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The journal retracts the article, “A Novel Herbal Hydrogel Formulation of Moringa oleifera for Wound Healing” [...]

[This corrects the article DOI: 10.1371/journal.pone.0286386.].

Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 µM; hBChE: IC50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 µM; IC50 (hBChE) = 0.659 ± 0.077 µM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.

IntroductionThe video head impulse test (vHIT) evaluates the vestibulo-ocular reflex (VOR). It’s usually recorded from only one eye. Newer vHIT devices allow a binocular quantification of the VOR.Purpose (Aim)To investigate the advantages of simultaneously recorded binocular vHIT (bvHIT) to detect the differences between the VOR gains of the adducting and the abducting eye, to define the most precise VOR measure, and to assess gaze dys/conjugacy. We aimed to establish normative values for bvHIT adducting/abducting eye VOR gains and to introduce the VOR dysconjugacy ratio (vorDR) between adducting and abducting eyes for bvHIT.MethodsWe enrolled 44 healthy adult participants in a cross-sectional, prospective study using a repeated-measures design to assess test–retest reliability. A binocular EyeSeeCam Sci 2 device was used to simultaneously record bvHIT from both eyes during impulsive head stimulation in the horizontal plane.ResultsPooled bvHIT retest gains of the adducting eye significantly exceeded those of the abducting eye (mean (SD): 1.08 (SD = 0.06), 0.95 (SD = 0.06), respectively). Both adduction and abduction gains showed similar variability, suggesting comparable precision and therefore equal suitability for VOR asymmetry assessment. The pooled vorDR here introduced to bvHIT was 1.13 (SD = 0.05). The test–retest repeatability coefficient was 0.06.ConclusionOur study provides normative values reflecting the conjugacy of eye movement responses to horizontal bvHIT in healthy participants. The results were similar to a previous study using the gold-standard scleral search coil, which also reported greater VOR gains in the adducting than in the abducting eye. In analogy to the analysis of saccade conjugacy, we propose the use of a novel bvHIT dysconjugacy ratio to assess dys/conjugacy of VOR-induced eye movements. In addition, to accurately assess VOR asymmetry, and to avoid directional gain preponderance between adduction and abduction VOR-induced eye movements leading to monocular vHIT bias, we recommend using a binocular ductional VOR asymmetry index that compares the VOR gains of only the abduction or only the adduction movements of both eyes.

BackgroundIn the last couple of years, viral infections have been leading the globe, considered one of the most widespread and extremely damaging health problems and one of the leading causes of mortality in the modern period. Although several viral infections are discovered, such as SARS CoV-2, Langya Henipavirus, there have only been a limited number of discoveries of possible antiviral drug, and vaccine that have even received authorization for the protection of human health. Recently, another virial infection is infecting worldwide (Monkeypox, and Smallpox), which concerns pharmacists, biochemists, doctors, and healthcare providers about another epidemic. Also, currently no specific treatment is available against Monkeypox. This research gap encouraged us to develop a new molecule to fight against monkeypox and smallpox disease. So, firstly, fifty different curcumin derivatives were collected from natural sources, which are available in the PubChem database, to determine antiviral capabilities against Monkeypox and Smallpox.Material and methodPreliminarily, the molecular docking experiment of fifty different curcumin derivatives were conducted, and the majority of the substances produced the expected binding affinities. Then, twelve curcumin derivatives were picked up for further analysis based on the maximum docking score. After that, the density functional theory (DFT) was used to determine chemical characterizations such as the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), softness, and hardness, etc.ResultsThe mentioned derivatives demonstrated docking scores greater than 6.80 kcal/mol, and the most significant binding affinity was at -8.90 kcal/mol, even though 12 molecules had higher binding scores (-8.00 kcal/mol to -8.9 kcal/mol), and better than the standard medications. The molecular dynamic simulation is described by root mean square deviation (RMSD) and root-mean-square fluctuation (RMSF), demonstrating that all the compounds might be stable in the physiological system.ConclusionIn conclusion, each derivative of curcumin has outstanding absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. Hence, we recommended the aforementioned curcumin derivatives as potential antiviral agents for the treatment of Monkeypox and Smallpox virus, and more in vivo investigations are warranted to substantiate our findings.

The main objective of the current research work was to synthesize mesoporous silica nanoparticles for controlled delivery of mometasone furoate for potential nasal delivery. The optimized sol–gel method was used for the synthesis of mesoporous silica nanoparticles. Synthesized nanoparticles were processed through Zeta sizer, SEM, TEM, FTIR, TGA, DSC, XRD, and BET analysis for structural characterization. The in vitro dissolution test was performed for the inclusion compound, while the Franz diffusion experiment was performed for permeability of formulation. For the determination of expression levels of anti-inflammatory cytokines IL-4 and IL-5, RNA extraction, reverse transcription, and polymerase chain reaction (RT-PCR) were performed. The MTT assay was also performed to determine cell viability. Synthesized and functionalized mesoporous silica nanoparticles showed controlled release of drugs. FT-IR spectroscopy confirmed the presence of the corresponding functional groups of drugs within mesoporous silica nanoparticles. Zeta sizer and thermal analysis confirmed the delivery system was in nano size and thermally stable. Moreover, a highly porous system was observed during SEM and TEM evaluation, and further it was confirmed by BET analysis. Greater cellular uptake with improved permeability characteristics was also observed. As compared to the crystalline drug, a significant improvement in the dissolution rate was observed. It was concluded that stable mesoporous silica nanoparticles with significant porosity were synthesized, efficiently delivering the loaded drug without any toxic effect.

BackgroundRivastigmine is a pseudo-irreversible cholinesterase inhibitor used for therapy of Alzheimer's disease and non-Alzheimer dementia syndromes. In humans, rivastigmine can cause significant gastrointestinal side effects that can limit its clinical use. The aim of this study was to assess the impact of rivastigmine on gastric motor function by means of electrogastrography (EGG) in experimental pigs.MethodsSix experimental adult female pigs (Sus scrofa f. domestica, hybrids of Czech White and Landrace breeds; 3-month-old; mean weight 30.7 ± 1.2 kg) were enrolled into the study twice and created two experimental groups. In group A, a single intragastric dose of 6 mg rivastigmine hydrogen tartate was administered in the morning to fasting pigs before EGG recording. In group B, rivastigmine was administered to overnight fasting animals in a dietary bolus in the morning for 7 days (6 mg per day). On day 8, an intragastric dose of 12 mg rivastigmine was given in the morning to fasting pigs before EGG. EGG recording was accomplished by means of an EGG standalone system. Recordings from both groups were evaluated in dominant frequency and EGG power (areas of amplitudes).ResultsIn total, 1,980 one-minute EGG intervals were evaluated. In group A, basal EGG power (median 1290.5; interquartile range 736.5-2330 μV2) was significantly higher in comparison with the power of intervals T6 (882; 577-1375; p = 0.001) and T10 (992.5; 385-2859; p = 0.032). In group B, the dominant frequency increased significantly from basal values (1.97 ± 1.57 cycles per minute) to intervals T9 (3.26 ± 2.16; p < 0.001) and T10 (2.14 ± 1.16; p = 0.012), respectively. In group B, basal EGG power (median 1030.5; interquartile range 549-5093) was significantly higher in comparison with the power of intervals T7 (692.5; 434-1476; p = 0.002) and T8 (799; 435-1463 μV2; p = 0.004).ConclusionsBoth single as well as repeated intragastric administration of rivastigmine hydrogen tartrate caused a significant decrease of EGG power (areas of amplitudes) in experimental pigs. EGG power may serve as an indirect indicator of gastric motor competence. These findings might provide a possible explanation of rivastigmine-associated dyspepsia in humans.

Background. The QuantiFERON®-Monitor (QFM) is an assay that measures interferon-γ production and was developed to provide an objective marker of complex immune response. In this study, we evaluated the use of the QFM test in patients with two forms of multiple sclerosis (MS), relapsing–remitting form treated with fingolimod (fMS) and secondarily progressive form not treated pharmacologically (pMS), and in healthy controls (HC). We hypothesized that IFN-γ levels would be lower in those subjects who are relatively more immunosuppressed and higher in those with normal or activated immune function. Methods. This single-center observational study was conducted from November 2020 to October 2021 and compared results in three groups of patients: 86 healthy controls, 96 patients with pMS, and 78 fMS. Combination of lyophilized stimulants was added to 1 ml heparinized whole blood within 8 hr of collection. Plasmatic IFN-γ was measured using the ELISA kit for the QFM and data were obtained in IU/ml. Results. The results showed that controls had nearly 2-fold higher levels of IFN-γ (QFM score) in median (q25, q75) 228.00 (112.20, 358.67) than the MS patient groups: pMS 144.80 (31.23, 302.00); fMS 130.50 (39.95, 217.07) which is statistically significant difference P-value: HC vs. pMS = 0.0071; HC vs. fMS = 0.0468. This result was also confirmed by a validation analysis to exclude impact of variable factors, such as disease duration and Expanded Disability Status Scale scores. Conclusions. Results showed that controls had higher levels of IFN-γ production than the MS patient groups and suggest that MS patients included in this study have a lower ability of immune system activation than HC. Results confirm that fingolimod is able to suppress production of IFN-γ. The fact that the QFM score of MS patients is significantly lower than that of HC may indicate a dysfunctional state of the immune system in baseline conditions.

To date, the most studied drug in anti-aging research is the mTOR inhibitor – rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation – inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available (4, 5, and 7) or their synthesis was feasible (1, 2, 3, and 6) and evaluated in vitro and subsequently in vivo. Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation.

Manufacturing of metal and metal oxide nanoparticles (M/MO NPs) in large quantities needed a strong reliable, sustainable, and eco-friendly protocol. Present work represents on biogenic approaches to fabricate green nanoparticles using green technology. The fabrications of M/MO NPs using natural bio-resources were engaged by means of alternative technique in place of conventional methods. These methods are naturally benign, straightforward, economical, and renewed technology; they does not content harmful chemicals, zero contaminants, and eco-friendly. The extracts from the biogenic resources are widely accepted owing to its capability to minimise and control the size and shape of metal and metal oxides NPs because of different structure directing agents, usually bioorganic phyto-chemicals. In this present review, we have summarized fabrication of different NPs like silver, gold, copper oxide, cobalt oxide, titanium oxide, cerium oxide, bismuth oxide, zinc oxide and nickel oxide nanoparticles using natural resources. The challenges, limiting factors and future directions of the bioinspired synthesis of metal/metal oxide NPs are also highlighted in this review. Moreover, biogenic materials has explored for further environmental remediation in terms of photocatalytic activity, elimination of organic waste, and antibacterial, antioxidant assay, and protein-metal complexes binding affinities by molecular docking.

Metformin is a plant-based drug belonging to the class of biguanides and is known to treat type-2 diabetes mellitus (T2DM). The drug, combined with controlling blood glucose levels, improves the body’s response to insulin. In addition, trials have identified the cardioprotective potential of metformin in the diabetic population receiving the drug. Activation of 5′ AMP-activated protein kinase (AMPK) is the major pathway for these potential beneficial effects of metformin. Historically, much emphasis has been placed on the potential indications of metformin beyond its anti-diabetic use. This review aims to appraise other potential uses of metformin primarily mediated by the activation of AMPK. We also discuss various mechanisms, other than AMPK activation, by which metformin could produce beneficial effects for different conditions. Databases including PubMed/MEDLINE and Embase were searched for literature relevant to the review’s objective. Reports from both research and review articles were considered. We found that metformin has diverse effects on the human body systems. It has been shown to exert anti-inflammatory, antioxidant, cardioprotective, metabolic, neuroprotective, anti-cancer, and antimicrobial effects and has now even been identified as effective against SARS-CoV-2. Above all, the AMPK pathway has been recognized as responsible for metformin’s efficiency and effectiveness. Owing to its extensive potential, it has the capability to become a part of treatment regimens for diseases apart from T2DM.

In recent decades, research scientists, molecular biologists, and pharmacologists have placed a strong emphasis on cutting-edge nanostructured materials technologies to increase medicine delivery to the central nervous system (CNS). The application of nanoscience for the treatment of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), brain cancer, and hemorrhage has the potential to transform care. Multiple studies have indicated that nanomaterials can be used to successfully treat CNS disorders in the case of neurodegeneration. Nanomedicine development for the cure of degenerative and inflammatory diseases of the nervous system is critical. Nanoparticles may act as a drug transporter that can precisely target sick brain sub-regions, boosting therapy success. It is important to develop strategies that can penetrate the blood–brain barrier (BBB) and improve the effectiveness of medications. One of the probable tactics is the use of different nanoscale materials. These nano-based pharmaceuticals offer low toxicity, tailored delivery, high stability, and drug loading capacity. They may also increase therapeutic effectiveness. A few examples of the many different kinds and forms of nanomaterials that have been widely employed to treat neurological diseases include quantum dots, dendrimers, metallic nanoparticles, polymeric nanoparticles, carbon nanotubes, liposomes, and micelles. These unique qualities, including sensitivity, selectivity, and ability to traverse the BBB when employed in nano-sized particles, make these nanoparticles useful for imaging studies and treatment of NDs. Multifunctional nanoparticles carrying pharmacological medications serve two purposes: they improve medication distribution while also enabling cell dynamics imaging and pharmacokinetic study. However, because of the potential for wide-ranging clinical implications, safety concerns persist, limiting any potential for translation. The evidence for using nanotechnology to create drug delivery systems that could pass across the BBB and deliver therapeutic chemicals to CNS was examined in this study.

PurposeWe aimed to assess the ability of a head-shaking test (HST) to reflect vestibular compensation in patients after unilateral peripheral vestibular loss and to provide missing evidence and new insights into the features of head-shaking-induced nystagmus (HSN) over a 2-year follow-up.BackgroundHSN may occur after a prolonged sinusoidal oscillation of the head. HSN is frequently observed in subjects with vestibular function asymmetry; it usually beats toward the functionally intact or “stronger” ear and can be followed by a reversal of its direction.Study designA prospective observational case-control study.SettingsA tertiary academic referral center.MethodsA total of 38 patients after acute unilateral vestibular loss (22 patients with vestibular neuronitis and 16 patients after vestibular neurectomy) and 28 healthy controls were followed for four consecutive visits over a 2-year period. A complex vestibular assessment was performed on all participants, which included spontaneous nystagmus (SPN), the caloric test, the head-shaking test (HST), the video head impulse test (vHIT), the Timed Up and Go (TUG) test, and the Dizziness Handicap Inventory (DHI) questionnaire. We established the criteria for the poorly compensated group to assess different compensatory behaviors and results.ResultsWe found a time-related decrease in HSN (ρ < −0.84, p < 0.001) after unilateral vestibular loss. After 2 years of follow-up, HSN intensity in compensated patients reached the level of the control group; TUG and DHI also improved to normal; however, the caloric and vHIT tests remained abnormal throughout all follow-ups, indicating a chronic vestibular deficit. Besides, poorly compensated patients had a well-detectable HSN throughout all follow-ups; TUG remained abnormal, and DHI showed at least a moderate deficit.ConclusionsOur study showed that, after a unilateral peripheral vestibular loss, the intensity of HSN decreased exponentially over time, reflecting an improvement in dynamic ability and self-perceived deficit. HSN tended to decline to the value of the control group once vestibular compensation was satisfactory and sufficient for a patient's everyday life. In contrast, well-detectable HSN in poorly compensated patients with insufficient clinical recovery confirmed the potential of HSN to reflect and distinguish between adequate and insufficient dynamic compensation. HSN could serve as an objective indicator of stable unilateral vestibular loss.

Zearalenone (ZEA) as an estrogen-like mycotoxin can cause the inflammatory injury of the cecum. How to reduce the harm that ZEA causes to humans and animals is a current concern for researchers. In this study, we aimed to ascertain whether Bacillus velezensis A2 (A2) could alleviate injury caused by ZEA by regulating the intestinal flora and the content of short chain fatty acids in the cecum among mice. Our results showed that Bacillus velezensis A2 improved the fold height, myometrial thickness, and crypt depth of the cecum induced by ZEA. Enzyme-linked immunosorbent assay and Western blotting results showed that A2 could decrease the ZEA-induced increase in expression levels of IL-2, IL-6, IFN-γ, TNF-α, and FC. Studies also showed that A2 increased the content of SCFA in the cecum which was decreased by ZEA. The microbial communities in the cecum were changed when given ZEA or A2. A2 was found to greatly reduce the ZEN-induced increase in the relative abundance of p_Actinobacteria, p_Protebacteria, o_Coriobacteriales, g_Anaerotruncus, g_Pseudoflavonifractor, g_Lachnoclostridium, g_Enterorhabdus, and f_Oscillospiraceae, and increase the ZEN-induced decrease in the relative abundance of f_Coriobacteriales. Results indicated that Bacillus velezensis A2 can largely ameliorate the intestinal inflammatory injury induced by ZEA in mice by regulating the microflora and short chain fatty acids content.

Antimicrobial peptides are an important component of many organisms’ innate immune system, with a good inhibitory or killing effect against the invading pathogens. As a type of biological polypeptide with natural immune activities, antimicrobial peptides have a broad spectrum of antibacterial, antiviral, and antitumor activities. Nevertheless, these peptides cause no harm to the organisms themselves. Compared with traditional antibiotics, antimicrobial peptides have the advantage of not producing drug resistance and have a unique antibacterial mechanism, which has attracted widespread attention. In this study, marine invertebrates were classified into arthropods, annelids, mollusks, cnidarians, and tunicata. We then analyzed the types, sources and antimicrobial activities of the antimicrobial peptides in each group. We also reviewed the immune mechanism from three aspects: membrane-targeted direct killing effects, non-membrane targeting effects and immunomodulatory effects. Finally, we discussed their applications and the existing problems facing antimicrobial peptides in actual production. The results are expected to provide theoretical support for future research and applications of antimicrobial peptides in marine invertebrates.

Abstract Background Present demographic trends show a considerable rise in elderly populations with aging disorders, such as dementia. The current article focused on the exploitation of e-learning as an informal support for caregivers of people with dementia and considered its benefits and limitations to provide proper and relevant care for this target group of people as well as maintain the quality of life of their caregivers. Methods The methodology of this study is based on a literature review of accessible peer-review articles from three recognized databases: Web of Science, Scopus, and PubMed. The findings of the selected studies were compared and evaluated. Results The findings showed that e-learning educational programs/courses helped caregivers feel more confident about dementia care, reduced their perceived stress and enhanced their feelings of empathy, understanding and concern. Conclusions The findings of this study reveal that the exploitation of e-learning as a support tool, especially for informal caregivers, in the management of dementia may be a promising method, but its implementation requires professional training of informal caregivers in the use of this technology. More evidence-based studies are needed on this topic.

Sox2 is one of the core transcription factors maintaining the embryonic stem cells (ES) pluripotency and, also indispensable for cellular reprogramming. However, limited data is available about the DNA methylation of pluripotency genes during lineage-specific differentiations. This study investigated the DNA methylation of Sox2 regulatory region 2 (SRR2) during directed differentiation of mouse ES into neural lineage. ES cells were first grown to form embryoid bodies in suspension which were then dissociated, and cultured in defined medium to promote neural differentiation. Typical neuronal morphology together with the up-regulation of Pax6, neuroepithelial stem cell intermediate filament and β-tubulin III and, down-regulation of pluripotency genes Oct4, Nanog and Sox2 showed the existence of neural phenotype in cells undergoing differentiation. Three CpGs in the core enhancer region of neural-specific SRR2 were individually investigated by direct DNA sequencing post-bisulfite treatment and, found to be unmethylated in differentiated cells at time-points chosen for analysis. This analysis does not limit the possibility of methylation at other CpG sites than those profiled here and/or transient methylation. Hence, similar analyses exploring the DNA methylation at other regions of the Sox2 gene could unravel the onset and transitions of epigenetic signatures influencing the outcome of differentiation pathways and neural development. The data presented here shows that in vitro neural differentiation of embryonic stem cells can be employed to study and characterize molecular regulatory mechanisms governing neurogenesis by applying diverse pharmacological and toxicological agents.

A core symptom that is frequently linked with dysregulation of glutamatergic neurotransmission in regard to schizophrenia is impairment or damage of executive functioning as a component of cognitive deficiency. The amino acid D-serine plays the role of an endogenous coagonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor glycine modulatory site. Considerably reduced serum levels of D-serine were found in patients suffering from schizophrenia compared with healthy control participants. An increase in D-serine led to augmented cognitive functionality in patients suffering from schizophrenia who were undergoing clinical trials and given the treatment of first- and second-generation antipsychotics. The study proposed the hypothesis that the D-serine blood serum levels may be linked with the extent of executive functionality in those suffering from the mental illness in question. For the purpose of examining executive function in such patients, the Rey–Osterrieth Complex Figure, Trail Making, and Wisconsin Card Sorting tests were applied (n = 50). High-performance liquid chromatography was used to gauge the total serine and D-serine levels. The extent of damage was examined through neuropsychological tests and was found to be considerably linked to D-serine serum level and the D-serine/total serine ratio (p < 0.05) in the sample being considered. A lower average serum level of D-serine and lower D-serine/total serine ratio were observed in participants with the worst performance compared with those displaying the best performance—this was true when the patients were split into quartile groups based on their results (p < 0.05). The findings of modified D-serine serum levels and the D-serine/total serine ratio linked to the extent of damage in executive functioning indicate that serine metabolism that is coresponsible for NMDA receptor dysfunction has been changed.

Background: Pediatric multiple sclerosis (MS) is rare: only 1.5–5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS.Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13–17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR).Results: Twenty participants [median (range) age, 17 (14–18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16–24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0–6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction (n = 20; 95% confidence interval: 66.8–92.8; p < 0.0001) vs. the year before DMF initiation.Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment.

Abstract Background The aim of our study was to compare the ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) with atropine to counteract acute sarin-induced brain damage with the efficacy of antidotal treatment involving single oxime (HI-6) and atropin using in vivo methods. Methods Brain damage and neuroprotective effects of antidotal treatment were evaluated in rats poisoned with sarin at a sublethal dose (108 μg/kg i.m.; 90% LD50) using histopathological, Fluoro-Jade B and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis 24 h after sarin administration. Results Both combinations of oximes reduce the number of rats that died before the end of experiment compared to non-treated sarin poisoning and sarin poisoning treated with HI-6 and atropine. In the case of treatment of sarin poisoning with HI-6 in combination with K203, all rats survived till the end of experiment. HI-6 with atropine was able to reduce sarin-induced brain damage, however, both combinations were slightly more effective. Conclusions The oxime HI-6 in combination with K203 and atropine seems to be the most effective. Thus, both tested oxime combinations bring a small benefit in elimination of acute sarin-induced brain damage compared to single oxime antidotal therapy.

Abstract Background Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. Methods To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). Results Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (k r) of 2142 min− 1. M− 1, which was 51 times higher than that obtained for obidoxime (k r = 42 min− 1. M− 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. Discussion According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.

Memantine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist utilized as a palliative cure for Alzheimer’s disease. This is the second study examining the memantine concentrations in cerebrospinal fluid. The previously published study enrolled six patients, and three of them were theoretically in a steady state. In our study, we enrolled 22 patients who regularly used a standard therapeutic dose of memantine (20 mg/day, oral administration) before the sample collection. Patients were divided into four groups, according to the time of plasma and cerebrospinal fluid collection: 6, 12, 18, and 24 h after memantine administration. The cerebrospinal fluid samples were also assessed for selected oxidative stress parameters (malondialdehyde, 3-nitrotyrosine, glutathione, non-protein thiols, and non-protein disulfides). The plasma/cerebrospinal fluid (CSF) ratio for all time intervals were within the range of 45.89% (6 h) to 55.60% (18 h), which corresponds with previously published findings in most patients. The other aim of our study was to deduce whether the achieved “real” memantine concentration in the central compartment was sufficient to block NMDA receptors. The IC50 value of memantine as an NMDA antagonist is in micromolar range; the lowest limit is 112 ng/ml (GluN2C), and this value was achieved only in three cases. The memantine cerebrospinal fluid concentration did not reach one quarter of the IC50 value in five cases (one patient was excluded for noncompliance); therefore, the potency of memantine as a therapeutic effect in patients may be questionable. However, it appears that memantine therapy positively affected the levels of some oxidative stress parameters, especially non-protein thiols and 3-nitrotyrosine.

The aim of this review is to summarize the effect of human intestinal microbiome on cognitive impairments and to focus primarily on the impact of diet and eating habits on learning processes. Better understanding of the microbiome could revolutionize the possibilities of therapy for many diseases. The authors performed a literature review of available studies on the research topic describing the influence of human microbiome and diet on cognitive impairment or learning processes found in the world’s acknowledged databases Web of Science, PubMed, Springer, and Scopus. The digestive tube is populated by billions of living microorganisms including viruses, bacteria, protozoa, helminths, and microscopic fungi. In adulthood, under physiological conditions, the intestinal microbiome appears to be relatively steady. However, it is not true that it would not be influenced, both in the positive sense of the word and in the negative one. The basic pillars that maintain a steady microbiome are genetics, lifestyle, diet and eating habits, geography, and age. It is reported that the gastrointestinal tract and the brain communicate with each other through several pathways and one can speak about gut-brain axis. New evidence is published every year about the association of intestinal dysbiosis and neurological/psychiatric diseases. On the other hand, specific diets and eating habits can have a positive effect on a balanced microbiota composition and thus contribute to the enhancement of cognitive functions, which are important for any learning process.

MicroRNAs (miRNAs) are small non-coding nucleic acids able to post-transcriptionally regulate gene expression by binding to complementary sequences of target messenger RNA (mRNA). It has been estimated that at least 1% of the human genome encodes miRNA and every miRNA can regulate up to 200 mRNAs. These findings suggest that dysregulation of miRNA expression could be associated with several human pathological conditions including central neurological disorders. Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia in the elderly. The characteristic symptoms are a progressive loss of memory and other cognitive functions due to the impairment of particular types of neurons and synapses, leading to neuronal death. At present, the available symptomatic treatments can only slow down disease progression without stopping it. miRNAs are widely found within the nervous system where they are key regulators of functions such as neurite outgrowth, dendritic spine morphology, neuronal differentiation, and synaptic plasticity. This has been the clue for considering miRNAs crucial molecules to be studied in AD, and nowadays, dysfunction of miRNAs in AD is increasingly recognized. In this review, we summarized existing evidence about miRNAs as biomarkers or therapeutic agents. The field of miRNAs as biomarkers is more advanced in terms of human data, and it is likely that miRNAs will be used successfully in the near future. Given the huge number of miRNAs potentially involved in diagnostics, miRNA panels will be used for specific tasks such as the stage of the disease, the risk prediction, and disease progression. The field of miRNAs as therapeutics is rapidly developing, and it offers a huge variety of solutions. These include positive effects related to beta-amyloid or tau reduction, increased number of neurons, inhibition of apoptosis, protection of synapses, transformation of other cellular elements into missing/deficient neurons in AD, and so on. It is predictable that both areas of research will be carried forward. However, given the absence of an AD therapy able to stop or reverse the disease, it is desirable to accelerate research on miRNAs as therapeutic agents.

Objective: Venous thromboembolism (VTE) is a serious multifactorial disorder. Patients with severe mental illness have a higher risk of developing the condition compared to the general population.Methods: We observed 10 cases of VTE in patients with mental illness who were treated with the antipsychotic drug olanzapine. The diagnosis of VTE was made at the University Hospital Hradec Kralove (UH HK) from 2004 to 2013. VTE was objectively determined by imaging techniques (duplex ultrasonography, CT angiography) and laboratory tests (D-dimer). The average age was 46 years. The clinical manifestation of VTE was deep vein thrombosis in nine cases, including one case of simultaneous pulmonary embolism and one case of a concurrent ischemic cerebrovascular accident (iCVA). None of our patients had a history of malignant disease, trauma, or surgery.Results: Apart from antipsychotic medication, all the patients had clinical or laboratory risk factors for VTE. The most frequent clinical risk factors were obesity (n = 7) and smoking (n = 6). The most frequent laboratory risk factors were increased levels of FVIII (n = 4), mild hyperhomocysteinemia (n = 3), and factor V Leiden mutation (n = 2). VTE developed within 3 months after antipsychotic drug initiation in three patients and within 6 months in three patients.Conclusion: Olanzapine can be considered a precipitating factor for VTE formation. When olanzapine is administered, we need to monitor for clinical signs and symptoms of VTE, especially when other risk factors are present.

Galantamine has been used as a treatment for Alzheimer disease. It has a unique, dual mode of action (inhibitor of acetylcholinesterase and allosteric modulator of nicotinic acetylcholine receptors). Nausea (in about 20%), vomiting (10%) and diarrhoea (5–7%) are the most common side effects. The aim of this study was to assess the effect of galantamine on porcine gastric myoelectric activity without (Group A) and with (Group B) dextran sodium sulphate (DSS)-induced gastrointestinal injury. Galantamine hydrobromide was administrated to twelve pigs as a single intragastric dose (24 mg). Gastric myoelectric activity was investigated by electrogastrography (EGG). Basal (15 min before galantamine administration) and study recordings after galantamine administration (300 min) were evaluated using a running spectral analysis. Results were expressed as dominant frequency of gastric slow waves and power analysis (areas of amplitudes). Altogether, 3780 one-minute EGG recordings were evaluated. In Group A, power was steady from basal values for 180 min, then gradually decreased till 270 min (p = 0.007). In Group B, there was a rapid gradual fall from basal values to those after 120 min (p = 0.007) till 300 min (p ˂ 0.001). In conclusion, galantamine alone revealed an unfavourable effect on porcine myoelectric activity assessed by gastric power. It can be a plausible explanation of galantamine-associated dyspepsia in humans. DSS caused further profound decrease of EGG power. That may indicate that underlying inflammatory, ischaemic or NSAIDs-induced condition of the intestine in humans can have aggravated the effect of galantamine on gastric myoelectric activity.

To develop a benign nanomaterial from biogenic sources, we have attempted to formulate and fabricate silver nanoparticles synthesized from the culture filtrate of an endophytic fungus Penicillium oxalicum strain LA-1 (PoAgNPs). The synthesized PoAgNPs were exclusively characterized through UV–vis absorption spectroscopy, Fourier Transform Infra-Red spectroscopy (FT-IR), X-ray powder diffraction (XRD), and Transmission Electron Microscopy (TEM) with energy dispersive X-ray spectroscopy (EDX). The synthesized nanoparticles showed strong absorbance around 430 nm with surface plasmon resonance (SPR) and exhibited a face-centered cubic crystalline nature in XRD analysis. Proteins presented in the culture filtrate acted as reducing, capping, and stabilization agents to form PoAgNPs. TEM analysis revealed the generation of polydispersed spherical PoAgNPs with an average size of 52.26 nm. The PoAgNPs showed excellent antibacterial activity against bacterial pathogens. The PoAgNPs induced a dose-dependent cytotoxic activity against human adenocarcinoma breast cancer cell lines (MDA-MB-231), and apoptotic morphological changes were observed by dual staining. Additionally, PoAgNPs demonstrated better larvicidal activity against the larvae of Culex quinquefasciatus. Moreover, the hemolytic test indicated that the as-synthesized PoAgNPs are a safe and biocompatible nanomaterial with versatile bio-applications.

Gastrointestinal side effects of donepezil, including dyspepsia, nausea, vomiting or diarrhea, occur in 20–30% of patients. The pathogenesis of these dysmotility associated disorders has not been fully clarified yet. Pharmacokinetic parameters of donepezil and its active metabolite 6-O-desmethyldonepezil were investigated in experimental pigs with and without small intestinal injury induced by dextran sodium sulfate (DSS). Morphological features of this injury were evaluated by a video capsule endoscopy. The effect of a single and repeated doses of donepezil on gastric myoelectric activity was assessed. Both DSS-induced small intestinal injury and prolonged small intestinal transit time caused higher plasma concentrations of donepezil in experimental pigs. This has an important implication for clinical practice in humans, with a need to reduce doses of the drug if an underlying gastrointestinal disease is present. Donepezil had an undesirable impact on porcine myoelectric activity. This effect was further aggravated by DSS-induced small intestinal injury. These findings can explain donepezil-associated dyspepsia in humans.

Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, still has uncertain effectiveness. Drug repurposing could be a promising strategy how to find an appropriate molecule: rapamycin could be one of them. The authors performed a systematic literature review of available studies on the research describing rapamycin in association with COVID-19 infection. Only peer-reviewed English-written articles from the world’s acknowledged databases Web of Science, PubMed, Springer and Scopus were involved. Five articles were eventually included in the final analysis. The findings indicate that rapamycin seems to be a suitable candidate for drug repurposing. In addition, it may represent a better candidate for COVID-19 therapy than commonly tested antivirals. It is also likely that its efficiency will not be reduced by the high rate of viral RNA mutation.

Background and objectives: For the treatment of chronic unilateral radicular syndrome, there are various methods including three minimally invasive computed tomography (CT)-guided methods, namely, pulsed radiofrequency (PRF), transforaminal oxygen ozone therapy (TFOOT), and transforaminal epidural steroid injection (TFESI). Despite this, it is still unclear which of these methods is the best in terms of pain reduction and disability improvement. Therefore, the purpose of this study was to evaluate the short and long-term effectiveness of these methods by measuring pain relief using the visual analogue scale (VAS) and improvement in disability (per the Oswestry disability index (ODI)) in patients with chronic unilateral radicular syndrome at L5 or S1 that do not respond to conservative treatment. Materials and Methods: After screening 692 patients, we enrolled 178 subjects, each of whom underwent one of the above CT-guided procedures. The PRF settings were as follows: pulse width = 20 ms, f = 2 Hz, U = 45 V, Z ˂ 500 Ω, and interval = 2 × 120 s. For TFOOT, an injection of 4–5 mL of an O2-O3 mixture (24 μg/mL) was administered. For the TFESI, 1 mL of a corticosteroid (betamethasone dipropionate), 3 mL of an anaesthetic (bupivacaine hydrochloride), and a 0.5 mL mixture of a non-ionic contrast agent (Iomeron 300) were administered. Pain intensity was assessed with a questionnaire. Results: The data from 178 patients (PRF, n = 57; TFOOT, n = 69; TFESI, n = 52) who submitted correctly completed questionnaires in the third month of the follow-up period were used for statistical analysis. The median pre-treatment visual analogue scale (VAS) score in all groups was six points. Immediately after treatment, the largest decrease in the median VAS score was observed in the TFESI group, with a score of 3.5 points (a decrease of 41.7%). In the PRF and TFOOT groups, the median VAS score decreased to 4 and 5 points (decreases of 33% and 16.7%, respectively). The difference in the early (immediately after) post-treatment VAS score between the TFESI and TFOOT groups was statistically significant (p = 0.0152). At the third and sixth months after treatment, the median VAS score was five points in all groups, without a statistically significant difference (p > 0.05). Additionally, there were no significant differences in the Oswestry disability index (ODI) values among the groups at any of the follow-up visits. Finally, there were no significant effects of age or body mass index (BMI) on both treatment outcomes (maximum absolute value of Spearman’s rank correlation coefficient = 0.193). Conclusions: Although the three methods are equally efficient in reducing pain over the entire follow-up, we observed that TFESI (a corticosteroid with a local anaesthetic) proved to be the most effective method for early post-treatment pain relief.

The changing climatic conditions have led to the concurrent emergence of virulent microbial pathogens that attack crop plants and exhibit yield and quality deterring impacts on the affected crop. To counteract, the widespread infections of fungal pathogens and post-harvest diseases it is highly warranted to develop sustainable techniques and tools bypassing traditional agriculture practices. Nanotechnology offers a solution to the problems in disease management in a simple lucid way. These technologies are revolutionizing the scientific/industrial sectors. Likewise, in agriculture, the nano-based tools are of great promise particularly for the development of potent formulations ensuring proper delivery of agrochemicals, nutrients, pesticides/insecticides, and even growth regulators for enhanced use efficiency. The development of novel nanocomposites for improved management of fungal diseases can mitigate the emergence of resilient and persistent fungal pathogens and the loss of crop produce due to diseases they cause. Therefore, in this review, we collectively manifest the role of nanocomposites for the management of fungal diseases.

Ethnomedicinal plants have a significant role in the lives of people of rural and tribal areas. Thousands of medicinal plant species are used to treat various diseases, including jaundice, and are considered an important therapeutic resource to minimize these diseases. Jaundice (icterus) is a chronic disease that occurs when the amount of bilirubin in the blood increases. This review describes different ethnomedicinal plants used for curing jaundice by tribal and rural people of Himachal Pradesh. The study reveals 87 ethnomedicinal plant species belonging to 51 different families, which are used for treating jaundice in Himachal Pradesh. These plants are arranged in a systematic way, which includes a description of their common name, botanical name, along with its family, plant parts used, region, and mode of use in tabulated form. Some of the plant extracts have already been explored for their phytochemical and pharmacological significance and proved their potential in the preparation of new medicines or drugs against the treatment of jaundice. This review is an attempt to highlight the indigenous knowledge of medicinal plants, which are specifically used for the treatment of jaundice. The data mentioned in the present review is compiled from various sources like existing literature, books, Google Scholar, and Scopus publications. Among all the observed plant species, most used medicinal plants for the treatment of jaundice include Justicia adhatoda, Emblica officinalis, Ricinus communis, Saccharum officinarum, Terminalia chebula, Berberis aristata, Cuscuta reflexa, and Tinospora cordifolia. Plants that are mostly utilized for the treatment of jaundice need to be scientifically validated by pharmacological analysis and should be subsequently used for the preparation of new drugs, which may prove far more beneficial than the existing one.

Treatment of wounds is essential as the wound can also be lethal at some point in time if not healed properly. Ethnomedicinal plants can treat wounds as they have no side effects, whereas, in the case of chemical drugs, the side effects are on the rise. In this study, seeds of Moringa oleifera which is the essential ethnomedicinal plant, were studied for wound healing efficacy. The study was planned for the assessment of in vitro (antioxidant and antimicrobial activities) and in vivo (excision and incision wound healing models) wound healing efficacy of n-hexane extract and hydrogels of Moringa oleifera seeds. The antioxidant and antimicrobial activities were assessed by DPPH free radical scavenging assay and Agar well diffusion method, respectively. In excision and incision wound models, Swiss albino mice were used for wound healing efficacy of hydrogels, i.e., 5% and 10% hexane extracts of Moringa oleifera seeds. The n-hexane extract showed antioxidant as well as antibacterial activities. Moreover, the hydrogels formulated using n-hexane extract of Moringa oleifera seeds showed significant wound healing activity compared to both control and standard until the end of the protocol in both the models. Furthermore, the histopathological investigation confirmed the findings of accelerated regeneration of tissue accompanied by a decrease in inflammatory cells and increased vascularity of the immediate skin. The results (both in vitro and in vivo) claimed conclusively that our n-hexane hydrogel formulation of Moringa oleifera seeds might serve as an alternative therapy in skin restoration during wound healing.

Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.

Fruit-derived bioactive substances have been spotlighted as a regulator against various diseases due to their fewer side effects compared to chemical drugs. Among the most frequently consumed fruits, apple is a rich source of nutritional molecules and contains high levels of bioactive compounds. The main structural classes of apple constituents include polyphenols, polysaccharides (pectin), phytosterols, and pentacyclic triterpenes. Also, vitamins and trace elements complete the nutritional features of apple fruit. There is now considerable scientific evidence that these bioactive substances present in apple and peel have the potential to improve human health, for example contributing to preventing cardiovascular disease, diabetes, inflammation, and cancer. This review will focus on the current knowledge of bioactive substances in apple and their medicinal value for human health.

The aim of this article is to discuss the effect of learning a non-native language on the enhancement of cognitive performance in healthy native Czech elderly. In addition, special emphasis is put on the qualitative assessment. To do this, 42 Czech cognitively unimpaired seniors were enrolled into the study. These were then divided into an experimental group (i.e., 20 healthy elderly studied English as a non-native language for three months) and a passive control group (22 healthy elderly, who did not undergo any non-native language intervention). The main outcome measures included the Montreal Cognitive Assessment, statistical processing of the data, and a qualitative content analysis. The results indicate that the cognitive performance of the intervention group did not differ from the control group. Therefore, no cognitive enhancement through non-native language learning was achieved. However, the findings of the qualitative analysis show that such non-native language learning with the peers of the same age is especially beneficial for the overall well-being of healthy seniors, especially as far as their social networks are concerned. Furthermore, participant’s subjective feelings from their self-reports indicate that foreign language learning also contributes to acquiring new English words and phrases. However, as there are very few empirical studies on this research topic, further research is needed in order to confirm or refute the present research findings on the enhancement of cognitive performance through non-native language learning in healthy seniors.

The purpose of this review study is to reveal a potential threat of one type of such widely used and freely distributed drugs, which are proton pump inhibitors that might be the cause of the onset of both dementia and depression. The authors performed a literature review of available studies on the research topic describing the adverse effect of proton pum inhibitors (PPIs) (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, dexrabeprazole, ilaprazole). For a long time, PPIs were considered to be completely safe drug substances for both short and long-term use. In recent years, there have been a few contradictory studis of absolute safety, especially in patients, who have long been using PPIs. At this time when depression and dementia are rising in the population, this is a very worrying fact that needs to be highlighted, and which needs to be carefully studied and evaluated, ideally trying to prevent it. The findings of most research studies described in this review indicate that there is a direct association between the onset of dementia and depression on one side and the long-term use of PPIs on the other.