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Candida albicansrepresents the most prevalent microbial population in mucosal and systemic infections, usually confined to severely immunocompromised people. Considering the increase of resistant strains and the demand for new antifungal drugs endowed with innovative mechanism of action, we performed a ligand-based virtual screening in order to identify new anti-Candidacompounds. Starting from a large library of natural/semisynthetic products and several published synthesized compounds, three coumarin derivatives were discoveredin silicoas new hit compounds and submitted to thein vitroassay in order to confirm their predicted biological activity. [ABSTRACT FROM PUBLISHER]

Several (thiazol-2-yl)hydrazone derivatives from 2-, 3- and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure–activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Crocus sativusL. is known in herbal medicine for the various pharmacological effects of its components, but no data are found in literature about its biological properties towardHelicobacter pylori, Plasmodiumspp.andLeishmaniaspp. In this work, the potential anti-bacterial and anti-parasitic effects of crocin and safranal, two important bioactive components inC. sativus, were explored, and also some semi-synthetic derivatives of safranal were tested in order to establish which modifications in the chemical structure could improve the biological activity. According to our promising results, we virtually screened our compounds by means of molecular modeling studies against the mainH. pylorienzymes in order to unravel their putative mechanism of action. [ABSTRACT FROM AUTHOR]

A new European telesurgical system, the Telelap Alf-x, is introduced. Its main features are individual arms, which enable free access to the patient throughout surgery, a large range of reusable surgical instruments, an open console with eye-tracking system, where the camera follows the eye and head movements of the surgeon, and the existing force feedback enables for the first time to feel the consistency of the tissues and avoid tearing of the stitches while suturing. The system combines the benefits of open surgery and endoscopy. The first clinical application, which involved 146 operations at the gynecological department of the Gemelli University Hospital in Rome, proved the safety and the surgical team's quick adaptation to the system. [ABSTRACT FROM AUTHOR]

In this study, the phytochemical profile, pharmacological and antibacterial activity of essential oil (EO) obtained from whole plant of Nepeta nervosa were investigated. The phytochemical analysis was carried out by gas chromatography-mass spectrometry (GC-MS) and about thirty-two chemical constituents were detected, accounting about 94.13% of total oil composition. From GC-MS chromatogram, the compounds like 2-Octanol (62.60%): Eucalyptol (14.68%) Nepetalactone (3.28%) and Neral (2.88%) were found in abundance. Furthermore, in-silico molecular docking of major constituents demonstrates the best structural features, which were used to elucidate the cytotoxic and antibacterial activity of the essential oils extracted from the plant. The essential oil showed good cytotoxic activity against breast cancer cell lines, MCF-7 and MDA-MB-231 with IC50 of 0.52v/v (5.0 μL/mL) and 0.87v/v (9.0 μL/mL): respectively. Moreover, the essential oils showed commendable antibacterial activity with characteristic zone of inhibition and the bacterial growth was inhibited upto minimal concentration of 4.31-7.25 μL/mL (minimum inhibitory concentration). It is noteworthy to mention that the present study revealed new bioactivities and pharmacological importance of Nepeta nervosa plant. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is a thrombocytopenic condition induced by autoimmune mechanisms and includes secondary ITP with underlying diseases such as connective tissue diseases (CTD). In recent years, it has been elucidated that the subsets of the ITP are associated with complement abnormalities but much remains unclear. To perform a literature review and identify the characteristics of complement abnormalities in ITP. PUBMED was used to collect the literature published up to June 2022 related to ITP and complement abnormalities. Primary and secondary ITP (CTD-related) were examined. Out of the collected articles, 17 were extracted. Eight articles were related to primary ITP (pITP) and 9 to CTDrelated ITP. Analysis of the literature revealed that the ITP severity was inversely correlated with serum C3, C4 levels in both ITP subgroups. In pITP, a wide range of complement abnormalities was reported, including abnormalities of initial proteins, complement regulatory proteins, or the end products. In CTD-related ITP, reported complement abnormalities were limited to the initial proteins. Activation of the early complement system, mainly through activation of C3 and its precursor protein C4, was reported for both ITPs. On the other hand, more extensive complement activation has been reported in pITP. [ABSTRACT FROM AUTHOR]

Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before and two, six and 12 weeks after the initiation of TPORA therapy. Plasma levels of complement degradation product C4d and soluble terminal complement complexes were assessed. Patients with significantly elevated baseline levels of terminal complement complexes exhibited more often an inadequate platelet response (p = .04), were exclusively subjected to rescue therapy with intravenous immunoglobulin (p = .02), and did not respond with a significant platelet count increase during the study period. C4d showed a significant (p = .01) ability to distinguish samples with significant terminal complement activation, implying engagement of the classical complement pathway. In conclusion, elevated levels of complement biomarkers were associated with a worse TPO-RA treatment response. Larger studies are needed to confirm these results. Biomarkers of complement activation may prove valuable as a prognostic tool to predict which patients that potentially could benefit from complement-inhibiting therapy in the future. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered to contribute to pathologies of AD. Therefore, we reviewed the dual inhibitors of acetylcholinesterase (AChE) and MAO-B developed in the last five years. In this review, these dual-target inhibitors were classified into six groups according to the basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine and hydrazine, and other scaffolds. Their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B were analysed and discussed, giving valuable insights for the subsequent development of AChE and MAO-B dual inhibitors. Challenges in the development of balanced and potent AChE and MAO-B dual inhibitors were noted, and corresponding solutions were provided. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a persistent neurological dysfunction, has an increasing prevalence with the aging of the world and seriously threatens the health of the elderly. Although there is currently no effective treatment for AD, researchers have not given up, and are committed to exploring the pathogenesis of AD and possible therapeutic drugs. Natural products have attracted considerable attention owing to their unique advantages. One molecule can interact with multiple AD-related targets, thus having the potential to be developed in a multi-target drug. In addition, they are amenable to structural modifications to increase interaction and decrease toxicity. Therefore, natural products and their derivatives that ameliorate pathological changes in AD should be intensively and extensively studied. This review mainly presents research on natural products and their derivatives for the treatment of AD. [ABSTRACT FROM AUTHOR]

The mitochondrial isoforms VA/VB of metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) are involved in metabolic processes, such as de novo lipogenesis and fatty acid biosynthesis. We review the drug design landscape for obtaining CA VA/VB-selective/effective inhibitors, starting from the clinical observations that CA inhibitory drugs, such as the antiepileptics topiramate and zonisamide, or the diuretic acetazolamide induce a significant weight loss. The main approaches for designing such compounds consisted in drug repurposing of already known CA inhibitors (CAIs); screening of synthetic/natural products libraries both in the classical and virtual modes, and de novo drug design using the tail approach. A number of such studies allowed the identification of lead compounds diverse from sulphonamides, such as tropolones, phenols, polyphenols, flavones, glycosides, fludarabine, lenvatinib, rufinamide, etc., for which the binding mode to the enzyme is not always well understood. Classical drug design studies of sulphonamides, sulfamates and sulfamides afforded low nanomolar mitochondrial CA-selective inhibitors, but detailed antiobesity studies were poorly performed with most of them. A breakthrough in the field may be constituted by the design of hybrids incorporating CAIs and other antiobesity chemotypes. [ABSTRACT FROM AUTHOR]

Pluteus cervinus is a mushroom species that demands a systematic study of its medicinal values. This study aims to explore the mycochemical contents of Pluteus cervinus extract, and evaluate their anti-diabetic and antioxidant potency. Twelve organic compounds were identified using Gas Chromatogram-Mass Spectroscopy(GC-MS) analysis of the methanolic extract. All the mycochemicals identified were evaluated for their drug-likeness, pharmacokinetics and bioactivity using admetSAR and molinspiration webservers. The extract was evaluated for the inhibitory effect of α-amylase and DPPH free radical scavenging ability. To further support the anti-diabetic and antioxidant characteristic, in silico molecular docking analysis was done for all the identified mycochemicals. It was found that, 2-(3,4-dimethoxyphenyl)-N-[4-(4-methoxyphenyl)-tetrahydropyran-4-ylmethyl]-acetamide, one of the compounds in the extract shares structural similarity and comparable docking binding energy with natural α-amylase inhibitor. Further, the 2-(3,4-dimethoxyphenyl)-N-[4-(4-methoxyphenyl)-tetrahydropyran-4-ylmethyl]-acetamide also showed high binding energy with Human peroxiredoxin 5 and has a structural relationship with natural antioxidants containing tetrahydropyran derivatives. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to examine the responsiveness and minimal clinically important difference of the Motor Function Measure 32-Chinese version (MFM 32-CN) in children and adolescents with Duchenne muscular dystrophy (DMD). Methods: This observational, prospective cohort study assessed changes in motor function over 12 months using the MFM 32-CN in 108 pediatric patients with DMD. Results: Moderate to high internal responsiveness was found for MFM total, D1, and D2 scores (SRM = 0.46–0.83). Sufficient external responsiveness was observed in all MFM scores, as determined by a good correlation with the Patient Global Impression of Change (PGIC) ratings (r = 0.54–0.72, p <.01). The estimated MCID values derived from different anchor-based methods ranged from 4.7 to 6.0, with a median of 5.0 points (%). Conclusion: The MFM 32-CN demonstrates sufficient internal and external responsiveness as a measure of motor function in children and adolescents with DMD. The present study established the MCID of MFM-32 in pediatric patients with DMD. [ABSTRACT FROM AUTHOR]

Obesity is a global public health concern brought on by a combination of excessive dietary intake, inactivity and genetic predisposition. Pyridopyrimidines have received considerable interest in the development of obesity and diabetes. Mannich reaction was applied on 2-thioxo-pyridopyrimidinone derivative with a variety of aromatic and heterocyclic aromatic amines and formaldehyde by grinding at 25°C in the presence of HCl to obtain 18 fused thiadiazinones and two bis-fused thiadiazinone derivatives. Additionally, in silico docking was performed to investigate the mode of actions of the 20 synthesized compounds against fat mass and obesity-associated (FTO) protein. The ligand molecules are nicely docked to the target FTO with binding energies (ΔGbind) ranging from −11.6 to −8.0 kcal/mol. Electrostatic potential map of semiempirical optimized compound 16 was performed using Gaussian 03. Interestingly, two bis-fused thiadiazinone derivatives showed marked amelioration of adiposity in the high-fat diet model especially in hepatic and adipose tissues. [ABSTRACT FROM AUTHOR]

Coagulation dysfunction is an evident factor in the clinical diagnosis and treatment of patients with coronavirus disease 2019 (COVID-19), appearing even in COVID-19 patients with normal inflammation indices. Therefore, this study aimed to analyze the characteristics of coagulation function indices in COVID-19 patients to investigate possible mechanisms through the comparison of non-severe and severe COVID-19 patients. We included 143 patients whose clinical characteristics, coagulation function, and other indices such as inflammatory factors were collected and compared based on disease severity. Activated partial thromboplastin time (APTT), D-dimer, and fibrinogen levels were evidently higher in the severe group than in the non-severe group. Among non-severe COVID-19 patients, the aforementioned indicators depicted increasing trends, but the fibrinogen level alone was higher than normal. However, in severe COVID-19 patients, values of all three indices were higher than normal. In severe COVID-19 patients, fibrinogen and D-dimer were correlated with several inflammation indices during the early stage of the disease. However, no correlation between fibrinogen and inflammatory factors was observed in non-severe COVID-19 patients at any time point. Results revealed that the hypercoagulability tendency of severe COVID-19 patients was more evident. The relationship between coagulation function and inflammatory factors showed that changes in coagulation function in severe COVID-19 patients may be related to abnormal increase in inflammatory factors at an early stage; however, in non-severe COVID-19 patients, there might be other factors leading to abnormal coagulation. Inflammatory factors were not the only cause of abnormal coagulation function in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Inorganic anions inhibit the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) generally by coordinating to the active site metal ion. Cyanate was reported as a non-coordinating CA inhibitor but those erroneous results were subsequently corrected by another group. We review the anion CA inhibitors (CAIs) in the more general context of drug design studies and the discovery of a large number of inhibitor classes and inhibition mechanisms, including zinc binders (sulphonamides and isosteres, dithiocabamates and isosteres, thiols, selenols, benzoxaboroles, ninhydrins, etc.); inhibitors anchoring to the zinc-coordinated water molecule (phenols, polyamines, sulfocoumarins, thioxocoumarins, catechols); CAIs occluding the entrance to the active site (coumarins and derivatives, lacosamide), as well as compounds that bind outside the active site. All these new chemotypes integrated with a general procedure for obtaining isoform-selective compounds (the tail approach) has resulted, through the guidance of rigorous X-ray crystallography experiments, in the development of highly selective CAIs for all human CA isoforms with many pharmacological applications. [ABSTRACT FROM AUTHOR]

Background: Chronic morphine induces physical and psychological dependence signs. Saffron (Crocus sativus L.) stigma has been shown to have anxiolytic, antidepressant, and antinociceptive properties and to alleviate naloxone-precipitated withdrawal signs.Objectives: Therefore, this study was designed to examine the effects of saffron aqueous extract on the severity of physical-psychological dependence, voluntary morphine consumption, and the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitization in morphine-dependent rats and in rats undergoing morphine withdrawal.Materials: Adult male rats were treated with morphine (10 mg/kg, sc twice daily) for 10 days. Rats received saffron extract (60 mg/kg, ip) daily, during the induction of morphine dependence and/or withdrawal. Then, rats were tested for spontaneous withdrawal signs, anxiety using the elevated plus-maze, depression using sucrose preference test, and voluntary morphine consumption using a two-bottle choice paradigm, and then challenged with morphine (1 mg/kg, ip) to evaluate of locomotor sensitization and CSF serotonin levels.Results: The results showed saffron extract during induction of morphine dependence decreased the severity of withdrawal signs (P = .05), while it had no effect on anxiety and depression-like behaviors. Saffron extract during morphine withdrawal exhibited an increase in the percentage (or ratio) of open/total arm entries (P = .017), higher levels of sucrose preference (P = .0001), a lower morphine preference ratio (P = .02) and also, a decrease in locomotor activity (P = .004) and an increase in the CSF serotonin levels (P = .041) in rats challenged to morphine.Conclusions: Saffron extract may exert a protective effect against morphine-induced behavioral sensitization in rats, probably through increasing serotonin levels. [ABSTRACT FROM AUTHOR]

Troxerutin is a natural flavonoid present abundantly in tea, coffee, olives, wheat, and a variety of fruits and vegetables. Due to its diverse pharmacological properties, this flavonoid has aroused interest for treatment of various diseases, and consequently prompted investigation into its toxicological characteristics. The aim of this study was to evaluate the genotoxic and mutagenic effects and chemoprotective activity attributed to troxerutin using human peripheral blood leukocytes (PBLs) through several well-established experimental protocols based upon different parameters. Data demonstrated that troxerutin (100 to 1000 µM) induced no marked cytotoxic effect on PBLs after 24 hr, and did not produce strand breaks and mutagenicity. Regarding chemoprevention, this flavonoid attenuated cytotoxicity, genotoxicity, and mutagenicity initiated by hydrogen peroxide (H2O2) in human PBLs. Further, troxerutin demonstrated no marked cytotoxic effect on PBLs and exerted a protective effect against oxidative stress induced by H2O2 through modulation of GSH-dependent enzymes. [ABSTRACT FROM AUTHOR]

In the current investigation, the chemical composition of the essential oils (EOs) from the stem and leaves of Acridocarpus orientalis A. Juss. were evaluated by gas chromatography (GC) and gas-chromatography-mass spectrometry (GC-MS). The main volatile constituents identified in the essential oil of stem were rich in methyl 8-pimaren-18-oate (43.8 %), octacosane (5.8 %), heptacosane (4.6 %) and hexacosane (4.1 %), methyl dehydroabietate (3.9 %) and methyl pimar-8(14)-en-18-oate (3.6 %), while tetracosane (16.6 %), heptacosane (16.4 %), docosane (13.9 %), hentriacontane (13.5 %), heneicosane (10.9 %) and α-pinene (7.7 %) were abundant in the EO of leaves. Both essential oils, screened against urease, α-glucosidase and carbonic anhydrase II (CA-II) enzyme inhibitory activities, were found active against CA-II and inactive against urease and α-glucosidase enzymes. The leaves of AO were found more active only against CA-II enzyme having IC50 values of 45.6 ± 1.0 μg/mL than stem (156.3 ± 1.5 μg/mL). The results determined that the EO of leaves could be a promising target for anti-cancer treatment. This is the first report, up to the best of the author's knowledge, on the chemical composition and CA-II activity of this essential oil. [ABSTRACT FROM AUTHOR]

In this study, a novel series of benzothiazole-thiazolylhydrazine (3a–3i) was synthesized and their structures were characterized by 1H-NMR, 13C-NMR spectrometry, and mass spectroscopy. These compounds were evaluated as inhibitors of type A and type B monoamine oxidase (MAO) enzymes. The most active compound 3b (2-((2-(2-(4-(4-Nitrophenyl)thiazol-2-yl)hydrazineylidene)-2-phenylethyl)thio)benzothiazole) showed strong inhibitory activity at hMAO-A (IC50 of 0.095 ± 0.004 µM). Furthermore, compound 3i (2-((2-(2-(4-(2,4-dichlorophenyl)thiazol-2-yl)hydrazineylidene)-2-phenylethyl)thio)benzothiazole) showed significant inhibition profile on hMAO-A with the IC50 values 0.141 ± 0.006 µM. [ABSTRACT FROM AUTHOR]

Dynamic stability of locomotion plays an important role in running injuries, particularly during trail running where ankle injuries occur frequently. Several studies have investigated dynamic stability of locomotion using wearable accelerometer measurements. However, no study has reviewed how dynamic stability of locomotion is quantified using accelerometry. Therefore, the present review aims to synthetise the methods and findings of studies investigating stability related parameters measured by accelerometry, during locomotion on various surfaces, and among asymptomatic participants. A systematic search of studies associated with locomotion was conducted. Only studies including assessment of dynamic stability parameters based on accelerometry, including at least one group of asymptomatic participants, and conditions that occur during trail running were considered relevant for this review. Consequently, all retrieved studies used a non-obstructive portable accelerometer or an inertial measurement unit. Fifteen studies used a single tri-axial accelerometer placed above the lumbar region allowing outdoor recordings. From trunk accelerations, a combination of index of cycle repeatability and signal dispersion can adequately be used to assess dynamic stability. However, as most studies included indoor conditions, studies addressing the biomechanics of trail running in outdoor conditions are warranted. [ABSTRACT FROM AUTHOR]

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid – DBMA hybrids (1–13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer's disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), β-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ1R/σ2R). After a funnel-type screening, 6,7-dimethoxychromone – DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ1R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration. [ABSTRACT FROM AUTHOR]

A new series of 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives were designed, synthesised, and evaluated to assess their inhibitory effect on the human monoamine oxidase (hMAO) A and B isoforms. Different (un)substituted (hetero)aromatic substituents were linked to N1 of the hydrazone in order to establish robust structure–activity relationships. The results of the biological testing demonstrated that the presence of the hydrazothiazole nucleus bearing at C4 a phenyl ring functionalised at the meta position with a nitro group represents an important pharmacophoric feature to obtain selective and reversible human MAO-B inhibition for the treatment of neurodegenerative disorders. In addition, the most potent and selective MAO-B inhibitors were evaluated in silico as potential cholinesterase (AChE/BuChE) inhibitors and in vitro for antioxidant activities. The results obtained from molecular modelling studies provided insight into the multiple interactions and structural requirements for the reported MAO inhibitory properties. [ABSTRACT FROM AUTHOR]

Introduction: Genetic neuromuscular diseases (NMDs) constitute a heterogeneous group of rare conditions, including some of the most disabling conditions in childhood. Recently, advanced technologies have greatly expanded preclinical and clinical research, and specific therapies have been developed. Area covered: We provide an overview of novel pharmacological approaches to the main NMDs, including Duchenne muscular dystrophy (DMD), spina muscular atrophy (SMA), X-linked myotubular myopathy, Pompe disease (PD), and myotonic dystrophy type 1, with attention to both achievements and unresolved therapeutic challenges. We conducted a selected review of relevant publications in the last five years identified through PubMed and Scopus. Additional information was derived from the website of clinicaltrials.gov and from the authors' direct knowledge of research activities. Expert Opinion: For the first time, targeted therapies have received conditional regulatory approval and have been introduced into clinical care: enzyme replacement therapy for PD, gene expression modulation for DMD and SMA, and gene therapy for SMA. Though not curative, these treatments can improve functioning and increase survival. Issues still to be addressed include: early recognition, definition of new emerging phenotypes, development of more sensitive outcome measures, long-term risk-benefit estimates, high costs sustainability, and criteria for therapy initiation and discontinuation. [ABSTRACT FROM AUTHOR]

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC50 values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles. [ABSTRACT FROM AUTHOR]

A series of 2-amino-5-nitrothiazole derived semicarbazones were designed, synthesised and investigated for MAO and ChE inhibition properties. Most of the compounds showed preferential inhibition towards MAO-B. Compound 4, (1-(1-(4-Bromophenyl)ethylidene)-4-(5-nitrothiazol-2-yl)semicarbazide) emerged as lead candidate (IC50 = 0.212 µM, SI = 331.04) against MAO-B; whereas compounds 21 1-(5-Bromo-2-oxoindolin-3-ylidene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50 = 0.264 µM) and 17 1-((4-Chlorophenyl) (phenyl)methylene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50 = 0.024 µM) emerged as lead AChE and BuChE inhibitors respectively; with activity of compound 21 almost equivalent to tacrine. Kinetic studies indicated that compound 4 exhibited competitive and reversible MAO-B inhibition while compounds 21 and 17 showed mixed-type of AChE and BuChE inhibition respectively. Docking studies revealed that these compounds were well-accommodated within MAO-B and ChE active sites through stable hydrogen bonding and/or hydrophobic interactions. This study revealed the requirement of small heteroaryl ring at amino terminal of semicarbazone template for preferential inhibition and selectivity towards MAO-B. Our results suggest that 5-nitrothiazole derived semicarbazones could be further exploited for its multi-targeted role in development of anti-neurodegenerative agents. A library of 2-amino-5-nitrothiazole derived semicarbazones (4-21) was designed, synthesised and evaluated for in vitro MAO and ChE inhibitory activity. Compounds 4, 21 and 17 (shown) have emerged as lead MAO-B (IC50:0.212 µM, competitive and reversible), AChE (IC50:0.264 µM, mixed and reversible) and BuChE (IC50:0.024 µM, mixed and reversible) inhibitor respectively. SAR studies disclosed several structural aspects significant for potency and selectivity and indicated the role of size of aryl binding site in potency and selectivity towards MAO-B. Antioxidant activity and neurotoxicity screening results further suggested their multifunctional potential for the therapy of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Mitochondria are dynamic and plastic organelles, which flexibly adapt morphology, ATP production, and metabolic function to meet extrinsic challenges and demands. Regulation of mitochondrial biogenesis is essential during development and in adult life to survive stress and pathological insults, and is achieved not only by increasing mitochondrial mass, but also by remodeling the organellar proteome, metabolome, and lipidome. In the last decade, the post-transcriptional regulation of the expression of nuclear-encoded mitochondrial proteins has emerged as a fast, flexible, and powerful mechanism to shape mitochondrial function and coordinate it with other cellular processes. At the heart of post-transcriptional responses are a number of RNA-binding proteins that specifically bind mRNAs encoding mitochondrial proteins and define their fate, by influencing transcript maturation, stability, translation, and localization. Thus, RNA-binding proteins provide a uniquely complex regulatory code that orchestrates mitochondrial function during physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

In this study, the antioxidant, carbohydrate metabolism, cholinergic, monoaminergic, and purinergic enzyme activities of ethyl acetate leaf fraction of Cnidoscolus aconitifolius were evaluated with the high-performance liquid chromatography (HPLC) analysis. The ethyl acetate fraction of the plant leaf was tested for antioxidant properties, key carbohydrate metabolism, cholinergic, monoaminergic, and purinergic enzyme activities using standard procedures, while the chemical composition of the fraction was evaluated using HPLC. The results revealed that the fraction has higher phenolic compounds than flavonoid and exhibited the ability to scavenge iron chelation and ABTS. The fraction also inhibited the activities of α-amylase and α-glucosidase, acetylcholinesterase, butyrylcholinesterase, monoamine oxidase, tyrosinase, arginase, Ecto-5'-nucleotidase, phosphodieterase-5, angiotensin-I-converting enzyme and encouraged the activity of Na+/K+-ATPase. The HPLC analysis revealed that the ethyl acetate fraction contained coumaric acid, amentoflavone, hesperidin, protocatechuic acid, kaempferol, dihydromyricetin, quercetin,and rutin. The obtained results in this study suggest that the ethyl acetate fraction obtained from aqueous extracts of Cnidoscolus aconitifolius leaf possessed outstanding antioxidative potentials. Thus, excellent enzyme inhibitory activities probably due to bioactive compounds are also observed in the leaf. [ABSTRACT FROM AUTHOR]

Introduction: In the modern antimicrobial era, the rapid spread of resistance to antibiotics and introduction of new and mutating viruses is a global concern. Combating antimicrobial resistant microbes (AMR) requires coordinated international efforts that incorporate new conventional antibiotic development as well as development of alternative drugs with antimicrobial activity, management of existing antimicrobials, and rapid detection of AMR pathogens. Areas covered: This manuscript discusses some conventional strategies to control microbial resistance. The main purpose of the manuscript is to present information on specific herbal medicines that may serve as good treatment alternatives to conventional antimicrobials for infections sensitive to conventional as well as resistant strains of microorganisms. Expert commentary: Identification of potential new antimicrobials is challenging; however, one source for potential structurally diverse and complex antimicrobials are natural products. Natural products may have advantages over other post-germ theory antimicrobials. Many antimicrobial herbal medicines possess simultaneous antibacterial, antifungal, antiprotozoal and/or antiviral properties. Herbal products have the potential to boost host resistance to infections, particularly in immunocompromised patients. Antimicrobial broad-spectrum activity in conjunction with immunostimulatory properties may help to prevent microbial resistance to herbal medicine. As part of the efforts to broaden use of herbal medicines to treat microbial infections, pre-clinical and clinical testing guidelines of these compounds as a whole should be implemented to ensure consistency in formulation, efficacy and safety. [ABSTRACT FROM AUTHOR]

A one-pot, three-component protocol for the synthesis of novel five-membered thiazole ring bonded to two hydrazone motifs is described. The acid-catalyzed reaction of one equivalent of thiocarbohydrazide, two equivalents of aromatic aldehydes, and one equivalent of phenacyl bromides afforded the five-membered thiazole ring. The reactions proceed with novel chemoselectivity. Similar reported protocols have always afforded 1,3,4-thiadiazines. [ABSTRACT FROM AUTHOR]

Objectives: Treatment with allergy immunotherapy improves allergic rhinoconjunctivitis, but can also improve comorbidities associated with allergic rhinitis such as asthma. Sublingual immunotherapy (SLIT)-tablets are a convenient and efficacious method of allergy immunotherapy. They are self-administered after the first tablet has been provided under medical supervision. Therapy may elicit local reactions or, rarely, systemic allergic reactions. The objective of this report is to inform healthcare practitioners about the safety and tolerability profile of SLIT-tablets and use this information to provide practical guidance that may inform patients regarding potential adverse reactions and how to manage them.Methods: Pooled analyses of safety data from completed randomized, multicenter, double-blind, placebo-controlled phase 2 and phase 3 US and EU trials of timothy grass, short ragweed, and SQ house dust mite SLIT-tablets were conducted to characterize safety and tolerability.Results: SLIT-tablets are generally well tolerated. No life-threatening events, serious systemic allergic reactions, or events that compromised the airway have been reported. The most common treatment-related adverse events (AEs) are oral site reactions, most of which begin on day 1 of treatment, recur for less than 2 weeks, and resolve after approximately 30-60 minutes. Systemic allergic reactions have been managed with conventional pharmacotherapy. Reactions treated with epinephrine are uncommon, but have been reported. Treatment of AEs, treatment discontinuation considerations, and patient FAQs regarding SLIT-tablet safety/tolerability are discussed.Conclusions: This report gives healthcare providers valuable information to educate patients regarding what to expect in terms of SLIT-tablet safety and tolerability. Practical guidance is also provided to ensure proper treatment of any adverse reactions. [ABSTRACT FROM AUTHOR]

This paper reports the MEPS-HPLC-DAD method for the simultaneous determination of 12 azole drugs (bifonazole, butoconazole, clotrimazole, econazole, itraconazole, ketoconazole, miconazole, posaconazole, ravuconazole, terconazole, tioconazole and voriconazole) administered to treat different systemic and topical fungal infections, in biological samples. Azole drugs separation was performed in 36 min. The analytical method was validated in the ranges as follows: 0.02–5 μg mL−1for ravuconazole; 0.2–5 μg mL−1for terconazole; 0.05–5 μg mL−1for the other compounds. Human plasma and urine were used as biological samples during the analysis, while benzyl-4-hydroxybenzoate was used as an internal standard. The precision (RSD%) and trueness (Bias%) values fulfill with International Guidelines requirements. To the best of our knowledge, this is the first HPLC-DAD procedure coupled to MEPS, which provides the simultaneous analysis of 12 azole drugs, available in the market, in human plasma and urine. Moreover, the method was successfully applied for the quantitative determination of two model drugs (itraconazole and miconazole) after oral administration in real samples. [ABSTRACT FROM PUBLISHER]

Goji (Lycium barbarumL.) leaves are emphasized as a functional tea or as dietary supplements. The phenolic compound profile, antioxidant, enzyme inhibitory, antimicrobial, and antimutagenic activities of leaf extracts from two selected cultivars in comparison with wild-growing plants have been evaluated. HPLC-DAD/ESI-ToF-MS analysis revealed the presence of phenolic acids and flavonoids with chlorogenic acid and rutin being the dominant compounds in the cultivated plants, whereas rutin and kaempeferol-3-O-rutinoside for wild growing ones. In particular, cv. Erma contained the highest amount of chlorogenic acid and showed a strong tyrosinase-inhibitory effect.Staphylococcus aureus,Listeria monocytogenes, andPenicillium funiculosumwere the most sensitive strains when exposed to extracts from cultivated plants. Antimutagenic activity was evaluated by Ames' test. The tested extracts provided high protection against mutagenicity induced by 2-anthramine (2-AA) toSalmonella typhimuriumstrains TA 98 and TA 100 (max. inhibition (%) 88% and 74.2%, respectively). Overall, Goji leaves are a rich source of bioactive compounds with functional properties that need further risk/benefit evaluation when used in foods or health-promoting formulations. [ABSTRACT FROM AUTHOR]

A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesizedN-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range withKis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors. [ABSTRACT FROM PUBLISHER]

A series ofN,N-dimethylcarbamates containing aN,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds4and8, showed 85 and 69% of inhibition at 50 μM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound4produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound4and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound4. Instead, compound4could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain. [ABSTRACT FROM PUBLISHER]

The multi-component fingerprint and the biological evaluation of plant-derived material are indispensable for the pharmaceutical field, in food quality control procedures, and in all plant-based products. We investigated the quantitative content of biologically active compounds (anthocyanins and chlorogenic acid) of microwave-assisted blueberry extracts from 14 different Italian cultivars, using validated high-performance liquid chromatography-photodiode array detector (HPLC-PDA) method and routinely instrument configuration. The carbonic anhydrase (CA, EC 4.2.1.1) inhibition profiles against several pharmacologically relevant CA isoforms of blueberry extracts and some bioactive compounds were also investigated. The various cultivars showed a highly variable content in anthocyanins and chlorogenic acid, and their CA inhibitory effects were also highly variable. Overall these data prove that antioxidant natural products found in blueberries may be useful for designing pharmacological agents in which various CAs are involved, e.g., antiobesity, antitumor, or anticonvulsants agents. [ABSTRACT FROM PUBLISHER]

The multicomponent pattern and biological characterization of plant material are essential for pharmaceutical field, in the food supplements quality control procedures and to all plant-based products. These nutrients often show valuable effects related to their consumption due to the occurrence of secondary metabolites that show useful properties on health. In this framework, researches performed on this topic play a central role for human health and drug development process. The aim of this study was to compare phenolics and free anthraquinones multicomponent pattern of two wild Turkish species:Asphodeline anatolicaandPotentilla speciosausing validated high-performance liquid chromatography–photogiode array (HPLC–PDA) assays, coupled to biological evaluation. Even if some variances related to biological and enzymatic inhibition activities can be ascribed to other phytochemicals, the reported data support traditional use ofAsphodeline anatolicaandPotentilla speciosaroots as valuable natural font for the development of novel natural-derived drug formulations and/or food supplements with health and nutritional benefits. [ABSTRACT FROM AUTHOR]

There is considerable interest in alternative approaches to inhibitHelicobacter pylori(H. pylori) and thus treat many stomach diseases. Propolis is a pharmaceutical mixture containing many natural bioactive substances. The aim of this study was to use propolis samples to treatH. pylori. The anti-H. pyloriand anti-urease activities of 15 different ethanolic propolis extracts (EPEs) were tested. The total phenolic contents and total flavonoid contents of the EPE were also measured. The agar-well diffusion assay was carried out onH. pyloristrain J99 and the inhibition zones were measured and compared with standards. All propolis extracts showed high inhibition ofH. pyloriJ99, with inhibition diameters ranging from 31.0 to 47.0 mm.Helicobacter pyloriurease inhibitory activity was measured using the phenol-hypochlorite assay; all EPEs showed significant inhibition against the enzyme, with inhibition concentrations (IC50; mg/mL) ranging from 0.260 to 1.525 mg/mL. The degree of inhibition was related to the phenolic content of the EPE. In conclusion, propolis extract was found to be a good inhibitor that can be used inH. pyloritreatment to improve human health. [ABSTRACT FROM AUTHOR]

The limited arsenal of synthetic antifungal agents and the emergence of resistantCandidastrains have prompted the researchers towards the investigation of naturally occurring compounds or their semisynthetic derivatives in order to propose new innovative hit compounds or new antifungal combinations endowed with reduced toxicity. We explored the anti-Candidaeffects, for the first time, of two bioactive compounds fromCrocus sativusstigmas, namely crocin 1 and safranal, and some semisynthetic derivatives of safranal obtaining promising biological results in terms of minimum inhibitory concentration/minimum fungicidal concentration (MIC/MFC) values, synergism and reduction in the germ tube formation. Safranal and its thiosemicarbazone derivative5were shown to display good activity againstCandidaspp. [ABSTRACT FROM AUTHOR]

A novel separate robotic system for minimally invasive surgery (MIS) has been presented in this paper. Control system architectures were designed, basing on versatile performance criteria. The compact control and mechanical structure were suitable for medical environment. Function and safety design satisfying medical application were integrated into the robot system as well. Additionally, intuitive control algorithm solved the problems of hand-eye incoordination and workspace mismatch between master hands and slave arms during the master–slave control process. A series of experiments have been accomplished to evaluate the performance of the robotic system at last. The results demonstrated that the robotic system was capable of executing surgical operation intuitively and implementing auxiliary functions perfectly, which meant that the control system was feasible and reliable. [ABSTRACT FROM PUBLISHER]

At present, much of the research conducted worldwide focuses on extending the ability of surgical robots. One approach is to extend robotic dexterity. For instance, accessibility and dexterity of the surgical instruments remains the largest issue for reduced port surgery such as single port surgery or natural orifice surgery. To solve this problem, a great deal of research is currently conducted in the field of robotics. Enhancing the surgeon's perception is an approach that uses advanced sensor technology. The real-time data acquired through the robotic system combined with the data stored in the robot (such as the robot's location) provide a major advantage. This paper aims at introducing state-of-the-art products and pre-market products in this technological advancement, namely the robotic challenge in extending dexterity and hopefully providing the path to robotic surgery in the near future. [ABSTRACT FROM AUTHOR]

Over the last 20 years, studies and clinical trials have demonstrated efficacy, safety and cost–effectiveness of sublingual immunotherapy (SLIT) for respiratory allergic diseases. Nevertheless, it seems to be mostly used as a second-line therapeutic option, and adherence to treatment is not always optimal. Selective literature research was done in Medline and PubMed, including guidelines, position papers and Cochrane meta-analyses concerning SLIT in adult patients. The most recent reviews confirm SLIT as viable and efficacious treatment especially for allergic rhinitis, even if the optimal dosage, duration, schedule are not clearly established for most of the products. Despite an optimal safety profile, tolerability and patient-reported outcomes concerning SLIT have received poor attention until now. Recently, new tools have been specifically developed in order to investigate these aspects. Regular assessment of tolerability profile and SLIT-related patient-reported outcomes will allow balancing efficacy with tolerability and all the other patient-related variables that may affect treatment effectiveness beyond its efficacy. [ABSTRACT FROM PUBLISHER]