A multistep approach for exploring quality markers of Shengjiang Xiexin decoction by integrating plasma pharmacochemistry-pharmacokinetics-pharmacology.

Shengjiang Xiexin decoction (SXD), a well-known traditional Chinese medicine (TCM), was used to alleviate delayed-onset diarrhea induced by the chemotherapeutic agent irinotecan (CPT-11). Our previous study showed that SXD regulated multidrug resistance-associated protein 2 (Mrp-2) to alter the pharmacokinetics of CPT-11 and its metabolites. However, the pharmacodynamic constituents and the related quality markers of SXD are unclear. In this study, ultra-high performance liquid chromatography coupled with quadrupole orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) was utilized to identify the prototypes and metabolites in rat plasma after oral administration of SXD. The pharmacokinetic markers (PK markers) were screened through quantification and semiquantification of SXD-related xenobiotics in plasma using liquid chromatography-mass spectrometry (LC-MS) combined with statistical analysis. Computational molecular docking was performed to assess the potential binding ability of the PK markers with the target Mrp-2. The results were verified by evaluating the impact on Mrp-2 function using Caco-2 cells. The quality markers were chosen from these PK markers based on the binding affinities with Mrp-2, the specificity and the traceability. As a result, a total of 142 SXD-related exogenous components, including 77 prototypes and 65 metabolites, were detected in rat plasma. Among these, 83 xenobiotics were selected as PK markers due to their satisfactory pharmacokinetic behaviors. Based on the characteristics of quality markers, the prototype-based PK markers were considered the indices of quality control for SXD, including baicalin, baicalein, wogonoside, wogonin, liquiritigenin, isoliquiritigenin, norwogonin, oroxylin A, dihydrobaicalin, chrysin, glycyrrhizic acid, glycyrrhetinic acid, oroxylin A 7-O-glucuronide, liquiritin and isoliquiritin. This study provided an interesting strategy for screening the quality markers involved in the pharmacokinetics of SXD and its action target, which offered important information for the modernization of SXD and other TCM formulae.

Piezoelectric polarization coupled with photoinduced catalytic oxidation technology for environmental pollution control: Recent advances and future prospects.

Energy scarcity and environmental pollution concerns have become substantial impediments to sustainable global economic development. The advent of semiconductor photocatalysis technology provides a potential possibility for effectively alleviating excessive energy consumption and maintaining the long-term stability of the aqueous ecosystem. However, the inefficient transmission efficiency of charge carriers and the high recombination rate of photogenerated electron-hole pairs will culminate in the mediocre catalytic performance observed in conventional semiconductor materials. Fortunately, the piezo-photocatalysis ingeniously integrates the piezoelectric properties of piezoelectric crystals with the optoelectronic properties of semiconductors, thus building a theoretical system of photo-electric-chemical three-phase coupled catalysis. Currently, the photo-mechanical energy synergistic catalytic oxidation degradation process, as a cutting-edge technology based on clean renewable energy, has been perceived as a promising environmental remediation strategy. Herein, a critical review of the application of piezo-photocatalysis in environmental pollution control was delivered. We undertook a comprehensive analysis to elucidate the underlying enhancement mechanism of the piezoelectric effect on photocatalysis in terms of charge migration dynamics and pertinent energy band bending phenomena. In addition, we meticulously summarized diverse innovative methods for introducing vibration energy in piezo-photocatalytic degradation systems (ultrasound, fluid mechanical energy, airflow, self-assembled reactors, etc.). Then, state-of-the-art research advances in the field of environmental pollution control and the corresponding environmental decontamination mechanisms were elaborated based on various integration modes of catalysts (single component, noble metal deposition, heterojunction, coupled substrate materials, etc.). Eventually, an in-depth assessment of current limitations and development trends of piezo-photocatalytic degradation technology has been proposed, along with proactive strategies aimed at surmounting the existing challenges.

Synthesis of chitin nanocrystals supported Zn2+ with high activity against tobacco mosaic virus.

Chitin is a kind of natural nitrogenous organic polysaccharide. It contains antibacterial and antiviral properties, and it can induce plant disease resistance and promote plant growth. However, its application is constrained due to its insolubility and intricate molecular structure. Tobacco mosaic disease is caused by tobacco mosaic virus (TMV) infection, which seriously harms tobacco production. Zinc-containing chemical agents are commonly used to control tobacco mosaic disease, but overuse of chemical agents will cause serious environmental pollution. In this study, a novel nanomaterial (ChNC@Zn) was prepared by using chitin nanocrystals loaded with Zn2+, which has the function of inducing disease resistance to plants and reducing virus activity. When the Zn2+ concentration of ChNC@Zn is 105.6 µg/mL, it shows higher resistance to TMV than Lentinan (LNT). ChNC@Zn can improve the enzymes activities of peroxidase (POD) and catalase (CAT) in tobacco, and reduce the damage of reactive oxygen species (ROS) caused by TMV infection, thereby inducing resistance to TMV in tobacco. Besides, it can promote the growth of tobacco. As a result, ChNC@Zn can exhibit strong antiviral activity at low Zn2+ concentration and minimize the pollution of Zn2+ to the environment, which has high potential application value in the control of virus disease.

Identifying novel selective PPO inhibitors through structure-based virtual screening and bio-evaluation.

Protoporphyrinogen oxidase (PPO) is a key enzyme in chlorophyll and heme biosynthesis, and the development of its inhibitors is of great importance both in the pharmaceutical and pesticide industries. However, the currently developed PPO inhibitors have insignificant bio-selectivity and have a serious impact on non-target organisms. In this study, a docking-based virtual screening approach combined with bio-activity testing was used to obtain novel selective inhibitors of PPO. The results of the bio-activity test showed that thirteen compounds showed 10-fold selectivity over human PPO. And the best selective compound, ZINC70338, has a K i value of 2.21 µM for Nicotiana tabacum PPO and >113-fold selectivity for human PPO. The selectivity mechanism of ZINC70338 in different species of PPO was then analyzed by molecular dynamics simulations to provide a design basis and theoretical guidance for the design of novel selective inhibitors.

Computational study reveals substituted benzimidazole derivatives' binding selectivity to PI3Kδ and PI3Kγ.

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors.

A coumarin-based fluorescent probe for NIR imaging-guided photodynamic therapy against S. aureus-induced infection in mouse models.

A coumarin-based viscosity-responsive fluorescent probe (HZAU800) was designed and synthesized. The probe, containing a strong electron-donating and rigid group on the 7-position of coumarin and a rhodamine derivative containing an oxonium ion on 3-position, could not only shift the emission wavelength to near-infrared region (NIR, λem = 800 nm) but also deliver a good PDT effect due to its high rigid planarity. The NIR fluorescence of HZAU800 can be lighted up in the S. aureus-infected region due to its high viscous environment. Under the laser's irradiation at 690 nm, the PDT effect was effectively triggered up, and the antibacterial evaluation in vitro and in vivo was successfully carried out. This study not only offers a new strategy for constructing coumarin-based phototherapy agents but also facilitates the exploration of the next generation of antibacterial materials based on coumarin architectures.

Network Pharmacology and Molecular Docking Study of the Chinese Miao Medicine Sidaxue in the Treatment of Rheumatoid Arthritis.

PURPOSE: This study aimed to investigate the molecular mechanisms of Compound Sidaxue (SX), a prescription of Chinese Miao medicine, in treating rheumatoid arthritis (RA) using network pharmacology and in vivo experimental approaches. METHODS: Network pharmacology was adopted to detect the active components of four Traditional Chinese herbal medicine (TCM) of SX, and the key targets and signaling pathways in the treatment of RA were predicted, and the key components and targets were screened for molecular docking. The predicted targets and pathways were validated in bovine type II collagen and incomplete Freund's adjuvant emulsifier-induced rat RA model. RESULTS: In this study, we identified 33 active components from SX, predicted to act on 44 RA-associated targets by network pharmacology. PPI network demonstrated that TNF-α, VEGF-A, IL-2, IL-6, AKT, PI3K, STAT1 may serve as the key targets of SX for the treatment of RA. The main functional pathways involving these key targets include PI3K-AKT signaling pathway, TNF signaling pathway, NF-κB signaling pathway. Molecular docking analysis found that the active components ß-amyrin, cajanin, eleutheroside A have high affinity for TNF-α, VEGFA, IL-2, AKT, and PI3K, etc. SX can improve joint swelling in Collagen-induced arthritis (CIA) rats, reduce inflammatory cell infiltration and angiogenesis in joint synovial tissue, and down-regulate IL-2, IL-6, TNF-α, VEGF, PI3K, AKT, p-AKT, NF-κBp65, the expression of p-NF-κBp65, STAT1, and PTGS2 are used to control the exacerbation of inflammation and alleviate the proliferation of synovial pannus, and at the same time play the role of cartilage protection to achieve the effect of treating RA. CONCLUSION: Through a network pharmacology approach and animal study, we predicted and validated the active compounds of SX and their potential targets for RA treatment. The results suggest that SX can markedly alleviate CIA rat by modulating the VEGF/PI3K/AKT signaling pathway, TNF-α signaling pathway, IL/NF-κB signaling pathway.

Genomic Landscape of Head and Neck Squamous Cell Carcinoma Across Different Anatomic Sites in Chinese Population.

BACKGROUND: The characteristics of head and neck squamous cell carcinoma (HNSCC) across different anatomic sites in the Chinese population have not been studied. To determine the genomic abnormalities underlying HNSCC across different anatomic sites, the alterations of selected cancer-related genes were evaluated. METHODS: Genomic DNA samples obtained from formalin-fixed, paraffin-embedded tissues were analyzed using targeted sequencing in a panel of 383 cancer-related genes to determine the genomic alterations. RESULTS: A total of 317 formalin-fixed, paraffin-embedded HNSCC specimens were collected, and a total of 2,156 protein-coding mutations, including 1,864 single nucleotide variants and 292 insertions and deletions, were identified across more than six different anatomic sites. Mutation loads were distinct across the anatomic sites. Larynx carcinoma was found with the highest mutation loads, whereas nasopharynx carcinoma showed the lowest mutation loads. A total of 1,110 gains and 775 losses were identified in the 317 specimens. Patients who had at least one clinically actionable alteration (levels 1-4 in OncoKB) were identified. One patient had an actionable alteration with level 1 evidence in OncoKB, TEX10-NTRK2 fusion, who may benefit from larotrectinib or entrectinib treatment. CONCLUSION: The genomic profiling of HNSCC using targeted sequencing can identify rational therapeutic candidate genes suitable for the treatment of the HNSCCs.

Design, synthesis and evaluation of tetrahydrocarbazole derivatives as potential hypoglycemic agents.

Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.

Brand equity and the Covid-19 stock market crash: Evidence from U.S. listed firms.

Brand equity has played an important role in firms' stock performance, especially during the stock market crash provoked by Covid-19. Our manuscript investigates how brand equity impacts stock performance during the Covid-19 crash. Firms with top brands should be a particularly attractive "safe harbor" in the crash to investors since consumer loyalty and demand advantages brought by brand equity enable firms to retain stable cash flows and mitigate the macroeconomic shock. Based on U.S. listed firms, we find that firms with top brands experience higher stock returns, lower systematic risk and lower idiosyncratic risk in the Covid-19 crash than other firms. Moreover, our findings are used to distinguish the brand equity effect from the corporate social responsibility (CSR) effect on stock performance during the Covid-19 crash.

Silent Counterattack: The Impact of Workplace Bullying on Employee Silence.

The purpose of this paper is to explore the relationship between workplace bullying (WB) and employee silence (ES) as well as its mechanism. This paper collects data from 322 employees of three Chinese enterprises in two waves, with a 2 months interval between the two waves. Moreover, this paper uses confirmatory factor analysis, a bootstrapping mediation test, a simple slope test, and other methods to verify the hypothesis. We find that: (1) WB is positively correlated with ES; (2) psychological safety (PS) and affective commitment mediated the relationship between WB and ES, respectively, and these two variables have a chain mediating effect in the above relationship; and (3) a forgiveness climate moderates this chain mediating effect by weakening the negative impact of WB on PS. Our findings can effectively guide organizations to ultimately adjust their management style, pay attention to employees' cognitive and emotional resources, and formulate some measures to curb WB in organizations.

Design, synthesis and bioevaluation of novel substituted triazines as potential dual PI3K/mTOR inhibitors.

A series of novel substituted triazines bearing a benzimidazole scaffold were designed and synthesized based on the structures of known anti-cancer agents, namely gedatolisib and alpelisib. All the target compounds were screened for inhibitory activity against PI3Kα and mTOR kinases. Notably, most analogs exhibited IC50 in the nanomolar range. Investigation of the isozyme selectivity indicated that the compounds exhibited remarkable inhibitory activity against PI3Kδ, especially compound 19f showed an IC50 value of 2.3 nM for PI3Kδ and moderate δ-isozyme selectivity over other class I PI3K isoforms and mTOR (with IC50 values of 14.6, 34.0, 849.0 and 15.4 nM for PI3Kα, ß, γ and mTOR, respectively). An in vitro MTT assay was conducted to assess the antiproliferative and cytotoxic effects of the prepared analogs. It was revealed that the compounds displayed significant inhibitory activities against the HCT116 human colon cancer cell line. Compound 19i showed 4.7-fold higher potency than the positive control gedatolisib (0.3 vs. 1.4 µM, IC50 values). Phosphoblot studies demonstrated that 19c and 19i could significantly suppress the PI3K/Akt/mTOR signaling pathway at 10 µM. Moreover, analogs 19b, 19c and 19i displayed better stability in artificial gastric fluids than gedatolisib, while 19i was indicated not very stable in rat liver microsomes, and may occur phase I metabolic transformations.

The implication of LncRNA MALAT1 in promoting chemo-resistance of laryngeal squamous cell carcinoma cells.

BACKGROUND: This study was aimed to evaluate the involvement of lncRNA MALAT1 in modifying chemo-sensitivity of laryngeal squamous cell carcinoma (LSCC) cell lines. METHODS: Totally 108 pairs of tumor tissues and matched para-tumor normal tissues were gathered from patients who were pathologically confirmed as LSCC. Meanwhile, LSCC cell lines, including TU686, TU177, AMC-HN-8, and LSC-1, were purchased to evaluate their tolerance to cisplatin, 5-fluorouracil, paclitaxel, and vincristine. Additionally, CCK-8 assay, flow cytometry, transwell assay, and wound healing assay were implemented to assess the part of MALAT1 in modulating viability, apoptosis, invasion, and migration of LSCC cell lines. RESULTS: MALAT1 expression was higher in LSCC tissues than in adjacent normal tissues (P < .05), and LSCC patients who carried highly expressed MALAT1 demonstrated poorer 5-year survival than ones with low MALAT1 expression (P < .05). For another, expression of MALAT1 was also unusually elevated within TU686, TU177, AMC-HN-8, and LSC-1 cell lines as relative to NHBEC cell line (P < .05). The TU686 cell line therein excelled in resisting the growth-curbing effects of 5-fluorouracil (IC50 = 20.44 µmol/L), paclitaxel (IC50 = 35.86 µg/L), and vincristine (IC50 = 0.12 µmol/L), when compared with TU177, AMC-HN-8, and LSC-1 cell line (P < .05). Moreover, there seemed great potential for over-expressed MALAT1 to enhance the chemo-resistance of both TU686 and LSC-1 cell lines (P < .05). Not only that, silencing of MALAT1 tended to undermine the proliferative and metastatic power of TU686 and LSC-1 cell lines (P < .05). CONCLUSION: LncRNA MALAT1 counted in triggering tolerance of LSCC against chemo-drugs by boosting metastasis and depressing apoptosis of tumor cells.

Ultrafast 2,7-Naphthyridine-Based fluorescent probe for detection of thiophenol with a remarkable Stokes shift and its application In vitro and in vivo.

2,7-Naphthyridine derivatives were developed as fluorophores for the first time to design two fluorescence probes, AND-DNP and ND-DNP, which can be applied for detecting thiophenol in aqueous media. Comparing with ND-DNP, AND-DNP showed more favorable properties such as lower background, larger Stokes shift, and higher fluorescence quantum yield for detecting thiophenol. Moreover, the experimental results were verified by theoretical calculations. Hence, AND-DNP was selected as the superior fluorescence probe to detect thiophenol because of its high sensitivity and selectivity. Based on the experimental results, AND-DNP showed a remarkably larger Stokes shift (225 nm), faster response speed (30 s) and higher fluorescence enhancement (240-fold) than most other fluorescent probes for thiophenol reported in the literature. For an extended application, AND-DNP was applied to detect thiophenol quantitatively in real water samples. Meanwhile, AND-DNP also detected thiophenol via red emission in living A549 cells and zebrafish. All these results proved AND-DNP's potential value as an accurate probe for imaging thiophenol in different environments.

Computational Discovery of Potent and Bioselective Protoporphyrinogen IX Oxidase Inhibitor via Fragment Deconstruction Analysis.

Tuning the binding selectivity through appropriate ways is a primary goal in the design and optimization of a lead toward agrochemical discovery. However, how to achieve rational design of selectivity is still a big challenge. Herein, we developed a novel computational fragment generation and coupling (CFGC) strategy that led to a series of highly potent and bioselective inhibitors targeting protoporphyrinogen IX oxidase. This enzyme plays a vital role in heme and chlorophyll biosynthesis, which has been proven to be associated with many drugs and agrochemicals. However, existing agrochemicals are nonbioselective, resulting in a great threat to nontargeted organisms. To the best of our knowledge, this is the first bioselective inhibitor targeting the tetrapyrrole biosynthesis pathway. In addition, the candidate showed excellent in vivo bioactivity and much better safety toward humans.

Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) for Conformational Space Search of Peptide and Miniprotein.

Protein and peptide structure predictions are of paramount importance for understanding their functions, as well as the interactions with other molecules. However, the use of molecular simulation techniques to directly predict the peptide structure from the primary amino acid sequence is always hindered by the rough topology of the conformational space and the limited simulation time scale. We developed here a new strategy, named Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) to identify the native states of a peptide and miniprotein. A cluster of near native structures could be obtained by using the MSA-MD method, which turned out to be significantly more efficient in reaching the native structure compared to continuous MD and conventional SA-MD simulation.

Synthesis and bioevaluation of pyrazole-benzimidazolone hybrids as novel human 4-Hydroxyphenylpyruvate dioxygenase inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme in tyrosine catabolism, is an important target for treating type I tyrosinemia. Inhibition of HPPD can effectively alleviate the symptoms of type I tyrosinemia. However, only one commercial HPPD inhibitor, 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione (NTBC), has been available for clinical use so far. In the present study, a series of novel pyrazole-benzimidazolone hybrids were designed, synthesized and evaluated as potent human HPPD inhibitors. Most of the new compounds displayed significant inhibitory activity against the recombinant human HPPD. Moreover, compound 9l was identified as the most potent candidate with IC50 value of 0.021 µM against recombinant human HPPD, about 3-fold more potent than NTBC. Thus the pyrazole-benzimidazolone hybrid has great potential to be further developed for the treatment of type I tyrosinemia.

Synthesis and herbicidal evaluation of triketone-containing quinazoline-2,4-diones.

Exploring novel 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors is one of the most promising research directions in herbicide discovery. To discover new triketone herbicides with broad-spectrum weed control as well as excellent crop selectivity, a series of (total 52) novel triketone-containing quinazoline-2,4-dione derivatives were synthesized and further bioevaluated. The greenhouse testing indicated that many of the newly synthesized compounds showed better or excellent herbicidal activity against broadleaf and monocotyledonous weeds at the dosages of 37.5-150 g of active ingredient (ai)/ha. The structure and activity relationship in this study indicated that the triketone-containing quinazoline-2,4-dione motif has possessed great impact on herbicide activity and may be used for further optimization. Among the new compounds, III-b and VI-a-VI-d displayed a broader spectrum of weed control than mesotrione. In addition, the compound III-b also demonstrated comparatively superior crop selectivity to mesotrione, thus possessing great potential for weed control in the field.

Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aß aggregation, and ß-secretase.

Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aß aggregation and ß-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.

Structure-based design of conformationally flexible reverse transcriptase inhibitors to combat resistant HIV.

Reverse transcriptase (RT) is one of the most important targets for HIV drug discovery. However, the emergence of resistant mutants has become one of the biggest challenges in HIV-1 RT drug discovery/development and attracted great research interests worldwide. It is particularly important to develop novel anti-HIV-1 RT agents that have improved potency and efficacy against the wild-type (WT) RT, but also target resistant RT forms. Previous crystal complex structures of HIV-1 RT revealed the interaction mechanism between the enzyme and inhibitors, which promoted the exploitation of inhibitor that had sufficient conformational flexibility to combat resistance. Hence, the potential flexibility of a drug should be part of the strategy considered in the early stages of designing drugs that are intended to be broadly effective against mutated targets associated with drug resistance. This review provides an overview of the state of the art in this field, including design strategies and challenges for medicinal chemists.