Development of Aromatic-Linked Diamino Acid Antimicrobial Peptide Mimics with Low Hemolytic Toxicity and Excellent Activity against Methicillin-Resistant Staphylococcus aureus (MRSA).

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have become one of the biggest threats to public health. To develop new antibacterial agents against MRSA, a series of diamino acid compounds with aromatic nuclei linkers were designed and synthesized. Compound 8j, which exhibited low hemolytic toxicity and the best selectivity against S. aureus (SI > 2000), showed good activity against clinical MRSA isolates (MIC = 0.5-2 µg/mL). Compound 8j was able to quickly kill bacteria without inducing bacterial resistance. A mechanistic study and transcriptome analysis revealed that compound 8j can act on phosphatidylglycerol and induce the accumulation of endogenous reactive oxygen species, which can destroy bacterial membranes. Importantly, compound 8j achieved a 2.75 log reduction of MRSA count at 10 mg/kg/d in a mouse subcutaneous infection model. These findings suggested that compound 8j had the potential to be an antibacterial agent against MRSA.

Phytoecdysteroids from Dianthus superbus L.: Structures and anti-neuroinflammatory evaluation.

Six undescribed C27-phytoecdysteroid derivatives, named superecdysones A-F, and ten known analogs were extracted from the whole plant of Dianthus superbus L. Their structures were identified by extensive spectroscopy, mass spectrometric methods, chemical transformations, chiral HPLC analysis, and the single-crystal X-ray diffraction analysis. Superecdysones A and B possess a tetrahydrofuran ring in the side chain and superecdysones C-E are rare phytoecdysones containing a (R)-lactic acid moiety, whereas superecdysone F is an uncommon B-ring-modified ecdysone. Notably, based on the variable temperature (from 333 K to 253 K) NMR experiments of superecdysone C, the missing carbon signals were visible at 253 K and assigned. The neuroinflammatory bioassay of all compounds were evaluated, and 22-acetyl-2-deoxyecdysone, 2-deoxy-20-hydroxyecdysone, 20-hydroxyecdysone, ecdysterone-22-O-benzoate, 20-hydroxyecdysone-20,22-O-R-ethylidene, and acetonide derivative 20-hydroxyecdysterone-20, 22-acetonide significantly suppressed the LPS-induced nitric oxide generation in microglia cells (BV-2), with IC50 values ranging from 6.9 to 23.0 µM. Structure-activity relationships were also discussed. Molecular docking simulations of the active compounds confirmed the possible mechanism of action against neuroinflammations. Furthermore, none compounds showed cytotoxicity against HepG2 and MCF-7. It is the first report about the occurrence and anti-neuroinflammatory activity of the phytoecdysteroids in the genus Dianthus. Our findings demonstrated that ecdysteroids may be used as potential anti-inflammatory drugs.

Neonatal Cri du chat syndrome with atypical facial appearance: A case report.

BACKGROUND: Cri du chat syndrome (CdCS), also known as 5p deletion syndrome (5p-) is a syndrome caused by partial deletion of the 5p chromosome in human beings. The incidence accounts for 1/50000 and the cause of CdCS is related to partial deletion of chromosome 5 short arm (p). CdCS is a sporadic event. Only one case of CdCS was detected by chromosome screening in 125 and 170 pregnant Iranian women[1]. The most prominent clinical manifestations of CdCS are typical high-pitched cat calls, severe mental retardation or mental retardation and is most harmful to both language and growth retardation[2]. CdCS is a chromosome mutation disease which occurs during embryonic development and the symptoms of some cases are extremely atypical. It is difficult to make an early diagnosis and screening in clinic. We can suspect the disease from its atypical manifestations in the weak crying of cats, and chromosome karyotype analysis can find some questionable gene deletion fragments to assist the clinical diagnosis and prognosis of CdCS. CASE SUMMARY: A 2-d-old male child who was admitted to our hospital with a poor postnatal reaction and poor milk intake. The baby's crying and sucking is weak, reaction and feeding time is poor and the baby has nausea and vomiting. Karyotype analysis showed that the chromosomes were 46, XY, deletion (5) p15. Whole genome microarray analysis (named ISCN2013) showed that the chromosomes of the child were male karyotypes and contained three chromosomal abnormalities. Among them, loss of 5p15.2pter (113576-13464559) was associated with cat call syndrome. After 3 mo of follow-up, the child still vomited repeatedly, had poor milk intake, did not return to normal growth, had developmental retardation and a poor directional response. CONCLUSION: Therefore, when cat crying and laryngeal sounds occur in the neonatal period, it should be considered that they are related to CdCS. Chromosome karyotype and genome analysis are helpful for the diagnosis of CdCS.

Mesoscopic sliding ferroelectricity enabled photovoltaic random access memory for material-level artificial vision system.

Intelligent materials with adaptive response to external stimulation lay foundation to integrate functional systems at the material level. Here, with experimental observation and numerical simulation, we report a delicate nano-electro-mechanical-opto-system naturally embedded in individual multiwall tungsten disulfide nanotubes, which generates a distinct form of in-plane van der Waals sliding ferroelectricity from the unique combination of superlubricity and piezoelectricity. The sliding ferroelectricity enables programmable photovoltaic effect using the multiwall tungsten disulfide nanotube as photovoltaic random-access memory. A complete "four-in-one" artificial vision system that synchronously achieves full functions of detecting, processing, memorizing, and powering is integrated into the nanotube devices. Both labeled supervised learning and unlabeled reinforcement learning algorithms are executable in the artificial vision system to achieve self-driven image recognition. This work provides a distinct strategy to create ferroelectricity in van der Waals materials, and demonstrates how intelligent materials can push electronic system integration at the material level.

Alpha-lipoic acid could attenuate the effect of chemerin-induced diabetic nephropathy progression.

OBJECTIVES: Chemerin is associated with insulin resistance, obesity, and metabolic syndrome. α-lipoic acid (α-LA) is a potent antioxidant involved in the reduction of diabetic symptoms. This study aimed to investigate the relationship between chemerin and P38 MAPK in the progression of diabetic nephropathy (DN) and examine the effects of α-LA on chemerin-treated human mesangial cells (HMCs). MATERIALS AND METHODS: HMCs were transfected with a chemerin-overexpressing plasmid. HMCs were also treated with high-glucose, chemerin, α-LA, PDTC (pyrrolidine dithiocarbamate ammonium, NF-κB p65 inhibitor), and/or SB203580 (P38 MAPK inhibitor). Cell proliferation was tested using the Cell Counting Kit-8 assay. Collagen type IV and laminin were tested by ELISA. Chemerin expression was detected by qRT-PCR. The chemerin receptor was detected by immunohistochemistry. Interleukin-6 (IL-6), tumor necrosis factor-a (TNF-α), nuclear factor-κBp-p65 (NF-κB p-p65), transforming growth factor-ß (TGF-ß), and p-P38 mitogen-activated protein kinase (p-P38 MAPK) were evaluated by western blot. RESULTS: High-glucose culture increased the expression of the chemerin receptor. α-LA inhibited HMC proliferation. Chemerin overexpression increased collagen type IV and laminin expression. P38 MAPK signaling was activated by chemerin, resulting in up-regulation of IL-6, TNF-α, NF-κB p-p65, and TGF-ß. SB203580, PDTC, and α-LA reversed the effects of chemerin, reducing IL-6, TNF-α, NF-κB p-p65, and TGF-ß expression. CONCLUSION: Chemerin might be involved in the occurrence and development of DN. α-LA might prevent the effects of chemerin on the progression of DN, possibly via the P38 MAPK pathway.

Field-effect at electrical contacts to two-dimensional materials.

The inferior electrical contact to two-dimensional (2D) materials is a critical challenge for their application in post-silicon very large-scale integrated circuits. Electrical contacts were generally related to their resistive effect, quantified as contact resistance. With a systematic investigation, this work demonstrates a capacitive metal-insulator-semiconductor (MIS) field-effect at the electrical contacts to 2D materials: The field-effect depletes or accumulates charge carriers, redistributes the voltage potential, and gives rise to abnormal current saturation and nonlinearity. On one hand, the current saturation hinders the devices' driving ability, which can be eliminated with carefully engineered contact configurations. On the other hand, by introducing the nonlinearity to monolithic analog artificial neural network circuits, the circuits' perception ability can be significantly enhanced, as evidenced using a coronavirus disease 2019 (COVID-19) critical illness prediction model. This work provides a comprehension of the field-effect at the electrical contacts to 2D materials, which is fundamental to the design, simulation, and fabrication of electronics based on 2D materials. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (results of the simulation and SEM) is available in the online version of this article at 10.1007/s12274-021-3670-y.

H2dpa derivatives containing pentadentate ligands: An acyclic adjuvant potentiates meropenem activity in vitro and in vivo against metallo-ß-lactamase-producing Enterobacterales.

The emergence and dissemination of metallo-ß-lactamases (MBLs) producing Enterobacterales is a great concern for public health due to the limited therapeutic options. No MBL inhibitors are currently available in clinical practice. Herein, we synthesized a series of H2dpa derivatives containing pentadentate-chelating ligands and evaluated their inhibitory activity against MBLs. Related compounds inhibited clinically relevant MBLs (Imipenemase, New Delhi metallo-ß-lactamase (NDM) and Verona integron-encoded metallo-ß-lactamase) with IC50 values of 1-4.9 µM. In vitro, the most promising compounds, 5b and 5c, which had a chiral methyl at the acid adjacent to 5a, demonstrated potent synergistic activity against engineered strains, with fractional inhibitory concentration index values as low as 0.07-0.18. The addition of 5b and 5c restored meropenem efficacy against 42 MBL-producing Enterobacterales and Pseudomonas aeruginosa to satisfactory clinical levels. In addition, safety tests revealed that 5b/5c showed no toxicity in red blood cells, cell lines or mouse model. Further studies demonstrated that compounds 5b and 5c were non-competitive MBL inhibitors. In vivo compounds 5b and 5c potentiated meropenem efficacy and increased the survival rate from 0 to at least 83% in mice with sepsis caused by an NDM-1-positive clinical strain. The activity of the compounds exhibited consistency at the molecular, cellular, and in vivo levels. These data indicated that H2dpa derivatives 5b and 5c containing pentadentate-chelating ligands may be worthy of further study.

Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-ß-lactamase-1.

New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.

Synthesis and Bioactivities of New Membrane-Active Agents with Aromatic Linker: High Selectivity and Broad-Spectrum Antibacterial Activity.

The worldwide emergence of microbial resistance to antibiotics constitutes an important and growing public health threat, and novel antibiotics are urgently needed. In this report, a series of symmetrical membrane-active agents linked by an aromatic nucleus were designed and synthesized. Some showed high antibacterial activity against clinical drug-resistant bacterial isolates including methicillin-resistant Staphylococcus aureus (MRSA), carbapenemase-producing Enterobacter aerogenes, and delhi metallo-ß-lactamase-1-producing Enterobacteriaceae (NDM-1), as well as drug-sensitive bacteria including Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Stenotrophomonas maltophilia. Lead compound 2n, with good selectivity for S. aureus (minimum inhibitory concentration [MIC] 0.25 µg/mL) versus mammalian erythrocytes (hemolytic concentration [HC50] 1211 µg/mL), had notable properties, including stability in complex mammalian fluids, rapid killing of pathogens, ability to eradicate established biofilms, and little induction of bacterial drug-resistance. In a mouse MRSA infection model, compound 2n exhibited a similar level of efficacy to vancomycin in killing bacteria and suppressing inflammation, demonstrating its therapeutic potential.

Low-toxicity amphiphilic molecules linked by an aromatic nucleus show broad-spectrum antibacterial activity and low drug resistance.

Amphiphilic molecules linked by an aromatic nucleus were developed that showed high selectivity toward bacteria over mammalian cells, and low drug resistance. A promising compound 4g exhibited strong bactericidal activity against a panel of sensitive and resistant bacteria, low toxicity, the ability to reduce cell viability in biofilms, stability in mammalian fluids, rapid killing of pathogens, and high in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA).

Association between vaspin level and coronary artery disease in patients with type 2 diabetes.

AIM: Adipokines contribute to the atherosclerotic process, connecting obesity and diabetes to cardiovascular disease. Vaspin is a recently discovered adipokine, so data about the relationship of vaspin to coronary artery disease in type-2 diabetes mellitus (T2DM) is limited. The current study was designed to evaluate the association of vaspin with the presence of coronary artery disease in T2DM. METHODS: We enrolled 228 patients with T2DM, with or without CAD, between March 2010 and July 2011, and 120 healthy control participants. Serum vaspin, homeostasis model assessment of insulin resistance (HOMA-IR) and other cardiovascular risk factors were assayed. RESULTS: Vaspin levels were significantly increased in patients with T2DM compared to healthy individuals, and were further increased in patients with both T2DM and CAD compared to those with T2DM but without CAD. Moreover, vaspin correlated positively with body mass index, fasting plasma glucose, insulin and HOMA-IR in all patients with T2DM (P<0.05). Furthermore, in multivariate logistic regression analysis, vaspin level was associated with the presence of CAD in patients with T2DM. CONCLUSIONS: Vaspin correlates with CAD in T2DM.

Effect of Irbesartan on Chemerin in the Renal Tissues of Diabetic Rats.

BACKGROUND/AIMS: Chemerin was introduced as a novel adipokine that plays a crucial role in insulin signaling and diabetic nephropathy. Serum chemerin levels are significantly elevated in type 2 diabetes patients with macroalbuminuria. However, the underlying mechanisms remain unclear. We conducted a preliminary investigation of the effects of the renin-angiotensin system (RAS) on chemerin expression in streptozotocin-induced diabetic rats. METHODS: Streptozotocin-induced diabetic rats were randomized into control, diabetic, and irbesartan-treated groups. Real-time polymerase chain reaction was used to detect mRNA expression of chemerin, angiotensin II type 1a receptor (AT1a), angiotensin II type 1b receptor (AT1b) and angiotensin II type 2 receptor (AT2). Immunohistochemical staining was used to detect chemerin in renal tissues. RESULTS: Expression levels of chemerin in renal tissues were significantly elevated in the diabetic group compared to the control group. In the irbesartan-treated group, chemerin expression levels and RAS-related protein levels (i.e. AT1a and AT1b) were markedly decreased compared to the diabetic group. Irbesartan treatment reduced chemerin overexpression and RAS-related protein levels in diabetic rats (i.e. AT1a and AT1b). CONCLUSION: Irbesartan may inhibit intrarenal RAS in diabetic rats, which may affect the expression of chemerin in the kidneys; however, the precise underlying mechanism remains to be determined.

Damage to vascular endothelial cells by high insulin levels is associated with increased expression of ChemR23, and attenuated by PPAR-gamma agonist, rosiglitazone.

OBJECTIVE: This study investigated the effect of different insulin concentrations on the activity of vascular endothelial cells (VECs), and the role of PPARγ activator rosiglitazone (RGZ) on the expression of the chemerin receptor, ChemR23, in insulin-treated human umbilical vein endothelial cells (HUVECs). METHODS: Cell viability was determined in HUVECs treated with different insulin concentrations. Immunofluorescence staining was used to detect ChemR23 expression in insulin-treated HUVECs. Western blot assays were used to evaluate ChemR23 and PPARγ protein expression in insulin-treated HUVECs after pretreatment with PPARγ activator (RGZ) or inhibitor (GW9662). RESULTS: High insulin concentrations significantly inhibited HUVEC cell viability compared to low insulin concentrations, and this inhibition was attenuated by pretreatment with RGZ. High concentrations of insulin caused a significant upregulation of ChemR23 and a significant downregulation of PPARγ. These effects were attenuated by RGZ pretreatment, while PPARγ antagonist, GW9662 reversed this attenuation. CONCLUSION: ChemR23 upregulation may play a role in VEC damage caused by high concentrations of insulin. The protective effect of PPARγ activation in VECs may be mediated via ChemR23 downregulation.

Soluble epoxide hydrolase inhibitory and anti-inflammatory components from the leaves of Eucommia ulmoides Oliver (duzhong).

Eucommia ulmoides leaves have been used as a functional food and drink in China. The purpose of this study was to identify the bioactive constituents with soluble epoxide hydrolase (sEH) inhibitory activity and anti-inflammatory properties. Twenty-seven known compounds (1-27) were isolated from the leaves of E. ulmoides Oliver, and their structures were identified by NMR and ESIMS analysis; three of these, 2,5-dimethoxy-3-glucopyranosyl cinnamic alcohol (11), foliasalacioside E2 (26), and icariside F2 (27), were obtained from this plant for the first time. Compounds 1-7 exhibited soluble epoxide hydrolase (sEH) inhibitory activity at 100 µM; among them, quercetin (1) and kaempferol (5) displayed potential activities with IC50 values of 22.5 ± 0.9 and 31.3 ± 2.6 µM, respectively, with noncompetitive inhibition mode. Nuclear factor kappa B (NF-κB) inhibitory activity of the isolated compounds was evaluated by the NF-κB liciferase assay in HepG2 cells. Compounds 1, 9, 20, and 27 displayed potent NF-κB inhibitory effects, with IC50 values of 15.14 ± 2.29, 15.23 ± 2.34, 16.88 ± 2.17, and 16.25 ± 2.19 µM, respectively, whereas other compounds showed weak inhibition of NF-κB transcriptional activity ranging from 17.54 to 92.6 µM. A structure-activity relationship of flavonoids 1-9 was also discussed. The results obtained in this work might contribute to the understanding of pharmacological activities of E. ulmoides leaves and further investigation on its potential application values for food and drug.

Anxiolytic and sedative activities of Passiflora edulis f. flavicarpa.

AIM OF THE STUDY: Many plants in the genus Passiflora have long been used in traditional folk medicines as a remedy for many neurogenic diseases in many countries. A number of species of the genus was studied about their neuropharmacological activities, but the results were inconsistent. No literature reported neuropharmacological studies on Passiflora edulis f. flavicarpa as yet. The present study was aimed at evaluating the anxiolytic and sedative activities of Passiflora edulis f. flavicarpa. MATERIALS AND METHODS: Swiss albino mice were used as experimental animals in elevated plus-maze (EPM) test and spontaneous activity (SA) test to assay the behavioral effects of ethanolic extract (EE) of the aerial part of Passiflora edulis f. flavicarpa and its fractions, viz. petrol ether extract (PEE), ethyl acetate extract (EAE), n-BuOH extract (BE) and aqueous extract (AE), together with subfractions of BE, viz. BEF-I, BEF-II, BEF-III, BEF-IV and isoorientin, a flavonoid component isolated from BEF-III. RESULTS: In the EPM test, single-dose oral administration of EE (300 mg/kg and 400mg/kg), BE (125 mg/kg and 200mg/kg), AE (200mg/kg and 300 mg/kg), BEF-I (200mg/kg), BEF-II (200mg/kg), BEF-III (100mg/kg), or isoorientin (20mg/kg) resulted in anxiolytic-like effects, but a sedative-like activity was produced at higher doses, such as 300 mg/kg of BE, 200mg/kg of BEF-III, or 40 mg/kg and 80 mg/kg of isoorientin. The results of the SA test manifested that treatment with 400mg/kg of EE, 300 mg/kg of BE, or 40 mg/kg and 80 mg/kg of isoorientin compromised motor activity in mice, which are in line with the results of the EPM test. CONCLUSIONS: The aerial part of Passiflora edulis f. flavicarpa was anxiolytic at low dose but sedative at high dose. Flavonoids are important active constituents. Since AE contained little flavonoids, it was conjectured that there were other components responsible for the anxiolytic effect of Passiflora edulis f. flavicarpa besides flavonoids.