ABSTRACT
BACKGROUND: Nutritional status and sarcopenia affects the prognosis of head and neck cancers including hypopharyngeal cancer. Hypopharyngeal cancer patients tend to exhibit sarcopenia, which is associated with poor treatment outcomes. This study aims to determine the correlation between nutritional status and sarcopenia, and their prognostic role in surgically treated hypopharyngeal cancer. MATERIALS AND METHODS: Patients who had been diagnosed with squamous cell carcinoma originating from the hypopharynx and underwent surgery between January 2009 and December 2019 were enrolled in this study. The median neutrophil-to-lymphocyte ratio and prognostic nutritional index (PNI) of the cohort were considered the cut-off values. Sarcopenia was evaluated by measuring skeletal muscle index (SMI) at the third lumbar vertebra. Clinical and serological factors predictive of survival outcomes were evaluated. RESULTS: Patients with high PNI showed better 5-year Overall survival (OS) (52.8% vs. 27.2%, p = 0.001) and disease-free survival (DFS) (59.6% vs. 44.6%, p = 0.033) than those with low PNI. Likewise, patients with low SMI showed worse 5-year OS (25.0% vs. 60.9%, p = 0.002) and DFS (42.4% vs. 68.7%, p = 0.034) than patients with high SMI. Among the patients with high PNI, those with sarcopenia displayed significantly worse OS than those with high SMI (78.0% vs. 34.4%, p = 0.049). High PNI with high SMI presented better overall (p = 0.010) and DFS (p = 0.055) than any other group. CONCLUSIONS: Both sarcopenia and PNI were associated with the prognosis of hypopharyngeal cancer. Considering that PNI and sarcopenia indicate the nutritional status, nutritional status may be a significant risk factor. Therefore, nutritional support that ameliorates sarcopenia may improve survival outcomes in surgically treated patients with hypopharyngeal cancer.
Subject(s)
Hypopharyngeal Neoplasms , Nutritional Status , Sarcopenia , Humans , Sarcopenia/complications , Hypopharyngeal Neoplasms/surgery , Hypopharyngeal Neoplasms/mortality , Hypopharyngeal Neoplasms/complications , Hypopharyngeal Neoplasms/pathology , Male , Female , Prognosis , Middle Aged , Aged , Retrospective Studies , Nutrition Assessment , Carcinoma, Squamous Cell/surgery , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/complications , Carcinoma, Squamous Cell/pathology , Survival Rate , AdultABSTRACT
Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/ß-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/ß-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.
Subject(s)
Verrucomicrobia , beta Catenin , Male , Mice , Animals , beta Catenin/metabolism , Verrucomicrobia/metabolism , Intestines , Cadherins/metabolism , AkkermansiaABSTRACT
Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Disease Models, Animal , Dyskinesia, Drug-Induced , Levodopa , Oxidopamine , Animals , Male , Mice , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiparkinson Agents/pharmacology , Astrocytes/drug effects , Astrocytes/metabolism , Captopril/pharmacology , Captopril/therapeutic use , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/prevention & control , Enalapril/pharmacology , Enalapril/therapeutic use , Levodopa/toxicity , Mice, Inbred C57BL , Microglia/drug effects , Microglia/metabolism , Parkinson Disease/drug therapy , Perindopril/pharmacology , Perindopril/therapeutic useABSTRACT
AIMS: The gut microbiota is increasingly recognised as a pivotal regulator of immune system homeostasis and brain health. Recent research has implicated the gut microbiota in age-related cognitive impairment and dementia. Agathobaculum butyriciproducens SR79 T (SR79), which was identified in the human gut, has been reported to be beneficial in addressing cognitive deficits and pathophysiologies in a mouse model of Alzheimer's disease. However, it remains unknown whether SR79 affects age-dependent cognitive impairment. MAIN METHOD: To explore the effects of SR79 on cognitive function during ageing, we administered SR79 to aged mice. Ageing-associated behavioural alterations were examined using the open field test (OFT), tail suspension test (TST), novel object recognition test (NORT), Y-maze alternation test (Y-maze), and Morris water maze test (MWM). We investigated the mechanisms of action in the gut and brain using molecular and histological analyses. KEY FINDINGS: Administration of SR79 improved age-related cognitive impairment without altering general locomotor activity or depressive behaviour in aged mice. Furthermore, SR79 increased mature dendritic spines in the pyramidal cells of layer III and phosphorylation of CaMKIIα in the cortex of aged mice. Age-related activation of astrocytes in the cortex of layers III-V of the aged brain was reduced following SR79 administration. Additionally, SR79 markedly increased IL-10 production and Foxp3 and Muc2 mRNA expression in the colons of aged mice. SIGNIFICANCE: These findings suggest that treatment with SR79 may be a beneficial microbial-based approach for enhancing cognitive function during ageing.
Subject(s)
Clostridiales , Cognition Disorders , Cognitive Dysfunction , Mice , Humans , Animals , Aged , Cognition Disorders/metabolism , Brain/metabolism , Aging/metabolismABSTRACT
Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease and is characterized by dopaminergic neuronal death in the midbrain. Recently, the association between alterations in PD pathology and the gut microbiota has been explored. Microbiota-targeted interventions have been suggested as a novel therapeutic approach for PD. Agathobaculum butyriciproducens SR79T (SR79) is an anaerobic bacterium. Previously, we showed that SR79 treatment induced cognitive improvement and reduced Alzheimer's disease pathologies in a mouse model. In this study, we hypothesized that SR79 treatment may have beneficial effects on PD pathology. To investigate the therapeutic effects of SR79 on PD, 6-hydroxydopamine (6-OHDA)-induced mouse models were used. D-Amphetamine sulfate (d-AMPH)-induced behavioral rotations and dopaminergic cell death were analyzed in unilateral 6-OHDA-lesioned mice. Treatment with SR79 significantly decreased ipsilateral rotations induced by d-AMPH. Moreover, SR79 treatment markedly activated the AKT/GSK3ß signaling pathway in the striatum. In addition, SR79 treatment affected the Nrf2/ARE signaling pathway and its downstream target genes in the striatum of 6-OHDA-lesioned mice. Our findings suggest a protective role of SR79 in 6-OHDA-induced toxicity by regulating the AKT/Nrf2/ARE signaling pathway and astrocyte activation. Thus, SR79 may be a potential microbe-based intervention and therapeutic strategy for PD.
Subject(s)
Neurodegenerative Diseases , Neuroprotective Agents , Parkinson Disease , Animals , Base Composition , Clostridiales , Dextroamphetamine/metabolism , Dextroamphetamine/pharmacology , Disease Models, Animal , Dopaminergic Neurons/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Mice , NF-E2-Related Factor 2/metabolism , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Oxidopamine/metabolism , Oxidopamine/pharmacology , Parkinson Disease/drug therapy , Phylogeny , Proto-Oncogene Proteins c-akt/metabolism , RNA, Ribosomal, 16S/metabolism , Sequence Analysis, DNAABSTRACT
BACKGROUND: Neuroinflammation plays an important role in cognitive decline and memory impairment in neurodegenerative disorders. Previously, we demonstrated that Humulus japonicus (HJ) has anti-inflammatory effects in rodent models of Alzheimer's disease and Parkinson's disease. The present study aimed to examine the protective potential of HJ extracts against lipopolysaccharide (LPS)-induced cognitive impairment and scopolamine-induced amnesia in mouse models. Cognitive improvement of mice was investigated by novel object recognition test. For analyzing effects on neuroinflammation, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed. RESULTS: We found that the oral administration of HJ significantly improved cognitive dysfunction induced by LPS in a novel object recognition test. The LPS-induced activation of microglia was notably decreased by HJ treatment in the cortex and hippocampus. HJ administration with LPS also significantly increased the mRNA expression of interleukin (IL)-10 and decreased the mRNA expression of IL-12 in the parietal cortex of mice. The increased expression of LPS-induced complement C1q B chain (C1bq) and triggering receptor expressed on myeloid cells 2 (Trem2) genes was significantly suppressed by HJ treatment. In addition, HJ administration significantly improved novel object recognition in a scopolamine-induced amnesia mouse model. CONCLUSIONS: These findings revealed that HJ has a beneficial effect on cognitive impairment and neuroinflammation induced by systemic inflammation and on amnesia induced by scopolamine in mice.
ABSTRACT
Humulus japonicus (HJ) is a traditional herbal medicine that exhibits antiinflammatory, antimicrobial and antitumor effects that is used for the treatment of hypertension, pulmonary disease and leprosy. Recently, it has also been reported that HJ demonstrates neuroprotective properties in animal models of neurodegenerative diseases. The current study hypothesised that the administration of HJ would exhibit therapeutic effects in autism spectrum disorder (ASD), a neurodevelopmental disorder with lifelong consequences. The BTBR T+ Itpr3tf/J mouse model of ASD was used to investigate the antiautistic like behavioural effects of HJ. Chronic oral administration of the ethanolic extract of HJ significantly increased social interaction, attenuated repetitive grooming behaviour and improved novelobject recognition in BTBR mice. Antiinflammatory effects of HJ in the brain were analysed using immunohistochemistry and reversetranscription quantitative PCR analysis. Microglia activation was markedly decreased in the striatum and hippocampus, and proinflammatory cytokines, including CC Motif Chemokine Ligand 2, interleukin (IL)1ß and IL6, were significantly reduced in the hippocampus following HJ treatment. Moreover, HJ treatment normalised the phosphorylation levels of: NmethylDaspartate receptor subtype 2B and calcium/calmodulindependent protein kinase type II subunit α in the hippocampus of BTBR mice. The results of the present study demonstrated that the administration of HJ may have beneficial potential for ameliorating behavioural deficits and neuroinflammation in ASD.
Subject(s)
Autistic Disorder/drug therapy , Humulus/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Autism Spectrum Disorder/drug therapy , Autistic Disorder/genetics , Behavior, Animal/drug effects , Brain/metabolism , Brain/pathology , Cytokines/metabolism , Disease Models, Animal , Hippocampus/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Phosphorylation/drug effectsABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)-induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.
Subject(s)
Autism Spectrum Disorder/drug therapy , Cognitive Dysfunction/drug therapy , Grooming/drug effects , Phenylbutyrates/therapeutic use , Social Behavior , Stereotyped Behavior/drug effects , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Autism Spectrum Disorder/chemically induced , Autism Spectrum Disorder/psychology , Brain/drug effects , Brain/physiology , Cognitive Dysfunction/psychology , Disease Models, Animal , Female , Grooming/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Transgenic , Phenylbutyrates/pharmacology , Stereotyped Behavior/physiology , Valproic Acid/toxicityABSTRACT
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation and presence of amyloid plaques (Aß), tangles, dementia, and cognitive impairment. Currently, there is no known cure for AD; however, recently, the association between alteration of the gut microbiota and AD pathology has been explored to find novel therapeutic approaches. Microbiota-targeted intervention has been suggested as an attractive therapeutic approach for AD. Agathobaculum butyriciproducens (SR79) is a strict anaerobic and butyric acid-producing bacteria. We hypothesized that administration of SR79 might have a beneficial effect on cognitive deficits and AD pathologies. To determine the therapeutic effects of SR79 on AD pathologies, APP/PS1 transgenic and lipopolysaccharide -induced cognitive impairment mouse models were used. In the lipopolysaccharide -induced cognitive deficit model, the administration of SR79 improved cognitive function and decreased microglia activation. In addition, the administration of SR79 to APP/PS1 mice significantly improved novel object recognition and percent alteration results in novel object recognition and Y-maze alteration tests. Furthermore, Aß plaque deposition and microglial activation were markedly reduced in the parietal cortex and hippocampus after SR79 treatment in APP/PS1 mice. SR79 treatment significantly decreased gene expression levels of IL-1ß and C1QB and increased the gene expression levels of IGF-1 and thereby the downstream signaling pathway in the cortex of APP/PS1 mice. In conclusion, SR79 administration improved cognitive function and AD pathologies through the regulation of neuroinflammation and IGF-1 signaling in an animal model.
Subject(s)
Alzheimer Disease/therapy , Clostridiales/physiology , Cognition , Cognitive Dysfunction/therapy , Gastrointestinal Microbiome/physiology , Probiotics , Alzheimer Disease/microbiology , Amyloid beta-Peptides/metabolism , Animals , Brain/pathology , Brain/physiopathology , Disease Models, Animal , Humans , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides , Maze Learning , Mice , Mice, Transgenic , Microglia/physiology , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Plaque, Amyloid/therapy , Recognition, PsychologyABSTRACT
The dopamine precursor 3,4dihydroxyphenyl lalanine (LDOPA) is the most widely used symptomatic treatment for Parkinson's disease (PD); however, its prolonged use is associated with LDOPAinduced dyskinesia in more than half of patients after 10 years of treatment. The present study investigated whether cotreatment with ßLapachone, a natural compound, and LDOPA has protective effects in a 6hydroxydopamine (6OHDA)induced mouse model of PD. Unilateral 6OHDAlesioned mice were treated with vehicle or ßLapachone (10 mg/kg/day) and LDOPA for 11 days. Abnormal involuntary movements (AIMs) were scored on days 5 and 10. ßLapachone (10 mg/kg) cotreatment with LDOPA decreased the AIMs score on both days 5 and 10. ßLapachone was demonstrated to have a beneficial effect on the axial and limb AIMs scores on day 10. There was no significant suppression in dopamine D1 receptorrelated and ERK1/2 signaling in the DAdenervated striatum by ßLapachonecotreatment with LDOPA. Notably, ßLapachonecotreatment with LDOPA increased phosphorylation at the Ser9 site of glycogen synthase kinase 3ß (GSK3ß), indicating suppression of GSK3ß activity in both the unlesioned and 6OHDAlesioned striata. In addition, astrocyte activation was markedly suppressed by ßLapachonecotreatment with LDOPA in the striatum and substantia nigra of the unilateral 6OHDA model. These findings suggest that ßLapachone cotreatment with LDOPA therapy may have therapeutic potential for the suppression or management of the development of LDOPAinduced dyskinesia in patients with PD.
Subject(s)
Dyskinesias , Levodopa/adverse effects , Naphthoquinones/pharmacology , Oxidopamine/adverse effects , Parkinson Disease, Secondary , Animals , Dyskinesias/drug therapy , Dyskinesias/metabolism , Dyskinesias/pathology , Levodopa/pharmacology , Male , Mice , Oxidopamine/pharmacology , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/drug therapy , Parkinson Disease, Secondary/metabolism , Parkinson Disease, Secondary/pathologyABSTRACT
Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms. Despite the remarkable improvements in the management of PD in recent decades, many patients remain significantly disabled. Metformin is a primary medication for the management of type 2 diabetes. We previously showed that co-treatment with metformin and 3,4-dihydroxyphenyl-l-alanine (l-DOPA) prevented the development of l-DOPA-induced dyskinesia in a 6-hydroxydopamine (6-OHDA)-lesioned animal model of PD. However, effects of metformin on PD- and aging-induced genes in reactive astrocytes remain unknown. In this study, we assessed the effect of metformin on motor function, neuroprotection, and reactive astrocytes in the 6-OHDA-induced PD animal model. In addition, the effects of metformin on the genes expressed by specific types of astrocytes were analyzed in PD model and aged mice. Here, we showed that metformin treatment effectively improves the motor symptoms in the 6-OHDA-induced PD mouse model, whereas metformin had no effect on tyrosine hydroxylase-positive neurons. The activation of AMPK and BDNF signaling pathways was induced by metformin treatment on the 6-OHDA-lesioned side of the striatum. Metformin treatment caused astrocytes to alter reactive genes in a PD animal model. Moreover, aging-induced genes in reactive astrocytes were effectively regulated or suppressed by metformin treatment. Taken together, these results suggest that metformin should be evaluated for the treatment of Parkinson's disease and related neurologic disorders characterized by astrocyte activation.
Subject(s)
Aging/physiology , Astrocytes/drug effects , Astrocytes/physiology , Corpus Striatum/physiology , Metformin/administration & dosage , Parkinson Disease/physiopathology , Animals , Corpus Striatum/drug effects , Disease Models, Animal , Female , Male , Mice, Inbred C57BL , Motor Activity/drug effectsABSTRACT
The NAD(P)H:quinone oxidoreductase 1 (NQO1) gene encodes a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones to hydroquinones. A polymorphic form of NQO1 is associated with mood disorders such as schizophrenia. However, the role of NQO1 in dopaminergic system has not yet been elucidated. To determine the role of NQO1 in the dopaminergic system, we investigated pharmaco-behavioral effects of d-amphetamine using NQO1-deficienct mice. According to our comparative study involving NQO1+/+ and NQO1-/- mice, NQO1 deficiency increased d-amphetamine-induced psychomotor activity and psychological dependency compared to wild-type mice. Basal and d-amphetamine-induced dopamine levels were also enhanced by NQO1 deficiency. In NQO1-/- mice, neural activation induced by d-amphetamine was higher in dorsolateral striatum, but not in dorsomedial and ventral striata. Although protein level of CaMKIIα, which is a key player in amphetamine-induced dopamine efflux, was decreased in striata of NQO1-/- mice, phosphorylation of CaMKIIα was markedly enhanced in NQO1-/- mice compared to wild-type mice. Interestingly, experiments with pharmacological antagonist showed that D2 antagonist-induced suppression of locomotion required activation of NQO1. Moreover, the rewarding effect in response to D1 agonist was increased by NQO1 deficiency. These results suggest that striatal NQO1 is of considerable interest to understand the mechanism of dopaminergic regulation of psychiatric disorders.
Subject(s)
Corpus Striatum/metabolism , Dextroamphetamine/pharmacology , Dopamine/metabolism , NAD(P)H Dehydrogenase (Quinone)/deficiency , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Animals , Corpus Striatum/drug effects , Dopamine D2 Receptor Antagonists/pharmacology , Locomotion/drug effects , Locomotion/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Dopamine D1/agonists , Receptors, Dopamine D1/antagonists & inhibitors , Receptors, Dopamine D2/agonistsABSTRACT
Red Liriope platyphylla extract (EtRLP) has been used as an oriental medicine for treatment of several chronic conditions, such as neurodegenerative disorders, diabetes, and obesity. To investigate the laxative activity of EtRLP, the levels of key constipation markers and their molecular regulators were examined following administration of EtRLP in constipation Sprague Dawley (SD) rats treated with loperamide (Lop). Compared with the Lop+Vehicletreated group, the excretion levels of urine and stool were significantly enhanced in the Lop+EtRLPtreated group, even though feeding levels were kept constant. There was a significant improvement in histological structure, cytological ultrastructure and mucin secretion in transverse colon sections from the Lop+EtRLPtreated group, compared with the Lop+Vehicletreated group. The Lop+EtRLPtreated group exhibited a rapid recovery of the muscarinic acetylcholine receptor (mAChR) signaling pathway and of the endoplasmic reticulum (ER) stress response, compared with Lop+Vehicletreated group. Spicatoside A, one of the key components detected in EtRLP, recovered the levels of inositol triphosphate (IP3) and Gα in primary rat intestinal smooth muscle cells (pRISMCs). Taken together, the present results indicated that spicatoside Acontaining EtRLP had therapeutic effects against Lopinduced constipation in SD rats via improvement of the mAChR downstream signaling pathway and the ER stress response.
Subject(s)
Constipation/drug therapy , Constipation/pathology , Endoplasmic Reticulum Stress , Laxatives/therapeutic use , Liriope Plant/chemistry , Receptors, Muscarinic/metabolism , Saponins/therapeutic use , Signal Transduction , Animals , Colon/drug effects , Colon/pathology , Colon/ultrastructure , Defecation/drug effects , Disease Models, Animal , Endoplasmic Reticulum Stress/drug effects , Feeding Behavior/drug effects , Flavonoids/analysis , Laxatives/pharmacology , Male , Models, Biological , Phenols/analysis , Rats, Sprague-Dawley , Saponins/chemistry , Saponins/pharmacologyABSTRACT
BACKGROUND The impact of hyperbaric oxygen (HBO) on the healing of soft tissues around dental implants was studied in a beagle model. MATERIAL AND METHODS Beagle dogs were randomized to receive implants, followed by postoperative HBO therapy or not (n=10 per group). On postoperative days 3, 7, and 14, tissue specimens were paraffin-embedded and analyzed by hematoxylin-eosin and Masson staining, as well as immunohistochemistry against CD31. RESULTS Scores for inflammation pathology based on hematoxylin-eosin staining and mean optical density of collagen fibers were significantly different between the HBO and control groups on postoperative days 3 and 7 (P<0.05), but not on day 14. Mean optical density due to anti-CD31 staining was significantly higher in the HBO group on postoperative days 3, 7, and 14 (P<0.05). CONCLUSIONS These results suggest that HBO may promote early osteogenesis and soft tissue healing after implantation.
Subject(s)
Dental Implantation/methods , Dental Implants , Hyperbaric Oxygenation/methods , Oxygen/administration & dosage , Wound Healing/drug effects , Animals , Dogs , Inflammation/metabolism , Models, Animal , Osteogenesis/drug effects , Random Allocation , Wound Healing/physiologyABSTRACT
Piperlongumine (PL), a biologically active compound from the Piper species, has been shown to exert various pharmacological effects in a number of conditions, including tumours, diabetes, pain, psychiatric disorders and neurodegenerative disease. In this study, we evaluated the therapeutic effects of PL on hippocampal function and cognition decline in aged mice. PL (50 mg/kg/day) was intragastrically administrated to 23monthold female C57BL/6J mice for 8 weeks. Novel object recognition and nest building behaviour tests were used to assess cognitive and social functions. Additionally, immunohistochemistry and western blot analysis were performed to examine the effects of PL on the hippocampus. We found that the oral administration of PL significantly improved novel object recognition and nest building behaviour in aged mice. Although neither the percentage area occupied by astrocytes and microglia nor the level of 4hydroxynonenal protein, a specific marker of lipid peroxidation, were altered by PL treatment, the phosphorylation levels of NmethylDaspartate receptor subtype 2B (NR2B), calmodulindependent protein kinase II alpha (CaMKIIα) and extracellular signalregulated kinase 1/2 (ERK1/2) were markedly increased in the hippocampus of aged mice following the administration of PL. We also found that PL treatment resulted in a CA3specific increase in the phosphorylation level of cyclic AMP response element binding protein, which is recognized as a potent marker of neuronal plasticity, learning and memory. Moreover, the number of doublecortinpositive cells, a specific marker of neurogenesis, was significantly increased following PL treatment in the dentate gyrus of the hippocampus. On the whole, these data demonstrate that PL treatment may be a potential novel approach in the treatment of agerelated cognitive impairment and hippocampal changes.
Subject(s)
Aging/metabolism , Astrocytes/metabolism , CA3 Region, Hippocampal/metabolism , Cognitive Dysfunction/drug therapy , Dioxolanes/pharmacology , MAP Kinase Signaling System/drug effects , Aging/pathology , Animals , Astrocytes/pathology , CA3 Region, Hippocampal/pathology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Female , Mice , Mitogen-Activated Protein Kinase 3/metabolismABSTRACT
Histone acetylation is a key regulatory factor for gene expression in cells. Modulation of histone acetylation by targeting of histone acetyltransferases (HATs) effectively alters many gene expression profiles and synaptic plasticity in the brain. However, the role of HATs on L-DOPA-induced dyskinesia of Parkinson's disease (PD) has not been reported. Our aim was to determine whether HAT inhibitors such as anacardic acid, garcinol, and curcumin from natural plants reduce severity of L-DOPA-induced dyskinesia using a unilaterally 6-hydroxydopamine (6-OHDA)-lesioned PD mouse model. Anacardic acid 2 mg/kg, garcinol 5 mg/kg, or curcumin 100 mg/kg co-treatment with L-DOPA significantly reduced the axial, limb, and orofacial (ALO) score indicating less dyskinesia with administration of HAT inhibitors in 6-OHDA-lesioned mice. Additionally, L-DOPA's efficacy was not altered by the compounds in the early stage of treatment. The expression levels of c-Fos, Fra-2, and Arc were effectively decreased by administration of HAT inhibitors in the ipsilateral striatum. Our findings indicate that HAT inhibitor co-treatment with L-DOPA may have therapeutic potential for management of L-DOPA-induced dyskinesia in patients with PD.
Subject(s)
Anacardic Acids/therapeutic use , Antiparkinson Agents/toxicity , Curcumin/therapeutic use , Dyskinesia, Drug-Induced/drug therapy , Enzyme Inhibitors/therapeutic use , Histone Acetyltransferases/antagonists & inhibitors , Levodopa/toxicity , Parkinsonian Disorders/drug therapy , Terpenes/therapeutic use , Anacardic Acids/pharmacology , Animals , Curcumin/pharmacology , Cytoskeletal Proteins/biosynthesis , Cytoskeletal Proteins/genetics , Drug Evaluation, Preclinical , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/genetics , Enzyme Inhibitors/pharmacology , Fos-Related Antigen-2/biosynthesis , Fos-Related Antigen-2/genetics , Gene Expression Regulation/drug effects , Histone Code/drug effects , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Oxidopamine/toxicity , Proto-Oncogene Proteins c-fos/biosynthesis , Proto-Oncogene Proteins c-fos/genetics , Specific Pathogen-Free Organisms , Substantia Nigra/drug effects , Substantia Nigra/pathology , Terpenes/pharmacologyABSTRACT
Metformin is a medication that is widely prescribed for the management of type 2 diabetes. In addition to its anti-diabetic uses, metformin has been proposed as a therapeutically effective drug candidate in various central nervous system disorders, including Parkinson's disease (PD). PD is characterized by severe movement defects and is commonly treated with the dopamine (DA) precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA). However, prolonged use of L-DOPA can lead to the development of L-DOPA-induced dyskinesia (LID). Here, we hypothesized that metformin co-treatment would improve LID in the 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Metformin did not interfere the pharmacotherapeutic effects of L-DOPA in the cylinder test. Furthermore, metformin co-treatment with L-DOPA attenuated the development of LID in unilaterally 6-OHDA-lesioned mice. Metformin showed a long-lasting effect on axial, limb, and orofacial abnormal involuntary movement scores for up to 20 days after treatment initiation. Interestingly, persistent enhancement of the mammalian target of rapamycin, dopamine D1 receptor, and extracellular signaling-regulated kinase 1/2 signaling was maintained in the DA-denervated striatum during metformin treatment. Metformin globally normalized the increased glycogen synthase kinase 3ß activity induced by chronic treatment of L-DOPA in a manner associated with Akt activation in unilaterally 6-OHDA-lesioned mice. These findings suggest that metformin may have therapeutic potential for the suppression or management of L-DOPA-induced motor complications in patients with PD.
Subject(s)
Dyskinesia, Drug-Induced/complications , Dyskinesia, Drug-Induced/drug therapy , Metformin/therapeutic use , Parkinson Disease/complications , Parkinson Disease/drug therapy , Amantadine/pharmacology , Amantadine/therapeutic use , Animals , Corpus Striatum/drug effects , Corpus Striatum/pathology , Disease Models, Animal , Dyskinesia, Drug-Induced/pathology , Levodopa , Male , Metformin/pharmacology , Mice, Inbred C57BL , Parkinson Disease/pathology , Signal TransductionABSTRACT
BACKGROUND: Gall (Galla Rhois [GR]) is known to have antibacterial, anti-inflammatory, antimetastatic, and anti-invasion activities and exert hepatoprotective effects. However, the hepatoprotective effects of gallotannin-enriched GR (GEGR) and their mechanisms have not yet been investigated. OBJECTIVE: The potential protective effect of GEGR against hepatotoxicity induced by hydrogen peroxide (H2O2) was investigated. MATERIALS AND METHODS: Changes in cell viability, apoptosis protein expression, and reactive oxygen species (ROS) generation were determined in HepG2 cells that were pretreated with four different concentrations of GEGR (6.25-50 µg/ml) for 24 h before H2O2 exposure. RESULTS: GEGR consisted of gallotannin (69.2%), gallic acid (26.6%), and methyl gallate (4.2%) and showed remarkable 2,2-diphenyl-1-picrylhydrazyl scavenging activity (inhibitory concentration 50% = 0.212 µg/ml). The lethal dose 50% and effective dose 50% values for the response of HepG2 cells to GEGR were determined to be 178 and 6.85 µg/ml, respectively. Significant reductions in the immunofluorescence intensity indicating apoptosis were also detected in the nuclei of HepG2 cells stained with 4',6-diamidino-2-phenylindole and Annexin V after GEGR treatment. The Bax/Bcl-2 ratio and active caspase-3 level were higher in H2O2 + vehicle-treated cells. However, these levels gradually decreased to those of the No-treated group in the GEGR pretreated group even though little or no decrease was observed in response to low GEGR concentrations. Furthermore, the GEGR pretreated group showed a reduced level of 2',7'-dichlorofluorescein diacetate stained cells, indicating ROS generation relative to the H2O2 + vehicle-treated group. CONCLUSION: The results of this study provide strong evidence that GEGR can prevent cell death induced by H2O2 in HepG2 cells through the induction of antioxidant conditions. SUMMARY: The gallotannin (69.2%), gallic acid (26.6%), and methyl gallate (4.2%) are the main constituents of water extracts of GRGEGR was more potent in DPPH scavenging, and gallotannin contributes to this extract activityGEGR significantly reduced the increase of apoptosis, Bax/Bcl-2 ratio, and active caspase-3 level after H2O2 treatmentGEGR pretreatment showed protection against H2O2-induced ROS production in DCFH-DA staining analysis. Abbreviations used: COX: Cyclooxygenase; DAPI: 4',6-diamidino-2-phenylindole; DMSO: Dimethyl sulfoxide; DPPH: 2,2-diphenyl-1-picrylhydrazyl; GEGR: Gallotannin-enriched Galla Rhois; GR: Galla Rhois; HPLC: High-performance liquid chromatography; H2O2: Hydrogen peroxide; MMP: Metallopeptidase; MTT: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; ROS: Reactive oxygen species; UV-Vis: Ultraviolet-visible.
ABSTRACT
Although the cephalic vein follows a fairly consistent course, numerous variants have been reported. We found a rare anatomical presentation of the cephalic vein in a 75-year-old Korean male cadaver. The left cephalic vein was identified in the deltopectoral groove, ascended over the clavicle, and terminated into the left subclavian vein just before its union with the left internal jugular vein. The detailed knowledge on the variations of the cephalic vein is important for clinicians as well as anatomists since the approach through the axillary base is favored in many invasive clinical procedures.