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Elucidating structural determinants in the functional regions of toxins can provide useful knowledge for designing novel analgesic peptides. A series of 100 ns MD simulations were performed on the scorpion toxin BmK AGAP in native and disulphide bond broken states. The comparison of disulphide bond broken states with the native state showed the α-helix was found to be the key to the analgesic activity. Furthermore, our results revealed disulphide bonds have considerable influence on the functionally important essential modes of motions and the correlations between the motions of the Core domain and the C-terminal region which are involved in the analgesic activity. Therefore, we can conclude that disulphide bonds have a crucial role in modulating the function via adjusting the dynamics of scorpion toxin BmK AGAP molecule. [ABSTRACT FROM PUBLISHER]

Analgesic-antitumor peptide (AGAP), one of the scorpion toxin polypeptides, has been shown to have an antitumor activity. Recombinant AGAP (rAGAP) was shown to affect the migration and invasion of HepG2 cells via a voltage-gated sodium channel (VGSC) β1 subunit. The VGSC β1 subunit was validated as a cell adhesion molecule (CAM) in human hepatocellular carcinoma (HCC) cell lines. rAGAP suppresses the migration and invasion of HepG2 cells but has no significant effect of human liver HL7702 cells without β1 subunit expression. rAGAP inhibits the migration and invasion of the cells when the VGSC β1 subunit is overexpressed in HL7702 cells. To explain these findings, VGSC β1 subunit messenger RNA (mRNA) and protein levels were measured. The β1 subunit protein level was upregulated in a dose-dependent manner following treatment with rAGAP while there was no significant change in the mRNA level, so rAGAP might be an active component of the VGSC β1 subunit. [ABSTRACT FROM AUTHOR]

Objective: To explore the suitable application of MCM-41 (Mobil Composition of Matter number forty-one)-type and MCM-48-type mesoporous silica in the oral water insoluble drug delivery system. Methods: Cilostazol (CLT) as a model drug was loaded into synthesized MCM-48 (Mobil Composition of Matter number forty-eight) and commercial MCM-41 by three common methods. The obtained MCM-41, MCM-48 and CLT-loaded samples were characterized by means of nitrogen adsorption, thermogravimetric analysis, ultraviolet-visible spectrophotometry, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry and powder X-ray diffractometer. Results: It was found that solvent evaporation method was preferred according to the drug loading efficiency and the maximum percent cumulative drug dissolution. MCM-48 with 3D cubic pore structure and MCM-41 with 2D long tubular structure are nearly spherical particles in 300-500 nm. Nevertheless, the silica carriers with similar large specific surface areas and concentrating pore size distributions (978.66 m2/g, 3.8 nm for MCM-41 and 1108.04 m2/g, 3.6 nm for MCM-48) exhibited different adsorption behaviors for CLT. The maximum percent cumulative drug release of the two CLT/silica solid dispersion (CLT-MCM-48 and CLT-MCM-41) was 63.41% and 85.78% within 60 min, respectively; while in the subsequent 12 h release experiment, almost 100% cumulative drug release were both obtained. In the pharmacokinetics aspect, the maximum plasma concentrations of CLT-MCM-48 reached 3.63 mg/L by 0.92 h. The AUC0-∞ values of the CLT-MCM-41 and CLT-MCM-48 were 1.14-fold and 1.73-fold, respectively, compared with the commercial preparation. Conclusion: Our findings suggest that MCM-41-type and MCM-48-type mesoporous silica have great promise as solid dispersion carriers for sustained and immediate release separately. [ABSTRACT FROM AUTHOR]

The scorpion Buthus martensii Karsch (BmK) has been one of the indispensable materials in Chinese traditional medicine for thousands of years. In this work, an analgesic peptide was purified through four continuous chromatographic steps. The mouse twisting test was used to identify the target peptides in every separation step. The molecular weight, isoelectric point, and N-terminal residues of the purified peptide were determined. Based on the N-terminal sequence, the cDNA was also cloned by rapid amplification of cDNA ends from the cDNA pool of scorpion glands. This peptide was identical to BmK AS, an agonist of rabbit skeletal muscle ryanodine receptors. Preliminary pharmacodynamics revealed the following: the dose-effect curve plotted by the mouse twisting test showed an ED50 of 1.42 mg/kg; and the time-effect curves plotted by a hot plate procedure showed a similar effect to the painkiller morphine. We report a purification procedure that yields substantial amounts of natural BmK AS having high activity. BmK AS has the potential to become a new analgesic medicine. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A facile colorimetric Pb2+ assay system has been developed based on the visible color change of gold nanoparticles (GNPs) modified with α2-microglobulin (α2M) protein. The α2M protein is a soluble and high-affinity receptor for Pb2+, which is well studied and regarded as the comparable positive control in Pb-binding protein researches. It was obtained through purifying recombinant protein from the expression of recombinant plasmids in Escherichia coli and was attached on GNPs to form GNPs-α2M sensor nanoparticles for detecting Pb2+, which has never been used for sensing Pb2+ in previous studies. When Pb2+ was introduced into the assay system, GNPs-α2M sensor nanoparticles can be triggered aggregation with the color change from pink to blue. The detection system exhibited good selectivity and sensitivity, which was attributed to the receptor specificity of α2M protein. Using this assay system, it can be distinguished 1.00 μM concentration of Pb2+ or more by naked eyes clearly. Furthermore, the UV-Vis absorbance ratio between 620 and 523 nm exhibited linearity relationship with the concentration of Pb2+ from 0.05 to 3 μM in assay system. In this research, GNPs-α2M sensor nanoparticles have highly specific capability to recognize Pb2+. The assay system constituted by GNPs-α2M sensor nanoparticles displays excellent convenience, selectivity, and sensitivity that provide promising potentials for on-site rapid test of Pb2+. [ABSTRACT FROM AUTHOR]

Bone cancer pain is a difficult-to-treat pathologic condition that impairs the patient's quality of life. The effective therapy options for BCP are restricted due to the unknown pathophysiology. Transcriptome data were obtained from the Gene Expression Omnibus database and differentially expressed gene extraction was performed. DEGs integrated with pathological targets found 68 genes in the study. Butein was discovered as a possible medication for BCP after the 68 genes were submitted to the Connectivity Map 2.0 database for drug prediction. Moreover, butein has good drug-likeness properties. To collect the butein targets, we used the CTD, SEA, TargetNet, and Super-PRED databases. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed butein's pharmacological effects, indicating that butein may aid in treating BCP by altering the hypoxia-inducible factor, NF-kappa B, angiogenesis, and sphingolipid signaling pathways. Moreover, the pathological targets integrated with drug targets were obtained as the shared gene set A, which was analyzed by ClueGO and MCODE. Biological process analysis and MCODE algorithm further analyzed that BCP related targets were mainly involved in signal transduction process and ion channel-related pathways. Next, we integrated targets related to network topology parameters and targets of core pathways, identified PTGS2 , EGFR , JUN , ESR1 , TRPV1 , AKT1 and VEGFA as butein regulated hub genes by molecular docking, which play a critical role in its analgesic effect. This study lays the scientific groundwork for elucidating the mechanism underlying butein's success in the treatment of BCP. • It is first found that butein possible is potential drug to treat bone cancer pain. • It is first found that TRPV1 and ESR1 might become new targets for butein. • Butein also has a good drug-likeness properties. [ABSTRACT FROM AUTHOR]

Scorpion venom is composed of a large number of bioactive peptides which display important pharmacological activities. In this study we have carried out a study of the functional role of the arginine residue at position 58 in the site RC comprising the reverse turn (8–12) and C-terminal residues 58–64. A polymerase chain reaction was used to substitute this arginine residue with a single amino acid such as alanine, glycine and lysine. The mutants were expressed in soluble form in E. coli , and purified by affinity chromatography. After target peptide purity identification, the recombinant peptides underwent a circular dichroism analysis and a study of their analgesic activity in mice. The results indicated that a single residue modification can affect the pharmacological activity. Our efforts establish a sound basis for further study of the structure-function determinants of the analgesic effect. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has received extensive attention due to its non-invasive, photo-stimuli-responsive advantages. However, the poor dispersibility of most photosensitizers in water and non-negligible phototoxicity limit their further clinical application. To surmount this dilemma, red-emitting carbon dots (RCDs) with good photothermal conversion ability were synthesized, and photosensitizers Chlorin-e6 (Ce6) were linked onto RCDs to construct the nano-platform RCDs-Ce6 through amide reaction. In this system, RCDs can increase the dispersion of Ce6 to enhance PDT and absorb partitions of daylight to reduce phototoxicity. At the same time, RCDs-Ce6 can achieve simultaneous excitation of photothermal therapy (PTT) and PDT under a single laser, which can overcome the drawbacks of monotherapy while simplifying the treatment procedure. Besides, the excellent fluorescence imaging capability of RCDs-Ce6 could achieve imaging-guided tumor treatment. Spontaneously, both the cytological and 3D multicellular spheroids (3D MCS) levels demonstrated that RCDs-Ce6 had a stronger synergic therapeutic effect with a combination index (CI) of 0.278 and lower phototoxicity. Meanwhile, in vivo experiments showed that RCDs-Ce6 (PTT and PDT) had a more substantial tumor inhibition effect and fluorescence imaging ability with more tumor distribution. This study widened the way for further applications of photodynamic-enhanced therapy with reduced phototoxicity in photosensitizer delivery based on RCDs. [Display omitted] [ABSTRACT FROM AUTHOR]

In order to achieve efficient siRNA delivery to the brain, we designed a novel polyion complex (PIC) micelles composed of rabies virus glycoprotein (RVG) peptide tagged PEGylated polyasparthydrazide (PAHy) derivatives. The synthesized derivatives were characterized using 1 H NMR. The PIC micelles were formed by electrostatic attraction between the polymer and siRNA. Then the micelles were decorated with RVG using PEG as a linker. The physiochemical properties of micelles, such as gel retardation assay, zeta potential, particle size, morphology and serum stability, were investigated. Moreover, the cytotoxicity, cellular uptake, gene silencing efficiency and in vivo distribution of micelles were also evaluated systematically. Compared with unmodified micelles, RVG-modified micelles can be more easily internalized by the neuro2a cells and efficiently silence gene expression. In vivo animal experiments further confirmed that RVG modified micelles had brain targeting ability. These results demonstrated that RVG-modified micelles were promising carriers for siRNA delivery to the brain. [ABSTRACT FROM AUTHOR]

Abstract: The evaluation of N-trimethyl chitosan (TMC)-coated liposomes containing Coenzyme Q10 as potential ophthalmic drug delivery system was carried out. Firstly, transcorneal permeation studies were conducted at 34°C using a side-by-side diffusion apparatus. The transport process of the fluorescent marker, rhodamine B, across the corneal epithelium was visualized with confocal laser scanning microscopy. Secondly, the human lens epithelial cells (HLECs) were cultured without or with Coenzyme Q10 followed by addition of H2O2. The cell viability and apoptosis were evaluated. The permeability coefficient for rhodamine B with TMC-coated liposomes increased more than two times in comparison with the value obtained for solution as control, from (0.42±0.018)×105 cms−1 to (1.31±0.030)×105 cms−1. Confocal laser scanning microscopy revealed that a TMC coating enhanced the transepithelial transport, dependent on the TMC concentration and contacting time. Coenzyme Q10 elevated the cell viability and reduced the oxidative damage with the decreased percentage of apoptotic cells in a positive concentration-dependent manner. The ATP content of liposome-treated cells was increased about 2-fold compared with that of H2O2-treated cells. Together, our findings demonstrate that with the enhanced permeation effect of the TMC coating, Coenzyme Q10-loaded TMC-coated liposomes appear to be a promising ophthalmic drug delivery carrier with an efficacy in protecting HLECs against H2O2-induced oxidative damage. [ABSTRACT FROM AUTHOR]

Pain often causes a series of abnormal changes in physiology and psychology, which can lead to disease and even death. Drug therapy is the most basic and commonly used method for pain relief and management. Interestingly, at present, hundreds of traditional Chinese medicines have been reported to be used for pain relief, most of which are monomer preparations, which have been developed into new painkillers. Corydalis yanhusuo is a representative of one of these medicines and is available for pain relief. This study aims to determine the analgesic effect and the potential targets of the monomers derived from Corydalis yanhusuo , and to explore any possible associated cardiac risk factors. In this study, four monomers derived from Corydalis yanhusuo (tetrahydropalmatine, corydaline, protopine, dehydrocorydaline) were tested in vivo , using the formalin-induced pain model to determine their analgesic properties. Their potential targets were also determined using whole cell patch clamp recordings and myocardial enzyme assays. The results showed that all monomers showed analgesic activity and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.7, which indicating that Nav1.7 might be involved in the analgesic mechanism of Corydalis yanhusuo. Protopine increased the level of creatine kinase-MB (CK-MB) and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.5, indicating that Nav1.5 might be involved in the cardiac risk associated with protopine treatment. These data showed that tetrahydropalmatine produced the best analgesic effect and the lowest cardiac risk. Thus, voltage gated sodium channels (VGSCs) might be the main targets associated with Corydalis yanhusuo. This study, therefore, provides valuable information for future studies and use of traditional Chines medicines for the alleviation of pain. [Display omitted] • It is first found that Nav1.7 is one analgesic target of Corydalis yanhusuo. • It is first found that Nav1.5 is one main cardiac risk target of Corydalis yanhusuo. • Tetrahydropalmatine showed the better analgesic effect and lower cardiac risk. • Tetrahydropalmatine and protopine were main components of Corydalis yanhusuo to exert analgesic action. [ABSTRACT FROM AUTHOR]

Pain is an unpleasant sensory and emotional experience, often accompanied by the occurrence of a variety of diseases. More than 800 kinds of traditional Chinese medicines (TCM) has now been reported for pain relief and several monomers have been developed into novel analgesic drugs. Bupleurum chinense and Angelica biserrata were representatives of the TCM that are currently available for the treatment of pain. The study aims to detect the potential analgesic activity of each monomer of Bupleurum chinense and Angelica biserrata and to explore whether Nav1.7 is one of the targets for its analgesic activity. In this study, five monomers from Bupleurum chinense (Saikosaponin A, Saikosaponin B1, Saikosaponin B2, Saikosaponin C, Saikosaponin D) and five monomers from the Angelica biserrata (Osthole, Xanthotoxin, Imperatorin, Isoimperatorin, Psoralen) were examined by whole-cell patch-clamp on Nav1.7, which was closely associated with pain. Classical mouse pain models were also used to further verify the analgesic activity in vivo. The results showed that monomers of Saikosaponins and Angelica biserrata all inhibited the peak currents of Nav1.7, indicating that Nav1.7 might be involved in the analgesic mechanism of Saikosaponins and Angelica biserrata. Among them, Saikosaponin A and Imperatorin showed the strongest inhibitory effect on Nav1.7. Furthermore, both Saikosaponin A and Imperatorin showed inhibitory effects on thermal pain and formalin-induced pain in phase II in vivo. The results provide valuable information for future studies on the potential of TCM in alleviating pain. Image 1 [ABSTRACT FROM AUTHOR]

Non-steroidal Anti-inflammatory Drugs (NSAIDs) are widely used because of their excellent anti-inflammatory and analgesic effects. However, NSAIDs could cause certain cardiac side effects, such as myocardial infarction, heart failure, atrial fibrillation, arrhythmia and sudden cardiac death. Therefore, meloxicam, nimesulide, piroxicam, and diclofenac were selected and the whole cell patch clamp technique was used to investigate the electrophysiological regulatory effects of them on the sodium channel hNav1.5 and potassium channel hKv11.1, which were closely associated to the biotoxicity of cardiac, and to explore the potential cardiac risk mechanism. The results showed that the four NSAIDs could inhibit the peak currents of hNav1.5 and hKv11.1. Furthermore, the four NSAIDs could affect both the activation and inactivation processes of hNav1.5 with I–V curves left-shifted to hyperpolarized direction in activation phase. These data indicate that the inhibition effects of Nav1.5 and Kv11.1 by meloxicam, nimesulide, piroxicam, and diclofenac might contribute to their potential cardiac risk. These findings provide a basis for the discovery of other potential cardiac risk targets for NSAIDs. [Display omitted] • NSAIDs act as inhibitors of hNav1.5 and hERG. • Nav1.5 and hERG might be involved in the cardiac side effects of NSAIDs. • Diclofenac showed the least inhibition effects on both hNav1.5 and hERG channels. • Minor perturbations of piroxicam and meloxicam lead to major changes in hNav1.5. [ABSTRACT FROM AUTHOR]

It has been documented that sialic acid-binding Ig-like lectin 1 (Siglec1) is a cell surface protein with a variety of functions in the immune system. In the present study, we evaluated whether Siglec1 plays a role in chronic obstructive pulmonary disease (COPD). Results show that the expression of Siglec1 was increased in the lung of COPD rats, and that Siglec1 overexpression greatly enhanced the expression of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6 in cigarette smoke extract (CSE)-treated NR8383 cells, a rat lung-derived macrophage cell line. Notably, the proinflammatory effect of Siglec1 was totally inhibited by overexpression of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (IκBα). Importantly, Siglec1 overexpression increased miR-1260, which then degraded IκBα through its 3′ untranslated region (3′UTR). Further study demonstrated that miR-1260 inhibitor attenuated inflammation in CSE-induced rat COPD lung and in CSE-treated NR8383 cells. Finally, the inhibitory effect of miR-1260 on inflammation was totally lost when IκBα was inhibited. In summary, the present study demonstrated that Siglec1 exerts its proinflammatory effects through increasing miR-1260, leading to decreased expression of IκBα. [ABSTRACT FROM AUTHOR]

Mucosal immunization is a powerful weapon against viral infection. In this paper, large pore mesoporous silica nanoparticles (LMSN) with different particle sizes were synthesized for loading influenza split vaccine (SV) to explore the effect of nanoparticle sizes on mucosal immunization and adjuvant efficacy. Interestingly, it was found that among the three particle sizes of nanoparticles, only LMSN-M with around 250 nm could significantly enhance the mucosal immune effect of SV, possessing adjuvant effect. The results indicated that particle size affected the adjuvant effect of LMSN. There was no apparent difference in vaccine loading capacity of LMSN with different particle sizes, but the release of SV depended on the pore length of LMSN. The adjuvant effect of LMSN-M was attributed to its higher cellular uptake performance, intestine absorption and transport efficiency, and the ability to stimulate the maturation of dendritic cells. Simultaneously, compared with LMSN-S and LMSN-L, the more retention of LMSN-M in mesenteric lymph nodes increased the chance of interaction between vaccine and immune system, resulting in the enhanced immunity. This is the first time to study the impact of particle size of LMSN adjuvant on improving mucosal immunity of oral influenza vaccine, and the present work provides a scientific reference for adjuvant design of oral vaccine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The emergence and widespread of multidrug-resistant Gram-negative bacteria have posed a severe threat to human health and environmental safety, escalating into a global medical crisis. Utilization of antibiotic adjuvants is a rapid approach to combat bacterial resistance effectively since the development of new antimicrobial agents is a formidable challenge. NhaA, driven by proton motive force, is a crucial secondary transporter on the cytoplasmic membrane of Escherichia coli. We found that 2-Aminoperimidine (2-AP), which is a specific inhibitor of NhaA, could enhance the activity of colistin against sensitive E. coli and reverse the resistance in mcr-1 positive E. coli. Mechanistic studies indicated that 2-AP induced dysfunction in cytoplasmic membrane through the suppression of NhaA, leading to metabolic inhibition and ultimately enhancing the sensitivity of E. coli to colistin. Moreover, 2-AP restored the efficacy of colistin against resistant E. coli in two animal infection models. Our findings reveal the potential of NhaA as a novel target for colistin adjuvants, providing new possibilities for the clinical application of colistin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Limited drug loading and incomplete drug release are two major obstacles that traditional polymeric microneedles (MNs) have to overcome. For smart controlled-release MNs, since drug release duration is uncertain, a clear indication of the finish of drug release is also important for patient guidance on the timing of the next dose. In this study, MN with a triple structure of a glucose-responsive shell, loaded insulin powders and a colored propelling inner core (inspired by the mechanism of osmotic pump) was innovatively constructed. The MN patch could release insulin according to blood glucose levels (BGLs) and had excellent drug loading, more complete drug release, and good drug stability, which significantly prolonged the normoglycemic time. An approximately 0.3 cm 2 patch has a hypoglycemic effect on diabetic mice for up to 24 h. Moreover, the fading of the inner core could indicate the release process of the loaded drug and can help to facilitate uninterrupted closed loop therapy for patients. The designed triple MN structure is also suitable, and can be used in the design of other smart MN drug delivery systems to further improve their drug loading capacity and simultaneously achieve more complete, smart controlled and visualized drug release., Competing Interests: Declaration of competing interest Authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered an elegant solution to eradicate tumors due to its minimal invasiveness and low systemic toxicity. Nevertheless, it is still challenging for phototherapy to achieve ideal outcomes and clinical translation due to its inherent drawbacks. Owing to the unique biological functions, diverse gases have attracted growing attention in combining with phototherapy to achieve super-additive therapeutic effects. Specifically, gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S) have been proven to kill tumor cells by inducing mitochondrial damage in synergy with phototherapy. Additionally, several gases not only enhance the thermal damage in PTT and the reactive oxygen species (ROS) production in PDT but also improve the tumor accumulation of photoactive agents. The inflammatory responses triggered by hyperthermia in PTT are also suppressed by the combination of gases. Herein, we comprehensively review the latest studies on gas-synergized phototherapy for cancer therapy, including (1) synergistic mechanisms of combining gases with phototherapy; (2) design of nanoplatforms for gas-synergized phototherapy; (3) multimodal therapy based on gas-synergized phototherapy; (4) imaging-guided gas-synergized phototherapy. Finally, the current challenges and future opportunities of gas-synergized phototherapy for tumor treatment are discussed. STATEMENT OF SIGNIFICANCE: 1. The novelty and significance of the work with respect to the existing literature. (1) Strategies to design nanoplatforms for gas-synergized anti-tumor phototherapy have been summarized for the first time. Meanwhile, the integration of various imaging technologies and therapy modalities which endow these nanoplatforms with advanced theranostic capabilities has been summarized. (2) The mechanisms by which gases synergize with phototherapy to eradicate tumors are innovatively and comprehensively summarized. 2. The scientific impact and interest. This review elaborates current trends in gas-synergized anti-tumor phototherapy, with special emphases on synergistic anti-tumor mechanisms and rational design of therapeutic nanoplatforms to achieve this synergistic therapy. It aims to provide valuable guidance for researchers in this field., Competing Interests: Declaration of Competing Interest The authors declare there is no conflict of interests., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Vanillin holds significant importance as a flavoring agent in various industries, including food, pharmaceuticals, and cosmetics. The CoA-dependent pathway for the biosynthesis of vanillin from ferulic acid involved feruloyl-CoA synthase (Fcs) and enoyl-CoA hydratase/lyase (Ech). In this research, the Fcs and Ech were derived from Streptomyces sp. strain V-1. The sequence conservation and structural features of Ech were analyzed by computational techniques including sequence alignment and molecular dynamics simulation. After detailed study for the major binding modes and key amino acid residues between Ech and substrates, a series of mutations (F74W, A130G, A130G/T132S, R147Q, Q255R, ΔT90, ΔTGPEIL, ΔN1-11, ΔC260-287) were obtained by rational design. Finally, the yield of vanillin produced by these mutants was verified by whole-cell catalysis. The results indicated that three mutants, F74W, Q147R, and ΔN1-11, showed higher yields than wild-type Ech. Molecular dynamics simulations and residue energy decomposition identified the basic residues K37, R38, K561, and R564 as the key residues affecting the free energy of binding between Ech and feruloyl-coenzyme A (FCA). The large changes in electrostatic interacting and polar solvating energies caused by the mutations may lead to decreased enzyme activity. This study provides important theoretical guidance as well as experimental data for the biosynthetic pathway of vanillin.

Ethnopharmacology Relevance: Tripterygium wilfordii Hook. f. has been widely used in clinical practice due to its good anti-inflammatory and analgesic activities. However, its application is limited by potential toxicity and side effects., Aim of the Study: The study aimed to identify the mechanisms responsible for the pharmacological activity and cardiotoxicity of the main monomers of Tripterygium wilfordii., Materials and Methods: Database analysis predicted that ion channels may be potential targets of Tripterygium wilfordii. The regulatory effects of monomers (triptolide, celastrol, demethylzeylasteral, and wilforgine) on protein Nav1.5 and Nav1.7 were predicted and detected by Autodock and patch clamping. Then, we used the formalin-induced pain model and evaluated heart rate and myocardial zymograms to investigate the analgesic activity and cardiotoxicity of each monomer in vivo., Results: All four monomers were able to bind to Nav1.7 and Nav1.5 with different binding energies and subsequently inhibited the peak currents of both Nav1.7 and Nav1.5. The monomers all exhibited analgesic effects on formalin-induced pain; therefore, we hypothesized that Nav1.7 is one of the key analgesic targets. Demethylzeylasteral reduced heart rate and increased the level of creatine kinase-MB, thus suggesting a potential cardiac risk; data suggested that the inhibitory effect on Nav1.5 might be an important factor underlying its cardiotoxicity., Conclusion: Our findings provide an important theoretical basis for the further screening of active monomers with higher levels of activity and lower levels of toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment, in addition to improving oral bioavailability relative to other means of delivery of oral drugs. Here, inspired by the specific invasion route of intestinal microorganisms, we pioneered an immune-awakening Saccharomyces -inspired mesoporous silicon nanoparticle (yMSN) for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors via the intestinal lymphatic pathway. Encouragingly, yMSN high-loaded tumor-specific antigens (OVA, 11.9%) and anti-tumor drugs (Len, 28.6%) with high stability, namely Len/OVA/yMSN, efficiently co-delivered OVA and Len to their desired target sites. Moreover, yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages, strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment. Surprisingly, Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice. This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment, and also represents a novel path for the oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)