Curvature-mediated rapid extravasation and penetration of nanoparticles against interstitial fluid pressure for improved drug delivery.

Elevated interstitial fluid pressure (IFP) within pathological tissues (e.g., tumors, obstructed kidneys, and cirrhotic livers) creates a significant hindrance to the transport of nanomedicine, ultimately impairing the therapeutic efficiency. Among these tissues, solid tumors present the most challenging scenario. While several strategies through reducing tumor IFP have been devised to enhance nanoparticle delivery, few approaches focus on modulating the intrinsic properties of nanoparticles to effectively counteract IFP during extravasation and penetration, which are precisely the stages obstructed by elevated IFP. Herein, we propose an innovative solution by engineering nanoparticles with a fusiform shape of high curvature, enabling efficient surmounting of IFP barriers during extravasation and penetration within tumor tissues. Through experimental and theoretical analyses, we demonstrate that the elongated nanoparticles with the highest mean curvature outperform spherical and rod-shaped counterparts against elevated IFP, leading to superior intratumoral accumulation and antitumor efficacy. Super-resolution microscopy and molecular dynamics simulations uncover the underlying mechanisms in which the high curvature contributes to diminished drag force in surmounting high-pressure differentials during extravasation. Simultaneously, the facilitated rotational movement augments the hopping frequency during penetration. This study effectively addresses the limitations posed by high-pressure impediments, uncovers the mutual interactions between the physical properties of NPs and their environment, and presents a promising avenue for advancing cancer treatment through nanomedicine.

Advances in the treatment of invasive fungal disease.

With over 300 million severe cases and 1.5 million deaths annually, invasive fungal diseases (IFDs) are a major medical burden and source of global morbidity and mortality. The World Health Organization (WHO) recently released the first-ever fungal priority pathogens list including 19 fungal pathogens, considering the perceived public health importance. Most of the pathogenic fungi are opportunistic and cause diseases in patients under immunocompromised conditions such as HIV infection, cancer, chemotherapy, transplantation, and immune suppressive drug therapy. Worryingly, the morbidity and mortality caused by IFDs are continuously on the rise due to the limited available antifungal therapies, the emergence of drug resistance, and the increase of population that is vulnerable to IFDs. Moreover, the COVID-19 pandemic worsened IFDs as a globe health threat as it predisposes the patients to secondary life-threatening fungi. In this mini-review, we provide a perspective on the advances and strategies for combating IFDs with antifungal therapies.

Investigation of the Stability Mechanism of Stimulus-Responsive Wormlike Micelle-CO2 Foams in the Oil Phase.

Foam flooding is an important tool for reservoir development. This study aims to further investigate the interaction between stimulus-responsive wormlike micelle (WLM)-CO2 foams and crude oil. We performed micromorphology experiments as our major studies and used molecular dynamics simulations as an auxiliary tool for interfacial analysis. We utilized foam generation, liquid separation, and defoaming as the entry points of experimental research and energy as the quantitative assessment index to investigate the dynamic process of the action of different oil contents and oil phase types in a DOAPA@NaSal-H+ foam system. We also examined the role of NaSal in the generation and development of the foam system. Results indicated that the law of crude oil's effect on foam could be summarized as "low contents are beneficial and high contents are harmful." In addition, although the DOAPA@NaSal-H+ foam system has high compatibility for saturated and aromatic hydrocarbons, it is highly suitable for application in reservoir environments with relatively high asphaltene and resin contents. Through combined experimental and simulation approaches, we clarified the law governing the stability of the DOAPA@NaSal-H+ foam system in different oil-containing environments, identified the key role of NaSal, and provided a reference for the targeted application of the DOAPA@NaSal-H+ foam system in different oil reservoirs.

Organoselenium-Catalyzed C2,3-Diarylation of N-H Indoles.

An organoselenium-catalyzed C2,3-diarylation of unprotected N-H indoles with electron-rich aromatics has been developed. This one-pot multicomponent tandem cross-dehydrogenation coupling reaction allows for the incorporation of two different aromatic groups to indoles. More importantly, this approach offers significant advantages, including a high atom and step economy, eliminating the need for prepreparation of the reaction substrates, streamlining the synthetic process and enhancing its practicality. Overall, this organoselenium-catalyzed C2,3-diarylation reaction presents an efficient and versatile strategy for the functionalization of indole derivatives.

[Research progress in Astragali Radix and its active ingredients in treatment of lung cancer].

Lung cancer is the leading cause of cancer death, and its effective treatment is a difficult medical problem. Lung cancer belongs to the traditional Chinese medicine(TCM) disease categories of lung accumulation, lung amassment, and overstrain cough. Rich theoretical basis and practical experience have been accumulated in the TCM treatment of lung cancer. Astragali Radix is one of the representatives of Qi-tonifying drugs. It mainly treat the lung cancer with the syndrome of Qi deficiency and pathogen stagnation, following the principle of reinforcing healthy Qi and eliminating patgogenic Qi. Astragali Radix exerts a variety of pharmacological activities in the treatment of lung cancer, including inhibiting tumor cell proliferation and promoting tumor cell apoptosis, inhibiting tumor invasion and migration, regulating the tumor microenvironment, suppressing tumor angiogenesis, modulating autophagy, inducing macrophage polarization, enhancing immunity, inhibiting immune escape, and reversing cisplatin resistance. The active ingredients of Astragali Radix in treating lung cancer include polysaccharides, saponins, and flavonoids. This study reviewed the pharmacological activities and active ingredients of Astragali Radix in the treatment of lung cancer, providing a basis for the development and utilization of Astragali Radix resources and active ingredients and the research and development of anti-tumor drugs.

Prospecting for natural products by genome mining and microcrystal electron diffraction.

More than 60% of pharmaceuticals are related to natural products (NPs), chemicals produced by living organisms. Despite this, the rate of NP discovery has slowed over the past few decades. In many cases the rate-limiting step in NP discovery is structural characterization. Here we report the use of microcrystal electron diffraction (MicroED), an emerging cryogenic electron microscopy (CryoEM) method, in combination with genome mining to accelerate NP discovery and structural elucidation. As proof of principle we rapidly determine the structure of a new 2-pyridone NP, Py-469, and revise the structure of fischerin, an NP isolated more than 25 years ago, with potent cytotoxicity but hitherto ambiguous structural assignment. This study serves as a powerful demonstration of the synergy of MicroED and synthetic biology in NP discovery, technologies that when taken together will ultimately accelerate the rate at which new drugs are discovered.

Iodine-Mediated C2,3-H Aminoheteroarylation of Indoles.

A metal-free one-pot oxidative cross-dehydrogenation coupling reaction for the formation of C-N/C-C bonds at the C2,3-positions of indoles with azoles and quinoxalinones has been developed. The proposed method has several notable features, including metal-free catalysis, the use of N-H free indoles as substrates, ease of operation, mild reaction conditions, and compatibility with a wide range of substrates.

Fast Lasso-type safe screening for Fine-Gray competing risks model with ultrahigh dimensional covariates.

The Fine-Gray proportional sub-distribution hazards (PSH) model is among the most popular regression model for competing risks time-to-event data. This article develops a fast safe feature elimination method, named PSH-SAFE, for fitting the penalized Fine-Gray PSH model with a Lasso (or adaptive Lasso) penalty. Our PSH-SAFE procedure is straightforward to implement, fast, and scales well to ultrahigh dimensional data. We also show that as a feature screening procedure, PSH-SAFE is safe in a sense that the eliminated features are guaranteed to be inactive features in the original Lasso (or adaptive Lasso) estimator for the penalized PSH model. We evaluate the performance of the PSH-SAFE procedure in terms of computational efficiency, screening efficiency and safety, run-time, and prediction accuracy on multiple simulated datasets and a real bladder cancer data. Our empirical results show that the PSH-SAFE procedure possesses desirable screening efficiency and safety properties and can offer substantially improved computational efficiency as well as similar or better prediction performance in comparison to their baseline competitors.

Intermolecular C-H Aminocyanation of Indoles via Copper-iodine Cocatalyzed Tandem C-N/C-C Bond Formation.

An efficient copper-iodine cocatalyzed intermolecular C-H aminocyanation of indoles with a broad substrate scope has been developed for the first time. This method enables highly step-economic access to 2-amino-3-cyanoindoles in moderate to good yields and provides a complementary strategy for the regioselective difunctionalization of carbon═carbon double bonds of interest in organic synthesis and related areas. Mechanistic studies suggest that these transformations are initiated by iodine-mediated C2-H amination with azoles, followed by copper-catalyzed C3-H cyanation with ethyl cyanoformate.

Effects of dexmedetomidine on cardiac electrophysiology in patients undergoing general anesthesia during perioperative period: a randomized controlled trial.

BACKGROUND: Dexmedetomidine has controversial influence on cardiac electrophysiology. The aim of this study was to explore the effects of dexmedetomidine on perioperative cardiac electrophysiology in patients undergoing general anesthesia. METHODS: Eighty-one patients were randomly divided into four groups: groups D1, D2, D3 receiving dexmedetomidine 1, 1, 0.5 µg/kg over 10 min and 1, 0.5, 0.5 µg/kg/h continuous infusion respectively, and control group (group C) receiving normal saline. Twelve-lead electrocardiograms were recorded at the time before dexmedetomidine/normal saline infusion (T1), loading dose finish (T2), surgery ending (T6), 1 h (T7) after entering PACU, 24 h (T8), 48 h (T9), 72 h (T10) and 1 month (T11) postoperatively. Cardiac circulation efficiency (CCE) were also recorded. RESULTS: Compared with group C, QTc were significantly increased at T2 in groups D1 and D2 while decreased at T7 and T8 in group D3 (P < 0.05), iCEB were decreased at T8 (P < 0.05). Compared with group D1, QTc at T2, T6, T7, T9 and T10 and iCEB at T8 were decreased, and CCE at T2-T4 were increased in group D3 significantly (P < 0.05). Compared with group D2, QTc at T2 and iCEB at T8 were decreased and CCE at T2 and T3 were increased in group D3 significantly (P < 0.05). CONCLUSIONS: Dexmedetomidine at a loading dose of 0.5 µg/kg and a maintenance dose of 0.5 µg/kg/h can maintain stability of cardiac electrophysiology during perioperative period and has no significant adverse effects on CCE. TRIAL REGISTRATION: ClinicalTrials.gov NCT04577430 (Date of registration: 06/10/2020).

Harzianic Acid from Trichoderma afroharzianum Is a Natural Product Inhibitor of Acetohydroxyacid Synthase.

Acetohydroxyacid synthase (AHAS) is the first enzyme in the branched-chain amino acid biosynthetic pathway and is a validated target for herbicide and fungicide development. Here we report harzianic acid (HA, 1) produced by the biocontrol fungus Trichoderma afroharzianum t-22 (Tht22) as a natural product inhibitor of AHAS. The biosynthetic pathway of HA was elucidated with heterologous reconstitution. Guided by a putative self-resistance enzyme in the genome, HA was biochemically demonstrated to be a selective inhibitor of fungal AHAS, including those from phytopathogenic fungi. In addition, HA can inhibit a common resistant variant of AHAS in which the active site proline is mutated. Structural analysis of AHAS complexed with HA revealed the molecular basis of competitive inhibition, which differs from all known commercial AHAS inhibitors. The alternative binding mode also rationalizes the selectivity of HA, as well as effectiveness toward resistant mutants. A proposed role of HA biosynthesis by Tht22 in the rhizosphere is discussed based on the data.

Biosynthesis of the Immunosuppressant (-)-FR901483.

We report characterization of the biosynthetic pathway of the potent immunosuppressant (-)-FR901483 (1) through heterologous expression and enzymatic assays. The biosynthetic logic to form the azatricyclic alkaloid is consistent with those proposed in biomimetic syntheses and involves aza-spiro annulation of dityrosyl-piperazine to form a ketoaldehyde intermediate, followed by regioselective aldol condensation, stereoselective ketoreduction, and phosphorylation. A possible target of 1 is proposed based on the biosynthetic studies.

Synthesis of 3-halogenated 2,3'-biindoles by a copper-mediated 2,3-difunctionalization of indoles.

A copper-mediated 2,3-difunctionalization of indoles to afford 3-halogenated 2,3'-biindoles is described herein. The protocol uses readily available feedstocks and a naturally abundant copper catalyst system, which allows the regioselective formation of C-C and C-X (X = Cl & Br) bonds in one single operation. Here the copper metal salt serves not only as a catalyst but also as a reactant to provide the source of halogen. This operationally simple procedure avoids the utilization of environmentally unfriendly reagents and displays good functional group compatibility. Noteworthily, the introduction of halogen into molecules would offer great potential for further chemical transformations.

Median Effective Dose of Lidocaine for the Prevention of Pain Caused by the Injection of Propofol Formulated with Medium- and Long-Chain Triglycerides Based on Lean Body Weight.

OBJECTIVE: To determine the median effective dose (ED50) of prophylactic intravenous lidocaine for the prevention of propofol medium-chain triglyceride/long-chain triglyceride (MCT/LCT) emulsion injection pain. DESIGN: Prospective trial, Dixon up-and-down sequential method. SETTING: Operating room of a single hospital. PATIENTS: Thirty patients aged 18-65 years with American Society of Anesthesiologists (ASA) status I or II who were scheduled for elective surgery under general anesthesia (GA) were included. INTERVENTIONS: The initial dose of prophylactic lidocaine before propofol MCT/LCT emulsion injection was set at 0.5 mg/kg lean body weight (LBW). The lidocaine dose was adjusted according to the degree of patients' injection pain using the Dixon up-and-down sequential method. MEASUREMENTS: The ED50 and 95% confidence intervals (CIs) of lidocaine were calculated using the Dixon-Massey formula. Vital signs and adverse effects were recorded. In the postanesthesia care unit (PACU), patients were asked if they recalled feeling any injection pain with visual analog scale (VAS) evaluation. RESULTS: The ED50 of lidocaine for the prevention of propofol MCT/LCT emulsion injection pain was 0.306 mg/kg LBW (95% CI, 0.262-0.357 mg/kg LBW). No adverse reactions to lidocaine occurred. In the PACU, 90.9% of patients who experienced injection pain recalled this pain (VAS score, 2.8±1.8). CONCLUSIONS: Prophylactic intravenous lidocaine (0.306 mg/kg LBW) effectively prevented propofol MCT/LCT emulsion injection pain in 50% of patients scheduled for elective surgery under GA with no adverse reaction occurring.

Genome Mining of Alkaloidal Terpenoids from a Hybrid Terpene and Nonribosomal Peptide Biosynthetic Pathway.

Biosynthetic pathways containing multiple core enzymes have potential to produce structurally complex natural products. Here we mined a fungal gene cluster that contains two predicted terpene cyclases (TCs) and a nonribosomal peptide synthetase (NRPS). We showed the flv pathway produces flavunoidine 1, an alkaloidal terpenoid. The core of 1 is a tetracyclic, cage-like, and oxygenated sesquiterpene that is connected to dimethylcadaverine via a C-N bond and is acylated with 5,5-dimethyl-l-pipecolate. The roles of all flv enzymes are established on the basis of metabolite analysis from heterologous expression.

Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade.

Ranking among the most effective anticancer drugs, anthracyclines represent an important family of aromatic polyketides generated by type II polyketide synthases (PKSs). After formation of polyketide cores, the post-PKS tailoring modifications endow the scaffold with various structural diversities and biological activities. Here we demonstrate an unprecedented four-enzyme-participated hydroxyl regioisomerization process involved in the biosynthesis of kosinostatin. First, KstA15 and KstA16 function together to catalyze a cryptic hydroxylation of the 4-hydroxyl-anthraquinone core, yielding a 1,4-dihydroxyl product, which undergoes a chemically challenging asymmetric reduction-dearomatization subsequently acted by KstA11; then, KstA10 catalyzes a region-specific reduction concomitant with dehydration to afford the 1-hydroxyl anthraquinone. Remarkably, the shunt product identifications of both hydroxylation and reduction-dehydration reactions, the crystal structure of KstA11 with bound substrate and cofactor, and isotope incorporation experiments reveal mechanistic insights into the redox dearomatization and rearomatization steps. These findings provide a distinguished tailoring paradigm for type II PKS engineering.

Concise Biosynthesis of Phenylfuropyridones in Fungi.

Phenylfuropyridone natural products from fungi exhibit a range of antibacterial and cytotoxicity activities, and can potentiate azole antifungal compounds. We elucidated the biosynthetic pathway of compounds in the citridone family through heterologous reconstitution of the pfp pathway. We demonstrate that multiple members of this family can be accessed from a reactive ortho-quinone methide (o-QM) intermediate through electrocyclization, cycloisomerization, or conjugate addition. Formation of the quaternary carbon center in citridone B is catalyzed by an epoxide-forming P450 enzyme, followed by carbon skeletal rearrangement. Our results showcase how nature harvests the reactivities of an o-QM intermediate to biosynthesize complex natural products.

Enzyme-Catalyzed Inverse-Electron Demand Diels-Alder Reaction in the Biosynthesis of Antifungal Ilicicolin H.

The pericyclases are a growing superfamily of enzymes that catalyze pericyclic reactions. We report a pericyclase IccD catalyzing an inverse-electron demand Diels-Alder (IEDDA) reaction with a rate acceleration of 3 × 105-fold in the biosynthesis of fungal natural product ilicicolin H. We demonstrate IccD is highly periselective toward the IEDDA cycloaddition over a competing normal electron demand Diels-Alder (NEDDA) reaction from an ambimodal transition state. A predicted flavoenzyme IccE was identified to epimerize the IEDDA product 8- epi-ilicicolin H to ilicicolin H, a step that is critical for the observed antifungal activity of ilicicolin H. Our results reveal the ilicicolin H biosynthetic pathway and add to the collection of pericyclic reactions that are catalyzed by pericyclases.

Thioesterase-Catalyzed Aminoacylation and Thiolation of Polyketides in Fungi.

Fungal highly reducing polyketide synthases (HRPKSs) biosynthesize polyketides using a single set of domains iteratively. Product release is a critical step in HRPKS function to ensure timely termination and enzyme turnover. Nearly all of the HRPKSs characterized to date employ a separate thioesterase (TE) or acyltransferase enzyme for product release. In this study, we characterized two fungal HRPKSs that have fused C-terminal TE domains, a new domain architecture for fungal HRPKSs. We showed that both HRPKS-TEs synthesize aminoacylated polyketides in an ATP-independent fashion. The KU42 TE domain selects cysteine and homocysteine and catalyzes transthioesterification using the side-chain thiol group as the nucleophile. In contrast, the KU43 TE domain selects leucine methyl ester and performs a direct amidation of the polyketide, a reaction typically catalyzed by nonribosomal peptide synthetase (NRPS) domains. The characterization of these HRPKS-TE enzymes showcases the functional diversity of HRPKS enzymes and provides potential TE domains as biocatalytic tools to diversify HRPKS structures.

RuIII@CMC/Fe3O4 hybrid: an efficient, magnetic, retrievable, self-organized nanocatalyst for green synthesis of pyranopyrazole and polyhydroquinoline derivatives.

RuIII incorporated with magnetic nanosized CMC/Fe3O4 hybrid (RuIII@CMC/Fe3O4) has readily developed by a very simple self-organized procedure of RuCl3 and Na-CMC/Fe3O4 organic/inorganic hybrid. The self-organized fresh and recovered catalyst was well characterized by ICP-AES, FTIR, XRD, TGA-DSC-DTG, SEM-EDS-mapping, TEM, and XPS techniques. The elemental maps confirmed that the RuIII species are well dispersed in a homogeneous manner on the surface of CMC/Fe3O4 magnetic hybrid nanoparticles. After full characterization, its catalytic activity was investigated in the synthesis of pyranopyrazole and polyhydroquinoline derivatives. Under optimal conditions, all reactions proceeded well and afforded the desired products in excellent yields. There was no significant effect of electron withdrawing or donating nature of substituent on aryl aldehydes in the formation of these target compounds. The salient features of the present new protocol are broad substrate scope, mild reaction conditions, good-to-excellent yields, operational simplicity, energy-efficiency, high atom-economy, easy isolation of products and no column chromatographic separation. Moreover, RuIII@CMC/Fe3O4 can be easily recovered by using a magnetic field and directly reused for several cycles without significant loss of its activity. The recovered catalyst was confirmed by TEM, XPS, XRD, and SEM-EDS analyses. One-pot multicomponent reactions for green synthesis of pyranopyrazole and polyhydroquinoline derivatives have been performed using a self-organized RuIII@CMC/Fe3O4 nanocatalyst.