Target organ damage in untreated hypertensive patients with primary aldosteronism.

An increased risk of target organ damage (TOD) has been reported in patients with primary aldosteronism (PA). However, there is relatively little related research on the correlation between the degree of TOD and those with and without PA in newly diagnosed hypertensive patients. The aim of this study was to assess the association between PA and TOD among patients with newly diagnosed hypertension. Newly diagnosed hypertensive patients were consecutively recruited from January 2015 to June 2020 at the University of Hong Kong-Shenzhen Hospital. Patients were stratified into those with and without PA. Data for left ventricular mass index (LVMI), carotid intima-media thickness (CIMT) and plaque, and microalbuminuria were systematically collected. A total of 1044 patients with newly diagnosed hypertension were recruited, 57 (5.5%) of whom were diagnosed with PA. Patients with PA had lower blood pressure, serum lipids, body mass index, and plasma renin activity and a higher incidence of hypokalemia than those without PA. In contrast, the prevalence of left ventricular hypertrophy, increased CIMT, and microalbuminuria was higher in patients with PA than in those without PA. Multivariable regression analysis demonstrated that PA was independently associated with increased LVMI, CIMT and microalbuminuria. Among patients with newly diagnosed hypertension, those with PA had more severe TOD, including a higher LVMI, CIMT and microalbuminuria, than those without PA. These findings emphasize the need for screening TOD in newly diagnosed hypertension due to underlying PA.

A de novo Mutation (p.Gln277X) of Cyclin D2 is Responsible for a Child with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), a type of overgrowth syndrome, is characterized by progressive megalencephaly, cortical brain malformations, and distal limb anomalies. Previous studies have revealed that the overactivity of the phosphatidylinositol 3-kinase-Protein kinase B pathway and the increased cyclin D2 (CCND2) expression were the main factors contributing to this disease. Here, we present the case of a patient who exhibited megalencephaly, polymicrogyria, abnormal neuronal migration, and developmental delay. Serum tandem mass spectrometry and chromosome examination did not detect any metabolic abnormalities or copy number variants. However, whole-exome sequencing and Sanger sequencing revealed a de novo nonsense mutation (NM_001759.3: c.829C>T; p.Gln277X) in the CCND2 gene of the patient. Bioinformatics analysis predicted that this mutation may disrupt the structure and surface charge of the CCND2 protein. This disruption could potentially prevent polyubiquitination of CCND2, leading to its resistance against degradation. Consequently, this could drive cell division and growth by altering the activity of key cell cycle regulatory nodes, ultimately contributing to the development of MPPH. This study not only presents a new case of MPPH and expands the mutation spectrum of CCND2 but also enhances our understanding of the mechanisms connecting CCND2 with overgrowth syndromes.

Case report: A novel variant (H49N) in Myelin Protein Zero gene is responsible for a patient with Charcot-Marie-Tooth disease.

This report presents a case of Charcot-Marie-Tooth dominant intermediate D (CMTDID), a rare subtype of Charcot-Marie-Tooth disease, in a 52 years-old male patient. The patient exhibited mobility impairment, foot abnormalities (pes cavus), and calf muscle atrophy. Whole exome sequencing and Sanger sequencing suggested that a novel variant (NM_000530.8, c.145C>A/p.His49Asn) of MPZ may be the genetic lesion in the patient. The bioinformatic program predicted that the new variant (p.His49Asn), located at an evolutionarily conserved site of MPZ, was neutral. Our study expands the variant spectrum of MPZ and the number of identified CMTDID patients, contributing to a better understanding of the relationship between MPZ and CMTDID.

Visible-light-induced synthesis of N-disulfanyl indoles, pyrroles or carbazoles via the construction of stable S-S-N bonds.

A simple and efficient visible-light-induced approach for the formation of stable S-S-N bonds has been developed. Through these photocatalytic reactions, a series of N-disulfanyl indoles, pyrroles and carbazoles were afforded with good to excellent yields. Moreover, the gram-scale experiment has confirmed the practicability of this approach.

Robust Mesoporous Functional Hydrogen-Bonded Organic Framework for Hypochlorite Detection.

Although tremendous progress has been achieved in the field of hydrogen-bonded organic frameworks (HOFs), the low stability, small/none pores, and difficult functionality severely obstruct their development. Herein, a novel robust mesoporous HOF (HOF-FAFU-1) decorated with a high density of free hydroxy moieties has been designed and readily synthesized in the de novo synthesis. In HOF-FAFU-1, the planar building blocks are connected to each other by typical intermolecular carboxylate dimers to form two-dimensional (2D) layers with sql topology, which are further connected to their adjacent layers by face-to-face π-π interactions to obtain a three-dimensional (3D) open mesoporous framework. Owing to the high density of intermolecular hydrogen bonding and strong π-π interactions, HOF-FAFU-1 is very stable, allowing it to retain its structure in aqueous solutions with a pH range of 1-9. Benefiting from the decorated hydroxy moieties, HOF-FAFU-1 was exploited as a fluorescent sensor for hypochlorite detection in water media by a turn-off mode, which cannot be realized by its nonhydroxy groups anchoring counterpart (HOF-TCBP). The proposed sensing system is highly efficient, validated by a very broad linear range (0-0.45 mM), fast response (15 s), and small limit of detection (LOD) (1.32 µM). The fluorescent quenching of HOF-FAFU-1 toward hypochlorite was also investigated, mainly being ascribed to the transformation of building blocks from the fluorescent reduced state to the nonfluorescent oxidative state. This work not only demonstrates that HOFs integrated with high stability and large pores as well as high density of functional groups can be simultaneously realized by judicious design of building blocks but also conceptually elucidates that such HOFs can effectively extend the application fields of HOFs.

VEGF aptamer/i-motif-based drug co-delivery system for combined chemotherapy and photodynamic therapy.

BACKGROUND: Nucleic acids used as drug delivery systems (DDS) have gained attention because of their biosafety and effortless synthesis. G-quadruplex (G4) structured aptamer such as AS1411 was frequently employed to deliver photosensitizers or chemotherapeutic agents while other aptamers were seldomly reported in this field. METHODS: Herein, a chemical anticancer drug daunomycin (DNM), and a photosensitizer 5, 10, 15, 20-tetra (phenyl-4-N-methyl-4-pyridyl) porphyrin (TMPyP) were physically assembled with a novel DNA structure composed of an aptamer of vascular endothelial growth factor (VEGF) and a cytosine (C)-rich DNA fragment (gc-34). Spectral and molecular mimicking methods were employed to research the drug loading/releasing process. The in vitro cytotoxicity was studied by MTT, ROS, cell cycle, and cell apoptotic assays and the in vivo anticancer efficiency was evaluated by the inhibitive effect on the cancerous growth of MCF-7 tumor-bearing nude mice. RESULTS: The G4-structured VEGF aptamer delivered TMPyP successfully for the first time. The designed DDS displayed sensitive VEGF/pH controlled drug release. The co-delivery of DNM and TMPyP exhibited high ROS production, significant cell cycle arresting and evident cell apoptosis, and displayed superior cytotoxicity against tumor cells compared with individual agents in vitro. In vivo studies showed that the dual-drug loaded system can greatly inhibit tumor growth with chemotherapeutic/photodynamic synergistic effects. CONCLUSION: The co-delivery of DNM and TMPyP with aptamer/C-rich DNA successfully integrates the functions of VEGF/pH stimuli-responsive drug release and chemotherapeutic/phototherapeutic modalities into one single system, and may have great potential in cancer treatment.

Dual-emissive metal-organic framework: a novel turn-on and ratiometric fluorescent sensor for highly efficient and specific detection of hypochlorite.

Hypochlorite (ClO-) is widely used as a disinfectant, whose residue content in water should be strictly controlled due to the potential threat to human health in an inappropriate concentration. Herein, dual-emissive metal-organic frameworks with a UiO-66 prototype structure, PDA/Eu/PDA-UiO-66-NH2(x), were elegantly designed and prepared by a mixed ligand assembly and sequential post-synthesis strategy. Since blue emission is sensitive to ClO-, PDA/Eu/PDA-UiO-66-NH2(40) was selected as a model nanosensor for ratiometric and turn-on sensing of ClO- while red emission acts as a reference signal. Remarkably, PDA/Eu/PDA-UiO-66-NH2(40) shows high efficiency and specificity toward ClO- detection, as verified by a very short response time of 15 s, a wide linear range of 0.1-60 µM, a low detection limit of 0.10 µM, and excellent selectivity toward common competing ions. The recovery experiments show that the recoveries of spiking ClO- in tap water range from 96 to 103%. The rigidification of the coordinated H2N-BDC2- ligands should be responsible for the turn-on fluorescence of PDA/Eu/PDA-UiO-66-NH2(40). This work not only shows a highly efficient and specific fluorescent nanosensor for ClO- detection but also presents the first MOF-based fluorescent probe for turn-on and ratiometric sensing of ClO-.

Dual-Emissive Metal-Organic Framework as a Fluorescent "Switch" for Ratiometric Sensing of Hypochlorite and Ascorbic Acid.

The detection of hypochlorite (ClO-) content in tap water is extremely important because excess amounts of hypochlorite can convert into highly toxic species and inadequate amounts of hypochlorite cannot fully kill bacteria and viruses. Although several metal-organic frameworks (MOFs) have been successfully employed as fluorescent sensors for hypochlorite detection, all these sensors are based on single emission that responds to the dose of hypochlorite. Ratiometric sensors are highly desirable, which can improve the sensitivity, accuracy, and reliability via self-calibration. Herein, a nanoscale dual-emission multivariate 5-5-Eu/BPyDC@MOF-253-NH2 was synthesized by sequential mixed-ligand self-assembly and postsynthesis method. Among the two emission bands of 5-5-Eu/BPyDC@MOF-253-NH2, the strong blue emitting derived from ligands is sensitive to hypochlorite, while the red emitting derived from Eu(III) almost keeps invariable. Therefore, 5-5-Eu/BPyDC@MOF-253-NH2 was exploited as a fluorescent ratiometric nanosensor for "on-off" sensing of hypochlorite. Notably, the proposed sensing system showed an excellent performance including fast response (within 15 s), relative high specificity, wide linear range (0.1-30 µM), and low detection limit (0.094 µM). Besides, the suppressed blue emitting was recovered after the addition of ascorbic acid (AA) that consumes ClO- via the redox reaction. Therefore, 5-5-Eu/BPyDC@MOF-253-NH2 was further employed as a fluorescent ratiometric nanosensor for the "on-off-on" sensing of AA. This work represents the first MOF-based fluorescent "switch" for the ratiometric sensing of hypochlorite and the second for ratiometric sensing of AA.

Paeoniflorin Prevents Intestinal Barrier Disruption and Inhibits Lipopolysaccharide (LPS)-Induced Inflammation in Caco-2 Cell Monolayers.

Inflammatory bowel disease (IBD) in humans is closely related to bacterial infection and the disruption of the intestinal barrier. Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora Pallas plants, exerts a potential effect of anti-inflammatory reported in various researches. However, the effect of PF on intestinal barrier function and its related mechanisms has not been identified. Here, we investigate the PF potential anti-inflammatory effect on lipopolysaccharide (LPS)-stimulated human Caco-2 cell monolayers and explore its underlying key molecular mechanism. In this context, PF significantly increased TEER value, decreased intestinal epithelium FITC-dextran flux permeability, and restored the expressions of occludin, ZO-1, and claudin5 in LPS-induced Caco-2 cell. In vitro, treatment of PF significantly inhibited LPS-induced expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). In addition, we found that PF suppressed nuclear factor kappa B (NF-κB) signaling via activating the Nrf2/HO-1 signaling pathways in ILPS-stimulated Caco-2 cells. Our findings indicate that PF has an inhibitory effect on endothelial injury. Our findings suggested that PF has an anti-inflammatory effect in ILPS-stimulated Caco-2 cells, which might be a potential therapeutic agent against IBD and intestinal inflammation.

Salicylic acid amplifies Carbachol-induced bronchoconstriction in human precision-cut lung slices.

BACKGROUND: Asthma exacerbations evoke emergency room visits, progressive loss of lung function and increased mortality. Environmental and industrial toxicants exacerbate asthma, although the underlying mechanisms are unknown. We assessed whether 3 distinct toxicants, salicylic acid (SA), toluene diisocyanate (TDI), and 1-chloro-2,4-dinitrobenzene (DNCB) induced airway hyperresponsiveness (AHR) through modulating excitation-contraction coupling in human airway smooth muscle (HASM) cells. The toxicants include a non-sensitizing irritant (SA), respiratory sensitizer (TDI) and dermal sensitizer (DNCB), respectively. We hypothesized that these toxicants induce AHR by modulating excitation-contraction (EC) coupling in airway smooth muscle (ASM) cells. METHODS: Carbachol-induced bronchoconstriction was measured in precision-cut human lung slices (hPCLS) following exposure to SA, TDI, DNCB or vehicle. Culture supernatants of hPCLS were screened for mediator release. In HASM cells treated with the toxicants, surrogate readouts of EC coupling were measured by phosphorylated myosin light chain (pMLC) and agonist-induced Ca2+ mobilization ([Ca2+]i). In addition, Nrf-2-dependent antioxidant response was determined by NAD(P) H quinone oxidoreductase 1 (NQO1) expression in HASM cells. RESULTS: In hPCLS, SA, but not TDI or DNCB, potentiated carbachol-induced bronchoconstriction. The toxicants had little effect on release of inflammatory mediators, including IL-6, IL-8 and eotaxin from hPCLS. In HASM cells, TDI amplified carbachol-induced MLC phosphorylation. The toxicants also had little effect on agonist-induced [Ca2+]i. CONCLUSION: SA, a non-sensitizing irritant, amplifies agonist-induced bronchoconstriction in hPCLS via mechanisms independent of inflammation and Ca2+ homeostasis in HASM cells. The sensitizers TDI and DNCB, had little effect on bronchoconstriction or inflammatory mediator release in hPCLS. IMPLICATIONS: Our findings suggest that non-sensitizing irritant salicylic acid may evoke AHR and exacerbate symptoms in susceptible individuals or in those with underlying lung disease.

Intrinsic catalytic activity of rhodium nanoparticles with respect to reactive oxygen species scavenging: implication for diminishing cytotoxicity.

Noble metal nanoparticles (NPs) and their hybrids have demonstrated a strong potential to mimic the catalytic activity of natural enzymes and diminish oxidative stress. There is a large space to explore the intrinsic catalytic activity of Rh NPs with respect to reactive oxygen species (ROS) scavenging. We found that Rh NPs can quench H2O2, •OH, O2•-, 1O2 and inhibit lipid peroxidation under physiological conditions. In vitro cell experiments proved that Rh NPs have great biocompatibility and protect cells from oxidative damage caused by H2O2. This study can provide important insights that could inform future biological applications.

Platinum nanoparticles: an avenue for enhancing the release of nitric oxide from S-nitroso-N-acetylpenicillamine and S-nitrosoglutathione.

Nitric oxide (NO) is an endogenous bioregulator with established roles in diverse fields. The difficulty in the modulation of NO release is still a significant obstacle to achieving successful clinical applications. We report herein our initial work using electron spin resonance (ESR) spectroscopy to detect NO generated from S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) donors catalyzed by platinum nanoparticles (Pt NPs, 3 nm) under physiological conditions. With ESR spectroscopy coupled with spin trapping and spin labeling techniques, we identified that Pt NPs can significantly promote the generation of NO from SNAP and GSNO under physiological conditions. A classic NO colorimetric detection kit was also employed to verify that Pt NPs truly triggered the release of NO from its donors. Pt NPs can act as promising delivery vehicles for on-demand NO delivery based on time and dosage. These results, along with the detection of the resulting disulfide product, were confirmed with mass spectrometry. In addition, cellular experiments provided a convincing demonstration that the triggered release of NO from its donors by Pt NPs is efficient in killing human cancer cells in vitro. The catalytic mechanism was elucidated by X-ray photo-electron spectroscopy (XPS) and ultra-high performance liquid chromatography/high-resolution mass spectrometry (UHPLC-HRMS), which suggested that Pt-S bond formation occurs in the solution of Pt NPs and NO donors. Identification of Pt NPs capable of generating NO from S-nitrosothiols (RSNOs) is an important step in harnessing NO for investigations into its clinical applications and therapies.

Exploring the activities of ruthenium nanomaterials as reactive oxygen species scavengers.

Research on noble metal nanoparticles (NPs) able to scavenge reactive oxygen species (ROS) has undergone a tremendous growth recently. However, the interactions between ruthenium nanoparticles (Ru NPs) and ROS have never been systematically explored thus far. This research focused on the decomposition of hydrogen peroxide (H2O2), scavenging of hydroxyl radicals (•OH), superoxide radical (O2•-), singlet oxygen (1O2), 2,2'-azino-bis(3-ethylbenzenothiazoline- 6-sulfonic acid ion (ABTS•+), and 1,1-diphenyl-2-picrylhydrazyl radical (•DPPH) in the presence of commercial Ru NPs using the electron spin resonance technique. In vitro cell studies demonstrated that Ru NPs have excellent biocompatibility and exert a cytoprotective effect against oxidative stress. These findings may spark fresh enthusiasm for the applications of Ru NPs under relevant physiologically conditions.

Lanthanide Germanate Cluster Organic Frameworks Based on {Ln8Ge12} Clusters: From One-Dimensional Chains to Two-Dimensional Layers and Three-Dimensional Frameworks.

Under hydrothermal conditions, six series of novel lanthanide (Ln) organogermanates (LnGs) [Ln8Ge12(µ3-O)24E12(H2O)16]·14H2O (Ln(3+) = Pr(3+), 1; Nd(3+), 2; Sm(3+), 3; Eu(3+), 4; Gd(3+), 5; one-dimensional (1-D) LnG cluster organic chain (LnGCOC)), {[Nd8Ge12(µ3-O)24E12(H2O)10](µ2-H2O)2[Nd8Ge12(µ3-O)24E12(H2O)16]}·18H2O (6, two-dimensional (2-D) planar LnG cluster organic layer (LnGCOL)), {[Ln2GeE(HO)2O(H2O)(CH3COO)2(CO3)]2[Ln8Ge12E12(µ3-O)24(H2O)10]}·6H2O (Ln(3+) = Pr(3+), 7; Nd(3+), 8; 2-D wave-shaped LnGCOL), [TbGeE(HO)2O(H2O)(pca)]2[Tb8Ge12E12(µ3-O)24(H2O)8]·10H2O (9, three-dimensional (3-D) LnG cluster organic framework (LnGCOF)), {([Nd(pza)2(H2O)2]2[Nd8Ge12E12(µ3-O)24(H2O)12])([Nd(pza)2]2[Nd8Ge12E12(Hpza)2(µ3-O)24(H2O)10])}·4OH·14H2O (10, 3-D LnGCOF), {[Nd8Ge12E12(µ3-O)24(H2O)10][Nd(pca)(pda)(H2O)]2}·12H2O (11, 3-D LnGCOF) and {[Nd8Ge12E12(µ3-O)24(H2O)10][Nd(pza)(pda)(H2O)]2}·12H2O (12, 3-D LnGCOF) (Hpca = 2-picolinic acid, H2pda = 2,6-pyridinedicarboxylic acid, Hpza = 2-pyrazinecarboxylic acid) were prepared by introducing the second auxiliary ligands into the organogermanate-lanthanide-oxide reaction system. The obtainment of these LnGs realized the utilization of the second auxiliary ligands inducing the assembly from 1-D LnGCOCs to 2-D LnGCOLs and 3-D LnGCOFs based on LnG cluster (LnGC) {Ln8Ge12E12(µ3-O)24(H2O)16}({Ln8Ge12}) units and Ln-organic complexes or organic ligand connectors. It should be noted that the well-organized structural constructions of 1-12 can be visualized as the gradual replacement of active water sites located at equatorial and polar positions on the hypothetical [Ln8Ge12(µ3-O)24E12(H2O)18] LnGC core with oxygen or nitrogen atoms from organic ligands. The solid-state luminescent properties of 2, 3, 4, 6, and 8-12 have been investigated at room temperature.

A zeolite CAN-type aluminoborate with gigantic 24-ring channels.

A cancrinite type aluminoborate with gigantic 24-ring channels has been made under solvothermal conditions using Al(i-PrO)3 as the Al source and amines as the structure directing agents. Its framework is alternately constructed from B5O10 clusters and AlO4 units, no Al-O-Al linkages exist in the structure. Notably, the wall of the 24-ring channels has odd 11-ring windows, resulting in an unprecedented 3D intersecting channel system.

A polyoxometalate-organic supramolecular nanotube with high chemical stability and proton-conducting properties.

The use of 1H-1,2,4-triazole-3-thiol (H2trzS) has led to a rare inorganic-organic hybrid supramolecular nanotube built from novel Ni5-substituted polyoxotungstates, which presents interesting structural characteristics, high chemical stability, and proton-conducting properties.

The coordination polymer poly[[aqua(µ-oxalato)[1H-1,2,4-triazole-5(4H)-thione]cadmium(II)] monohydrate].

The title complex, {[Cd(C2O4)(C2H3N3S)(H2O)]·H2O}n, has a two-dimensional metal-organic framework, with the Cd(II) cation coordinated by three oxalate ligands, a 1H-1,2,4-triazole-5(4H)-thione (H2trzS) ligand and a water molecule. The CdO6S and oxalate units form an extended two-dimensional layered structure, with the terminal H2trzS ligands bonded to the Cd(II) sites through the thione S atoms. Hydrogen-bond interactions exist between adjacent layers.

A tubular one-dimensional polymer constructed from alternating clusters of europium(III)-water and copper(I) chloride bridged by 4-(pyridin-4-yl)benzoate.

A new 3d-4f heterometallic polymer, poly[[aqua-µ3-chlorido-[µ3-4-(pyridin-4-yl)benzoato]tris[µ2-4-(pyridin-4-yl)benzoato]dicopper(I)erbium(III)] dihydrate], {[Cu2Er(C12H8NO2)4Cl(H2O)]·2H2O}n, was synthesized by the hydrothermal reaction of Er2O3, CuCl2·2H2O and 4-(pyridin-4-yl)benzoic acid in the presence of HClO4. The asymmetric unit contains one Er(3+) cation, two Cu(+) cations, one Cl(-) anion, four deprotonated 4-(pyridin-4-yl)benzoate ligands, one coordinated aqua ligand and two solvent water molecules. This tubular one-dimensional polymer is constructed from alternating clusters of europium(III)-water and copper(I) chloride bridged by 4-(pyridin-4-yl)benzoate ligands. Extensive hydrogen-bonding interactions involving both the coordinated and the solvent water molecules provide further stabilization to the structure.