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The activity of miRNA varies across different cell populations and systems, as part of the mechanisms that distinguish cell types and roles in living organisms and in human health and disease. Typically, miRNA regulation drives changes in the composition and levels of protein-coding RNA and of lncRNA, with targets being down-regulated when miRNAs are active. The term "miRNA activity" is used to refer to this transcriptional effect of miRNAs. This study introduces miTEA-HiRes, a method designed to facilitate the evaluation of miRNA activity at high resolution. The method applies to single-cell transcriptomics, type-specific single-cell populations, and spatial transcriptomics data. By comparing different conditions, differential miRNA activity is inferred. For instance, miTEA-HiRes analysis of peripheral blood mononuclear cells comparing Multiple Sclerosis patients to control groups revealed differential activity of miR-20a-5p and others, consistent with the literature on miRNA underexpression in Multiple Sclerosis. We also show miR-519a-3p differential activity in specific cell populations. This study introduces miTEA-HiRes, a method designed to facilitate the evaluation of miRNA activity at high resolution. The method applies to single cell transcriptomics, type-specific single cell populations, and spatial transcriptomics data. [ABSTRACT FROM AUTHOR]

The study of potential-dependent calcium channels sheds light on the formation of systems responsible for the coupling of sensors and actuators in a living cell. Based on data on the potential-sensitive calcium channel TCav3 (2063 amino acid residues) from Trichoplax adhaerens cells, homologues of 2090 amino acid residues in the scaffold of Trichoplax sp. H2 and an incomplete polypeptide with a length of 1510 amino acid residues in the scaffold of Trichoplax adhaerens are identified. The latter hypothetical protein is annotated as a Cav3 channel. An EEDD selective filter is found for all three proteins and the core structure of the calcium channel consisting of 24 transmembrane α-helices is reconstructed. Nevertheless, the studied proteins differ in cytoplasmic domains, which indicates a different specialization of Cav3 channels when conducting a signal into the cell. For example, part of the AID motif (alpha-interacting domain) and the adjacent potential sensor from the annotated channel have homology in 25 species of bony fish, and the corresponding region from other channels in 41 species of bony fish and in 4 species of snakes. Significantly, a highly conserved IIS1-S2 loop with the IEHHNQP sequence is found below the AID motif of bony fish, as in trichoplax; while a homologous IEHHEQP sequence is found in snakes, characterized by a negative glutamic acid residue, which is also present in the corresponding rat and human proteins. Based on the analysis of primary transcripts and mature polypeptides, a modular mechanism for the evolution of Cav3 channels is proposed by inserting and combining protein domains performing various regulatory functions. [ABSTRACT FROM AUTHOR]

Cloud storage and computing offer significant convenience and management efficiency in the information era. Privacy protection is a major challenge in cloud computing. Public key encryption with keyword search (PEKS) is an ingenious tool for ensuring both privacy and functionality in certain scenarios, such as ensuring privacy for data retrieval appearing in cloud computing. Despite much attention received, PEKS schemes still face several challenges in practical applications, such as low computational efficiency, high end-to-end delay, vulnerability to inside keyword guessing attacks, and key management defects in multi-user scenarios. In this work, we first propose a post-quantum secure PEKS scheme in the standard model. The resulting PEKS scheme is based on Ring-LWE/ISIS assumptions. Then, we present two extended schemes. The first is a public-key authenticated encryption with keyword search scheme, which prevents servers from initiating inside keyword guessing attacks. The second is an identity-based public-key authenticated encryption with keyword search scheme, which reduces the complexity of key management in practical applications. Theoretical analyses prove that these schemes enjoy high security. Experimental results indicate that these schemes provide lower end-to-end delay and higher computational efficiency compared to similar ones. [ABSTRACT FROM AUTHOR]

Purpose: Liquid biopsy is a promising technological method in patient management of early-stage non-small-cell lung cancer (NSCLC). The detection platforms exhibit high efficiency and related clinical applications also emerge with high-quality performance. An overview of the current status is in need for an integrated perception on this field. Methods: NSCLC takes up the largest proportion of lung cancer and there is a tendency for more early-stage patients in real practice. Hence, early-stage NSCLC participants occupy an important position in clinical work. Liquid biopsy, as a promising non-invasive detection method, had great potential in various aspects of the whole diagnosis-treatment procedure. We went through the landmark articles according to liquid biopsy in the field of early-stage NSCLC management and concluded the status quo of it. Results: In this review, we summarized the improvement of the detection technologies regarding the most widely studied biomarkers and elucidated the current clinical applications of liquid biopsy in early detection, prognostic performance assessment, and predictive value respectively, in early-stage NSCLC patients. Conclusion: Liquid biopsy has achieved favorable outcomes in different aspects of early-stage NSCLC. Although there are still barriers yet to conquer, liquid biopsy is a hopeful detection means to be put into clinical use. [ABSTRACT FROM AUTHOR]

The voltage-sensing domain (VSD) is a module capable of responding to changes in the membrane potential through conformational changes and facilitating electromechanical coupling to open a pore gate, activate proton permeation pathways, or promote enzymatic activity in some membrane-anchored phosphatases. To carry out these functions, this module acts cooperatively through conformational changes. The VSD is formed by four transmembrane segments (S1–S4) but the S4 segment is critical since it carries positively charged residues, mainly Arg or Lys, which require an aqueous environment for its proper function. The discovery of this module in voltage-gated ion channels (VGICs), proton channels (Hv1), and voltage sensor-containing phosphatases (VSPs) has expanded our understanding of the principle of modularity in the voltage-sensing mechanism of these proteins. Here, by sequence comparison and the evaluation of the relationship between sequence composition, intrinsic flexibility, and structural analysis in 14 selected representatives of these three major protein groups, we report five interesting differences in the folding patterns of the VSD both in prokaryotes and eukaryotes. Our main findings indicate that this module is highly conserved throughout the evolutionary scale, however: (1) segments S1 to S3 in eukaryotes are significantly more hydrophobic than those present in prokaryotes; (2) the S4 segment has retained its hydrophilic character; (3) in eukaryotes the extramembranous linkers are significantly larger and more flexible in comparison with those present in prokaryotes; (4) the sensors present in the kHv1 proton channel and the ciVSP phosphatase, both of eukaryotic origin, exhibit relationships of flexibility and folding patterns very close to the typical ones found in prokaryotic voltage sensors; and (5) archaeal channels KvAP and MVP have flexibility profiles which are clearly contrasting in the S3–S4 region, which could explain their divergent activation mechanisms. Finally, to elucidate the obscure origins of this module, we show further evidence for a possible connection between voltage sensors and TolQ proteins. [ABSTRACT FROM AUTHOR]

Excessive melanogenesis leads to hyperpigmentation, which is one of the common skin conditions in humans. Existing whitening cosmetics cannot meet market needs due to their inherent limitations. Thus, the development of novel skin-whitening agents continues to be a challenge. The peptide OA-VI12 from the skin of amphibians at high altitude has attracted attention due to its remarkable anti light damage activity. However, whether OA-VI12 has the skin-whitening effect of inhibiting melanogenesis is still. Mouse melanoma cells (B16) were used to study the effect of OA-VI12 on cell viability and melanin content. The pigmentation model of C57B/6 mouse ear skin was induced by UVB and treated with OA-VI12. Melanin staining was used to observe the degree of pigmentation. MicroRNA sequencing, quantitative real-time PCR (qRT-PCR), immunofluorescence analysis and Western blot were used to detect the change of factor expression. Double luciferase gene report experiment was used to prove the regulatory relationship between miRNA and target genes. OA-VI12 has no effect on the viability of B16 cells in the concentration range of 1–100 μM and significantly inhibits the melanin content of B16 cells. Topical application of OA-VI12, which exerted transdermal potency, prevented UVB-induced pigmentation of ear skin. MicroRNA sequencing and double luciferase reporter analysis results showed that miR-122-5p, which directly regulated microphthalmia-associated transcription factor (Mitf), had significantly different expression before and after treatment with OA-VI12. Mitf is a simple helix loop and leucine zipper transcription factor that regulates tyrosinase (Tyr) expression by binding to the M-box promoter element of Tyr. qRT-PCR, immunofluorescence analysis and Western blot showed that OA-VI12 up-regulated the expression of miR-122-5p and inhibited the expression of Mitf and Tyr. The effects of OA-VI12 on melanogenesis inhibition in vitro and in vivo may involve the miR-122-5p/Mitf/tyr axis. OA-VI12 represents the first report on a natural amphibian-derived peptide with skin-whitening capacity and the first report of miR-122-5p as a target for regulating melanogenesis, thereby demonstrating its potential as a novel skin-whitening agent and highlighting amphibian-derived peptides as an underdeveloped resource. [ABSTRACT FROM AUTHOR]

Dysregulation of Th17 cell differentiation and pathogenicity contributes to multiple autoimmune and inflammatory diseases. Previously growth hormone releasing hormone receptor (GHRH-R) deficient mice have been reported to be less susceptible to the induction of experimental autoimmune encephalomyelitis. Here, we show GHRH-R is an important regulator of Th17 cell differentiation in Th17 cell-mediated ocular and neural inflammation. We find that GHRH-R is not expressed in naïve CD4+ T cells, while its expression is induced throughout Th17 cell differentiation in vitro. Mechanistically, GHRH-R activates the JAK-STAT3 pathway, increases the phosphorylation of STAT3, enhances both non-pathogenic and pathogenic Th17 cell differentiation and promotes the gene expression signatures of pathogenic Th17 cells. Enhancing this signaling by GHRH agonist promotes, while inhibiting this signaling by GHRH antagonist or GHRH-R deficiency reduces, Th17 cell differentiation in vitro and Th17 cell-mediated ocular and neural inflammation in vivo. Thus, GHRH-R signaling functions as a critical factor that regulates Th17 cell differentiation and Th17 cell-mediated autoimmune ocular and neural inflammation. Endocrine factors have been shown to alter functions of pathogenic Th17 cells that are involved in autoimmunity. Here the authors study the influence of growth hormone releasing hormone receptor and show that this receptor is found on Th17 cells and promotes ocular autoimmunity. [ABSTRACT FROM AUTHOR]

Nav1.3, encoded by the SCN3A gene, is a voltage-gated sodium channel on the cell membrane. It is expressed abundantly in the fetal brain but little in the normal adult brain. It is involved in the generation and conduction of action potentials in excitable cells. Nav1.3 plays an important role in many neurological diseases. The aim of this review is to summarize new findings about Nav1.3 in the field of neurology. Many mutations of SCN3A can lead to neuronal hyperexcitability and then cause epilepsy. The rapid recovery from inactivation and slow closed-state inactivation kinetics of Nav1.3 leads to a reduced activation threshold of the channel and a high frequency of firing of neurons. Hyperactivity of Nav1.3 also induces increased excitability of sensory neurons, a lower nociceptive threshold, and neuropathic pain. This review summarizes the structure and the function of Nav1.3 and focuses on its relationship with epilepsy and neuropathic pain. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. The etiology and pathology of AD are complicated, variable, and yet to be completely discovered. However, the involvement of inflammasomes, particularly the NLRP3 inflammasome, has been emphasized recently. NLRP3 is a critical pattern recognition receptor involved in the expression of immune responses and has been found to play a significant role in the development of various immunological and neurological disorders such as multiple sclerosis, ulcerative colitis, gout, diabetes, and AD. It is a multimeric protein which releases various cytokines and causes caspase-1 activation through the process known as pyroptosis. Increased levels of cytokines (IL-1β and IL-18), caspase-1 activation, and neuropathogenic stimulus lead to the formation of proinflammatory microglial M1. Progressive researches have also shown that besides loss of neurons, the pathophysiology of AD primarily includes amyloid beta (Aβ) accumulation, generation of oxidative stress, and microglial damage leading to activation of NLRP3 inflammasome that eventually leads to neuroinflammation and dementia. It has been suggested in the literature that suppressing the activity of the NLRP3 inflammasome has substantial potential to prevent, manage, and treat Alzheimer's disease. The present review discusses the functional composition, various models, signaling molecules, pathways, and evidence of NLRP3 activation in AD. The manuscript also discusses the synthetic drugs, their clinical status, and projected natural products as a potential therapeutic approach to manage and treat NLRP3 mediated AD. [ABSTRACT FROM AUTHOR]

Almost all clinical oncologists agree that the discovery of reliable, accessible, and non-invasive biomarkers is necessary to decrease cancer mortality. It is possible to employ reliable biomarkers to diagnose cancer in the early stages, predict the patient prognosis, follow up the response to treatment, and estimate the risk of disease recurrence with high sensitivity and specificity. Extracellular vesicles (EVs), especially exosomes, have been the focus of translational research to develop such biomarkers over the past decade. The abundance and distribution of exosomes in bodily fluids, including serum, saliva, and urine, as well as their ability to transport various biomolecules (nucleic acids, proteins, and lipids) derived from their parent cells, make exosomes reliable, accessible, and potent biomarkers for diagnosis and follow-up of solid and hematopoietic tumors. In addition, exosomes play a vital role in various cellular processes, including tumor progression, by participating in intercellular communication. Although these advantages underline the high potential of tumor-derived exosomes as diagnostic biomarkers, the lack of standardized effective methods for their isolation, identification, and precise characterization makes their application challenging in clinical settings. We discuss the importance of non-coding RNAs (ncRNAs) in cellular processes, and the role of tumor-derived exosomes containing ncRNAs as potential biomarkers in several types of cancer. In addition, the advantages and challenges of these studies for translation into clinical applications are covered. [ABSTRACT FROM AUTHOR]

To cope with the local storage stress that has resulted from the increase in data volumes and to keep data privacy, users outsource their data to cloud servers after encrypting these data. Public key encryption with keyword search (PEKS) is a technique that can achieve the search function on encrypted data. However, most existing PEKS schemes are based on bilinear pairing which will be broken under the quantum computing attack. Moreover, the traditional PEKS schemes have an inherent security issue: They cannot resist the keywords guessing attack (KGA) which can cause devastating damage to the encrypted database. To address these problems, this paper proposes a KGA-resistance encrypted search scheme on lattice that is post-quantum secure. Furthermore, to achieve rich queries, our scheme is also designed to support the conjunctive query. Finally, the security analysis and performance evaluation are presented, which demonstrates that our scheme realizes a good balance between security and efficiency compared with related works. [ABSTRACT FROM AUTHOR]

Random and block copolymers of 2-methoxyethyl vinyl ether (MOVE) and 2-ethoxyethyl vinyl ether (EOVE) were synthesized within 180 s via IBVE-HCl/SnCl4 initiating system in the presence of THF in a microflow system. The polymers can be produced continuously and efficiently with extremely narrow molecular weight distributions (Mw/Mn=1.09–1.18) even at the existence of pendant oxyethylene units. Polymerization rate can be accelerated by reducing THF to very low concentration ([THF]=50 mmol/L), reaching conversions over 60% and 70% in 60 s for EOVE and MOVE, respectively. Random copolymers poly(MOVE100x−r-EOVE100(1−x)) (x=0.25, 0.5, 0.75) experienced very sensitive phase separation process, of which phase separation temperature (Tps) can be adjusted between 20 and 70 °C by controlling monomer composition. On the other hand, thermally induced phase separation of diblock copolymers poly(MOVE100-b-EOVE100) was not so sensitive as its random copolymer counterpart. Relatively bigger difference between phase separation temperatures of heating and cooling process (ΔTps) was found for diblock copolymer. [ABSTRACT FROM AUTHOR]

Nonionic surfactant vesicles (Niosomes) were prepared using polyoxyethylene alkyl ether (Brij 58).The impact of variation of the Brij: cholesterol molar ratio on the niosomal structure was studied. Fluorescence studies performed with the membrane probe 1,6-Diphenyl-1,3,5-triene (DPH) gave important insight on the bilayer integrity of the niosomes in response to environmental perturbations. The aim of the work being assessment of the efficacy of the niosomes as "drug release vehicles", release studies were performed with a xanthene dye Carboxyfluorescein (CF). Further, the vesicles were used as nanoreactors for the synthesis of gold nanoparticles (GNPs) as it is often useful to house nanoparticles in biological /biomimicking environments. Stable, spherical GNPs of diameter 6–10 nm were formed in these vesicles. As the vesicular bilayer mimics the cell membrane, the present work is relevant to the use of the GNPs for diagnostic and therapeutic purpose. It has also been established that fluorescence resonance energy transfer (FRET) effectively occurs between DPH and CF in the niosomes. The FRET studies provide important insight on the location of dyes within the vesicles thus indicating the prospective applications of this fluorescence technique for tracking the location of probes in biomimicking systems which maybe extrapolated to in vivo biological systems in future. [ABSTRACT FROM AUTHOR]

The stable isotope ratios of sulfur (δ34S relative to Vienna Cañon Diablo Troilite) in sulfates and sulfides determined by elemental analysis and isotope ratio mass spectrometry (EA/IRMS) have been proven to be a remarkable tool for studies of the (bio)geochemical sulfur cycles in modern and ancient environments. However, the use of EA/IRMS to measure δ34S in arsenides and sulfarsenides may not be straightforward. This difficulty can lead to potential health and environmental hazards in the workplace and analytical problems such as instrument contamination, memory effects, and a non-matrix-matched standardization of δ34S measurements with suitable reference materials. To overcome these practical and analytical challenges, we developed a procedure for sulfur isotope analysis of arsenides, which can also be safely used for EA/IRMS analysis of arsenic sulfides (i.e., realgar, orpiment, arsenopyrite, and arsenian pyrite), and mercury sulfides (cinnabar). The sulfur dioxide produced from off-line EA combustion was trapped in an aqueous barium chloride solution in a leak-free system and precipitated as barium sulfate after quantitative oxidation of hydrogen sulfite by hydrogen peroxide. The derived barium sulfate was analyzed by conventional EA/IRMS, which bracketed the δ34S values of the samples with three international sulfate reference materials. The protocol (BaSO4-EA/IRMS) was validated by analyses of reference materials and laboratory standards of sulfate and sulfides and achieved accuracy and precision comparable with those of direct EA/IRMS. The δ34S values determined by BaSO4-EA/IRMS in sulfides (arsenopyrite, arsenic, and mercury sulfides) samples from different origins were comparable to those obtained by EA/IRMS, and no sulfur isotope fractionations were introduced during sample preparation. We report the first sulfur isotope data of arsenides obtained by BaSO4-EA/IRMS. [ABSTRACT FROM AUTHOR]

The analysis of glycosaminoglycans (GAGs) is a challenging task due to their high structural heterogeneity, which results in diverse GAG chains with similar chemical properties. Simultaneously, it is of high importance to understand their role and behavior in biological systems. It has been known for decades now that GAGs can interact with lipid molecules and thus contribute to the onset of atherosclerosis, but their interactions at and with biological interfaces, such as the cell membrane, are yet to be revealed. Here, analytical approaches that could yield important knowledge on the GAG-cell membrane interactions as well as the synthetic and analytical advances that make their study possible are discussed. Due to recent developments in laser technology, we particularly focus on nonlinear spectroscopic methods, especially vibrational sum-frequency generation spectroscopy, which has the potential to unravel the structural complexity of heterogeneous biological interfaces in contact with GAGs, in situ and in real time. [ABSTRACT FROM AUTHOR]

A simple nanoplatform based on molybdenum disulfide (MoS2) nanosheets, a fluorescence quencher (signal off), and a hybridization chain reaction (HCR) signal amplification (signal on) used for the enzyme-free, label-free, and low-background signal quantification of microRNA-21 in plasma exosome is reported. According to the sequence of microRNA-21, carboxy-fluorescein (FAM)-labeled hybridization probe 1 (FAM-H1) and hybridization probes 2 (FAM-H2) were designed with excitation maxima at 488 nm and emission maxima at 518 nm. MoS2 nanosheets could adsorb FAM-H1 and FAM-H2 and quenched their fluorescence signals to reduce the background signal. However, HCR was triggered when microRNA-21 was present. Consequently, HCR products containing a large number of FAM fluorophores can emit a strong fluorescence at 518 nm and could realize the detection of microRNA-21 as low as 6 pmol/L and had a wide linear relation of 0.01–25 nmol/L. This assay has the ability of single-base mismatch recognition and could identify microRNA-21 with high specificity. Most importantly, this approach was successfully applied to the detection of plasma exosomal microRNA-21 in patients with lung cancer, and it is proposed that other targets can also be detected by changing the FAM-H1 and FAM-H2 corresponding to the target sequence. Thus, a novel, hands-on strategy for liquid biopsy was proposed and has a potential application value in the early diagnosis of lung cancer. [ABSTRACT FROM AUTHOR]

Psoriasis is a common inflammatory dermatology disease. Strongly expressed serum amyloid A (SAA) promotes psoriasis exacerbation through inducing IL-17 secretion. What's more, SAA can stimulate the release of cathepsin B. The current work was performed to demonstrate the specific effects of cathepsin B silencing on inflammatory response, proliferation, and differentiation of IL-17A and SAA-induced keratinocytes and to report the precise role of cathepsin B in psoriasis-like lesion. HaCaT keratinocytes received treatment with IL-17A (0, 10, 50, 100 ng/ml) or SAA (0, 1, 5, 10, 20 μg/ml) for 24 h to establish psoriasis-like keratinocytes model. HaCaT keratinocytes were transfected with small interfering RNA (siRNA)-cathepsin B for the functional experiments. Cathepsin B mRNA and protein levels were separately assessed by performing RT-qPCR and Western blot analysis. Then, CCK-8 for detection of cell proliferative capacity and Western blot assay for detection of Ki67 and PCNA expression were adopted to evaluate the influence of silenced cathepsin B on proliferation of IL-17A/SAA-induced HaCaT keratinocytes. Furthermore, IL-6, IL-1β, TNF-α, and p-NF-κB p65 were detected to assess the effects of cathepsin B knockdown on inflammatory response in IL-17A/SAA-induced HaCaT keratinocytes. In addition, assessment of KRT10, FLG, and LOR levels were applied to analyze the function of cathepsin B silencing on differentiation of IL-17A/SAA-induced HaCaT keratinocytes. Cathepsin B expression is distinctly elevated in IL-17A/SAA-induced HaCaT keratinocytes. IL-17A or SAA treatment enhanced proliferation, promoted the release of inflammatory factors, and arrested differentiation in HaCaT keratinocytes. Furthermore, downregulation of cathepsin B reduced proliferation, suppressed inflammatory response, and boosted differentiation in IL-17A/SAA-induced HaCaT keratinocytes. To sum up, cathepsin B silencing rescued excessive proliferation and inflammatory response and scarce differentiation in HaCaT keratinocytes induced by IL-17A and SAA. These findings prompted that cathepsin B might be a promising therapeutic target for psoriasis-like lesion, which helps to develop an anti-psoriatic agent. [ABSTRACT FROM AUTHOR]

I investigated the causative agents of licorice-induced pseudoaldosteronism, which is a frequent side effect of Japanese traditional Kampo medicines. Glycyrrhizin (GL), the main ingredient of licorice, is absorbed after being metabolized to glycyrrhetinic acid (GA) by intestinal bacteria, and then metabolized in liver to 3-monoglucuronyl-glycyrrhetinic acid (3MGA). In normal condition, 3MGA is excreted into bile via a multidrug resistance-related protein (Mrp) 2, therefore, 3MGA does not appear in blood circulation. However, under the dysfunction of Mrp2, 3MGA appears in the blood circulation and is excreted into the urine by not glomerular filtration but tubular secretion via organic anion transporter (OAT) 1 and 3. At this time, 3MGA inhibits type 2 11β-hydroxysteroid dehydrogenase (11βHSD2) in tubular cells to cause pseudoaldosteronism. Since GA is not the substrates of these transporters, GA cannot inhibit 11βHSD2 in tubular cells. Therefore, it was considered that 3MGA was the causative agents of licorice-induced pseudoaldosteronism. After that, I isolated and identified three other GL metabolites, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate (2), and 18β-glycyrrhetyl-3-O-sulfate (3) from the urine of Mrp2-deficient rats orally treated with GA, and found that their blood and urinary concentrations were much higher than 3MGA and that their pharmacokinetic behaviors were similar to 3MGA. 3MGA was not detected in the blood of patients with pseudoaldosteronism who developed rhabdomyolysis due to licorice, and compound 3 was detected at a high concentration. In addition, a multicenter retrospective study was conducted using the serum and urine of 97 patients who took Kampo medicines containing licorice. Of a total of 97 patients, 67 detected GA in the serum (median 122 nM, 5 nM–1.8 µM) and 68 detected compound 3 (median 239 nM, 2 nM–4.2 µM), and there were no cases of detection of GL, 3MGA, compounds 1, and 2. High blood concentrations of compound 3 were associated with low plasma renin activity, plasma aldosterone levels, and serum potassium levels. It is highly probable that compound 3 is the true causative agent of pseudoaldosteronism. [ABSTRACT FROM AUTHOR]

Background and Objective: Ginseng is usually consumed as a dietary supplement for health care in the normal state or prescribed as a herbal medicine in pathologic conditions. Although metabolic studies of ginseng are commonly performed on healthy organisms, the metabolic characteristics in pathologic organisms remain unexplored. This study aimed to uncover the difference in intestinal metabolism of ginseng between normal and cyclophosphamide-induced immunosuppressed rats and further discuss the potential mechanisms involved. Methods: Twelve Sprague-Dawley rats (6–8 weeks old) were randomly divided into two groups: the normal group (NG) and immunosuppressed group (ISG). Rats in the NG and ISG groups were intraperitoneally administered normal saline and cyclophosphamide injections (40 mg/kg) on the 1st, 2nd, 3rd and 10th days; on the 12th day, all rats were intragastrically administered ginseng water extract (900 mg/kg). The difference in intestinal metabolism of ginseng was compared using an ultra-high-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry-based metabolomics approach, and the diversities of gut microbiota were analyzed by 16S rRNA gene sequencing between the two groups. Results: The intestinal metabolomic characteristics of ginseng were significantly different between the normal and immunosuppressed rats, with the ginsenoside F2 (F2), 20S-ginsenoside Rg3 (20(S)-Rg3), pseudo-ginsenoside Rt5 (Pseudo-Rt5), ginsenoside Rd (Rd), ginsenoside Rh1 (Rh1), 20S-ginsenoside Rg1 (20(S)-Rg1), ginsenoside compound K (CK), ginsenoside Rg2 (Rg2) and 20S-panaxatriol (S-PPT) more abundant in immunosuppressed ones (P < 0.05). Additionally, the composition of gut microbiota was remarkably altered in the two groups, with some specific bacterial communities such as Bacteroides spp., Eubacterium spp. and Lachnospiraceae_UCG-010 spp. increased and Bifidobacterium spp. decreased in immunosuppressed rats compared with normal ones. Conclusion: The intestinal metabolism of ginseng in immunosuppressed rats was significantly different from that in normal ones, which might be partly attributed to the changes in the intensity of specific gut bacteria. The outcomes of this study could provide scientific data for rationalization of ginseng use as both a dietary supplement and herbal medicine. [ABSTRACT FROM AUTHOR]

Ginseng is an ancient perennial herb belonging to the family Araliaceae and genus Panax which has been used for medical therapeutics for thousands of years, particularly in China and other Asian cultures although increasing interest in ginseng has recently emerged in western societies. Ginseng is a complex substance containing dozens of bioactive and potentially effective therapeutic compounds. Among the most studied are the ginsenosides, which are triterpene saponins possessing a wide array of potential therapeutic effects for many conditions. The quantity and type of ginsenoside vary greatly depending on ginseng species and their relative quantity in a given ginseng species is greatly affected by extraction processes as well as by subjecting ginseng to various procedures such as heating. Adding to the complexity of ginsenosides is their ability to undergo biotransformation to bioactive metabolites such as compound K by enteric bacteria following ingestion. Many ginsenosides exert vasodilatating effects making them potential candidates for the treatment of hypertension. Their vascular effects are likely dependent on eNOS activation resulting in the increased production of NO. One proposed end-mechanism involves the activation of calcium-activated potassium channels in vascular smooth cells resulting in reduced calcium influx and a vasodilatating effect, although other mechanisms have been proposed as discussed in this review. [ABSTRACT FROM AUTHOR]

The radiation performance of a dipole antenna on a diamond-structured photonic crystal (PC) substrate with point defects fabricated using three-dimensional (3D) printing technology has been investigated. Meanwhile, according to the reflection properties of the PCs, corresponding dipole antennas were fabricated and packaged with standard coaxial lines. The experimental results showed a strong radiation frequency of the dipole antenna at about 13 GHz, in basic agreement with the strongest reflection frequency of the PCs with point defects. The experimental results also show that the maximum gain of the major lobe in the dipole antenna was close to −67 dB, while the angular range of the major lobe was 5–55°. The maximum gain of the major lobe increased to −60 dB in the composite antenna, representing an improvement of 7 dB compared with the dipole antenna, while the width range of the major lobe was 240–270°. These results show that the use of such substrates based on diamond-structure PCs with point defects could significantly improve the gain and directivity of the antenna, providing a basis for engineering applications. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is among the leading causes of death all over the world and it is often diagnosed at advanced or metastatic stages. Exosomes, derived from circulating vesicles that are released from the multivesicular body, can be utilized for diagnosis and also the prognosis of LC at early stages. Exosomal proteins, RNAs, and DNAs can help to better discern the prognostic and diagnostic features of LC. To our knowledge, there are various reviews on LC and the contribution of exosomes, but none of them are about the exome techniques and also their efficiency in LC. To fill this gap, in this review, we summarize the recent investigations regarding isolation and also the characterization of exosomes of LC cells. Furthermore, we discuss the noncoding RNAs as biomarkers and their applications in the diagnosis and prognosis of LC. Finally, we compare the efficacy of exosome isolation methods to better fi + 6 + guring out feasible techniques. [ABSTRACT FROM AUTHOR]

The removal of Hg from contaminated aquatic media is of major importance, taking into consideration the highly toxic character of the element. One of the most promising water treatment technologies is adsorption by low cost adsorbents, such as activated carbon produced by agricultural byproducts. In this study, activated carbon in granular form (GAC) was produced using pistachio shells from Aegina Island (Greece). Two main GAC products have been synthesized. The first one was chemically activated using ZnCl2. The second one was further treated with Na2S in order to introduce S atoms on the functional groups. The effectiveness of synthesized GAC products for Hg removal was evaluated by conducting batch equilibrium and kinetic experiments. It was found that sulfurization was able to increase by a factor of more than 2 the adsorptive capacity of activated carbon. Namely the maximum adsorption capacity was 73 mg/g for the simple GAC and increased up to 166 mg/g for the S-modified product. The kinetics of adsorption was described with almost equivalent precision using the pseudo-first and the pseudo-second order models, a behavior which is often observed in adsorption experiments, depending on the experimental conditions. The value of activation energy EA was found to be negative (− 18.8 kJ/mol) in the case of simple GAC and positive (8.27 kJ/mol), in the case of S-modified GAC, suggesting that Hg adsorption on the modified carbon follows a different mechanism, closer to chemisorption processes. [ABSTRACT FROM AUTHOR]

Allopolyploids possess complete sets of genomes derived from different parental species and exhibit a range of variation in various traits. Reproductive traits may play a key role in the reproductive isolation between allopolyploids and their parental species, thus affecting the thriving of allopolyploids. However, empirical data, especially in natural habitats, comparing reproductive trait variation between allopolyploids and their parental species remain rare. Here, we documented the flowering phenology and floral morphology of the allopolyploid wild plant Cardamine flexuosa and its diploid parents C. amara and C. hirsuta in their native range in Switzerland. The flowering of C. flexuosa started at an intermediate time compared with those of the parents and the flowering period of C. flexuosa overlapped with those of the parents. Cardamine flexuosa resembled C. hirsuta in the size of flowers and petals and the length/width ratio of petals, while it resembled C. amara in the length/width ratio of flowers. These results provide empirical evidence of the trait-dependent variation of allopolyploid phenotypes in natural habitats at the local scale. They also suggest that the variation in some reproductive traits in C. flexuosa is associated with self-fertilization. Therefore, it is helpful to consider the mating system in furthering the understanding of the processes that may have shaped trait variation in polyploids in nature. [ABSTRACT FROM AUTHOR]

Security and privacy are the key issues for the Internet of Things (IoT) systems. Especially, secure search is an important functionality for cooperation among users' devices and non-trusted servers. Public-key encryption with keyword search (PEKS) enables us to search encrypted data and is expected to be used between a cloud server and users' mobile devices or IoT devices. However, those mobile devices might be lost or stolen. For IoT devices, it might be difficult to store keys in a tamper-proof manner due to prohibitive costs. In this paper, we deal with such a key-exposure problem on PEKS and introduce the concept of PEKS with key-updating functionality, which we call key-updatable PEKS (KU-PEKS). Specifically, we propose two models of KU-PEKS: the key-evolution model and the key-insulation model. In the key-evolution model, a pair of public and secret keys can be updated if needed (e.g., the secret key is exposed). In the key-insulation model, the public key remains fixed while the secret key can be updated if needed. The former model makes a construction simple and more efficient than the latter. On the other hand, the latter model is preferable for practical use since a user never updates their public key. We show constructions in each model in a black-box manner. We also give implementation results on Raspberry Pi 3, which can be regarded as a reasonable platform of IoT devices. [ABSTRACT FROM AUTHOR]

Voltage-dependent K channels open and close in response to voltage changes across the cell membrane. This voltage dependence was postulated to depend on the presence of charged particles moving through the membrane in response to voltage changes. Recording of gating currents originating from the movement of these particles fully confirmed this hypothesis, and gave substantial experimental clues useful for the detailed understanding of the process. In the absence of structural information, the voltage-dependent gating was initially investigated using discrete Markov models, an approach only capable of providing a kinetic and thermodynamic comprehension of the process. The elucidation of the crystal structure of the first voltage-dependent channel brought in a dramatic change of pace in the understanding of channel gating, and in modeling the underlying processes. It was now possible to construct quantitative models using molecular dynamics, where all the interactions of each individual atom with the surroundings were taken into account, and its motion predicted by Newton's laws. Unfortunately, this modeling is computationally very demanding, and in spite of the advances in simulation procedures and computer technology, it is still limited in its predictive ability. To overcome these limitations, several groups have developed more macroscopic voltage gating models. Their approaches understandably require a number of approximations, which must however be physically well justified. One of these models, based on the description of the voltage sensor as a Brownian particle, that we have recently developed, is able to simultaneously describe the behavior of a single voltage sensor and to predict the macroscopic gating current originating from a population of sensors. The basics of this model are here described, and a typical application using the Kv1.2/2.1 chimera channel structure is also presented. [ABSTRACT FROM AUTHOR]

The novel organic selenium compound, selenoneine, is found in the blood of tuna and has metal-binding activity. In this report, selenoneine displays tyrosinase inhibitory activity. When murine B16 melanoma cells were cultured in the presence of 1.0 μM selenoneine, the melanin content in the cells was reduced to 46.5% compared with the cell-induced melanin synthesis, and cellular tyrosinase activity was suppressed. In 3D-cultured human melanocytes, melanin accumulation was also decreased, to 39.7% and 23.0% by 1.0 and 5.0 μM selenoneine, respectively, compared with the control cells. Both cellular and purified enzyme assays showed that selenoneine inhibited tyrosinase activity against the substrate, l-3,4-dihydroxyphenylalanine (l-DOPA). An in silico docking simulation study supported a molecular mechanism in which selenoneine chelates copper ions in the active center of tyrosinase and prevents the reaction between tyrosinase and l-DOPA. These findings suggest that selenoneine has a novel biological function by inhibiting tyrosinase via copper chelation. [ABSTRACT FROM AUTHOR]

Lung cancer remains the leading cause of cancer-related death worldwide, and the high incidence rates are worrisome. Exosomes are a class of extracellular vesicles secreted by most cells, including RNAs, proteins and lipids. Exosomes can mediate cell-to-cell communication in both physiologic and pathologic processes. Accumulated evidences show that cancer-derived exosomes aid in the recruitment and reprogramming of constituents correlated with tumor microenvironment. Furthermore, exosome-based clinical trials have been completed in advanced lung cancer patients. In this review, we discuss the roles of exosomes in a lung cancer microenvironment, such as its participation in lung cancer initiation, progression and metastasis as well as being involved in angiogenesis, epithelial–mesenchymal transition (EMT), immune escape, and drug resistance. In addition, we focus on the potential of exosomes as diagnostic and prognostic biomarkers in lung cancer, as well as the challenges faced by and advantages of exosomes as drug delivery vehicles and in exosome-based immunotherapy. [ABSTRACT FROM AUTHOR]

Liquorice [main ingredient, glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18β-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM–1.8 µM) and 18β-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM–4.2 µM). 3-Monoglucuronyl 18β-glycyrrhetinic acid, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker. [ABSTRACT FROM AUTHOR]

The influence of anemia on the long-term clinical outcomes has not been fully evaluated in patients with venous thromboembolism (VTE). We evaluated the influence of anemia among 3012 patients in the COMMAND VTE Registry with a median follow-up period of 1219 days. The outcomes measures were ISTH major bleeding, recurrent VTE and all-cause death. There were 1012 patients (34%) with moderate/severe anemia (Hb ≤ 10.9 g/dl), 615 patients (20%) with mild anemia (Hb 11.0–12.9 g/dl for men, and 11.0–11.9 g/dl for women), and 1385 patients (46%) without anemia. The cumulative 5-year incidence of major bleeding was significantly higher in patients with anemia (moderate/severe anemia: 17.6%, mild anemia: 12.1%, and no anemia: 8.7%, P < 0.001). After adjusting the confounders, the excess risk of mild and moderate/severe anemia, respectively, relative to no anemia for major bleeding remained significant (mild: adjusted HR 1.41: [95% CI 1.00–1.98], P = 0.048; moderate/severe: adjusted HR 1.91: [95% CI 1.42–2.58], P < 0.001, respectively). The excess risk of moderate/severe anemia relative to no anemia was also significant for mortality (adjusted HR 2.89: 95% CI 2.45–3.42, P < 0.001), but the risk was neutral for recurrent VTE (adjusted HR 1.05: 95% CI 0.76–1.45, P = 0.77). In conclusions, VTE patients with mild and moderate/severe anemia had higher risk for major bleeding events without significant excess risk for recurrent VTE events, and the risk for major bleeding events increased according to the severity of anemia. We should pay more attention to the optimal intensity and duration of anticoagulation in VTE patients with anemia. [ABSTRACT FROM AUTHOR]

The Antarctic marine environment provides a good source of novel lipolytic enzymes that possess beneficial properties, i.e., resistance to extreme physical and chemical conditions. We found a lipolytic Escherichia coli colony that was transformed using genomic DNA from Marinobacter lipolyticus 27-A9 isolated from the Antarctic Ross Sea. DNA sequence analysis revealed an open reading frame of lipolytic enzyme gene. The gene translates a protein (LipA9) of 404 amino acids with molecular mass of 45,247 Da. Recombinant LipA9 was expressed in E. coli BL21 (DE3) cells and purified by anion exchange and gel filtration chromatography. The kcat/Km of LipA9 was 175 s−1 μM−1, and the optimum temperature and pH were 70 °C and pH 8.0, respectively. LipA9 had quite high organic solvent stability; it was stable toward several common organic solvents up to 50% concentration. Substrate specificity studies showed that LipA9 preferred a short acyl chain length of p-nitrophenyl ester and triglyceride. Sequence analysis showed that LipA9 contained catalytic Ser72 and Lys75 in S-x-x-K motif, like family VIII esterases. Homology modeling and site-directed mutagenesis studies revealed that Tyr141 and Tyr188 residues were located near the conserved motif and played an important role in catalytic activity. [ABSTRACT FROM AUTHOR]

Purkinje neurons, the sole output of the cerebellar cortex, deliver GABA-mediated inhibition to the deep cerebellar nuclei. To subserve this critical function, Purkinje neurons fire repetitively, and at high frequencies, features that have been linked to the unique properties of the voltage-gated sodium (Nav) channels expressed. In addition to the rapidly activating and inactivating, or transient, component of the Nav current (INaT) present in many types of central and peripheral neurons, Purkinje neurons, also expresses persistent (INaP) and resurgent (INaR) Nav currents. Considerable progress has been made in detailing the biophysical properties and identifying the molecular determinants of these discrete Nav current components, as well as defining their roles in the regulation of Purkinje neuron excitability. Here, we review this important work and highlight the remaining questions about the molecular mechanisms controlling the expression and the functioning of Nav currents in Purkinje neurons. We also discuss the impact of the dynamic regulation of Nav currents on the functioning of individual Purkinje neurons and cerebellar circuits. [ABSTRACT FROM AUTHOR]

Considering the high mortality rate encountered in lung cancer, there is a strong need to explore new biomarkers for early diagnosis and also improved therapeutic targets to overcome this issue. The implementation of microRNAs as important regulators in cancer and other pathologies expanded the possibilities of lung cancer management and not only. MiR-21 represents an intensively studied microRNA in many types of cancer, including non-small cell lung cancer (NSCLC). Its role as an oncogene is underlined in multiple studies reporting the upregulated expression of this sequence in patients diagnosed with this malignancy; moreover, several studies associated this increased expression of miR-21 with a worse outcome within NSCLC patients. The same pattern is supported by the data existent in the Cancer Genome Atlas (TCGA). The carcinogenic advantage generated by miR-21 in NSCLC resides in the target genes involved in multiple pathways such as cell growth and proliferation, angiogenesis, invasion and metastasis, but also chemo- and radioresistance. Therapeutic modulation of miR-21 by use of antisense sequences entrapped in different delivery systems has shown promising results in impairment of NSCLC. Hereby, we review the mechanisms of action of miR-21 in cancer and the associated changes upon tumor cells together a focused perspective on NSCLC signaling, prognosis and therapy. [ABSTRACT FROM AUTHOR]

The conduction characteristics of a L-shaped waveguide in a diamond structure photonic crystal is investigated in this paper. The waveguides were fabricated with titanium dioxide ceramic via 3-D printing and sintering. The effects of the position and size of line defects on the transmission characteristics are first simulated using a finite-difference time-domain method. The simulated results show that, when the length of the rectangular defect equals the lattice constant, multiple extended modes are generated. When the centers of the single unit cell of the diamond structure and the line defect waveguide coincide, higher transmission efficiency in the line defect can be achieved. In addition, the corner of the L-shaped waveguide was optimized to reduce reflection loss at the turning point using the arc transition of the large diameter. Our experimental results indicate that L-shaped waveguides with an optimized photonic band gap structure and high-K materials can produce a pass-band between 13.8 GHz and 14.4 GHz and increase transmission efficiency. The computed results agree with the experimental results. Our results may help the integration of microwave devices in the future and possibly enable new applications of photonic crystals. [ABSTRACT FROM AUTHOR]

Exosomes are microvesicles released by cells in both physiological and pathological situations. They are surrounded by a lipid bilayer with proteins derived from the origin cell, and contain a variety of molecules, such as nucleic acids. They represent an emerging mechanism of intercellular communication, and they play an important role in the pathogenesis of cancer, stimulating proliferation and aggressiveness of cancer cells, inducing a microenvironment favorable to tumor development and controlling immune responses. Because of the growing understanding of the potential implications of extracellular vesicles in the development of malignancies, research on exosomes, and its role as a diagnostic and therapeutic tool, constitutes nowadays a very exciting and promising field. [ABSTRACT FROM AUTHOR]

Purpose of review: Exosomes are extracellular vesicles of 30-150 nm diameter, secreted from nearly all mammalian cells through fusion of multivesicular bodies with the plasma membrane. Owing to the differences in the properties of exosomes and microvesicles released through outward budding of the plasma membrane, exosomes have recently received increasing interest. This review discusses the current status of exosome research for diagnostic biomarkers in cancers. The scope of information that can be acquired from exosomal contents potentially include tumour progression, detection of metastasis, and possible chemotherapeutic resistance, which can facilitate clinical decisions in precision medicine.Recent findings: Exosomes protect molecular components including miRNAs and proteins from enzymatic degradation during circulation and serve as stable cargo for them. miRNAs transferred by exosomes have emerged as novel regulators of cellular function in various types of cancers. In addition, exosomes contain numerous plasma membrane and cytosolic proteins and exosome- specific proteins. However, many of the experiments are limited in their methods for the isolation and purification of exosomes. Nevertheless, the physiological and pathological significance of the role of exosomes in miRNA- or protein-based cell-to-cell or tissue-to-tissue communication has been highlighted. [ABSTRACT FROM AUTHOR]

Stibnite (SbS) semiconducting material was successfully synthesized by a rapid and facile microwave route using antimony chloride (SbCl) and sodiumthiosulfate (NaSO) dissolved in propylene glycol (PG) containing different hydroxyethyl cellulose (HEC) masses. The phase identification, morphology, and elemental composition of products were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), field- emission scanning electron microscopy (FE-SEM), energy dispersive X-ray (EDX) spectroscopy, and Fourier transform infrared spectroscopy (FTIR). The results revealed the orthorhombic phase of SbS single crystal-forming sheaf-like nanostructure, and a possible formation mechanism was proposed and discussed. Its direct band gap calculated from UV-visible absorption is 1.60 eV. In this research, the photocatalytic activities of SbS nanostructure were investigated through the degradation of methyl orange (MO) and methylene blue (MB) under visible light irradiation. The as-obtained 0.30 g HEC-added solution (0.3 HEC-SbS) photocatalyst exhibited better photocatalytic activity than the other products, which degraded 91% of MO within 300 min and 90% of MB within 240 min under the Xe-lamp irradiation. The first-order plot was fitted with this experiment which the rate constant ( k) of 0.3 HEC-SbS for MO and MB degradation are 0.0085 and 0.0098 min, respectively. Therefore, the new experience with a novel and simple synthetic procedure of SbS photocatalyst that exhibits the characteristics of a highly effective photocatalyst under visible light irradiation was discovered. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium channels initiate action potentials in brain neurons. In the 1970s, much was known about the function of sodium channels from measurements of ionic currents using the voltage clamp method, but there was no information about the sodium channel molecules themselves. As a postdoctoral fellow and staff scientist at the National Institutes of Health, I developed neurotoxins as molecular probes of sodium channels in cultured neuroblastoma cells. During those years, Bruce Ransom and I crossed paths as members of the laboratories of Marshall Nirenberg and Philip Nelson and shared insights about sodium channels in neuroblastoma cells from my work and electrical excitability and synaptic transmission in cultured spinal cord neurons from Bruce's pioneering electrophysiological studies. When I established my laboratory at the University of Washington in 1977, my colleagues and I used those neurotoxins to identify the protein subunits of sodium channels, purify them, and reconstitute their ion conductance activity in pure form. Subsequent studies identified the molecular basis for the main functions of sodium channels-voltage-dependent activation, rapid and selective ion conductance, and fast inactivation. Bruce Ransom and I re-connected in the 1990s, as ski buddies at the Winter Conference on Brain Research and as faculty colleagues at the University of Washington when Bruce became our founding Chair of Neurology and provided visionary leadership of that department. In the past decade my work on sodium channels has evolved into structural biology. Molecular modeling and X-ray crystallographic studies have given new views of sodium channel function at atomic resolution. Sodium channels are also the molecular targets for genetic diseases, including Dravet Syndrome, an intractable pediatric epilepsy disorder with major co-morbidities of cognitive deficit, autistic-like behaviors, and premature death that is caused by loss-of-function mutations in the brain sodium channel Na1.1. Our work on a mouse genetic model of this disease has shown that its multi-faceted pathophysiology and co-morbidities derive from selective loss of electrical excitability and action potential firing in GABAergic inhibitory neurons, which disinhibits neural circuits throughout the brain and leads directly to the epilepsy, premature death and complex co-morbidities of this disease. It has been rewarding for me to use our developing knowledge of sodium channels to help understand the pathophysiology and to suggest potential therapeutic approaches for this devastating childhood disease. [ABSTRACT FROM AUTHOR]

1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels. Compounds 7c, 7g and 7i appear to be the most effective positive inotropes, even at low doses, and bind with the calcium channels even more strongly than Bay K 8644, a well-known calcium channel activator. The chronotropic effect for the new compounds was also studied. The target and off-target affinity profiling supported the in vivo results and revealed that the hybridized pyranopyrazole dihydropyridine scaffold has delivered new moderate hits, to be optimized, for the cytochrome P450 3A4 enzymes, opening avenues for combined pharmacological activity through standard structural modification. Graphical Abstract : [ABSTRACT FROM AUTHOR]

Ginsenosides are believed to be the principal components behind the pharmacological actions of ginseng, and their bioactive properties are closely related to the type, position, and number of sugar moieties attached to the aglycone; thus, modification of the sugar chains may markedly change their biological activities. In this study, major protopanaxadiol type ginsenosides (PD) Rb1, Rc, and Rb2 were isolated from Panax ginseng and were transformed using two probiotic strains namely Bifidobacterium lactis Bi-07 and Lactobacillus rhamnosus HN001 to obtain specific deglycosylated ginsenosides. It was demonstrated that B. lactis transformed ginsenosides Rb1, Rc, and Rb2 to Rd within 1 h of fermentation and rare ginsenoside F2 by the conversion of Rd after 12-h fermentation. The maximum Rd concentration was 147.52 ± 1.45 μg/mL after 48-h fermentation as compared to 45.85 ± 0.71 μg/mL before fermentation. In contrast, L. rhamnosus transformed Rb1, Rc, and Rb2 into Rd as the final metabolite after 72-h fermentation. B. lactis displayed significantly ( p < 0.05) higher β-glucosidase activity against p-nitrophenyl-β-glucopyranoside than L. rhamnosus and higher bioconversion efficiency during fermentation. The present study suggests that the fermentation of major PD type ginsenosides with B. lactis Bi-07 may serve as an effective means to afford bioactive deglycosylated ginsenosides and to create novel ginsenoside extracts. [ABSTRACT FROM AUTHOR]

Umbelliferone, 4-methyl-umbelliferone and their farnesyloxy and geranyloxy analogues were synthesized and evaluated for their antioxidant and soybean lipoxygenase inhibitory activity as well as their cytotoxicity against human neuroblastoma cell line SK-N-SH and human hepatoma cell line HepG2. Auraptene ( 3), followed by 4-methyl-auraptene ( 4) exhibit modest cytotoxity against the HepG2 cell line. The novel coumarin 6 combines a satisfactory lipoxygenase inhibitory activity with potent cytotoxicity against SK-N-SH cells, but not against HepG2 cells, thus it could be considered as a lead compound for the development of novel therapeutic agents against neuroblastoma. [ABSTRACT FROM AUTHOR]

Microsatellite instability (MSI) refers to the biochemical detection of frameshifted microsatellite sequences from genomic DNA. Genesis of MSI is due to defective DNA mismatch repair (MMR) that fails to correct post-DNA replicative slippage mistakes at microsatellites. Most of the estimated 100,000 genomic microsatellites are non-coding; however, ∼150-300 microsatellites are coding such that, when frameshifted during the pathogenesis of an MSI tumor, they can generate immunogenic neopeptide antigens that limit the growth of tumor and prolong patient survival. In addition to the immune reaction and longer survival, patients with MSI colorectal cancers tend to have poorly differentiated tumors with mucinous features that are located in the right colon. Patients with MSI tumors are more resistant to 5-fluorouracil-based adjuvant chemotherapy but may be responsive to PD-1 immune checkpoint blockade. Specific defects of MMR function not only drive MSI but also elevate microsatellite alterations at selected tetranucleotide repeats that may further modify patient outcome. [ABSTRACT FROM AUTHOR]

2-Hydroxyethylammonium acetate ionic liquid was found to be an excellent catalyst for the one-pot synthesis of 1,4-dihydropyridine derivatives via Hantzsch reaction of ethyl acetoacetate or acetoacetanilide, ammonium acetate, and various aromatic aldehydes. The combinatorial syntheses were achieved for the first time using 2-hydroxyethylammonium acetate ionic liquid as a homogeneous catalyst. The catalyst was active for the Hantzsch reaction in alcohol at reflux. The products were isolated in good yields (78-93 %). The resulting substituted dihydropyridines were characterized and confirmed byH NMR spectral data. The catalyst offers simple means for recovery and the isolated catalyst was reused for three rounds for the synthesis without significant loss of catalytic activity. For all the other reactions carried out with the recycled catalyst, results were similar to that with the fresh catalyst. Graphical abstract: [ABSTRACT FROM AUTHOR]

Ginseng has been used for thousands of years in Asian countries as a traditional medicinal herb and has gained great popularity in the past decade. Ginsenosides are the major pharmacological components in ginseng. We here show that Cladosporium cladosporioide is able to convert the major ginsenoside Rb1 into four known metabolites (ginsenosides Rd, F2, CK and PPD) and two new metabolites [12 β-hydroxydammar-3-one-20( S)- O- β- d-glucopyranoside (3-oxo-CK) and dammar-24-en-12 β,20( S)-diol-3-one (3-oxo-PPD)]. CK, PPD and 3-oxo-PPD were shown to have a potent antiproliferative activity against A549 lung cancer cells. We found that Rb1 → Rd → F2 → CK → PPD or 3-oxo-CK → 3-oxo-PPD represents the ginsenoside metabolic pathway. [ABSTRACT FROM AUTHOR]