Progress in research on gut microbiota in ethnic minorities in China and consideration of intervention strategies based on ethnic medicine: A review.

One of the variables affecting gut microbiota is ethnicity. There are 56 ethnic subgroups in China, and their intestinal flora differs. A wealth of medical resources has also been produced by the presence of numerous ethnic minorities. In this study, we reviewed the pertinent literature on the intestinal flora of ethnic minorities in China and abroad using the CiteSpace visualization software, and we used bibliometric techniques to find the most widely prescribed medications for preventing and treating endemic diseases in ethnic minorities. Based on the gut microbiology of minority populations, we suggest that by comprehensive development involving literature, experimental, and clinical research, the pharmacological action mechanisms for interventions in endemic diseases can be drawn from ethnic medicine. This point of view has not been discussed before and will offer a fresh perspective on the creation and application of ethnic medications as well as a fresh method for the management of prevalent diseases in ethnic communities.

In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization.

Therapeutic peptides have been widely concerned, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK]2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP), KYp can be dephosphorylated and self-assembles in situ, which induces the aggregation of ALP and the protein-lipid phase separation on cell membrane. Consequently, KYp internalization is 2-fold enhanced compared to non-responsive peptide, and IC50 value of KYp is approximately 5 times lower than that of free peptide. Therefore, the in vivo self-assembly induced phase separation on cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.

Pityriacitrin marine alkaloids as novel antiviral and anti-phytopathogenic-fungus agents.

BACKGROUND: Plant diseases have been gripping agricultural production, seriously affecting the growth and yields of crops. Marine natural products are an important source for novel drugs discovery. In this work, pityriacitrin marine alkaloids were selected as the parent structures. A series of pityriacitrin alkaloid analogues were rationally designed, synthesized and evaluated for their antiviral activities and fungicidal activities. RESULT: Most of these compounds were demonstrated to have higher antiviral activities than ribavirin. Particularly, compounds 3a, 3e, 8f, 8g, and 9g displayed higher anti-TMV activities than ningnanmycin at 500 µg·mL-1 . Mechanism research revealed that 3a could bind to TMV CP with an excellent affinity (Ka  = 8.67 × 106 L·mol-1 ), thus interfere with the assembly of virus particles. These alkaloids also showed broad-spectrum fungicidal activities against eight kinds of phytopathogenic fungi. Compound 5f with 1.43-3.84 µg·mL-1 EC50 value against three fungi emerged as a new fungicidal candidate. CONCLUSION: Pityriacitrin alkaloids and their derivatives were synthesized and evaluated for anti-TMV and fungicidal activities for the first time. Compounds 3a and 5f with excellent activities emerged as new candidates for antiviral research and fungicidal research, respectively. Current work provided a new idea for the molecular design and development of novel plant virus and fungi inhibitors in the future. © 2021 Society of Chemical Industry.

Recent progress of therapeutic peptide based nanomaterials: from synthesis and self-assembly to cancer treatment.

Peptides have shown great potential in cancer treatment due to their good biocompatibility and low toxicity. However, the bioavailability and adverse immune response of peptides limit their further translation from bench to bedside. Over the past few decades, various peptide-based nanomaterials have been developed for drug delivery and cancer treatment. Compared with therapeutic peptides alone, self-assembled peptide nanomaterials have obvious advantages, such as improved stability and biodistribution for high-performance cancer therapy. In this review, we have described the synthesis, self-assembly and the anti-cancer application of therapeutic peptides and their conjugates, particularly polymer-peptide conjugates (PPCs).

Enzyme-sensitive cytotoxic peptide-dendrimer conjugates enhance cell apoptosis and deep tumor penetration.

Peptide nanodrugs have been developed as promising antitumor chemotherapeutics because they partially overcome the drawbacks of free peptide drugs, but insufficient tumor penetration and interference of peptide function limit their further application. In this work, we have developed multifunctional peptide conjugated dendrimers for improving tumor penetration, cancer cell-specific peptide delivery and anticancer ability. The cytotoxic peptide KLAK, cell-penetrating peptide TAT and matrix metalloproteinase 2 (MMP2)-sensitive peptide-poly(ethylene glycol) (PEG) were conjugated onto dendrimers by one-pot synthesis to gain PKT-S-PEG. The enzyme-sensitive properties and incubation stability of the dendrimers were investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Moreover, the cell viability, internalization pathway, mitochondria-regulated apoptosis and tumor penetration ability were measured by CCK-8 assay, lysosome colocalization, JC-1 assay and multicellular spheroid (MCS) experiments, respectively, in human primary glioblastoma (U87) cells. PKT-S-PEG showed significantly enhanced intracellular delivery performance, antitumor efficacy and deep tumor penetration capacity compared to a control non-MMP2 sensitive dendrimer PKT-C-PEG. The MMP2-overexpressing tumor microenvironment caused deprotection by removal of PEG, resulting in the decrease of particle size and exposure of KLAK and TAT, which enhanced tumor penetration, the entry of bioactive peptides into cells and subsequently the effective disruption of mitochondria. We believe that the peptide-dendrimer conjugate has potential for specific and effective delivery of peptide-based therapeutics into tumors.

Self-Assembled ROS-Sensitive Polymer-Peptide Therapeutics Incorporating Built-in Reporters for Evaluation of Treatment Efficacy.

One of the major challenges in current cancer therapy is to maximize therapeutic effect and evaluate tumor progression under the scheduled treatment protocol. To address these challenges, we synthesized the cytotoxic peptide (KLAKLAK)2 (named KLAK) conjugated amphiphilic poly(ß-thioester)s copolymers (H-P-K) composed of reactive oxygen species (ROS) sensitive backbones and hydrophilic polyethylene glycol (PEG) side chains. H-P-K could self-assemble into micelle-like nanoparticles by hydrophobic interaction with copolymer backbones as cores and PEG and KLAK as shells. The assembled polymer-peptide nanoparticles remarkably improved cellular internalization and accumulation of therapeutic KLAK in cells. Compared to free KLAK peptide, the antitumor activity of H-P-K was significantly enhanced up to ∼400 times, suggesting the effectiveness of the nanoscaled polymer-peptide conjugation as biopharmaceuticals. The higher antitumor activity of nanoparticles was attributed to the efficient disruption of mitochondrial membranes and subsequent excessive ROS production in cells. To realize the ROS monitoring and treatment evaluation, we encapsulated squaraine (SQ) dyes as built-in reporters in ROS-sensitive H-P-K micelles. The overgenerated ROS around mitochondria stimulated the swelling of nanoparticles and subsequent release of SQ, which formed H-aggregates and significantly increased the photoacoustic (PA) signal. We believed that this self-assembled polymer-peptide nanotherapeutics incorporating built-in reporters has great potential for high antitumor performance and in situ treatment evaluation.

Meta-analysis of the MDM2 T309G polymorphism and gastric cancer risk.

BACKGROUND: Mdm2 binds to the amino-terminus of p53 to induce its degradation and a single nucleotide polymorphism in the MDM2 promoter region (T309G) has been reported to increase the risk of several carcinomas, such as gastric cancer. However, the results of published studies to analyze the association between MDM2 T309G and gastric cancer havve often conflicted. METHODS: To better illustrate the filiation between MDM2 T309G and gastric cancer, we performed a meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the relationship. The pooled ORs were performed for 4 models, additive, recessive, co-dominant model, and dominant. RESULTS: Nine published case-control studies including 3,225 gastric cancer cases and 4,118 controls were identified. The MDM2 T309G polymorphism was associated with a significantly increased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR=1.57; 95%CI=1.57-2.12; p=0.003) and GG versus GT/TT, OR=1.52; 95%CI=1.217-1.90; p<0.001). Furthermore, Egger

Anti-bacterial and in vivo tumor treatment by reactive oxygen species generated by magnetic nanoparticles.

Photodynamic therapy is widely used in clinics and for anti-bacterial applications. The major challenge is the limited depth of tissue penetration of light and poor targetability. In this study, magnetite nanoparticles were used as a highly sensitive T2-weighted MR imaging contrast agents to target the tumor and mimic horseradish peroxidase (HRP), which could catalyze the decomposition of hydrogen peroxide to generate reactive oxygen species (ROS) to inhibit the tumor in vivo. In these experiments, MNPs were demonstrated to possess the enzyme-mimicking activity in different pH values, and the activity was dependent on the size of the MNPs: the smaller the size, the higher the activity. We demonstrated that MNPs showed highly efficient anti-bacterial (E. coli) activity in presence of H2O2. The E. coli inhibition ratio reached nearly 100% at optimal concentration. The anti-tumor activity was evaluated through HeLa cell viability under treatment with MNPs and H2O2. Consequently, the cell viability was significantly decreased and more than 80% of HeLa cells were dead after treatment with MNPs and H2O2 under different pH values. MR imaging was used to demonstrate the tumor targetability of 13 nm MNPs in vitro and in vivo. Consequently, the relaxivity of the 13 nm MNPs was determined to be r2 = 104 s-1 mM-1. The MR signal was much more negative and the intensity was significantly diminished with the increase of the concentration of 13 nm MNPs in vitro. The tumor signal was clearly visualized and a 3-fold decrease of the MR signal intensity of the tumor site of the mice was observed after 24 h-post treatment with the 13 nm MNPs. Finally, the tumor inhibition in vivo was investigated using 6 nm MNPs in BALB/c nude female mice bearing subcutaneously implanted HeLa cells on the right flank. The results show statistically significant efficacy in delaying tumor growth from day 6, and an approximately 99% tumor inhibition ratio was shown by the combination of MNPs and H2O2 after treatment for 17 days. By leveraging the passive targeting and MR imaging properties, we expect that the enzyme-mimicking MNPs could be used for cancer theranostics and may open up a new avenue for the treatment of epidermal infections.

(E)-4-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino-meth-yl]-2-meth-oxy-phenyl 4-bromo-benzene-sulfonate.

In the title compound, C(25)H(22)BrN(3)O(5)S, the central benzene ring makes dihedral angles of 4.41 (10), 67.09 (9) and 62.05 (10)°, respectively, with the pyrazolone, bromo-benzene and terminal phenyl rings. The dihedral angle between the pyrazolone and phenyl rings is 57.75 (11)°. In the crystal, two pairs of C-H⋯O hydrogen bonds link the mol-ecules into inversion dimers. A weak intra-molecular C-H⋯O hydrogen bonds is also observed.

(E)-2-Bromo-4-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino-meth-yl]-6-meth-oxy-phenyl 4-methyl-benzene-sulfonate.

In the title compound, C(26)H(24)BrN(3)O(5)S, the central benzene ring makes dihedral angles of 6.27 (6), 33.63 (6) and 69.31 (5)°, respectively, with the pyrazolone ring, the bromo-benzene ring and the terminal phenyl ring. An intra-molecular C-H⋯O hydrogen bond occurs. The crystal packing features weak non-classical C-Br⋯O inter-actions [Br⋯O = 3.222 (2) Å] that form inversion-related dimers.

4-Meth-oxy-3-(4-nitro-benz-yloxy)benzaldehyde.

In the title compound, C(15)H(13)NO(5), the two benzene rings make a dihedral angle of 3.98 (7)°. The crystal packing is stabilized by weak non-classical inter-molecular C-H⋯O inter-actions that link mol-ecules into centrosymmetric tetra-mers.

A luminescent beta-cyclodextrin-based Ru(phen)3 complex as DNA compactor, enzyme inhibitor, and translocation tracer.

A beta-cyclodextrin-based Ru(phen)(3) complex (1) has been synthesized and exhibits good luminescent behavior. Atomic force microscopic and scanning electron microscopic studies show that 1 can induce the aggregation of originally circular DNA to toroidal or spherical shapes. The morphology of these DNA aggregates changes following a pathway of naked circular DNA --> toroid with gaps --> solid toroid --> spherical aggregate, depending on the different 1/DNA (w/w) ratios, and their average diameters vary from the nanometer to micrometer scale. Owing to its capability of inducing the aggregation of DNA, 1 can be used as an inhibitor for DNA topoisomerase and DNA cleavage enzymes. Further studies by means of fluorescence microscopy indicate that 1 can also efficiently trace the translocation of DNA into 293T cells (the human embryonic kidney cell line). These observations consequently establish 1 as not only a potential DNA carrier but also a fluorescent DNA probe.

Selective binding and inverse fluorescent behavior of magnesium ion by podand possessing plural imidazo[4,5-f]-1,10-phenanthroline groups and its Ru(II) complex.

[structure: see text] Two podands, 4,4'-[(ethylenedioxy)bis(ethyleneoxy)]bis[1-(2-imidazo[4,5-f]-1,10-phenanthroline)benzene] (1) and [Ru(phen)(2)](2)(1)(PF(6))(4) (2) complex, were synthesized from 1,10-phenanthroline. The photophysical behavior and the binding ability of 1 and 2 with some alkali metal and alkaline earth cations were investigated by UV-vis and fluorescence spectrometry and (1)H NMR experiments as well as fluorescence lifetime measurements. The complex stability constants (K(S)) and Gibbs free energy changes (DeltaG degrees ) for the stoichiometric 1:1 complexation of 1 and 2 with the cations were obtained by the fluorimetric titrations. The podands 1 and 2 exhibit different fluorescent behavior in the cations examined, i.e., fluorescence quenching for 1, and fluorescence enhancement for 2. In particular, 1 showed responses specific for Mg(2+), resulting in readily distinguishable by eye.

Cooperative self-assembly and molecular binding behavior of cyclodextrin-crown ether conjugates mediated by alkali metal ions.

In order to quantitatively investigate their molecular binding ability, a series of cyclodextrin-crown ether conjugates containing beta-cyclodextrin (beta-CyD) and crown ether units, i.e.N-(benzoaza-15-crown-5)acylaminomethylene tethered 6-diethylenetriamino-6-deoxy-beta-CyD, N-(benzoaza-15-crown-5)acylaminomethylene tethered 6-triethylenetetraamino-6-deoxy-beta-CyD and 4',5'-dimethylene-benzo-15-crown-5 tethered 6-diethylenetriamino-6-deoxy-beta-CyD, have been prepared as ditopic molecular receptors. Their inclusion complexation behavior with four representative fluorescent dyes, i.e. ammonium 8-anilino-1-naphthalenesulfonate (ANS), sodium 6-toluidino-2-naphthalenesulfonate (TNS), acridine red (AR) and rhodamine B (RhB), has been comprehensively investigated in aqueous NaH2PO4/Na2HPO4 or KH2PO4/K2HPO4 buffer solution (pH 7.20) by means of circular dichroism, fluorescence, and 2D NMR spectra. The results indicate that the self-assembly of crown ether modified beta-CyD mediated by potassium ion exhibits a dimeric structure, which significantly enhances the original binding ability and molecular selectivity of parent beta-CyD and its derivatives towards guest molecules through the cooperative binding of two hydrophobic CyD cavities with one guest. This cooperative binding mode of K+/CyD-crown ether systems are further confirmed by Job's experiments and 2D NMR investigations. Attributed to the positive contributions from the metal-ligated crown ether cap and K+-mediated dimerization of CyDs, the binding constant (Ks) values of CyD-crown ether conjugates toward ANS are 10-83 times higher than that of beta-CyD. The increased binding ability and molecular selectivity of CyD-crown ether conjugates are discussed from the viewpoints of size/shape-fit and multiple recognition mechanism.