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The most common form of dementia, Alzheimer's disease (AD), is characterized by gradual declines in cognitive abilities and behavior. It is caused by a combination of factors, including amyloid-β (Aβ) accumulation, acetylcholine (ACh) loss, oxidative stress, and inflammation. Phenolic compounds have a variety of health benefits, including antioxidant activities. Thus, the purpose of this study was to investigate how resveratrol (RES) alone and in combination with vitamin E affected rats with AD using scopolamine (SCO). Animals are categorized into groups; (i) control, (ii) SCO (1 mg/kg i.p.), (iii) SCO + donepezil, (iv) SCO + RES (50 mg/kg, p.o.), (v) SCO + RES (75 mg/kg, p.o.), (vi) SCO + RES (50 mg/kg + vitamin E 1 mg/kg, p.o.) for 17 days. In rats, studied behavioural (NOR and EPM) and biochemical characteristics. In addition, brain histopathology was examined to investigate any damage to the hippocampus and neuroprotection. SCO-induced changes in acetylcholinesterase, protein carbonyl, and TNF-α improved after resveratrol treatment. RES increased antioxidant levels, decreased SCO-induced lipid peroxidation, and reversed SCO-mediated changes compared with the drug donepezil. The results indicated that RES and vitamin E had nootropic action in the NOR and EPM tests, measured by the recognition index and the inflection ratio. This study supports the efficacy of RES as a preventive and treatment agent for AD. Vitamin E showed a synergistic effect on RES, which helps in managing cognitive impairment AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Foudah, Devi, Alam, Salkini and Ross.)

Adenanthera pavonina L. has been used traditionally to relieve inflammation. This study aimed to expand the phytochemical knowledge of A. pavonina and evaluate its constituents for their antioxidant and anti-inflammatory potentials as tumor necrosis factor alpha (TNF-α) inhibitors. The antioxidant activity was evaluated using the DPPH radical scavenging assay, and the inhibition of TNF-α was assessed through ELISA and qRT-PCR techniques. Interestingly, five previously undescribed metabolites, including a pentadienoic acid derivative, a triterpenoid glycoside, and three tamarixetin glycosides, were identified alongside seven known compounds. Most compounds evaluated had higher DPPH radical scavenging capabilities than the standard, trolox. Tamarixetin 3- O -( α -ʟ-rhamnopyranosyl)-(1→2)- β -ᴅ-galactopyranoside ( 11 ), a previously undescribed compound, was the most effective at suppressing TNF-α protein and m-RNA levels. Other flavonoid glycosides, quercetin 3- O -( α -ʟ-rhamnopyranosyl-(1→2)- β -ᴅ-xylopyranoside ( 4 ), isovitixin ( 5 ), and quercetin-3- O -[ α -ʟ-rhamnopyranosyl-(1→2)]-[ α -ʟ-rhamnopyranosyl-(1→6)]- β -ᴅ-galactopyranoside ( 9 ), also significantly lowered TNF-α production.

Bioassay-guided fractionation technique of roots of Paeonia officinalis led to isolation and structure elucidation of seven known compounds, including four monoterpene glycosides: lactiflorin ( 1 ), paeoniflorin ( 4 ), galloyl paeoniflorin ( 5 ), and ( Z )-(1 S ,5 R )- β -pinen-10-yl β -vicianoside ( 7 ); two phenolics: benzoic acid ( 2 ) and methyl gallate ( 3 ); and one sterol glycoside: β -sitosterol 3- O - β -D-glucopyranoside ( 6 ). The different fractions and the isolated compounds were evaluated for their antimicrobial and antimalarial activities. Fraction II and III showed antifungal activity against Candida neoformans with IC 50 values of 28.11 and 74.37 µg/mL, respectively, compared with the standard fluconazole (IC 50 = 4.68 µg/mL), and antibacterial potential against Pseudomonas aeruginosa (IC 50 = 20.27 and 24.82 µg/mL, respectively) and Klebsiella pneumoniae (IC 50 = 43.21 and 94.4 µg/mL, respectively), compared with the standard meropenem (IC 50 = 28.67 and 43.94 µg/mL, respectively). Compounds 3 and 5 showed antimalarial activity against Plasmodium falciparum D6 with IC 50 values of 1.57 and 4.72 µg/mL and P. falciparum W2 with IC 50 values of 0.61 and 2.91 µg/mL, respectively, compared with the standard chloroquine (IC 50 = 0.026 and 0.14 µg/mL, respectively).

Medicines, their safety, effectiveness and quality are indispensable factors of national security, important on a global scale. The COVID-19 pandemic has once again emphasized the importance of improving the immune response of the body in the face of severe viral infections. Plants from the Salvia L. genus have long been used in traditional medicine for treatment of inflammatory processes, parasitic diseases, bacterial and viral infections. The aim of the current study was to evaluate the immunomodulatory effects of plant extracts LS-1, LS-2 from Salvia deserta Schang. and LS-3, LS-4 from Salvia sclarea L. plants growing in southern Kazakhstan by conventional and ultrasonic-assisted extraction, respectively. The cytotoxic effects of the named sage extracts on neonatal human dermal fibroblasts (HDFn) were evaluated using the MTT assay. Immunomodulatory effects of the studied extracts were compared by examining their influence on pro-inflammatory cytokine secretion and phagocytic activity of murine immune cells. Depending on the physiological state of the innate immune cells, sage extracts LS-2 and LS-3 had either a stimulating effect on inactivated macrophages or suppressed cytokine-producing activity in LPS-activated macrophages. The greatest increase in TNF-α secretion was found after treatment of spleen T lymphocytes with sage extract LS-2, obtained by ultrasonic-assisted extraction.

Berberine (BBR) is a pentacyclic benzylisoquinoline alkaloid that can be found in diversity of medicinal plants. BBR has a wide range of pharmacological bioactivities, in addition when administrated orally, it has a broad safety margin. It has been used as an antidiarrheal, antimicrobial, and anti-diabetic drug in Ayurvedic and Chinese medicine. Several scholars have found that BBR has promising renoprotective effects against different renal illnesses, including diabetic nephropathy, renal fibrosis, renal ischemia, renal aging, and renal stones. Also, it has renoprotective effects against nephrotoxicity induced by chemotherapy, heavy metal, aminoglycosides, NSAID, and others. These effects imply that BBR has an evolving therapeutic potential against acute renal failure and chronic renal diseases. Hence, we report herein the beneficial therapeutic renoprotective properties of BBR, as well as the highlighted molecular mechanism. In conclusion, the studies discussed throughout this review will afford a comprehensive overview about renoprotective effect of BBR and its therapeutic impact on different renal diseases., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Methicillin-resistant Staphylococcus aureus (MRSA) is a foremost treatment challenge in today's clinical practice. Natural coumarins contain a variety of bioactivities and have the ability to alter resistance in several ways. In developing effective drug delivery methods, the goal is to maximize biocompatibility while minimizing toxicity. With this in mind, this work investigated the site-specific potential of dendrimer G4 poloxamer nanoparticles loaded with bioactive coumarin. The goal of the current work is to deliver a complete evaluation of dendrimer G4 poloxamer nanoparticles against MRSA. Coumarin-loaded dendrimer G4 poloxamer nanoparticles were thoroughly investigated and characterized using various techniques, including particle size, shape, entrapment efficiency, in vitro drug release, hemolysis assay, cytotoxicity, antibacterial activity, and bactericidal kinetics. Studies showed that the newly developed dendrimer G4 poloxamer nanoparticles exhibited significantly lower levels of hemolysis and cytotoxicity. The results showed that the in vitro drug release of coumarin from dendrimer G4 poloxamer nanoparticles was slower compared to coumarin in its free form. This innovative therapeutic delivery technology may enhance the defense of coumarin against MRSA., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Congenital cytomegalovirus (cCMV) infection is the leading non-genetic cause of long-term neurological and sensory sequelae, the most common being sensorineural hearing loss (SNHL). Standard therapy for infants with symptomatic cCMV is valganciclovir for six months. However, little is known about the effects of antiviral therapy on CMV diversity while patients are on treatment. In this study, CMV variation was analyzed from urine specimens isolated from two patients with cCMV shortly after birth and at seven months. One was treated with valganciclovir for six weeks and the other for six months. In order to track these variants a novel bioinformatic approach was employed to analyze changes in low frequency variants over time. In the infant receiving antivirals for only six weeks, there was a fourfold increase in variation in UL97 from the seven month specimen. Furthermore, an eightfold increase in variation was seen in UL83 (pp65) with seven potential escape mutations occurring, and a twofold increase in UL73 (gN). In contrast variation did not increase or was reduced in these coding regions in the infant receiving valganciclovir for six months. However, there were increases in other CMV regions in samples isolated from both patients indicating further longitudinal studies are warranted to better understand the interplay between CMV diversity, antiviral therapy and patient outcome., (Published by Elsevier B.V.)

Background: Through the systematic large-scale profiling of metabolites, metabolomics provides a tool for biomarker discovery and improving disease monitoring, diagnosis, prognosis, and treatment response, as well as for delineating disease mechanisms and etiology. As a downstream product of the genome and epigenome, transcriptome, and proteome activity, the metabolome can be considered as being the most proximal correlate to the phenotype. Integration of metabolomics data with other -omics data in multi-omics analyses has the potential to advance understanding of human disease development and treatment., Aim of Review: To understand the current funding and potential research opportunities for when metabolomics is used in human multi-omics studies, we cross-sectionally evaluated National Institutes of Health (NIH)-funded grants to examine the use of metabolomics data when collected with at least one other -omics data type. First, we aimed to determine what types of multi-omics studies included metabolomics data collection. Then, we looked at those multi-omics studies to examine how often grants employed an integrative analysis approach using metabolomics data., Key Scientific Concepts of Review: We observed that the majority of NIH-funded multi-omics studies that include metabolomics data performed integration, but to a limited extent, with integration primarily incorporating only one other -omics data type. Some opportunities to improve data integration may include increasing confidence in metabolite identification, as well as addressing variability between -omics approach requirements and -omics data incompatibility., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Vitamin E acetate, which is used as a diluent of tetrahydrocannabinol (THC), has been reported as the primary causative agent of e-cigarette, or vaping, product use-associated lung injury (EVALI). Here, we employ in vitro assays, docking, and molecular dynamics (MD) computer simulations to investigate the interaction of vitamin E with the membrane-bound cannabinoid 2 receptor (CB2R), and its role in modulating the binding affinity of THC to CB2R. From the MD simulations, we determined that vitamin E interacts with both CB2R and membrane phospholipids. Notably, the synchronized effect of these interactions likely facilitates vitamin E acting as a lipid modulator for the cannabinoid system. Furthermore, MD simulation and trajectory analysis show that when THC binds to CB2R in the presence of vitamin E, the binding cavity widens, facilitating the entry of water molecules into it, leading to a reduced interaction of THC with CB2R. Additionally, the interaction between THC and vitamin E in solution is stabilized by several H bonds, which can directly limit the interaction of free THCs with CB2R. Overall, both the MD simulations and the in vitro dissociation assay results indicate that THC binding to CB2R is reduced in the presence of vitamin E. Our study discusses the role of vitamin E in limiting the effect of THCs and its implications on the reported pathology of EVALI.

A meta-analysis was conducted to examine the effect of supplementing mannan oligosaccharide (MOS; Bio-Mos, Alltech Inc., Nicholasville, KY) in the diets of laying hens on the performance and environmental impact of egg production. Data on production performance (feed intake, hen-day production [HDP], feed conversion ratio [FCR], and mortality) and egg quality attributes (egg weight, egg mass, and eggshell thickness) were extracted from 18 studies to build a database of comparisons between nonsupplemented diets (control) and diets supplemented with MOS. A total of 4,664 laying hens were involved in the comparisons and the average MOS dosage and age of hens were 0.97 kg/ton and 44 wk, respectively. The dataset was analyzed using the random-effects model to estimate the effect size of MOS supplementation on production performance and egg quality attributes. The impact of feeding MOS on the carbon footprint (feed and total emission intensities) of egg production was evaluated by using the meta-analysis results of production performance to develop a scenario simulation that was analyzed by a life cycle assessment (LCA) model. Overall pooled effect size (raw mean difference) indicated that MOS supplementation did not affect feed intake. In contrast, HDP increased by +1.76% and, FCR and mortality reduced by -26.64 g feed/kg egg and -2.39%, respectively. Dietary MOS did not influence egg weight while egg mass increased (P < 0.01) by +0.95 g/day/hen and eggshell thickness tended to increase (P = 0.07) by +0.05 mm. Subgroup analysis indicated that dietary MOS exhibited consistent improvement on HDP and FCR under several study factors (age of hens, number of hens, production challenges, MOS dosage, and study duration). Additionally, the simulated LCA revealed that supplementing MOS decreased feed and total emission intensities of egg production by -1.3 and -1.5%, respectively. Overall, dietary supplementation of MOS at 1.0 kg/ton improved the production performance of laying hens and reduced the carbon footprint and, therefore, can enhance the sustainability credentials of egg production., Competing Interests: DISCLOSURES The authors (S.A.S, A.P, C.A.M, and J.T-P) are employees of Alltech Inc., the company which produces and markets Bio-Mos, the commercial mannan oligosaccharide product evaluated in this study. This does not alter our adherence to publishing policies on sharing data and materials., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Thymoquinone (TQ) is a naturally derived bioactive compound with several therapeutic effects., Objective: The highly sensitive, rapid and green normal-phase (NP)/reversed-phase (RP) high-performance thin-layer chromatography (HPTLC) densitometry technique was developed for the determination of TQ in various plant extracts of different geographical regions, commercial capsules, creams and essential oils., Methodology: The NP densitometry estimation of TQ was performed using a cyclohexane-ethyl acetate (90:10, v/v) green solvent system, while, the RP-densitometry estimation of TQ was performed using an ethanol-water (80:20, v/v) green solvent system. The estimation of TQ was conducted at 259 nm., Results: The NP and RP densitometry techniques were observed linear in the range of 25-1000 and 50-600 ng/band, respectively. All validation parameters such as accuracy, precision, robustness and sensitivity of NP/RP densitometry were observed within the limit of regulatory requirements and hence found to be suitable for the determination of TQ. The TQ contents were found to be highest in the Saudi Arabian extract followed by the Syrian extract, Indian extract, commercial capsules, commercial creams, Jordanian extract, Egyptian extract, Palestinian extract and commercial essential oils using NP densitometry. The TQ contents were found in same order using RP densitometry, but they were much lower than those recorded using NP densitometry. The Analytical GREEnness (AGREE) scores of NP and RP densitometry were found to be 0.82 and 0.84, respectively, suggesting an excellent greenness profile., Conclusions: Based on these results, NP/RP densitometry was found to be suitable for the pharmaceutical assay of TQ., (© 2021 John Wiley & Sons, Ltd.)

In our ongoing effort to investigate active specialised metabolites from genus Glandularia, phytochemical studies on the ethanolic extract of Glandularia × hybrida (Groenl. & Rümpler) G.L. Nesom & Pruski leaves resulted in the isolation of three undescribed compounds, a dibenzylbutyrolactolic lignan and two echinocystic acid based triterpenoid saponins, in addition to two known compounds. Interestingly, this study reports isolation of chemo-systematically valuable specialised metabolites for the first time from the genus under investigation. Additionally, the isolated metabolites were evaluated for their iNOS inhibition and cytotoxic activities using a combination of in silico and in vitro studies. The pharmacokinetics properties (ADMET) of some of the isolated compounds were determined using pkCSM-pharmacokinetics server. Molecular docking analysis showed that saponin compound possesses higher negative score (-9.59 kcal/mol) than the lignan compound (-6.56 kcal/mol). The isolated compounds also showed iNOS inhibition activity with IC 50 values ranging between 6.6 and 49.7 μM and significant cytotoxic activity against a series of cell lines including SK-MEL, KB, BT-549, SK-OV-3, LLC-PK1 and VERO cells. Hence, this study reveals that specialised metabolites from G. hybrida plant are of significant anti-inflammatory and cytotoxicity potentials., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The herbal plant Petroselinum crispum ( P. crispum ) (Mill) is commonly available around the world. In this study, the leaves of the herbal plant P. crispum were collected from the central region of Al-Kharj, Saudi Arabia, to explore their in vitro pharmacological activity. Essential oil from the leaves of P. crispum was isolated using the hydrodistillation method. The composition of P. crispum essential oil (PCEO) was determined using Gas chromatography-mass spectrometry (GC-MS). A total of 67 components were identified, representing approximately 96.02% of the total volatile composition. Myristicin was identified as the principal constituent (41.45%). The in vitro biological activity was assessed to evaluate the antioxidant, antimicrobial, and anti-inflammatory potential of PCEO. PCEO showed the highest antimicrobial activity against Candida albicans and Staphylococcus aureus among all the evaluated microbial species. In vitro anti-inflammatory evaluation using albumin and trypsin assays showed the excellent anti-inflammatory potential of PCEO compared to the standard drugs. An in silico study of the primary PCEO compound was conducted using online tools such as PASS, Swiss ADME, and Molecular docking. In silico PASS prediction results supported our in vitro findings. Swiss ADME revealed the drug likeness and safety properties of the major metabolites present in PCEO. Molecular docking results were obtained by studying the interaction of Myristicin with an antifungal (PDB: 1IYL and 3LD6), antibacterial (PDB: 1AJ6 and 1JIJ), antioxidant (PDB: 3NM8 and 1HD2), and anti-inflammatory (3N8Y and 3LN1) receptors supported the in vitro results. Therefore, PCEO or Myristicin might be valuable for developing anti-inflammatory and antimicrobial drugs.

Cerebral palsy results from an upper motor neuron lesion and significantly affects skeletal muscle stiffness. The increased stiffness that occurs is partly a result of changes in the microstructural components of muscle. In particular, alterations in extracellular matrix, sarcomere length, fibre diameter, and fat content have been reported; however, experimental studies have shown wide variability in the degree of alteration. Many studies have reported changes in the extracellular matrix, while others have reported no differences. A consistent finding is increased sarcomere length in cerebral palsy affected muscle. Often many components are altered simultaneously, making it difficult to determine the individual effects on muscle stiffness. In this study, we use a three dimensional modelling approach to isolate individual effects of microstructural alterations typically occurring due to cerebral palsy on whole muscle behaviour; in particular, the effects of extracellular matrix volume fraction, stiffness, and sarcomere length. Causation between the changes to the microstructure and the overall muscle response is difficult to determine experimentally, since components of muscle cannot be manipulated individually; however, utilising a modelling approach allows greater control over each factor. We find that extracellular matrix volume fraction has the largest effect on whole muscle stiffness and mitigates effects from sarcomere length., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Konno, Nigam, Wakeling and Ross.)

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [ 3 H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q , as potent and selective CB2 ligands with sub-micromolar activities ( K i = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.

Purpose: Producing a steady cadence and power while cycling results in fairly consistent average pedal forces for every revolution, although small fluctuations about an average force do occur. This force can be generated by several combinations of muscles, each with slight fluctuations in excitation for every pedal cycle. Fluctuations such as these are commonly thought of as random variation about average values. However, research into fluctuations of stride length and stride time during walking shows information can be contained in the order of fluctuations. This order, or structure, is thought to reveal underlying motor control strategies. Previously, we found persistent structure in the fluctuations of EMG signals during cycling using entropic half-life analysis. These EMG signals contained fluctuations across multiple timescales, such as those within a burst of excitation, between the burst and quiescent period of a cycle, and across multiple cycles. It was not clear which sources of variation contributed to the persistent structure in the EMG., Methods: In this study, we manipulated variation at different timescales in EMG intensity signals to identify the sources of structure observed during cycling. Nine participants cycled at a constant power and cadence for 30 min while EMG was collected from six muscles of the leg., Results: We found persistent structure across multiple pedal cycles of average EMG intensities, as well as average pedal forces and durations. In addition, we found the entropic half-life did not quantify fluctuations within a burst of EMG intensity; instead, it detected unstructured variation between the burst and quiescent period within a cycle., Conclusions: The persistent structure in average EMG intensities suggests that fluctuations in muscle excitation are regulated from cycle to cycle., (Copyright © 2021 by the American College of Sports Medicine.)

An investigation of the secondary metabolites was carried out on Thymelaea hirsuta collected from Lampedusa, the largest island of the Pelagie archipelago, located about 100 km from the North African coast and 200 km from the coast of Sicily. Ten compounds were isolated and found to belong to different classes of natural products as chromenes, cyclohexanones, furanyl, bis-furanyl and furanone polyphenols, and acrylates. Compounds 7 , 8 , 9 and 10 were slightly phytotoxic to lettuce reaching phytotoxicity of 1 ( 7 , 8 and 9 ) and 2 ( 10 ) using a 1-5 point scale. None of the compounds were active against Agrostis stolonifera L., a perennial grass of the Poaceae family. Tested against three Colletotrichum species ( C. acutatum , C. fragarie and C. gloeosporioides ) pathogenic for agricultural plants, only compound 6 had activity against all three species, but it was not as active as captan, the commercial fungicide used as a positive control.

While skeletal muscle mass has been shown to decrease mass-specific mechanical work per cycle, it is not yet known how muscle mass alters contraction efficiency. In this study, we examined the effect of muscle mass on mass-specific metabolic cost and efficiency during cyclic contractions in simulated muscles of different sizes. We additionally explored how tendon and its stiffness alters the effects of muscle mass on mass-specific work, mass-specific metabolic cost and efficiency across different muscle sizes. To examine contraction efficiency, we estimated the metabolic cost of the cycles using established cost models. We found that for motor contractions in which the muscle was primarily active during shortening, greater muscle mass resulted in lower contraction efficiency, primarily due to lower mass-specific mechanical work per cycle. The addition of a tendon in series with the mass-enhanced muscle model improved the mass-specific work and efficiency per cycle with greater mass for motor contractions, particularly with a shorter excitation duty cycle, despite higher predicted metabolic cost. The results of this study indicate that muscle mass is an important determinant of whole muscle contraction efficiency.

Simple isoquinoline alkaloids (heliamine, dehydroheliamine), a phthalide isoquinoline alkaloid noscapine, and an aporphine alkaloid boldine are biosynthetically derived from an amino acid tyrosine. These substrates and a simple synthetic isoquinoline alkaloid (2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline) contain an isoquinoline nucleus. The biotransformation of these substrates via reduction, oxidation, hydroxylation, and N-oxidation reactions with different microorganism produced nine metabolites, namely: N-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl) acetamide (Metabolite 1), heliamine N-oxide (Metabolite 2), 6,7-dimethoxyisoquinoline (Metabolite 3), 3,4-dihydro-6,7-dimethoxy isoquinolin-1-one (Metabolite 4), heliamine (Metabolite 5), dehydroheliamine N-oxide (Metabolite 6), cotarnine (Metabolite 7), 5-hydroxy cotarnine (Metabolite 8), and boldine N-oxide (Metabolite 9). Primarily, the metabolites are structurally elucidated by one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses, and high-resolution electrospray ionization mass spectrometry (HR-ESIMS). Furthermore, the substrates and their isolated metabolites are evaluated in vitro for their anti-inflammatory, antimicrobial, cytotoxicity, and anticancer activities. The in vitro studies reveal that some of the isolated compounds are potential as anti-inflammatory, antitumor, and antimicrobial leads., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Congenital cytomegalovirus (cCMV) infection is a leading cause of hearing loss and neurological disabilities in children worldwide. Although a minority of infants with cCMV will have symptoms at a birth, these children are at high risk of long-term sequelae. Most infants with cCMV have no clinical signs at birth (asymptomatic), but 10-15% will develop hearing loss. The diagnosis of cCMV relies on detection of the virus from urine or saliva within the first three weeks of life, with saliva PCR being the preferred method due to ease of collection and high sensitivity of the assay. Measures to prevent mother-to-child transmission of CMV are limited, and antiviral therapy with valganciclovir for 6 months is the standard of care for infants with symptomatic cCMV. As more infants with cCMV are being identified through newborn screening, studies are urgently needed to address antiviral treatment in asymptomatic infants and the implementation of prevention strategies to prevent fetal infection. This article is part of the symposium "New drugs and vaccines for DNA virus infections: a symposium in memory of Mark Prichard.", (Copyright © 2021 Elsevier B.V. All rights reserved.)

Phytochemical investigation of Callistemon citrinus (Curtis) Skeels (syn. Callistemon lanceolatus (Sm.) Sweet and Melaleuca citrina (Curtis) Dum.Cours.) leaves resulted in the isolation of five undescribed compounds, including one acylphloroglucinol derivative and four monoterpene galloylglucosides, in addition to 29 known diverse secondary metabolites. Interestingly, this study reports chemosystematically significant isolation of the monoterpene galloylglucosides from the genus for the first time. Furthermore, exploration of the isolated compounds as inhibitors of inflammation-related molecular targets, molecular docking studies targeting human adipocyte lipid-binding protein FABP4 (3P6H) and human nitric oxide synthase (3E7G) were carried out in order with the in vitro evaluation of the isolated compounds for their anti-microbial and inhibitory of inducible nitric oxide synthase (iNOS) activities. Molecular docking studies revealed that eighteen compounds showed lower docking scores than ibuprofen, the native ligand in the crystal structure 3P6H, and nine compounds showed lower docking scores than AR-C95791, the native ligand in the binding site of 3E7G. Additionally, in vitro studies revealed that seven compounds showed moderate iNOS inhibitory activity. They also were moderately cytotoxic to HepG2, LLC-PK 1 and Vero cells. Pulverulentone A showed moderate antibacterial activity against MRSA (IC 50 22.2 μM) and antifungal activity against C. neoformans, while corosolic acid showed strong antibacterial activity against VRE (IC 50 15.9 μM).Thus, the in silico and in vitro studies indicated that some isolated compounds hold potentials as inhibitors of iNOS activity and anti-microbial agents., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding.

Mirabilis multiflora is an acclaimed hallucinogen consumed traditionally by the Hopi Indians to induce diagnostic visions. Its root extract afforded a new ( 3 ) and four known ( 2 , 5 , 6 , and 7 ) 12a-hydroxyrotenoids, a known rotenoid ( 4 ), and two known secondary metabolites ( 1 and 8 ). The structures of the compounds were elucidated based on spectroscopic and spectrometric data analysis. Electronic circular dichroism data were used to define the (6a S ,12a R ) absolute configuration of the 12a-hydroxyrotenoids. Compounds 2 - 7 were screened for their radioligand binding affinities toward the opioid (δ, κ, and μ) and cannabinoid (CB1 and CB2) receptor subtypes. The 6-methoxy-substituted rotenoids 3 , 4 , and 7 showed the highest receptor binding affinity with moderate selectivity toward the δ-opioid receptor subtype, with negligible binding affinities for CB1 and CB2. Their binding affinities toward the δ-opioid receptor were 64.5% ( 4 ), 58.7% ( 7 ), and 55.3% ( 3 ) at 10 μM, respectively.

The taste of drug substances plays a key role in the development of paediatric formulations with suitable organoleptic properties. The aim of the study was to evaluate the taste masking effectiveness of Smartseal 30D and ReadyMix on a range of bitter drug substances such as diphenhydramine HCl (DPD), ibuprofen lysine (IBU-LS), and phenylephrine HCl (PPH) for the development of paediatric dosage forms. The drugs were microencapsulated in the polymer carriers at 10-20% loadings using spray-drying processing. Spray drying of drug formulations was optimized in terms of percent yield and encapsulation efficiency followed by physicochemical characterization in order to identify the drugs' physical state in the polymer microparticles. The in vivo taste masking efficiency was evaluated using human test panel and showed noticeable reduction of drug's bitterness at all loadings in comparison to the bulk substances.

During muscle contraction, chemical energy is converted to mechanical energy when ATP is hydrolysed during cross-bridge cycling. This mechanical energy is then distributed and stored in the tissue as the muscle deforms or is used to perform external work. We previously showed how energy is distributed through contracting muscle during fixed-end contractions; however, it is not clear how the distribution of tissue energy is altered by the kinetic energy of muscle mass during dynamic contractions. In this study we conducted simulations of a 3D continuum muscle model that accounts for tissue mass, as well as force-velocity effects, in which the muscle underwent sinusoidal work-loop contractions coupled with bursts of excitation. We found that increasing muscle size, and therefore mass, increased the kinetic energy per unit volume of the muscle. In addition to greater relative kinetic energy per cycle, relatively more energy was also stored in the aponeurosis, and less was stored in the base material, which represented the intra and extracellular tissue components apart from the myofibrils. These energy changes in larger muscles due to greater mass were associated lower mass-specific mechanical work output per cycle, and this reduction in mass-specific work was greatest for smaller initial pennation angles. When we compared the effects of mass on the model tissue behaviour to that of in situ muscle with added mass during comparable work-loop trials, we found that greater mass led to lower maximum and higher minimum acceleration in the longitudinal ( x ) direction near the middle of the muscle compared to at the non-fixed end, which indicates that greater mass contributes to tissue non-uniformity in whole muscle. These comparable results for the simulated and in situ muscle also show that this modelling framework behaves in ways that are consistent with experimental muscle. Overall, the results of this study highlight that muscle mass is an important determinant of whole muscle behaviour., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ross, Domínguez, Nigam and Wakeling.)

A wide range of analytical techniques are reported for the determination of cinnamaldehyde (CCHO) and eugenol (EOH) in plant extracts and herbal formulations either alone or in combination. Nevertheless, sustainable/green analytical techniques for the estimation of CCHO and EOH either alone or in combination are scarce in the literature. Accordingly, the present research was carried out to establish a rapid, highly sensitive, and sustainable high-performance thin-layer chromatography (HPTLC) technique for the simultaneous estimation of CCHO and EOH in the traditional and ultrasound-assisted methanolic extracts of Cinnamomum zeylanicum, C. burmannii , and C. cassia and their essential oils. The simultaneous estimation of CCHO and EOH was performed through NP-18 silica gel 60 F254S HPTLC plates. The cyclohexane/ethyl acetate (90:10, v v -1 ) solvent system was optimized as the mobile phase for the simultaneous estimation of CCHO and EOH. The greenness score of the HPTLC technique was predicted using AGREE software. The entire analysis was carried out at a detection wavelength of 296 nm for CCHO and EOH. The sustainable HPTLC technique was observed as linear in the range 10-2000 ng band -1 for CCHO and EOH. The proposed technique was found to be highly sensitive, rapid, accurate, precise, and robust for the simultaneous estimation of CCHO and EOH. The content of CCHO in traditional methanolic extracts of C. zeylanicum, C. burmannii , and C. cassia was found to be 96.36, 118.49, and 114.18 mg g -1 , respectively. However, the content of CCHO in ultrasound-assisted methanolic extracts of C. zeylanicum, C. burmannii , and C. cassia was found to be 111.57, 134.39, and 129.07 mg g -1 , respectively. The content of CCHO in essential oils of C. zeylanicum, C. burmannii , and C. cassia was found to be 191.20, 214.24, and 202.09 mg g -1 , respectively. The content of EOH in traditional methanolic extracts of C. zeylanicum, C. burmannii , and C. cassia was found to be 73.38, 165.41, and 109.10 mg g -1 , respectively. However, the content of EOH in ultrasound-assisted methanolic extracts of C. zeylanicum, C. burmannii , and C. cassia was found to be 87.20, 218.09, and 121.85 mg g -1 , respectively. The content of EOH in essential oils of C. zeylanicum, C. burmannii , and C. cassia was found to be 61.26, 79.21, and 69.02 mg g -1 , respectively. The amounts of CCHO and EOH were found to be significantly higher in ultrasound-assisted extracts of all species compared to its traditional extraction and hence ultrasound extraction has been proposed as a superior technique for the extraction of CCHO and EOH. The AGREE analytical score of the present analytical technique was predicted as 0.75, suggesting excellent greenness profile of the proposed analytical technique. Based on all these observations and results, the proposed sustainable HPTLC technique can be successfully used for the simultaneous estimation of CCHO and EOH in different plant extracts and herbal products.

The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions.

Selective factor Xa inhibitors effectively block coagulation cascade with a broader therapeutic window than multitargeted anticoagulants. They have evolved as a crucial part of prevention and treatment of thromboembolic diseases and in therapeutic protocols involved in many clinical trials in coronavirus disease 2019 (COVID-19) patients. Biologically-guided isolation of specific FXa inhibitors from licorice ( Glycyrrhiza glabra ) root extract furnished ten flavonoids. By detailed analysis of their 1 H, 13 C NMR and MS data, the structures of these flavonoids were established as 7,4'-dihydroxyflavone (1), formononetin (2), 3- R -glabridin (3), isoliquiritigenin (4), liquiritin (5), naringenin 5- O -glucoside (6), 3,3',4,4'-tetrahydroxy-2-methoxychalcone (7), liquiritinapioside (8) and the two isomers isoliquiritigenin-4'- O -β-d-apiosylglucoside (9) and isoliquiritigenin-4- O -β-d-apiosylglucoside (10). All the isolated compounds were assessed for their FXa inhibitory activity using in vitro chromogenic assay for the first time. Liquirtin (5) showed the most potent inhibitory effects with an IC 50 of 5.15 μM. The QikProp module was implemented to perform ADMET predictions for the screened compounds., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The metabolism of papaverine, the opium benzylisoquinoline alkaloid, with Aspergillus niger NRRL 322, Beauveria bassiana NRRL 22864, Cunninghamella echinulate ATCC 18968 and Cunninghamella echinulate ATCC 1382 has resulted in O-demethylation, O-methylglucosylation and N-oxidation products. Two new metabolites (4″-O-methyl-β-D-glucopyranosyl) 4'-demethyl papaverine and (4″-O-methyl-β-D-glucopyranosyl) 6-demethyl papaverine, (Metabolites 5 and 6) together with 4'-O-demethylated papaverine (Metabolite 1), 3'-O-demethylated papaverine (Metabolite 2), 6-O-demethylated papaverine (Metabolite 3) and papaverine N-oxide (Metabolite 4) were isolated. The structure elucidation of the metabolites was based primarily on 1D, 2D-NMR analyses and HRMS. These metabolism results were consistent with the previous plant cell transformation studies on papaverine and isopapaverine and the microbial metabolism of papaveraldine. In silico docking studies of the metabolites using crystals of human phosphodiesterase 10a (hPDE10a) revealed that compounds 4, 1, 6, 3, and 5 possess better docking scores and binding poses with favorable interactions than the native ligand papaverine., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Newly designed pyrrolo[2,1-c][1,4]benzodiazepines tricyclic skeleton has shown potential clusters of cannabinoid receptors CB1/CB2 selective ligands. CB2 plays a critical role in microglial-derived neuroinflammation, where it modulates cell proliferation, migration, and differentiation into M1 or M2 phenotypes. Beginning with computer-based docking studies accounting the recently discovered X-ray crystal structure of CB2, we designed a series of PBD analogs as potential ligands of CB2 and tested their binding affinities. Interestingly, computational studies and theoretical binding affinities of several selected ( S , E )-11-[2-(arylmethylene)hydrazono]-PBD analogs, have revealed the presence of potential selectivity in binding attraction towards CB1 and CB2. Reported here is the discovery of the first representatives of this series of selective binding to CB2. Preliminary data showed that this class of molecules display potential binding efficacy towards the cannabinoid receptors tested. Intriguingly, initial cannabinoid binding assay showed a selective binding affinity of 4g and 4h showed K i of 0.49 and 4.7 μM towards CB2 receptors while no binding was observed to CB1. The designed leads have shown remarkable stability pattern at the physiological pH magnifying their therapeutic values. We hypothesize that the PBD tricyclic structure offers the molecule an appropriate three-dimensional conformation to fit snugly within the active site of CB2 receptors, giving them superiority over the reported CB2 agonists/inverse agonists. Our findings suggested that the attachment of heterocyclic ring through the condensation of diazepine hydrazone and S- or N-heterocyclic aldehydes enhances the selectivity of CB2 over CB1., Competing Interests: Conflict of Interest Authors declare no conflict of interest.

In the present study, urine samples were collected from healthy human volunteers to determine the metabolic fates of phenolic compounds and glucosinolates after a single meal of kale and daikon radish. The major glucosinolates and phenolic compounds in kale and daikon radish were measured. The urinary metabolome after feeding at different time periods was investigated. A targeted metabolite analysis method was developed based on the known metabolic pathways for glucosinolates and phenolic compounds. Using a targeted approach, a total of 18 metabolites were found in urine: 4 from phenolic compounds and 14 from glucosinolates. Among these metabolites, 4-methylsulfinyl-3-butenyl isothiocyanate, 4-methylsulfinyl-3-butenyl isothiocyanate-cysteine, and 4-methylsulfinyl-3-butenylglucosinolate- N -acetyl cysteine were reported for the first time in human urine. The combination of non-targeted and targeted metabolomic approaches can gain a full metabolite profile for human dietary intervention studies.

In this study we examined how the strain energies within a muscle are related to changes in longitudinal force when the muscle is exposed to an external transverse load. We implemented a three-dimensional (3D) finite element model of contracting muscle using the principle of minimum total energy and allowing the redistribution of energy through different strain energy-densities. This allowed us to determine the importance of the strain energy-densities to the transverse forces developed by the muscle. We ran a series of in silica experiments on muscle blocks varying in initial pennation angle, muscle length, and external transverse load. As muscle contracts it maintains a near constant volume. As such, any changes in muscle length are balanced by deformations in the transverse directions such as muscle thickness or muscle width. Muscle develops transverse forces as it expands. In many situations external forces act to counteract these transverse forces and the muscle responds to external transverse loads while both passive and active. The muscle blocks used in our simulations decreased in thickness and pennation angle when passively compressed and pushed back on the load when they were activated. Activation of the compressed muscle blocks led either to an increase or decrease in muscle thickness depending on whether the initial pennation angle was less than or greater than 15°, respectively. Furthermore, the strain energy increased and redistributed across the different strain-energy potentials during contraction. The volumetric strain energy-density varied with muscle length and pennation angle and was reduced with greater transverse load for most initial muscle lengths and pennation angles. External transverse load reduced the longitudinal muscle force for initial pennation angles of β 0 = 0°. Whereas for pennate muscle (β 0 > 0°) longitudinal force changed (increase or decrease) depending on the muscle length, pennation angle and the direction of the external load relative to the muscle fibres. For muscle blocks with initial pennation angles β 0 ≤ 20° the reduction in longitudinal muscle force coincided with a reduction in volumetric strain energy-density., (Copyright © 2020 Ryan, Domínguez, Ross, Nigam and Wakeling.)

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas., (Published by Oxford University Press on behalf of the American Society for Nutrition 2020.)

Background: Patients and clinicians can choose from several treatment options to address acute pain from non-low back, musculoskeletal injuries., Purpose: To assess the comparative effectiveness of outpatient treatments for acute pain from non-low back, musculoskeletal injuries by performing a network meta-analysis of randomized clinical trials (RCTs)., Data Sources: MEDLINE, EMBASE, CINAHL, PEDro (Physiotherapy Evidence Database), and Cochrane Central Register of Controlled Trials to 2 January 2020., Study Selection: Pairs of reviewers independently identified interventional RCTs that enrolled patients presenting with pain of up to 4 weeks' duration from non-low back, musculoskeletal injuries., Data Extraction: Pairs of reviewers independently extracted data. Certainty of evidence was evaluated by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach., Data Synthesis: The 207 eligible studies included 32 959 participants and evaluated 45 therapies. Ninety-nine trials (48%) enrolled populations with diverse musculoskeletal injuries, 59 (29%) included patients with sprains, 13 (6%) with whiplash, and 11 (5%) with muscle strains; the remaining trials included various injuries ranging from nonsurgical fractures to contusions. Topical nonsteroidal anti-inflammatory agents (NSAIDs) proved to have the greatest net benefit, followed by oral NSAIDs and acetaminophen with or without diclofenac. Effects of these agents on pain were modest (around 1 cm on a 10-cm visual analogue scale, approximating the minimal important difference). Regarding opioids, compared with placebo, acetaminophen plus an opioid improved intermediate pain (1 to 7 days) but not immediate pain (≤2 hours), tramadol was ineffective, and opioids increased the risk for gastrointestinal and neurologic harms (all moderate-certainty evidence)., Limitations: Only English-language studies were included. The number of head-to-head comparisons was limited., Conclusion: Topical NSAIDs, followed by oral NSAIDs and acetaminophen with or without diclofenac, showed the most convincing and attractive benefit-harm ratio for patients with acute pain from non-low back, musculoskeletal injuries. No opioid achieved benefit greater than that of NSAIDs, and opioids caused the most harms., Primary Funding Source: National Safety Council. (PROSPERO: CRD42018094412).

Most of what we know about whole muscle behaviour comes from experiments on single fibres or small muscles that are scaled up in size without considering the effects of the additional muscle mass. Previous modelling studies have shown that tissue inertia acts to slow the rate of force development and maximum velocity of muscle during shortening contractions and decreases the work and power per cycle during cyclic contractions; however, these results have not yet been confirmed by experiments on living tissue. Therefore, in this study we conducted in situ work-loop experiments on rat plantaris muscle to determine the effects of increasing the mass of muscle on mechanical work during cyclic contractions. We additionally simulated these experimental contractions using a mass-enhanced Hill-type model to validate our previous modelling work. We found that greater added mass resulted in lower mechanical work per cycle relative to the unloaded trials in which no mass was added to the muscle ( P =0.041 for both 85 and 123% increases in muscle mass). We additionally found that greater strain resulted in lower work per cycle relative to unloaded trials at the same strain to control for length change and velocity effects on the work output, possibly due to greater accelerations of the muscle mass at higher strains. These results confirm that tissue mass reduces muscle mechanical work at larger muscle sizes, and that this effect is likely amplified for lower activations., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Introduction: Preclinical studies suggest that brassica vegetable diets decrease cancer risk, but epidemiological studies show varied effects, resulting in uncertainty about any health impact of brassicas. Factors controlling absorption of glucosinolate metabolites may relate to inconsistent results. We reported previously that subjects with BMI > 26 kg/m 2 (HiBMI), given cooked broccoli plus raw daikon radish (as a source of plant myrosinase) daily for 17 days, had lower glucosinolate metabolite absorption than subjects given a single broccoli meal. This difference was not seen in subjects with BMI < 26 kg/m 2 (LoBMI). Our objective in this current study was to determine whether a similar response occurred when cooked broccoli was consumed without a source of plant myrosinase. Methods: In a randomized crossover study ( n = 18), subjects consumed no broccoli for 16 days or the same diet with 200 g of cooked broccoli daily for 15 days and 100 g of broccoli on day 16. On day 17, all subjects consumed 200 g of cooked broccoli. Plasma and urine were collected for 24 h and analyzed for glucosinolate metabolites by LC-MS. Results: There was no effect of diet alone or interaction of diet with BMI. However, absorption doubled in HiBMI subjects (AUC 219%, plasma mass of metabolites 202% compared to values for LoBMI subjects) and time to peak plasma metabolite values and 24-h urinary metabolites also increased, to 127 and 177% of LoBMI values, respectively. Conclusion: BMI impacts absorption and metabolism of glucosinolates from cooked broccoli, and this association must be further elucidated for more efficacious dietary recommendations. Clinical Trial Registration: This trial was registered at clinicaltrials.gov (NCT03013465)., (Copyright © 2020 Charron, Vinyard, Jeffery, Ross, Seifried and Novotny.)

During contraction the energy of muscle tissue increases due to energy from the hydrolysis of ATP. This energy is distributed across the tissue as strain-energy potentials in the contractile elements, strain-energy potential from the 3D deformation of the base-material tissue (containing cellular and extracellular matrix effects), energy related to changes in the muscle's nearly incompressible volume and external work done at the muscle surface. Thus, energy is redistributed through the muscle's tissue as it contracts, with only a component of this energy being used to do mechanical work and develop forces in the muscle's longitudinal direction. Understanding how the strain-energy potentials are redistributed through the muscle tissue will help enlighten why the mechanical performance of whole muscle in its longitudinal direction does not match the performance that would be expected from the contractile elements alone. Here we demonstrate these physical effects using a 3D muscle model based on the finite element method. The tissue deformations within contracting muscle are large, and so the mechanics of contraction were explained using the principles of continuum mechanics for large deformations. We present simulations of a contracting medial gastrocnemius muscle, showing tissue deformations that mirror observations from magnetic resonance imaging. This paper tracks the redistribution of strain-energy potentials through the muscle tissue during fixed-end contractions, and shows how fibre shortening, pennation angle, transverse bulging and anisotropy in the stress and strain of the muscle tissue are all related to the interaction between the material properties of the muscle and the action of the contractile elements., (Copyright © 2020 Wakeling, Ross, Ryan, Bolsterlee, Konno, Domínguez and Nigam.)

Various analytical methodologies have been reported for the determination of 6-shogaol (6-SHO) and 6-gingerol (6-GIN) in ginger extracts and commercial formulations. However, green analytical methods for the determination of 6-SHO and 6-GIN, either alone or in combination, have not yet been reported in literature. Hence, the present study was aimed to develop a rapid, simple, and cheaper green reversed phase high-performance thin-layer chromatography (RP-HPTLC) densitometry method for the simultaneous determination of 6-SHO and 6-GIN in the traditional and ultrasonication-assisted extracts of ginger rhizome, commercial ginger powder, commercial capsules, and commercial ginger teas. The simultaneous analysis of 6-SHO and 6-GIN was carried out via RP-18 silica gel 60 F254S HPTLC plates. The mixture of green solvents, i.e., ethanol:water (6.5:3.5 v/v ) was utilized as a mobile phase for the simultaneous analysis of 6-SHO and 6-GIN. The analysis of 6-SHO and 6-GIN was performed at λ max = 200 nm for 6-SHO and 6-GIN. The densitograms of 6-SHO and 6-GIN from traditional and ultrasonication-assisted extracts of ginger rhizome, commercial ginger powder, commercial capsules, and commercial ginger teas were verified by obtaining their single band at R f = 0.36 ± 0.01 for 6-SHO and R f = 0.53 ± 0.01 for 6-GIN, compared to standard 6-SHO and 6-GIN. The green RP-HPTLC method was found to be linear, in the range of 100-700 ng/band with R 2 = 0.9988 for 6-SHO and 50-600 ng/band with R 2 = 0.9995 for 6-GIN. In addition, the method was recorded as "accurate, precise, robust and sensitive" for the simultaneous quantification of 6-SHO and 6-GIN in traditional and ultrasonication-assisted extracts of ginger rhizome, commercial ginger powder, commercial capsules, and commercial ginger teas. The amount of 6-SHO in traditional extracts of ginger rhizome, commercial ginger powder, commercial capsules, and commercial ginger teas was obtained as 12.1, 17.9, 10.5, and 9.6 mg/g of extract, respectively. However, the amount of 6-SHO in ultrasonication-assisted extracts of ginger rhizome, commercial ginger powder, commercial capsules, and commercial ginger teas were obtained as 14.6, 19.7, 11.6, and 10.7 mg/g of extract, respectively. The amount of 6-GIN in traditional extracts of ginger rhizome, commercial ginger powder, commercial capsules, and commercial ginger teas were found as 10.2, 15.1, 7.3, and 6.9 mg/g of extract, respectively. However, the amount of 6-GIN in ultrasonication-assisted extracts of ginger rhizome, commercial ginger powder, commercial capsules, and commercial ginger teas were obtained as 12.7, 17.8, 8.8, and 7.9 mg/g of extract, respectively. Overall, the results of this study indicated that the proposed analytical technique could be effectively used for the simultaneous quantification of 6-SHO and 6-GIN in a wide range of plant extracts and commercial formulations.

Phytochemical investigation of the ethanolic extract of Glandularia x hybrida roots resulted in the isolation and identification of five previously undescribed saponins, 3-O-β-ᴅ-xylopyranosyl-hederagenin-28-O-β-ᴅ-glucopyranosyl (1→2)-O-β-ᴅ-glucopyranosyl ester, 3-O-β-ᴅ-xylopyranosyl-hederagenin-28-O-β-ᴅ-glucopyranosyl (1→2)-[β-ᴅ-glucopyranosyl (1→6)]-β-ᴅ-glucopyranosyl ester, hederagenin-28-O-β-ᴅ-glucopyranosyl (1→2)-[β-ᴅ-glucopyranosyl (1→6)]-β-ᴅ-glucopyranosyl ester, 23-O-acetyl-3-O-β-ᴅ-xylopyranosyl-pomolic acid-28-O-β-ᴅ-glucopyranosyl ester, and 23-O-acetyl-pomolic acid-3-O-β-ᴅ-xylopyranoside, along with eleven structurally diverse compounds. The structural characterizations of the isolated compounds were determined using physical data, comprehensive 1D and 2D NMR spectral analysis, and HRESIMS. All isolated saponins are hederagenin or pomolic acid glycosides conjugated with differentiable sugar units bound to C-3 and/or C-28 of the aglycone through ether and/or ester glycosidic linkages, respectively. Structural diversity of these isolated secondary metabolites would have a great impact on the future chemosystematic studies of this plant. Four saponins, obtained in good yield were evaluated for their anti-inflammatory activities in a rat model using the carrageenan-induced paw edema protocol. Two of these exhibited significant anti-inflammatory activities demonstrated through inhibition of the paw edema by 64 and 60%., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Interindividual variability and sexual dimorphisms in the development of nonalcoholic fatty liver disease (NAFLD) are still poorly understood. In the present study, male and female strains of Collaborative Cross (CC) mice were fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks to investigate interindividual- and sex-specific variations in the development of NAFLD. The severity of liver steatosis varied between sexes and individual strains and was accompanied by an elevation of serum markers of insulin resistance, including increases in total cholesterol, low-density lipoproteins, high-density lipoproteins, phospholipids, and glucose. The development of NAFLD was associated with overexpression of the critical fatty acid uptake and de novo lipogenesis genes Pparg, Mogat1, Cd36, Acaab1, Fabp2, and Gdf15 in male and female mice. The expression of Pparg, Mogat1, and Cd36 was positively correlated with liver triglycerides in male mice, and Mogat1 and Cd36 expression were positively correlated with liver triglycerides in female mice. Our results indicate the value of CC mice in combination with HF/HS diet-induced alterations as an approach to study the susceptibility and interindividual variabilities in the pathogenesis of nonalcoholic fatty liver and early nonalcoholic steatohepatitis at the population level, uncovering of susceptible and resistant cohorts, and identifying sex-specific molecular determinants of disease susceptibility., (© 2020 Federation of American Societies for Experimental Biology.)

Monoamine oxidase inhibition is an important therapeutic approach for various neurodegenerative disorders. Reversible MAO inhibitors selectively targeting only one isoform possess substantial merit in terms of safety, efficacy, and side effect profile. This study aimed to isolate the secondary metabolites of Zanthoxylum flavum stems and evaluate their recombinant human MAO inhibition, antimicrobial, and antiprotozoal activities. As a result, fourteen compounds were isolated and identified (nine of them were reported from Z. flavum for the first time). Compound 3 (sesamin) exhibited potent selective MAO-B inhibition (IC 50 value of 1.45 ± 0.05  µM) which reported herein for the first time. Compound 2 showed selective MAO-A inhibition activity, compound 5 exhibited good trypanocidal activity, and compound 7 displayed moderate antibacterial activity. The promising MAO-B inhibitory activity of sesamin provoked us to further explore the kinetic properties, the binding mode, and the underlying mechanism of MAO-B inhibition by this lignan. This detailed investigation substantiated a reversible binding and mixed MAO-B catalytic function inhibition via sesamin (K i : 0.473 ± 0.076 μM). Selectivity and reversibility of sesamin on MAO-B provide exciting prerequisites for further in vivo investigation to confirm its therapeutic potentiality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Eleven diarylpentanoid/norlignan glucosides, along with five other specialized metabolites, were isolated and characterized from the hydro-alcoholic extract of Hypoxis hemerocallidea corms. Hypoxhemerolosides A-F were found to be undescribed compounds. Curcapicycloside was isolated and identified for the first time in its original form, previously it was reported as a methylated derivative. In addition, (1S,2R)-1-(3,4-dihydroxyphenyl)-5-(4-β-D-glucopyranoxy-3-hydroxyphenyl)-1-methoxypent-4-yn-2-ol and (1S,2R)-1-(3,4-dihydroxyphenyl)-1-ethoxy-5-(4-β-D-glucopyranoxy-3-hydroxyphenyl)pent-4-yn-2-ol were isolated and characterized as artifacts, generated during extraction/isolation procedures from possible 1-(3,4-dihydroxyphenyl)-5-(4-β-D-glucopyranoxy-3-hydroxyphenyl)pent-4-yne-1,2-diol. Structure elucidation was mainly achieved by the interpretation of 1D and 2D NMR and HRESIMS data. The isolated compounds were screened for anti-inflammatory activity in terms of iNOS and NF-κB inhibition as well as for cytotoxicity. Hypoxhemerolosides C-E and obtuside A moderately inhibited nitric oxide production in LPS-stimulated mouse macrophages (RAW 264.7)., Competing Interests: Declaration of competing interest The authors declare no conflict of interest regarding this article., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Agrimonia asiatica is a perennial plant with deep green color and covered with soft hairs and has a slightly aromatic odor. This genus Agrimonia has been used in traditional medicines of China, Greece, and European countries. It was mainly used as a haemostatic, a tonic for asthenia, and an astringent for diarrhea. Agrimony is part of the division Magnoliophyta; class is represented by order Rosales, family Rosaceae, of the genus Agrimonia . Family Rosaceae-or pink eels-is one of the largest families of flowering plants, including about 100 genera and 3000 species. Rosaceae is common in almost all areas of the globe where flowering plants can grow, but most of them are concentrated in the temperate and subtropical zones of the Northern Hemisphere. Phytochemical investigation on ethanolic extract of A. asiatica led to isolation of four flavonoid derivatives (kaempferol-3-glycoside, quercetin-3-O- α -arabinofuranosyl- β -D-galactopyranoside, 3-O-kaempherol 2,3-di-O-acetyl-4-O-(cis-p-coumaroyl)-6-O-(trans-p-coumaroyl)- β -D-glucosopyranoside, and catechin) alongside of sucrose. All the extracts, fractions, and isolated compounds were tested for antimicrobial and antiplasmodial activities. We also studied the chemical composition of essential oil obtained from the aerial part of A. asiatica . The essential oil constituents from the aerial part of A. asiatica were obtained using a steam-distillation method in wild growing conditions in Kazakhstan. The essential oil extracted from the aerial part of the plant was analyzed by gas chromatography-mass spectroscopy and its major components amounting to 100% were found to be β -selinene (36.370%), α -panasinsene (21.720%), hexadecanoic acid (7.839%), and 1,2-nonadiene (6.199%). Neither the extract nor the isolated compounds showed antimicrobial and antiplasmodial activities., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Raushan A. Kozykeyeva et al.)

Congenital cytomegalovirus (cCMV) infection is a leading cause of hearing loss and neurological disabilities in children, with the disease burden and disabilities due to cCMV greater than many other well recognized childhood conditions. A minority of infants with cCMV will have symptoms at birth. Infants with symptomatic cCMV are at higher risk for sequelae than those born without symptoms. The majority of infants with cCMV are asymptomatic at birth, but 10%-15% will develop hearing loss. Although clinical symptoms can help predict which infants will have sensorineural hearing loss, among asymptomatic cCMV there are currently no predictors of adverse outcome. The identification of a biomarker to identify those at highest risk of sequelae is highly desirable to target interventions to those who could potentially benefit. Because there is increasing rationale for establishing both targeted and universal screening programs for cCMV in the United States and worldwide, this is an urgent priority., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

While conventional nutrition research has yielded biomarkers such as doubly labeled water for energy metabolism and 24-h urinary nitrogen for protein intake, a critical need exists for additional, equally robust biomarkers that allow for objective assessment of specific food intake and dietary exposure. Recent advances in high-throughput MS combined with improved metabolomics techniques and bioinformatic tools provide new opportunities for dietary biomarker development. In September 2018, the NIH organized a 2-d workshop to engage nutrition and omics researchers and explore the potential of multiomics approaches in nutritional biomarker research. The current Perspective summarizes key gaps and challenges identified, as well as the recommendations from the workshop that could serve as a guide for scientists interested in dietary biomarkers research. Topics addressed included study designs for biomarker development, analytical and bioinformatic considerations, and integration of dietary biomarkers with other omics techniques. Several clear needs were identified, including larger controlled feeding studies, testing a variety of foods and dietary patterns across diverse populations, improved reporting standards to support study replication, more chemical standards covering a broader range of food constituents and human metabolites, standardized approaches for biomarker validation, comprehensive and accessible food composition databases, a common ontology for dietary biomarker literature, and methodologic work on statistical procedures for intake biomarker discovery. Multidisciplinary research teams with appropriate expertise are critical to moving forward the field of dietary biomarkers and producing robust, reproducible biomarkers that can be used in public health and clinical research., (Published by Oxford University Press on behalf of the American Society for Nutrition 2019.)

Background: Infection with multiple cytomegalovirus (CMV) strains (mixed infection) was reported in a variety of hosts. As the virus genetic diversity in primary CMV infection and the changes over time remain incompletely defined, we examined CMV diversity and changes in diversity over time in healthy adolescent females who participated in a phase 2 CMV gB/MF59 vaccine trial., Methods: CMV genetic diversity was determined by genotyping of 5 genes-gB (UL55), gH (UL75), gN (UL73), US28, and UL144-in urine, saliva, and plasma samples from 15 study subjects., Results: At the time of primary infection, 5 of 12 (42%) urine samples had multiple virus strains, and 50% of vaccine recipients were infected with gB1 genotype (vaccine strain). Mixed infection was documented in all 15 subjects within 3 months after primary infection, and the majority had different CMV genotypes in different compartments. Changes in genotypes over time were observed in all subjects., Conclusions: Infection with multiple CMV genotypes was common during primary infection and further diversification occurred over time. Infection with gB1 genotype in vaccine recipients suggests a lack of strain-specific protection from the vaccine. As only 5 polymorphic genes were assessed, this study likely underestimated the true genetic diversity in primary CMV infection., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)