-
Cell Biochemistry and Biophysics Jun 2024Chronic arsenic-exposure causes neuromuscular disorders and other health anomalies. Damage to DNA and cytoskeletal/extracellular matrix is brought on by...
Arsenic Induced Oxidative Neural-Damages in Rat are Mitigated by Tea-Leave Extract via MMPs and AChE Inactivation, Shown by Molecular Docking and in Vitro Studies with Pure Theaflavin and AChE.
BACKGROUND
Chronic arsenic-exposure causes neuromuscular disorders and other health anomalies. Damage to DNA and cytoskeletal/extracellular matrix is brought on by reactive-oxygen-species (ROS)-induced intrinsic antioxidant depletion (thiols/urate). Therapeutic chelating-agents have multiple side-effects.
OBJECTIVES
The protection of (Camellia sinensis) tea-extract and role of uric-acid (UA) or allopurinol (urate-depletor) on arsenic-toxicity were verified in rat model.
METHODS
Camellia sinensis (CS dry-leaves), UA or allopurinol was supplemented to arsenic-intoxicated rats for 4-weeks. Purified theaflavins and their galloyl-ester were tested in-vitro on pure AChE (acetylcholinesterase) and their PDB/PubChem 3-D structures were utilized for in-silico binding studies. The primary chemical components were evaluated from CS-extracts. Biochemical analysis, PAGE-zymogram, DNA-stability comet analysis, HE-staining was performed in arsenic-exposed rat brain tissues.
RESULTS
Animals exposed to arsenic showed symptoms of erratic locomotion, decreased intrinsic antioxidants (catalase/SOD1/uric acid), increased AChE, and malondialdehyde. Cerebellar and cerebrum tissue damages were shown with increased levels of matrix-metalloprotease (MMP2/9) and DNA damage (comets). Allopurinol- supplemented group demonstrated somewhat similar biochemical responses. In the CS-group brain tissues especially cerebellum is considerably protected which is evident from endogenous antioxidant and DNA and cytoskeleton protection with concomitant inactivation of MMPs and AChE. Present study indicates theaflavin-digallate (TFDG) demonstrated the highest inhibition of purified AChE (IC = 2.19 µg/ml with the lowest binding free-energy; -369.87 kcal/mol) followed by TFMG (IC = 3.86 µg/ml, -347.06 kcal/mol) suggesting their possible restoring effects of cholinergic response.
CONCLUSIONS
Favorable responses in UA-group and adverse outcome in allo-group justify the neuro-protective effects of UA as an endogenous antioxidant. Role of flavon-gallate in neuro protection mechanism may be further studied.
PubMed: 38943009
DOI: 10.1007/s12013-024-01369-8 -
Scientific Reports Jun 2024Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of...
Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of various neurological disorders. Most positive allosteric modulators (PAMs) of mAChR enhance agonist affinity and potency, while very few PAMs (e.g., amiodarone) selectively enhance G protein coupling efficacy. The key structural features of amiodarone responsible for enhancement of mAChR efficacy were examined in CHO cells expressing M receptors. Subsequent incorporation of these structural features into previously identified allosteric modulators of potency (i.e., n-benzyl isatins) generated ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable ligands include 8a, c which respectively demonstrated the strongest binding affinity and the most robust enhancement of mAChR efficacy as calculated from an allosteric operational model. Amiodarone derivatives and hybrid ligands were additionally screened in wildtype zebrafish (Danio rerio) to provide preliminary in vivo toxicity data as well as to observe effects on locomotor and turning behaviors relative to other mAChR PAMs. Several compounds, including 8a, c, reduced locomotor activity and increased measures of turning behaviors in zebrafish, suggesting that allosteric modulation of muscarinic receptor efficacy might be useful in the treatment of repetitive behaviors associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders.
Topics: Animals; Zebrafish; Receptor, Muscarinic M1; Allosteric Regulation; CHO Cells; Cricetulus; Acetylcholine; Locomotion; Ligands; Muscarinic Agonists
PubMed: 38942828
DOI: 10.1038/s41598-024-65445-y -
Biomedicine & Pharmacotherapy =... Jun 2024Alzheimer's disease (AD) is characterized by cognitive impairment, loss of learning and memory, and abnormal behaviors. Scopolamine (SCOP) is a non-selective antagonist...
Ameliorative effect of vanillic acid against scopolamine-induced learning and memory impairment in rat via attenuation of oxidative stress and dysfunctional synaptic plasticity.
Alzheimer's disease (AD) is characterized by cognitive impairment, loss of learning and memory, and abnormal behaviors. Scopolamine (SCOP) is a non-selective antagonist of muscarinic acetylcholine receptors that exhibits the behavioral and molecular hallmarks of AD. Vanillic acid (VA), a phenolic compound, is obtained from the roots of a traditional plant called Angelica sinensis, and has several pharmacologic effects, including antimicrobial, anti-inflammatory, anti-angiogenic, anti-metastatic, and antioxidant properties. Nevertheless, VA's neuroprotective potential associated with the memory has not been thoroughly investigated. Therefore, this study investigated whether VA treatment has an ameliorative effect on the learning and memory impairment induced by SCOP in rats. Behavioral experiments were utilized to assess the learning and memory performance associated with the hippocampus. Using western blotting analysis and assay kits, the neuronal damage, oxidative stress, and acetylcholinesterase activity responses of hippocampus were evaluated. Additionally, the measurement of long-term potentiation was used to determine the function of synaptic plasticity in organotypic hippocampal slice cultures. In addition, the synaptic vesicles' density and the length and width of the postsynaptic density were evaluated using electron microscopy. Consequently, the behavioral, biochemical, electrophysiological, and ultrastructural analyses revealed that VA treatment prevents learning and memory impairments caused by SCOP in rats. The study's findings suggest that VA has a neuroprotective effect on SCOP-induced learning and memory impairment linked to the hippocampal cholinergic system, oxidative damage, and synaptic plasticity. Therefore, VA may be a prospective therapeutic agent for treating AD.
PubMed: 38941895
DOI: 10.1016/j.biopha.2024.117000 -
Respiratory Investigation Jun 2024Gastroesophageal reflux disease (GERD) is one of the most common comorbidities of chronic obstructive pulmonary disease (COPD). Decreased lower and upper esophageal... (Review)
Review
Gastroesophageal reflux disease (GERD) is one of the most common comorbidities of chronic obstructive pulmonary disease (COPD). Decreased lower and upper esophageal sphincter pressures, esophageal dysmotility, high transdiaphragmatic pressure, and decreased saliva secretion have been implicated as mechanisms leading to the development of GERD in COPD. Clinically, comorbid GERD in COPD is reportedly associated with worse symptoms, quality of life, and lung function, as well as a high risk of exacerbations. Aspiration of regurgitation and the cholinergic-mediated esophagobronchial reflex play a significant role in the pathophysiology. Abnormal swallowing reflexes and discoordination of swallowing can worsen aspiration. The diagnosis of GERD is not based on a single criterion; however, various approaches, including questionnaires and endoscopic evaluations, can be widely applied in clinical settings. Due to the increased risk of esophageal and gastric cancers in patients with COPD, the threshold for endoscopic examination should be low. Acid inhibitory agents, such as proton pump inhibitors and histamine H2 receptor antagonists, and prokinetic agents, including mosapride and itopride, are clinically used to treat GERD. Endoscopic fundoplication can be performed in patients with GERD refractory to medical treatment. There is still insufficient evidence, but an increasing number of studies have suggested the clinical efficacy of treatment in patients with COPD and GERD. As GERD is an evaluative and treatable common disease, and access to evaluation and treatment is relatively easy, clinicians should provide adequate care for GERD in the management of COPD.
PubMed: 38941760
DOI: 10.1016/j.resinv.2024.06.004 -
Scientific Reports Jun 2024The tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through...
The tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through conventional smoking, e-cigarettes, snuff or nicotine pouches. The use of snuff has been associated with several adverse health effects, such as inflammatory reactions of the oral mucosa and oral cavity cancer. We performed a metabolomic analysis of nicotine-exposed THP-1 human monocytes. Cells were exposed to 5 mM of the alkaloid for up to 4 h, and cell extracts and medium subjected to untargeted liquid chromatography high-resolution mass spectrometry. Raw data processing revealed 17 nicotine biotransformation products. Among these, cotinine and nornicotine were identified as the two major cellular biotransformation products. The application of multi- and univariate statistical analyses resulted in the annotation, up to a certain level of identification, of 12 compounds in the cell extracts and 13 compounds in the medium that were altered by nicotine exposure. Of these, four were verified as methylthioadenosine, cytosine, uric acid, and L-glutamate. Methylthioadenosine levels were affected in both cells and the medium, while cytosine, uric acid, and L-glutamate levels were affected in the medium only. The effects of smoking on the pathways involving these metabolites have been previously demonstrated in humans. Most of the other discriminating compounds, which were merely tentatively or not fully identified, were amino acids or amino acid derivatives. In conclusion, our preliminary data suggest that some of the potentially adverse effects related to smoking may also be expected when nicotine is consumed via snuff or nicotine pouches.
Topics: Humans; Nicotine; Metabolomics; Monocytes; Mass Spectrometry; THP-1 Cells; Cotinine; Chromatography, Liquid; Metabolome; Glutamic Acid
PubMed: 38942832
DOI: 10.1038/s41598-024-65733-7 -
JAMA Network Open Jun 2024Significant evidence gaps exist regarding the safety of smoking cessation pharmacotherapies during pregnancy, especially for the risk of congenital malformations....
IMPORTANCE
Significant evidence gaps exist regarding the safety of smoking cessation pharmacotherapies during pregnancy, especially for the risk of congenital malformations. Consequently, professional bodies advise against the use of varenicline and bupropion and recommend caution with nicotine replacement therapy (NRT). Contemporary estimates of the use of smoking cessation pharmacotherapies during pregnancy are lacking.
OBJECTIVE
To quantify the proportion of individuals using prescribed smoking cessation pharmacotherapies during pregnancy and during the first trimester specifically, in 4 countries.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective, population-based cohort study used linked birth records, hospital admission records, and dispensing records of prescribed medications from all pregnancies resulting in birth between 2015 and 2020 in New South Wales, Australia; New Zealand; Norway; and Sweden. Data analyses were conducted in October and November 2023.
EXPOSURE
Prescribed smoking cessation pharmacotherapy use (varenicline, NRT, and bupropion) during pregnancy was defined as days' supply overlapping the period from date of conception to childbirth.
MAIN OUTCOMES AND MEASURES
Prevalence of use among all pregnancies and pregnancies with maternal smoking were calculated. Among women who used a pharmacotherapy, the proportion of women with use during the first trimester of pregnancy was also calculated.
RESULTS
Among 1 700 638 pregnancies in 4 countries, 138 033 (8.1%) had maternal smoking and 729 498 (42.9%) were younger than 30 years. The prevalences ranged from 0.02% to 0.14% for varenicline, less than 0.01% to 1.86% for prescribed NRT, and less than 0.01% to 0.07% for bupropion. Among pregnant individuals who smoked, use of pharmacotherapies was up to 10 times higher, with maximum prevalences of 1.25% for varenicline in New South Wales, 11.39% for NRT in New Zealand, and 0.39% for bupropion in New Zealand. Use in the first trimester occurred among more than 90% of individuals using varenicline, approximately 60% among those using NRT, and 80% to 90% among those using bupropion.
CONCLUSIONS AND RELEVANCE
In this cohort study of pregnant individuals in 4 high-income countries, the low prevalence of varenicline and bupropion use during pregnancy and higher prevalence of NRT use aligned with current clinical guidelines. As most use occurred in the first trimester, there is a need for evidence on the risk of congenital malformations for these medications.
Topics: Humans; Female; Pregnancy; Smoking Cessation; Adult; Retrospective Studies; Smoking Cessation Agents; Varenicline; Bupropion; New Zealand; Tobacco Use Cessation Devices; Pregnancy Complications; Sweden; New South Wales; Norway; Young Adult; Smoking; Pregnancy Trimester, First
PubMed: 38941092
DOI: 10.1001/jamanetworkopen.2024.19245 -
Translational Vision Science &... Jun 2024To compare changes in superficial retinal vascular density (SRVD), deep retinal vascular density (DRVD), and retinal thickness (RT) of the macular zone after repeated... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
PURPOSE
To compare changes in superficial retinal vascular density (SRVD), deep retinal vascular density (DRVD), and retinal thickness (RT) of the macular zone after repeated low-level red light (RLRL) and 0.01% atropine exposure in premyopic schoolchildren.
METHODS
Prospective randomized trial. Sixty-nine schoolchildren with cycloplegic refraction >-0.75 D and ≤0.50 D were randomly assigned to RLRL and 0.01% atropine groups. SRVD, DRVD, and RT were measured using swept-source optical coherence tomography at baseline and six months. The macular zone was divided into three concentric rings (fovea, parafovea, and perifovea) using the Early Treatment Diabetic Retinopathy Study.
RESULTS
After six months, the whole, parafoveal, and perifoveal SRVD significantly increased in the two groups (all P < 0.05). Multivariate regression analyses showed that none of these changes varied significantly between the two groups (all P > 0.05), whereas foveal SRVD remained stable in both groups (all P > 0.05). In the RLRL group, the whole and perifoveal DRVD increased significantly (all P < 0.05), whereas no statistical difference was observed in the foveal and parafoveal DRVD. DRVD remained stable in the 0.01% atropine group (all P > 0.05). No significant differences were observed in RT changes between the two groups (all P > 0.05). In comparison, there were no significant changes in SRVD, DRVD, or RT after six months in the placebo group in our previous study.
CONCLUSIONS
SRVD increased similarly in the RLRL and 0.01% atropine groups, whereas DRVD increased only in the former group. There were no significant RT changes in either group after six months of treatment in premyopic schoolchildren.
TRANSLATIONAL RELEVANCE
This research observed the effects of low-level red light and 0.01% atropine on retinal vasculature, offering valuable insights into myopia progression prevention.
Topics: Humans; Atropine; Male; Female; Child; Prospective Studies; Retinal Vessels; Mydriatics; Tomography, Optical Coherence; Myopia; Ophthalmic Solutions; Phototherapy; Microvascular Density; Red Light
PubMed: 38940757
DOI: 10.1167/tvst.13.6.23 -
Trials Jun 2024Hemiplegic shoulder pain (HSP) is a common complication after stroke. It severely affects the recovery of upper limb motor function. Early shoulder pain in hemiplegic...
Effect of ultrasound-guided injection of botulinum toxin type A into shoulder joint cavity on shoulder pain in poststroke patients: study protocol for a randomized controlled trial.
BACKGROUND
Hemiplegic shoulder pain (HSP) is a common complication after stroke. It severely affects the recovery of upper limb motor function. Early shoulder pain in hemiplegic patients is mainly neuropathic caused by central nerve injury or neuroplasticity. Commonly used corticosteroid injections in the shoulder joint can reduce shoulder pain; however, the side effects also include soft tissue degeneration or increased tendon fragility, and the long-term effects remain controversial. Botulinum toxin injections are relatively new and are thought to block the transmission of pain receptors in the shoulder joint cavity and inhibit the production of neuropathogenic substances to reduce neurogenic inflammation. Some studies suggest that the shoulder pain of hemiplegia after stroke is caused by changes in the central system related to shoulder joint pain, and persistent pain may induce the reorganization of the cortical sensory center or motor center. However, there is no conclusive evidence as to whether or not the amelioration of pain by botulinum toxin affects brain function. In previous studies of botulinum toxin versus glucocorticoids (triamcinolone acetonide injection) in the treatment of shoulder pain, there is a lack of observation of differences in changes in brain function. As the content of previous assessments of pain improvement was predominantly subjective, objective quantitative assessment indicators were lacking. Functional near-infrared imaging (fNIRS) can remedy this problem.
METHODS
This study protocol is designed for a double-blind, randomized controlled clinical trial of patients with post-stroke HSP without biceps longus tenosynovitis or acromion bursitis. Seventy-eight patients will be randomly assigned to either the botulinum toxin type A or glucocorticoid group. At baseline, patients in each group will receive shoulder cavity injections of either botulinum toxin or glucocorticoids and will be followed for 1 and 4 weeks. The primary outcome is change in shoulder pain on the visual analog scale (VAS). The secondary outcome is the assessment of changes in oxyhemoglobin levels in the corresponding brain regions by fNIRS imaging, shoulder flexion, external rotation range of motion, upper extremity Fugl-Meyer, and modified Ashworth score.
DISCUSSION
Ultrasound-guided botulinum toxin type A shoulder joint cavity injections may provide evidence of pain improvement in patients with HSP. The results of this trial are also help to analyze the correlation between changes in shoulder pain and changes in cerebral hemodynamics and shoulder joint motor function.
TRIAL REGISTRATION
Chinese clinical Trial Registry, ChiCTR2300070132. Registered 03 April 2023, https://www.chictr.org.cn/showproj.html?proj=193722 .
Topics: Humans; Shoulder Pain; Ultrasonography, Interventional; Stroke; Botulinum Toxins, Type A; Randomized Controlled Trials as Topic; Injections, Intra-Articular; Treatment Outcome; Pain Measurement; Shoulder Joint; Time Factors; Hemiplegia; Recovery of Function; Range of Motion, Articular; China; Neuromuscular Agents; Double-Blind Method; Biomechanical Phenomena
PubMed: 38937804
DOI: 10.1186/s13063-024-08258-8 -
JAMA Network Open Jun 2024Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated.
OBJECTIVE
To examine whether hospitalized smokers treated with varenicline and NRT lozenges achieve higher prolonged smoking abstinence rates compared with those treated with varenicline alone.
DESIGN, SETTING, AND PARTICIPANTS
A double-blind, placebo-controlled randomized clinical trial was conducted in adult medical or surgical inpatients of 5 Australian public hospitals with a history of smoking 10 cigarettes or more per day, interested in quitting, and available for 12-month follow-up between May 1, 2019, and May 1, 2021 (final 12-month data collection in May 2022). Data analysis was performed from June 1 to August 30, 2023.
INTERVENTIONS
A 12-week varenicline regimen was initiated during hospitalization at standard doses in all participants. Participants were randomized to additionally use NRT (2 mg) or placebo lozenges if there was an urge to smoke. Behavioral support (Quitline) was offered to all participants.
MAIN OUTCOMES AND MEASURES
The primary outcome was biochemically verified sustained abstinence at 6 months. Secondary outcomes included self-reported prolonged abstinence, 7-day point prevalence abstinence (3, 6, and 12 months), and medicine-related adverse events.
RESULTS
A total of 320 participants (mean [SD] age, 52.5 [12.1] years; 183 [57.2%] male) were randomized. The conduct of biochemical verification was affected by COVID-19 restrictions; consequently, the biochemically verified abstinence in the intervention vs control arms (18 [11.4%] vs 16 [10.1%]; odds ratio [OR], 1.14; 95% CI, 0.56-2.33) did not support the combination therapy. The secondary outcomes in the intervention vs control arms of 7-day point prevalence abstinence at 6 months (54 [34.2%] vs 37 [23.4%]; OR, 1.71; 95% CI, 1.04-2.80), prolonged abstinence at 12 months (47 [29.9%] vs 30 [19.1%]; OR, 1.77; 95% CI, 1.05-3.00), and 7-day point prevalence abstinence at 12-months (48 [30.6%] vs 31 [19.7%]; OR, 1.79; 95% CI, 1.07-2.99) significantly improved with the combination therapy. The self-reported 6-month prolonged abstinence (61 [38.6%] vs 47 [29.7%]; OR, 1.49; 95% CI, 0.93-2.39) favored the combination therapy but was not statistically significant. Medicine-related adverse events were similar in the 2 groups (102 [74.5%] in the intervention group vs 86 [68.3%] in the control group).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of the combination of varenicline and NRT lozenges in hospitalized adult daily smokers, the combination treatment improved self-reported abstinence compared with varenicline alone, without compromising safety, but it did not improve biochemically validated abstinence.
TRIAL REGISTRATION
anzctr.org.au Identifier: ACTRN12618001792213.
Topics: Humans; Varenicline; Male; Female; Smoking Cessation; Tobacco Use Cessation Devices; Middle Aged; Double-Blind Method; Adult; Smoking Cessation Agents; Australia; Hospitalization; Smokers; Aged; Treatment Outcome; Nicotine Replacement Therapy
PubMed: 38935378
DOI: 10.1001/jamanetworkopen.2024.18120 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding...
The Influence of an Acute Administration of Cannabidiol or Rivastigmine, Alone and in Combination, on Scopolamine-Provoked Memory Impairment in the Passive Avoidance Test in Mice.
Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding environment. However, sometimes there are unfavourable changes in the functioning of the brain and memory deficits occur, which may be associated with various diseases. Disturbances in the cholinergic system lead to abnormalities in memory functioning and are an essential part of clinical symptoms of many neurodegenerative diseases. However, their treatment is difficult and still unsatisfactory; thus, it is necessary to search for new drugs and their targets, being an alternative method of mono- or polypharmacotherapy. One of the possible strategies for the modulation of memory-related cognitive disorders is connected with the endocannabinoid system (ECS). The aim of the present study was to determine for the first time the effect of administration of natural cannabinoid compound (cannabidiol, CBD) and rivastigmine alone and in combination on the memory disorders connected with cholinergic dysfunctions in mice, provoked by using an antagonist of muscarinic cholinergic receptor-scopolamine. To assess and understand the memory-related effects in animals, we used the passive avoidance (PA) test, commonly used to examine the different stages of memory. An acute administration of CBD (1 mg/kg) or rivastigmine (0.5 mg/kg) significantly affected changes in scopolamine-induced disturbances in three different memory stages (acquisition, consolidation, and retrieval). Interestingly, co-administration of CBD (1 mg/kg) and rivastigmine (0.5 mg/kg) also attenuated memory impairment provoked by scopolamine (1 mg/kg) injection in the PA test in mice, but at a much greater extent than administered alone. The combination therapy of these two compounds, CBD and rivastigmine, appears to be more beneficial than substances administered alone in reducing scopolamine-induced cognitive impairment. This polytherapy seems to be favourable in the pharmacotherapy of various cognitive disorders, especially those in which cholinergic pathways are implicated.
PubMed: 38931476
DOI: 10.3390/ph17060809