Maintaining calcium homeostasis as a strategy to alleviate nephrotoxicity caused by evodiamine.

Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs.

Low pressure reversibly driving colossal barocaloric effect in two-dimensional vdW alkylammonium halides.

Plastic crystals as barocaloric materials exhibit the large entropy change rivalling freon, however, the limited pressure-sensitivity and large hysteresis of phase transition hinder the colossal barocaloric effect accomplished reversibly at low pressure. Here we report reversible colossal barocaloric effect at low pressure in two-dimensional van-der-Waals alkylammonium halides. Via introducing long carbon chains in ammonium halide plastic crystals, two-dimensional structure forms in (CH3-(CH2)n-1)2NH2X (X: halogen element) with weak interlayer van-der-Waals force, which dictates interlayer expansion as large as 13% and consequently volume change as much as 12% during phase transition. Such anisotropic expansion provides sufficient space for carbon chains to undergo dramatic conformation disordering, which induces colossal entropy change with large pressure-sensitivity and small hysteresis. The record reversible colossal barocaloric effect with entropy change ΔSr ~ 400 J kg-1 K-1 at 0.08 GPa and adiabatic temperature change ΔTr ~ 11 K at 0.1 GPa highlights the design of novel barocaloric materials by engineering the dimensionality of plastic crystals.

Detection and Analysis of Blood Dexmedetomidine in Drug-Facilitated Cases.

OBJECTIVES: To establish a simple and rapid qualitative and quantitative detection method of dexmedetomidine in blood. METHODS: Blood was separated on the Allure PFP Propyl liquid chromatography column with isocratic elution after it was precipitated by acetonitrile and filtered. Qualitative and quantitative analysis of dexmedetomidine was performed using positive ion scan mode and multi-reaction monitoring mode. RESULTS: The limit of detection of dexmedetomidine in blood was 0.2 ng/mL and the limit of quantification was 0.5 ng/mL. The linearity of the method was good in the range of 0.5-1 000 ng/mL, and the correlation coefficient was greater than 0.99. The accuracy of the method was 90.34%-112.67% and the extraction recovery was 50.05%-91.08%, with no significant matrix effect. CONCLUSIONS: This method is simple, selective and suitable for the qualitative and quantitative analysis of dexmedetomidine in blood, which can provide a reference for drug-facilitated cases involving dexmedetomidine.

Asymmetric Synthesis of Triphenylmethanes via Organocatalytic Regio- and Enantioselective Friedel-Crafts Alkylation of Aniline Derivatives.

Herein, we described a highly regio- and enantioselective Friedel-Crafts alkylation of aniline derivatives with in situ generated ortho-quinone methides enabled by chiral phosphoric acid, furnishing a wide range of enantioenriched triarylmethanes bearing three similar benzene rings in high yields (up to 98%) with excellent stereoselectivities (up to 98% ee). Furthermore, the large-scale reactions and diversified transformations of product demonstrate the practicality of the protocol. Density functional theory calculations elucidate the origin of the enantioselectivity.

Viral contamination on the surfaces of the personal protective equipment among health care professionals working in COVID-19 wards: A single-center prospective, observational study.

OBJECTIVE: To evaluate potential viral contamination on the surfaces of personal protective equipment (PPE) in COVID-19 wards. METHODS: Face shields, gloves, the chest area of PPE and shoe soles were sampled at different time points. The samples were tested for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by PCR, and the cycle threshold (CT) values were recorded. RESULTS: The positive rate was 74.7% (239/320) for all PPE specimens. The CT values of the samples were ranked in the following order: face shields > chests > gloves > shoe soles (37.08±1.38, 35.48±2.02, 34.17±1.91 and 33.52±3.16, respectively; P for trend < .001). After disinfection, the CT values of shoe soles decreased compared with before disinfection (32.78±3.47 vs. 34.3±2.61, P = .037), whereas no significant effect of disinfection on the CT values of face shields, chests and gloves was observed. After disinfection, the CT values of specimens collected from shoe soles gradually increased; before disinfection, the CT values of shoe sole specimens were all less than 35. CONCLUSIONS: SARS-CoV-2 can attach to the surfaces of the PPE of healthcare professionals in COVID-19 wards, especially the shoe soles and undisinfected gloves. Shoe soles had the highest SARS-CoV-2 loads among all tested PPE items.

Mycena subpiligera sp. nov., a Symbiotic Species from China Associated with the Seed Germination of Gastrodia elata.

Mycena subpiligera, a new taxon in sect. Fragilipedes that can strongly enhance the germination efficiency of Gastrodia elata seeds, was discovered in subtropical areas of China. As revealed by a morphological comparison with related Mycena species as well as maximum likelihood (ML) and Bayesian phylogenetic analyses based on sequences of the internal transcribed spacer (ITS) and the large subunit (LSU) regions of nuclear ribosomal RNA, the new taxon can be distinguished from phenotypically similar and phylogenetically related species. Optimal cultural conditions for M. subpiligera basidiomata are reported, and the germination rate of the new species is compared with that of M. citrinomarginata.

Forensic Analysis of 9 Poisoning Death Cases Caused by Oral Administration of Diphenidol.

OBJECTIVES: To analyze the characteristics of diphenidol poisoning cases and to provide clues and technical means for the identification of such cases. METHODS: Biological samples of 9 deaths caused by diphenidol poisoning were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and the characteristics of these cases were analyzed retrospectively. RESULTS: Most of the deaths caused by diphenidol poisoning were young females. The dosage was between 60 and 300 tablets, and the mass concentration of diphenidol in the postmortem blood ranged from 0.87 to 99.00 µg/mL. There was no correlation between the dosage and the concentration of diphenidol in the blood. CONCLUSIONS: Diphenidol poisoning has the characteristics of high concealment and lethality. More attention should be paid to suicide cases, and diphenidol should be recommended as a routine detection item to avoid missing detection.

Strategies for Collection and Analysis of Samples in Simple Asphyxiant Gas Acute Poisoning Death Cases.

At present, the death cases of simple asphyxiant gas acute poisoning are increasing sharply. Common asphyxiant gases in death cases include nitrogen, helium, carbon dioxide, methane, propane, laughing gas, etc. Simple asphyxiant gas has no affinity for biological matrices and escapes quickly, which puts forward new requirements for autopsy procedures, selection and collection of samples, laboratory analysis and identification. This paper reviews the research and development process of death cases caused by simple asphyxiant gas acute poisoning and put forwards the collection and analysis strategy of the samples in such cases. The most valuable biological samples in such cases should be lung tissues associated with the airways, followed by brain tissue and cardiac blood. Gaseous samples from the esophageal cavity, tracheal cavity, pulmonary bronchi, gastric and cardiac areas are also recommended as valuable samples. In the case of postmortem examination, the gas should be injected into gas sample bag directly. Biological materials such as tissue and blood should be directly sealed in head-space vials and analyzed by using the headspace gas chromatography-mass spectrometry.

Pinelliae rhizoma alleviated acute lung injury induced by lipopolysaccharide via suppressing endoplasmic reticulum stress-mediated NLRP3 inflammasome.

Pinelliae rhizoma (PR), one kind of commonly-used Chinese herbs, is generally prescribed to treat various respiratory diseases, including acute lung injury (ALI). However, the accurate bioactive ingredients of PR and the underlying pharmacological mechanism have both not been fully elucidated. Therefore, this study aimed to identify the bioactive ingredients that could alleviate lipopolysaccharide (LPS)-induced ALI and explore the possible mechanism involved. Our results confirmed that LPS infection indeed caused acute inflammatory damage in mice lung, accompanying with the enhancement of IL-1ß contents and the activation of the NLRP3 inflammasome in lung tissue and macrophagocyte, all of which were remarkably ameliorated by PR treatment. Next, mechanistically, LPS was found to trigger endoplasmic reticulum (ER) stress and downstream cellular calcium ions (Ca2+) release via activating Bip/ATF4/CHOP signaling pathway. Like PR, 4-PBA (a specific inhibitor of ER stress) not only obviously reversed Bip/ATF4/CHOP-mediated ER stress, but also significantly attenuated LPS-induced activation of the NLRP3 inflammasome. Furthermore, the bioactive ingredients of PR, which generated the anti-inflammatory effects, were screened by metabolomics and network pharmacology. In vitro experiments showed that chrysin, dihydrocapsaicin, and 7,8-dihydroxyflavone (7,8-DHF) notably suppressed LPS-induced ER stress and following NLRP3 inflammasome activation. In conclusion, our findings suggested that PR alleviated LPS-induced ALI by inhibiting ER stress-mediated NLRP3 inflammasome activation, which is mainly relevant with these three bioactive ingredients. This study provided a theoretical basis for the clinical application of PR to treat ALI, and these bioactive ingredients of PR would be promising therapeutic drugs for the treatment of ALI.

Analysis of the Distribution of Total Phosphine and the Characteristics of Phosphine Poisoning in 29 Victims.

OBJECTIVES: To study the distribution of total phosphine in phosphine poisoning victims and summarize the characteristics of phosphine poisoning cases. METHODS: The phosphine and its metabolites in the biological samples of 29 victims in 16 phosphine poisoning cases were qualified and quantified by headspace gas chromatography-mass spectrometry. RESULTS: Five victims among 29 were poisoned by ingestion of aluminium phosphide and 24 by inhalation of phosphine gas. Phosphine metabolites were detected in the biological samples of 23 victims, and the concentrations of total phosphine in blood ranged 0.5-34.0 µg/mL. The total concentration of phosphine in liver tissue was up to 71.0 µg/g. Phosphine was not detected in the blood of the other six survived victims, which may be related to the small amount of phosphine exposure and the delay in blood sampling. CONCLUSIONS: The total concentration of phosphine in blood and tissues caused by aluminum phosphine ingestion is higher than that caused by phosphine gas inhalation. The death cases of phosphine inhalation are characterized by long exposure time, repeated exposures and age susceptibility.

High expression of eIF4A1 predicts unfavorable prognosis in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a worldwide malignancy with high morbidity and mortality. Translation initiation factor 4A1 (eIF4A1), which is an ATP-dependent RNA helicase as a part of eIF4F complex, has been linked to malignant transformation and progression, and a variety of cancers display dysregulation of this enzyme. However, its role in ccRCC remains unclear. In our study, we examined its potential effects in ccRCC. METHODS: Based on Proteomic data, TCGA and ONCOMINE database, RCC cell lines and tissues, the expression of eIF4A1 between ccRCC and normal tissues were investigated. A correlation was evaluated between the prognostic model for OS and ccRCC progression. Analysis of functional enrichment and PPI network were performed. After examining differentially expressed genes between the eIF4A1 high and low-expression groups, we performed GSEA analysis. Furthermore, we investigated immune cell infiltration of eIF4A1. Then we determined eIF4A1 functions in the establishment and maintenance of cell viability, migration and invasion of cell lines. Flow cytometry was utilized to detect cell cycle. RESULTS: The eIF4A1 was up-regulated in ccRCC tissues and cell lines. An increased level of eIF4A1 was linked to lower survival rates and impaired immunity. Depletion of eIF4A1 could arrest tumor cells in G1 phase, so as to seriously limit cell proliferation and weaken the capacity of cell migration. CONCLUSION: ccRCC patients with high eIF4A1 expression are at increased risk of poor prognosis, furthermore eIF4A1 plays a prominent role in facilitating tumor cell proliferation and migration which may further be a potential prognostic biomarker and therapeutic target.

[Preparation and in vitro release of quercetin nanocrystals self-stabilized Pickering emulsion].

A new quercetin nanocrystals self-stabilized Pickering emulsion(QT-NSSPE) was prepared by high-pressure homogenization combined with probe ultrasonic method. The influences of oil fraction, quercetin(QT) concentration, and pH of water phase on the formation of QT-NSSPE were investigated. On this basis, the QT-NSSPE prepared under optimal conditions was evaluated in terms of microstructure, stability, and in vitro release and the droplet size and drug loading were 15.82 µm and 4.87 mg·mL~(-1), respectively. The shell structure formed by quercetin nanocrystals(QT-NC) on the emulsion droplet surface was observed under a scanning electron microscope(SEM). X-ray diffraction(XRD) showed that the crystallinity of adsorbed QT-NC decreased significantly as compared with the raw QT. There were not significant changes of QT-NSSPE properties after 30 days of storage at room temperature. The in vitro release experiment confirmed that QT-NSSPE has a higher accumulative release rate than the raw QT. All these results indicated that QT-NSSPE has a great stability and a satisfactory in vitro release behavior, which is a promising new oral delivery system for QT.

[Advances in formation and application of self-assembled nanoparticles from traditional Chinese medicine].

Due to the diverse sources and unique structures, the chemical components of Chinese medicinal materials are easy to self-assemble to form nanoparticles. The formation of self-assembled nanoparticles(SAN) can not only affect the absorption and distribution of the effective ingredients in Chinese medicinal materials but also may improve the biological activity of the effective ingredients or their simple mixtures, which is of great significance for revealing the compatibility mechanism of Chinese medicine prescription, developing new Chinese medicine products, and producing new nanomaterials. This paper reviews the formation, isolation, characterization, and application of SAN of Chinese medicines, and discusses the problems and development trends of the relevant research, which can provide reference for the further study and promote the innovation and application of such SAN.

Enantioselective decarboxylative Mannich reaction of ß-keto acids with C-alkynyl N-Boc N,O-acetals: access to chiral ß-keto propargylamines.

The chiral keto-substituted propargylamines are an essential class of multifunctional compounds in the field of organic and pharmaceutical synthesis and have attracted considerable attention, but the related synthetic approaches remain limited. Therefore, a concise and efficient method for the enantioselective synthesis of ß-keto propargylamines via chiral phosphoric acid-catalyzed asymmetric Mannich reaction between ß-keto acids and C-alkynyl N-Boc N,O-acetals as easily available C-alkynyl imine precursors has been demonstrated here, affording a broad scope of ß-keto N-Boc-propargylamines in high yields (up to 97%) with generally high enantioselectivities (up to 97 : 3 er).

Origin and Composition of Nanoparticles Induced in a Complex Plastic-Brittle Transition Process of Xiaomei Shear Zone, Hainan Island, China.

Micro and nano structures of quartz schist, plagioclase granite, and granitic gneiss in the Xiaomei Shear Zone located in southeastern Hainan Island, China are observed using Scanning Electron Microscope (SEM). Ultramicroscopic analyses indicate that three types of nanoparticles were found in the samples, including spherical nanoparticles, agglomerated nanoparticles and nanofibers. These nanoparticles are mainly developed in the fracture zones. The more fractures there are, the more nanoparticles are developed. Energy dispersive spectrometer (EDS) and X-ray diffraction (XRD) are used to ascertain the composition of the nanoparticles. The results suggest that the nanoparticles are mainly composed of silicate, dolomite and calcite, rich in O, Si, Al, Ca. Based on our results, we suggest that nanoparticle formation is a complex, plastic-brittle transition process. Thermal decomposition driven by steady shearing possibly forms well-organized nanoparticles, while fast-moving dislocations by shock-like stress release possibly forms radial nanofibers.

[Effect of self-assembled nanoparticles from Shaoyao Gancao Decoction on release and absorption of main components of Baishao].

To study the effect of self-assembled nanoparticles from Shaoyao Gancao Decoction(SGD-SAN) on the encapsulation, in vitro release and intestinal absorption of the main components of Baishao. Particle size analysis and morphological observation were used to verify the formation of SGD-SAN in the decoction. The entrapment efficiency(EE) of SGD-SAN on the main components of Baishao was determined by ultrafiltration centrifugation. The dialysis bag method was used to study the in vitro release of the main components of Baishao with pH 6.8 phosphate buffer solution as the release media. Single-pass intestinal perfusion study was performed to investigate the effect of SGD-SAN on the absorption of the main components of Baishao. The results showed that there were nanoparticles in the SGD, and the particle sizes and PDI of SGD-SAN were about 200 nm and 0.38, respectively. SGD-SAN was irregularly spherical under transmission electron microscope(TEM). The EEs of albiflorin, paeoniflorin and benzoylpaeoniflorin in SGD-SAN were 33.78%±1.03%,33.61%±0.90%,88.53%±0.58%, respectively. The release characteristics of albiflorin, paeoniflorin and benzoylpaeoniflorin from SGD-SAN showed a slow-release effect on pH 6.8 phosphate buffer solution media. SGD-SAN could significantly enhance the absorption of albiflorin, paeoniflorin and benzoylpaeoniflorin in the ileum. The results of this study indicated that SAN could be formed during the mixed decoction of Baishao and Gancao, and SGD-SAN could encapsulate the components of Baishao, with a certain slow-release effect, and the formation of SAN facilitated the absorption of drugs in the ileum.

Current Situation of Methamphetamine Abuse and Related Research Progress.

Drug problem is a major social and public security problem in the world. Drug abuse poses a great threat to economic development, social stability and public health. In recent years, synthetic drugs represented by methamphetamine have surpassed traditional drugs such as morphine, heroin, ketamine and become one of the most abused drugs in the world. In order to solve the problem of drug abuse, it is of great theoretical value and practical significance to carry out all-round and multi-level scientific research on drug-related issues. Based on the current situation of drug abuse, this article reviews research progresses on the epidemiology of methamphetamine abuse, the monitoring technology, the basic researches on toxicity damage, the withdrawal drug screening, the related clinical comorbidity and the testing technologies, comprehensively presenting the development trend of methamphetamine abuse related issues.

Penisarins A and B, Sesquiterpene Coumarins Isolated from an Endophytic Penicillium sp.

Penisarins A (1) and B (2), sesquiterpene coumarins with an unusual tricyclic sesquiterpene system, were isolated from endophytic Penicillium sp. KMU18029. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compound 2 showed significant cytotoxicities against two human cancer cell lines, HL-60 and SMMC-7721, with IC50 values of 3.6 ± 0.2 and 3.7 ± 0.2 µM, respectively.

[Preparation and in vitro release of ginkgolide B nanosuspension].

To prepare ginkgolide B nanosuspension(GB-NS), and investigate its dissolution behaviors in vitro. The miniaturized media milling method was used to prepare nanosuspensions, with average particle size and polydispersity index as the evaluation indexes. The formulation and process of GB-NS were optimized by single factor experiment and Box-Behnken design-response surface method. The morphology was observed by scanning electron microscope(SEM), and thecrystallinity of GB-NS was investigated by X-rays diffraction(XRD). The paddle method was used to study the dissolution of GB-NS in vitro. The mean particle size of optimized GB-NS was(180±7) nm, with a polydispersity index of 0.196±0.036. SEM showed that GB-NS was rod-like or irregular granular. XRD showed that the crystallinity of GB-NS was significantly reduced compared with GB raw material. The cumulative dissolution rate of GB-NS reached 90% in 30 min, which was higher than that of GB raw material. The findings suggested that the miniaturized media milling method was simple, efficient and feasible to prepare GB-NS. And the dissolution rate of GB was significantly improved by nanosuspension technology.

MON2 Guides Wntless Transport to the Golgi through Recycling Endosomes.

Endocytic cargos are transported to recycling endosomes (RE) but how these sorting platforms are generated is not well understood. Here we describe our biochemical and live imaging studies of the conserved MON2-DOPEY complex in RE formation. MON2 mainly co-localized with RE marker RAB4B in peripheral dots and perinuclear region. The peripheral RE approached, interacted with, and separated from sorting nexin 3 (SNX3)-positive early endosomes (EE). Membrane-bound DOPEY2 was recruited to RE dependent upon MON2 expression, and showed binding abilities to kinesin and dynein/dynactin motor proteins. MON2-knockout impaired segregation of RE from EE and led to a decreased tubular recycling endosomal network, whereas RE was accumulated at perinuclear regions in DOPEY2-knockout cells. MON2 depletion also impaired intracellular transferrin receptor recycling, as well as retrograde transport of Wntless during its passage through RE before delivery from EE to the Golgi. Together, these data suggest that the MON2 drives separation of RE from EE and is required for efficient transport of endocytic cargo molecules.Key words: membrane trafficking, MON2, recycling endosomes, Wntless.