ABSTRACT

This study analyzed and compared the effects of EGCG treatment on the expression of NTFs and NTF receptors expression in the sciatic nerve and the L3-L6 spinal cord segments at the early phase of regeneration following sciatic nerve crush injury. Analysis of BDNF, GDNF and NT3 neurotropic factors and Trk-B, Trk-C and NGFR-p75 receptors in neurons in the spinal cord of CRUSH and CRUSH + EGGC rats showed significant (p < 0.0001) decrease compared to NAÏVE and SHAM at day 1, 3, 7 and 14 after nerve injury. EGCG treatment significantly (p < 0.0001) increased the BDNF, GDN, NT3, Trk-B, Trk-C and NGFR-p75 immunostaining in the L3-L6 spinal cord compared to CRUSH animals. Also, EGCG treatment significantly increased the Trk-B protein concentration and Trk-B, NT3 and Trk-C gene expression in the spinal cords compared to CRUSH group. However, at day 1 and 3 post nerve injury, EGCG treatment significantly decreased the NGFR-p75 expression compared to CRUSH rats. In the sciatic nerve, EGCG treatment significantly (p < 0.01) increased the Trk-B and NGFR-p75 protein concentration in the controls. EGCG treatment significantly (p < 0.0001) increased the Trk-B, Trk-C and NGFR-p75 mRNA gene expressions in the sciatic nerves compared to CRUSH group. Only at day 1, CRUSH + EGCG animals displayed significant rise in the sciatic nerves NT3 gene expression compared to CRUSH group. Our data suggest that the EGCG neuroprotective effect on the spinal cord neurons may be mediated through the modulation of NTFs and NTF receptors following nerve crush injury in a rat model.


Subject(s)
Brain-Derived Neurotrophic Factor/therapeutic use , Catechin/analogs & derivatives , Glial Cell Line-Derived Neurotrophic Factor/therapeutic use , Neuroprotective Agents/therapeutic use , Neurotrophin 3/therapeutic use , Peripheral Nerve Injuries/drug therapy , Receptors, Nerve Growth Factor/metabolism , Sciatic Nerve/injuries , Animals , Brain-Derived Neurotrophic Factor/pharmacology , Catechin/pharmacology , Catechin/therapeutic use , Drug Interactions , Glial Cell Line-Derived Neurotrophic Factor/pharmacology , Male , Nerve Regeneration/drug effects , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/pharmacology , Neurotrophin 3/pharmacology , Peripheral Nerve Injuries/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar
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