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Pectin-stabilized nanoceria double coated with lactoferrin/chitosan for management of experimental autoimmune encephalomyelitis

Cerium oxide nanoparticles are a unique antioxidant mimicking the activity of natural antioxidant enzymes. Previous research showed its’ promising effect mitigating free radical damage in neurodegenerative disorders. However, there is still unmet therapeutic needs due to poor BBB penetration, a high accumulation in liver, kidney and spleen. This study aimed to synthesize and optimize nanoceria stabilized by natural bioactive polymers suitable for intranasal administration to manage multiple sclerosis. Among the different employed biopolymers, pectin-stabilized nanoceria exhibited the ideal properties with small particles size 87.20±3.43nm, high zeta potential -56.37±2.39mV and high free radical scavenging activity 85.27±0.07%. Then coating was achieved for the first time by two biopolymers: lactoferrin and chitosan producing a double coated cationic nanoceria. Biological assessment involved using experimental autoimmune encephalomyelitis animal model treated in a dose of 1mg/kg nanoceria for 15 days. Motor function testing in rats revealed 6- and 17-folds increase in latency time in rotating rod and hanging wire tests, respectively. Biochemical analysis revealed significant reduction in lipid peroxidation along with about 1-fold upgrading of the intrinsic antioxidant system. Moreover, histologic examination disclosed decreased degeneration of the brain and spinal cord of treated rats and much decreased liver toxicity.

Dual Approach to Depression: The Combined Efficacy of Intermittent Hypoxia and Fluoxetine in Modulating Behavioral and Inflammatory Responses.

Background/Objectives: Mental disorders pose a significant public health challenge, affecting millions worldwide. Given the limitations of current therapies, many patients experience inadequate responses and adverse effects. Intermittent hypoxia (IH) has demonstrated anxiolytic, antidepressant, and neuroprotective properties in various protocols. This study investigated the effects of acute IH (13% O2, 1 h), fluoxetine (FLX) and their combination on depression-like behavior, serum corticosterone, and inflammatory cytokine levels induced by acute restraint stress in C57BL/6 female mice. Methods: Behavioral assessments included the tail suspension test, forced swim test, and open field test. Results: The combined IH + FLX treatment exhibited a synergistic effect, reducing immobility time and increasing latency time, respectively, in the tail suspension test (46%, p = 0.0014; 73%, p = 0.0033) and forced swim test (56%, p = 0.0082; 48%, p = 0.0322) compared to the ARS group. Biochemical analysis revealed that individual and combined treatments significantly reduced most inflammatory interleukins by up to 96%. Corticosterone levels were reduced by 30% only in the IH group. Conclusions: These findings highlight the potential of a one-hour IH session, particularly when combined with fluoxetine, to alleviate depressive-like behaviors and exert anti-inflammatory effects, suggesting a promising therapeutic approach for depression.

Inhibition of nitric oxide production in RAW 264.7 cells and cytokines IL-1β in osteoarthritis rat models of 70 % ethanol extract of Arcangelisia flava (L.) merr stems

IntroductionOne of the most frequent types of arthritis is osteoarthritis, also referred to as a degenerative joint disease. Interleukin-1β (IL-1β) and nitric oxide (NO) are essential factors in the pain response; IL-1β and NO are responsible for increasing the production of matrix metalloproteinases (MMP) and a disintegrin-like and metalloproteinases with thrombospondin motifs (ADAMS) in chondrocytes. Arcangelisia flava (L.) Merr. Has been traditionally used to treat jaundice, liver disease, diarrhea, fever, and inflammation. MethodsThis study used in vitro and in vivo models to determine the effect of a 70 % ethanol extract of Arcangelisia flava (L.) Merr. stems on the inhibition of NO production in RAW 264.7 cells induced with lipopolysaccharide (LPS) and IL-1β in osteoarthritis rats induced with monosodium iodoacetate (MIA). The NO inhibition test was determined by the NO colorimetric assay using Griess reagent and measured by the ELISA plate reader. The measurement of joint diameter and hyperalgesia in osteoarthritis rats was carried out once a week for 7 weeks, and then the IL-1β levels were measured at weeks 3 and 7. ResultThe viability of cell line this extract was greater than 80 %, and the extract at 25, 50, and 100 μg/mL significantly inhibited NO production (p < 0.0001) in RAW 264.7 cells induced with LPS. Meanwhile, this extract at 10, 30, and 90 mg/200g BW increased latency time, reduced joint swelling, and reduced IL-1β levels in the serum in the osteoarthritis rat model. Conclusion70 % ethanol extract of Arcangelisia flava (L.) Merr. Has the potential to be an anti-osteoarthritis drug.

Antinociceptive and anti-inflammatory activities of Ayapana triplinervis essential oil rich in thymohydroquinone dimethyl ether from Brazil.

Ayapana triplinervis (M.Vahl) R.M.King & H.Rob. (Asteraceae), popularly known as japana, is a tropical, aromatic subshrub widely used as tea to combat some diseases. The essential oil was obtained from the leaves by hydrodistillation (3h), and the chemical composition was analyzed by gas chromatography coupled to mass spectrometry. For in vivo assays, Mus musculus/Swiss mice were used to evaluate oral acute toxicological (at dose of 2000mg/kg); peripheral and central analgesic for abdominal contortion (doses of 6.25, 12.5, 25, 50 and 100mg/kg), hot plate test (12.5, 25, 50, and 100mg/kg) and formalin (25, 50 and 100mg/kg); open field test (100mg/kg); and anti-inflammatory by ear swelling induced by xylene (6.25,12.5, 25, 50, and 100mg/kg). The yield of A. triplinervis essential oil (AtEO) was 4.6%, and the oxygenated monoterpene 2,5-dimethoxy-p-cymene was the major compound in this study (63.6%). AtEO at a dose of 2,000mg/kg orally did not change the behavior patterns or mortality of the animals; liver and kidney biochemical levels were similar to the control group, indicating no liver and kidney toxicity. Moreover, AtEO, at doses of 6.25, 12.5, 25, 50, and 100mg/kg, reduced abdominal contortions by 21%, 54%, 91%, 58%, and 55%, respectively. In the hot plate test, AtEO showed a significant increase in latency time in the 60-min interval at doses of 25mg/kg (11.3 ± 3.3s) and 100mg/kg (11.9 ± 0.9s). In the first phase of the formalin test, AtEO decreased paw licking time at doses of 25, 50, and 100mg/kg, with inhibition of 22%, 38%, and 83%; in the second phase, the same doses, decreased licking time with inhibition of 24%, 34%, and 76%. AtEO did not present a significant change in the spontaneous locomotor activity of the animals. Doses of 6.25, 12.5, 25, 50, and 100mg/kg significantly reduced ear edema induced by topical application of xylene with percentages of 40%, 39%, 54%, 45%, and 45%, respectively. So, AtEO demonstrated low acute oral toxicity and exhibited significant antinociceptive and anti-inflammatory actions, consistent with the use of A. triplinervis in traditional medicine.

The Effect of Chronic Restraint Stress Induced Alzheimer Like Changes In Male Adult Rats

Abstract Chronic stress has become a common problem that cannot be ignored and has become an important risk factor for the onset of many diseases. Responses to chronic stress are systemic reactions involving multiple organs and can induce symptoms such as depression, cognitive impairment, cardiovascular disease, immune dysfunctions, impaired reproductive ability, bone loss, and reduced life expectancy. Aim The present study was designed to investigate the effect of chronic restraint stress on the cognitive function in male albino rats, further to demonstrate its relation to amyloid and tau protein accumulation. Methods 24-albino male wistar rats were divided into 2 groups as Control group and Chronic restraint stress (CRS) subjected group (done by restraining rats for 3 hours daily for 4 weeks). Body weight, morris water maze test (MWM) and brain levels of p tau and amyloid beta were investigated Results CRS increased body weight significantly in week 4 and increased latency time as observed in MWM test compared to control group. Additionally, p tau and amyloid beta levels in CRS group were significantly increased. Conclusion chronic stress is able to accelerate the appearance of Alzheimer’s disease (AD) Changes upon chronic stress in the brain were related to accumulation of β-amyloid, TAU hyperphosphorylation in males.

Antinociceptive and anti-inflammatory effects of the essential oil of Lippia hermannioides, an endemic species of Brazil

Abstract Lippia hermannioides (Verbenaceae) is a species endemic to Brazil with reported antioxidant and antimicrobial activity. The objective of this study was to determine the chemical composition of the essential oil of L. hermannioides leaves (EOLH), using chromatographic and spectrometric methods, as well as its antinociceptive and anti-inflammatory potential by implementing of chemical and thermal nociception models. The results revealed germacrene D (18.39%) as the major compound of the essential oil, followed by bicyclogermacrene (11.72%), 1,8-cineole (11.24%), sabinene (10.38%), E-caryophyllene (8.33%), β-pinene (7.37%), and α-pinene (6.18%). Intraperitoneal administration of EOLH at doses of 300 and 2,000 mg.kg-1 showed no signs of toxicity in mice. EOLH doses of 75 and 300 mg.kg-1 did not affect the animals’ motor coordination in the rotarod test but reduced the number of abdominal writhing induced by acetic acid and decreased paw licking time in both phases of the formalin test. There was also an increased latency time in the hot plate test. These results indicate that this essential oil has antinociceptive and anti-inflammatory activity, thus supporting further research on the use of this phytotherapeutic resource in the health field.

Antinociceptive effect of Nephelium lappaceum L. fruit peel and the participation of nitric oxide, opioid receptors, and ATP-sensitive potassium channels.

Introduction: Nephelium lappaceum L. (Sapindaceae) is a plant known as rambutan. It is used for various purposes in traditional medicine. Objective: We aimed to evaluate the antinociceptive effects of the ethanol extract of the fruit peel of N. lappaceum (EENL), the mechanisms involved in these effects, and the acute toxicity in zebrafish. Methods: We performed chromatography coupled to mass spectrometry, acute toxicity assay in zebrafish, and evaluation in mice submitted to models of nociception and locomotor activity. Results: We identified (epi)-catechin, procyanidin B, and ellagic acid and its derivatives in EENL. We did not find any toxicity in zebrafish embryos incubated with EENL. The locomotor activity of mice submitted to oral pretreatment with EENL was not changed, but it reduced the abdominal constrictions induced by acetic acid, the licking/biting time in both the first and second phase of formalin testing and capsaicin testing, and carrageenan-induced paw mechanical allodynia. Oral pretreatment with EENL increased latency time in the hot plate test. This antinociceptive effect was significantly reversed by naloxone, L-arginine, and glibenclamide respectively showing the participation of opioid receptors, nitric oxide, and KATP channels as mediators of EENL-induced antinociception. Conclusion: EENL causes antinociception with the participation of opioid receptors, nitric oxide, and KATP channels, and is not toxic to zebrafish.

Xanthohumol relieves arthritis pain in mice by suppressing mitochondrial-mediated inflammation.

Chronic pain is the most common symptom for people who suffer from rheumatoid arthritis and it affects approximately 1% of the global population. Neuroinflammation in the spinal cord induces chronic arthritis pain. In this study, a collagen-induced arthritis (CIA) mice model was established through intradermally injection of type II collagen in complete Freund's adjuvant solution. Following CIA inducement, the paws and ankles of mice were found to swell, mechanical pain and spontaneous pain were induced, and their motor coordination was impaired. The spinal inflammatory reaction was triggered, which presented as severe infiltration of inflammatory cells, and the expression levels of GFAP, IL-1β, NLRP3, and cleaved caspase-1 increased. Oxidative stress in the spinal cord of CIA mice was manifested as reduced Nrf2 and NDUFB11 expression and SOD activity, and increased levels of DHODH and Cyto-C. At the same time, spinal AMPK activity was decreased. In order to explore the potential therapeutic options for arthritic pain, Xanthohumol (Xn) was intraperitoneally injected into mice for three consecutive days. Xn treatment was found to reduce the number of spontaneous flinches, in addition to elevating mechanical pain thresholds and increasing latency time. At the same time, Xn treatment in the spinal cord reduced NLRP3 inflammasome-mediated inflammation, increased the Nrf2-mediated antioxidant response, and decreased mitochondrial ROS level. In addition, Xn was found to bind with AMPK via two electrovalent bonds and increased AMPK phosphorylation at Thr174. In summary, the findings indicate that Xn treatment activates AMPK, increases Nrf2-mediated antioxidant response, reduces Drp1-mediated mitochondrial dysfunction, suppresses neuroinflammation, and can serve to relieve arthritis pain.

A study of the lightweight algorithm for recognizing masks incorporating attention mechanism and G-GhostNet

As COVID-19 and humanity's protracted battle makes wearing masks a norm, intelligent recognition of mask-wearing and wearing criteria is investigated to lessen the labor of epidemic control and detection personnel. To achieve the purpose of not having to manually identify mask use in a busy, open setting, to be able to provide a real-time warning of the whole mask non-wearing phenomenon in mobile devices, and to address the issue of sluggish efficiency and poor precision of traditional target detection and tracking means in complex scenes, this work presents a lightweight mask identification method that combines G-GhostNet with an attention mechanism. Firstly, YoLov5's BackBone network is replaced with a more lightweight G-GhostNet with fewer convolution kernels to reduce the parameters and computation more significantly; secondly, an attention mechanism is introduced to G-GhostNets feature mixing process to increase discovered features weight values.Then, the dichotomous unmasked and masked datasets are prepared to enhance the model accuracy and speed by the loss function. The experiments compare the effects of Squeeze-and-Excitation Networks (SE), Convolutional Block Attention Module(CBAM), Efficient Channel Attention (ECA), and Coordinate Attention (CA), the four attention processes on the enhanced model with the model without the added attention mechanisms. The results show that adding the attention mechanisms all make the model recognize masks better, among which adding CA has the best recognition effect with a 2% improvement in accuracy but 1.3 times increase in Latency time; in contrast, adding SE, ECA balanced speed and accuracy.

Preparation and characterization of naproxen solid dispersion using different hydrophilic carriers and in-vivo evaluation of its analgesic activity in mice

BackgroundSolid dispersion (SD) has been used conventionally as a successful technique for improving the dissolution profile and bioavailability of poorly water-soluble drugs. The aim of this study was to progress the dissolution rate and bioavailability of naproxen (BCS class II) by SD technique. Materials & methodsIn this study, hydrophilic carriers are used for preparing solid dispersion of naproxen by evaporation method. The prepared optimized SDNs were evaluated by in-vitro drug dissolution test, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The in-vivo analgesic effects tests of the optimized SDNs (SDN-2 and SDN-5) were performed by tail immersion method and writhing method. ResultsAll the prepared SDNs exhibited a significant increase in the dissolution of naproxen compared to that of the pure drug. Among them, SDN-2 (the dispersion with sodium starch glycolate at 1:2 ratio of naproxen and sodium starch glycolate) and SDN-5 (using the combination of PEG-8000 and sodium starch glycolate with naproxen at 1:1:1 ratio) showed faster dissolution rate as compared to other solid dispersions (SDNs) and pure naproxen. SDN-2 showed 5.4 times better dissolution rate and SDN-5 depicted 6.5-fold increment of dissolution rate compared to pure naproxen drug. DSC, PXRD and SEM microscopy showed that the drugs crystallinity was decreased during the preparation process. FTIR study revealed that naproxen was stable in polymeric dispersions and there was no interaction among the drug and polymers. In writhing method, the percentage inhibition of the number of writhes showed significantly greater (p < 0.01), (p < 0.0001) analgesic activity for the higher dose treatment groups SDN-2(H), and SDN-5(H), respectively, when contrasted to the pure drug naproxen. For tail immersion test, there is increase in latency time at 90 min which is significantly greater (P < 0.01), (P < 0.05), (P < 0.01) for treatment groups SDN-2(H), SDN-5(L), and SDN-5(H), respectively that ultimately authenticates that the optimized SDNs (SDN-2, SDN-5) showed better analgesic activity in mice in comparison with the pure drug. ConclusionIt can be concluded that dissolution of the naproxen could be improved by the making solid dispersion using sodium starch glycolate and/or combination of sodium starch glycolate and PEG 8000 due to the complete transformation of drug into amorphous form with the entire loss of crystallinity, as evidenced by DSC, PXRD, and SEM and also consequences the enhanced analgesic activity in mice.

The effect of gabapentin and pregabalin administration on memory in clinical and preclinical studies: a meta-analysis and systematic review

BackgroundToday, gabapentinoids such as Gabapentin (GBP) and pregabalin (PGB) are widely used as painkillers. This may alter the function of the nervous system; hence their results may include a difference in memory and processes that end in memory formation. This study aims to conclude whether gabapentinoids can alter memory or not by reviewing and analyzing clinical and preclinical studies.Material and methodsA comprehensive search was carried out in databases including PUBMED, EMBASE, SCOPUS, and Web of Science. In the included studies, memory was measured as an outcome variable in clinical or preclinical studies.ResultA total of 21 articles (4 clinical, 17 preclinical) were included in the meta-analysis by STATA Software. The results showed that memory changes under the influence of GBP. Both the administrated dosage and the time of administration are important in the final results and latency time of retention. GBP administration in healthy animals increased latency time, whereas if the administration of GBP took place exactly before training, the latency time increased slightly.Short-term administration of PGB in healthy volunteers is accompanied by transient side effects on the CNS. However, the number and homogeneity of the studies were not such that a meta-analysis could be performed on them.ConclusionClinical and preclinical studies showed that PGB administration did not confirm its improving memory effect. GBP administration in healthy animals increased latency time and improved memory. Although it depended on the time of administration.

Chemical composition, antinociceptive and anti-inflammatory effects in mice of the essential oil of Psidium cattleyanum Sabine leaves

Ethnopharmacological relevanceOne of the native species of the genus most often mentioned by traditional people is Psidium cattleyanum Sabine, which is used mostly to treat disorders of the respiratory, genitourinary, and digestive systems. These symptoms are mainly treated by the decoction of the leaves. Additionally, there are gaps in the in vivo and toxicity investigations of this species. Aim of the studyThe aim of this study was evaluate antinociceptive and anti-inflammatory potential of essential oil from P. cattleyanum leaves in vivo. Materials and methodsGas chromatography-mass spectrometry (GC/MS) was used to examine the essential oil of P. cattleyanum. The acute toxicity test was then done with a 2000 mg/kg dosage. The oil at 50, 100, and 200 mg/kg orally, as well as the reference medications Morphine 10.0 mg/kg IP and/or Indomethacin 20.0 mg/kg IP, were tested using nociception (abdominal writhing, formalin, and tail immersion) and inflammatory models (paw edema and peritonitis). ResultsThe phytochemical assay showed a high concentration of β-caryophyllene (46.68%) and α-caryophyllene (10.81%). In the in vivo assays, P. cattleyanum essential oil proved to be an important antinociceptive agent, reaching 76.96% inhibition of abdominal writhing with acetic acid and 67.12% in the formalin assay. An increase in latency time in the tail test was also reported. In the test with carrageenan, the oil showed significant inhibition compared to the control. A decrease in the migration of leukocytes was also reported in the group treated with P. cattleyanum, reaching 60.49% at the dose of 200 mg/kg. ConclusionsThe essential oil from the leaves of P. cattleyanum has anti-inflammatory and antinociceptive action and has potential for application in the pharmaceutical and food industry.

Neuroprotective Effect of Stachytarpheta angustifolia Methanol Extract Against Aluminium Chloride (AlCl3) Induced Alzheimer’s Disease in Albino Rats

Aim: This study was aim to evaluate the neuroprotective effect of Stachytarpheta angustifolia methanol extract on aluminium chloride induced Alzheimer’s disease in Albino rats.&#x0D; Study Design: This is an experimental study.&#x0D; Location and Duration of the Study: The research was conducted at the Central Research Laboratory of Nasarawa State University, Keffi, Nigeria from 7th October, 2022 to 12th January, 2023.&#x0D; Methodology: The whole plant was extracted using soxhlet extraction method with methanol as solvent. Thirty Albino rats of both sexes were divided into six groups with five rats in each. Aluminum chloride (AlCl3) was used to induced Alzheimer and treated with vitamin E and various doses of the plant extract. Behavioural test was carried out using T-maze to assess learning and memory. Antioxidant parameters (SOD, CAT, GPx, GSH, MDA and NO), cyclooxygenase-2 (COX-2) and acetylcholinesterase (AChE) were determined using ELISA kits. Histopathological examination was carried out using hematoxylin and eosin.&#x0D; Results: The results showed a significant (p = .05) decrease in the correct percentage number of alternations and a significant (p = .001) increase in latency time spent in the maze in the aluminum chloride (AlCl3) induced and untreated group compared to the control. There were significant (p = .05) decreased in SOD, CAT activities and GSH (p = .001) level. While, there were significant increase in MDA (p = .001), NO (p = .01), COX-2 (p = .05) and AChE (p = .05) compared to the control. Treatment with the plant extract significantly (p = .001) increased the SOD, CAT, GPx and GSH compared to the aluminum chloride (AlCl3) group. While, MDA, NO, COX-2 and AChE decreases significantly (p = .001) compared to the aluminum chloride (AlCl3) group. Histopathological examination of hippocampus sections tallied with the biochemical parameters.&#x0D; Conclusion: These results may justify the ethnomedicinal use of Stachytarpheta angustifolia, especially in the treatment of Alzheimer’s disease.

Association between radiotherapy for surgically treated oral cavity cancer and secondary lung cancer.

There is limited research on the incidence of secondary lung cancer (SLC) after radiotherapy (RT) for oral cavity cancer (OCC). Therefore, we investigated the association between RT for OCC and the risk of SLC and the overall survival of these patients. Patients diagnosed with OCC between 1975 and 2015 were selected from the Surveillance, Epidemiology, and End Results database. The cumulative incidence of SLC, relative risk (RR) of RT vs. no RT (NRT), standardized incidence ratios (SIR), and survival outcomes were assessed. A total of 10,936 patients with OCC were included. Of these, 429 (3.92%) patients developed SLC, where 136 (5.02%) received RT and 293 (3.56%) did not. The cumulative incidence of SLC during follow-up was 6.89% and 4.84% in the RT and NRT patients, respectively. RT was associated with a higher risk of SLC. In the subset analysis, the results showed that a higher risk of developing SLC among patients with index OCC in most subgroups. Dynamic RR and SIR revealed a decreased risk of SLC with increasing latency time. No difference was observed in the 10-year survival rates for patients with SLC who received RT or not or compared with primary lung cancer. RT was associated with a higher risk of SLC, and patients diagnosed with OCC could be followed for 5-10 years after diagnosis.

Assessment of analgesic properties of alcohol and aqueous extracts of Opuntia ficus-indica flowers

The cactus (Opuntia ficus-indica (L.) Mill.) belongs to the Cactaceae family and it’s used in traditional folk medicine in treating a number of diseases and conditions. Due to the remarkable biological activity and to the bioactive (phytochemicals) compounds of O. ficus-indica, it becomes the aim of many research studies. The current study aimed to evaluate the analgesic activity of various solvent fractions (aqueous and ethanol) prepared from the O. ficus-indica flowers. The centrally analgesic potential was evaluated using tail flick latency in tail immersion and hot plate methods in mice. Morphine was used as a positive control at a dose of 3 mg kg-1, s.c.. Intra-peritoneal administration of the aqueous extract of O. ficus-indica flowers at the highest dose did not produce any toxicity symptoms, thus the median lethal dose (LD50) was estimated to be greater than 2,500 mg kg-1. The results of the pain behavior evaluation according to the gender approach of mice showed that the pain tolerance threshold is high in males compared to females. We found that various plant extracts at doses of 300, 500, and 1,000 mg kg-1 i.p., displayed significant and dose-dependent protective effects (p &lt; 0.01, p &lt; 0.001, and p &lt; 0.0001) as measured by increased latency time compared to vehicle control. The maximum anti-nociceptive effect was with the ethanol extract (71%) at 60 minutes at a dose of 1,000 mg kg-1, which was equivalent to the effect of morphine (70%). The results suggested that O. ficus-indica might possess significant analgesic effects, supporting the use of this plant in traditional medicine.

Chemical profiling and evaluation of toxicological, antioxidant, anti-inflammatory, anti-nociceptive and tyrosinase inhibitory potential of Portulacaria afra using in-vitro, in-vivo and in-silico studies

Portulacaria afra Jacq (Portulacaceae) is a medicinal plant used traditionally in the treatment of pain and inflammation. This study aimed to evaluate the phytochemical composition, toxicity, antinociceptive, and enzyme inhibition potential of P. afra. The methanol extract (PAME) was prepared through maceration and fractionated with ethanol to ethanol fraction of P. afra (ETPA). Both PAME and ETPA were found to be rich in total phenolic (TPC) and total flavonoid contents (TFC). Similarly, PAME showed the highest antioxidant potential through ABTS 93.16 ± 0.05 mg TE /g of dry extract (D.E.) while ETPA showed maximum results (462 ± 1.44 mg TE/g) in the CUPRAC method. The RP-UHPLC-MS analysis of PAME showed tentative identification of 101 compounds in the positive mode and 14 compounds in the negative mode of ionization while GC–MS profiling gave a total of 15 compounds. The acute oral toxicity study of PAME revealed the safety and biocompatibility of the extract up to a dose of 5000 mg/kg orally in rats. In-vitro data revealed that varying concentrations of P. afra significantly (p < 0.05) inhibited heat-induced BSA denaturation compared to indomethacin in a concentration-dependent manner. PAME suppressed carrageenan-induced paw edema at the 4th hr with maximum inhibition. The analgesic efficacy of PAME was determined by the hotplate, writhing method, and tail-flicking rat models. In the hot plate method, PAME treated groups showed a significant effect (p < 0.0001). While in the writhing model, the PAME treated groups showed a significant (p < 0.0001) anti-nociceptive effect at 200 mg/kg and 400 mg/kg compared to the control group. Similarly, PAME treated groups in the tail flicking model showed a significant (p < 0.001) anti-nociceptive effect at 200 mg/kg and 400 mg/kg. A dose-dependent increase in latency time (8.78 ± 0.090 at (30 min), 11.39 ± 0.005 at (60 min), 12.14 ± 0.01 at (90 min) 15.19 ± 0.03 at (120 min), p < 0.0001 was observed, compared to the control group. Similarly, the extract and fraction showed significant inhibitory potential against tyrosinase in in vitro and in-silico studies. Conclusively the current study unveiled P. afra as a novel non-toxic source with good total antioxidant-mediated anti-inflammatory and analgesic potential.

Minocycline alleviated scopolamine-induced amnesia by regulating antioxidant and cholinergic function

Background and aimMinocycline, a tetracycline derivative, has been found to exert neuroprotective properties. The current project aimed to assess the antioxidant status and cholinergic function in the amnesia induced by scopolamine. MethodsWe evaluated the passive avoidance performance, acetylcholine esterase (AChE) enzyme activity, and the oxidative stress indicators in the following groups: Normal control, scopolamine, and the treatment groups (the animals were given minocycline (10–30 mg/kg)). ResultsScopolamine (intraperitoneal) injection was associated with impairment of passive avoidance performance and neurotoxicity. Minocycline pronouncedly ameliorated scopolamine injury as presented by the increased latency time to darkness and stay time in lightness along with the decreased darkness entry. Moreover, minocycline decreased lipid peroxidation, while it elevated the levels of superoxide dismutase, AChE enzymes, and thiol groups in both the cortex and hippocampus. ConclusionOur data suggested that minocycline modulated the antioxidant status and AChE in the brains, which may contribute to its protective effects against scopolamine-induced amnesia.

Memory enhancement of the new tryptamine-like components in the walnut kernel

Walnut kernel has been applied in daily diets for thousands of years with its memory enhancement effect. For further observing the effect of memory enhancement, the walnut kernel was extracted and separated into active parts, with the evaluation in mice. 30% ethanol elution from AB-8 macroporous resin showed a decreased escape latency time and increased cumulative time and crossing frequency through the Morris test. It also increased the latency time and decreased jumps in the step-down test. These results indicated the memory enhancement effect of the fraction. After further separation and purification, four compounds were acquired with tryptamine-like structures first found in the walnut kernel, and compounds III and IV were new ones. Compound III showed decreased escape latency time, increased cumulative time, increased crossing frequency through the Morris test, and increased latency time, decreased jumps in the step-down test. Compound III also alleviated acetylcholinesterase activity and promoted acetylcholine transferase activity. In silico docking and molecular dynamic studies displayed the most polar interactions of compound III on 5-hydroxytryptamine receptor 4 (5-HTR4) with the most polar interactions and the lowest binding energies, and anti-degeneration effect to monoamine oxidase A (MAO-A) with the high binding energy and sizeable steric hindrance. These results illustrated the memory enhancement of compound III in the walnut kernel, indicating more potential activities of tryptamine-like components and more applications for walnut kernel in clinical use or daily diets.

Handwriting fluency, latency, and kinematic in Portuguese writing system: Pilot study with school children from 3rd to 5th grade.

Studies have referred to the interaction between orthographic and motor aspects during the production of handwriting. However, studies with Brazilian Portuguese are still lacking. Hence, the aim of this study was to compare orthographic regularity, based on the Portuguese writing system, in high (HF) and low (LF) frequency words, in relation to latency and kinematic variables in students from the 3rd to the 5th grade of elementary school. This is a cross-sectional pilot study, with a convenience sample of 95 children participated in this study, from 3rd to 5th grade level attending a state elementary school. All were submitted to the following procedures of computerized evaluation of handwriting and submitted to the task of writing 15 HF and 15 LF words, selected according to the frequency criteria and classified according writing coding rule. Results indicated that for HF words, there was a decrease in writing and disfluencies production time, for all coding rules, from 3rd to 5th grade. However, for LF words, the more unpredictable orthographic affect production duration time, movement fluency, and students became more dependent on the use of gaze to check spelling aspects. This study revealed that lexical and sub-lexical activation affected motor production. For HF and LF words, lexical and sublexical process favored motor programming. However, for LF words, despite the maturation and school progression for the motor planes, there was an increase in latency time and in the need to search for word information, measured by the gaze variable for words with greater irregularity. This study has provided some evidence that linguistic variables such as orthographic regularity and word familiarity affect handwriting performance in Brazilian Portuguese written language.

Development of charybdotoxin Q18F variant as a selective peptide blocker of neuronal BK(α + β4) channel for the treatment of epileptic seizures.

Epilepsy is the results from the imbalance between inhibition and excitation in neural circuits, which is mainly treated by some chemical drugs with side effects. Gain-of-function of BK channels or knockout of its β4 subunit associates with spontaneous epilepsy. Currently, few reports were published about the efficacy of BK(α + β4) channel modulators in epilepsy prevention. Charybdotoxin is a non-specific inhibitor of BK and other K+ channels. Here, by nuclear magnetic resonance (NMR) and other biochemical techniques, we found that charybdotoxin might interact with the extracellular loop of human β4 subunit (i.e., hβ4-loop) of BK(α + β4) channel at a molar ratio 4:1 (hβ4-loop vs. charybdotoxin). Charybdotoxin enhanced its ability to prevent K+ current of BK(α + β4 H101Y) channel. The charybdotoxin Q18F variant selectively reduced the neuronal spiking frequency and increased interspike intervals of BK(α + β4) channel by π-π stacking interactions between its residue Phe18 and residue His101 of hβ4-loop. Moreover, intrahippocampal infusion of charybdotoxin Q18F variant significantly increased latency time of seizure, reduced seizure duration and seizure numbers on pentylenetetrazole-induced pre-sensitized rats, inhibited hippocampal hyperexcitability and c-Fos expression, and displayed neuroprotective effects on hippocampal neurons. These results implied that charybdotoxin Q18F variant could be potentially used for intractable epilepsy treatment by therapeutically targeting BK(α + β4) channel.