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This paper summered the clinical application of Guizhi decoction combined with Guizhigancaolonggumuli decoction in treating one case of insomnia. Based on the Traditional Chinese Medicine syndrome differentiation, Guizhi decoction combined with Guizhigancaolonggumuli decoction was administrated orally, and comprehensive nursing interventions on environment, dietary, exercise, mental health of the patient were carried out to improve the sleep quality of the patient. (本文总结1例采用桂枝汤合桂枝甘草龙骨牡蛎汤加减治疗失眠患者的临床经验。失眠患者多为阴阳不调, 久则易伤阴阳, 故而引起“不寐”。基于中医辨证分型, 桂枝汤合桂枝甘草龙骨牡蛎汤加减, 温补心阳, 调理营卫, 使阴阳调和, 并配合环境、饮食、运动、心理等护理干预, 有效改善了患者睡眠质量。)

Antitumour treatments are evolving, including bacteria-mediated cancer therapy which is concurrently an ancient and cutting-edge approach. Salmonella typhimurium is a widely studied bacterial species that colonizes tumor tissues, showing oncolytic and immune system-regulating properties. It can be used as a delivery vector for genes and drugs, supporting conventional treatments that lack tumor-targeting abilities. This article summarizes recent evidence on the anticancer mechanisms of S. typhimurium alone and in combination with other anticancer treatments, suggesting that it may be a suitable approach to disease management.

The composition and content of aroma substances in flue-cured tobacco (Nicotiana tabacum L.) will affect the quality of tobacco. To investigate the correlation between various aroma substances of K326 before and after flue-curing, and their impact on tobacco quality and diversity, this study employed the middle leaves of K326 and KRK26 as test materials. Samples were collected both before and after flue-curing for untargeted metabolomics analysis. The results of K326 showed that 584 metabolites were significantly different and there were 44 aroma-related metabolites, including alcohols, aldehydes, phenols, organic acids, etc. The analyzed aroma compounds consist of 37 known tobacco aroma substances, while 7 metabolites, previously not associated with tobacco aroma, have been identified as aroma substances in other food products. These findings suggest that these seven metabolites might may be potential tobacco aroma compounds. Further analysis showed that the content of phenols, alcohols, and aldehydes increased significantly after flue-curing, but the content of organic acids decreased. Furthermore, the analysis of KRK26 revealed a correlation between the quantity of aroma substances and the type of tobacco. These findings serve as a reference for enhancing the flue-curing process of K326 and optimizing the industrial production of cigarettes that use cured K326 tobacco leaves.

Objective To investigate the effects of srtA on the oxidation tolerance of the Streptococcus mutans UA159 strain and to explore the potential mechanism. Methods The oxidation tolerance in the planktonic state and biofilm state were compared among UA159, the srtA-deleted strain and the complementary strain through oxidative tolerance experiments. The RNA-sequencing data from both the exponential and stationary phases of UA159 and the srtA-deleted strain were obtained by using the Illumina HiSeq 4 000 sequencing platform to determine the impact of srtA knockout on S. mutans genomic transcription. We compared the differences in the transcriptional expression of oxidative tolerance-related genes between the UA159 strain and the srtA gene deletion strain and further explored the intrinsic relationship between the changes in oxidative tolerance and the genetic transcriptome. qPCR was used to verify the changes in the expression level of oxidation tolerance-related genes. Results The oxidation tolerance of the srtA-deleted strain decreased significantly in both the planktonic state and the biofilm state compared to that of UA159 (P < 0.05). A total of 33 oxidation tolerance-related genes were differentially expressed according to transcriptome sequencing. There was no significant change in the expression of peroxide synthesis- and metabolic-related enzyme genes, but in the stationary phase samples, the two-component signal transcription systems lrgA, lrgB, and lytT were significantly downregulated (2.2- to 2.4-fold) in the srtA-deleted strain. qPCR further confirmed that in both the exponential and stationary phases, lrgB and lytT expression in the planktonic state was reduced 11.01-53.51-fold, while the expression of the other two-component system-encoding gene vicK was reduced by 6.57-10.88-fold (P < 0.001). Conclusion SrtA gene deletion did not change the expression level of peroxide synthesis-related and metabolic enzyme-encoding genes but downregulated the expression of the associated transcription regulation factors to reduce the oxidation tolerance of S. mutans.

Dentin hypersensitivity is mainly associated with abrasion, wear, acid etching, cracking, wedge⁃shaped defects, enamel hypoplasia, caries, a lack of neck enamel, and cementum coverage accompanied by gingival recession, resulting in direct exposure of dentin tubules to the oral environment. Dentin hypersensitivity is mainly treated by seal⁃ ing the exposed dentin tubules and reducing the excitability of the pulpal nerves. Laser therapy, as a safe, fast and con⁃ venient treatment measure, has achieved good results both alone and in combination with other medicines and has at⁃ tracted increasing attention. This paper reviews the research progress in the treatment of dentin hypersensitivity using several common laser therapy mechanisms with parameter selections in various scopes of application. A review of the lit⁃ erature shows that the Nd:YAG laser has a strong penetrating power and a large thermal effect and can denature and co⁃ agulate proteins in dentin tubules in a very short time; while the CO2 laser causes little damage to the dental pulp and has an obvious immediate curative effect by high absorption of water molecules in hydroxyapatite and the dentin surface is melted and recrystallized; the Er:YAG laser has high water absorption and a large thermal effect and can block the tu⁃ bules by evaporating the fluid in the tubules and depositing salts; Er, Cr:YSGG laser energy can be fully absorbed by hy⁃ droxyapatite and water and result in desensitization by cutting hard tissues and melting periodontal dentin of the tube si⁃multaneously; The Ga⁃Al⁃As semiconductor laser and He:Ne laser are low energy. The laser dosage mainly changes the permeability of nerve fibers to potassium and sodium ions and depolarizes the nerve fibers, producing an analgesic ef⁃ fect. The combination of a laser with a desensitizer can improve the clinical efficacy of treating dentin hypersensitivity.

Conventional root canal therapy can not completely treat all periradicular lesions, especially combined endodontic⁃periodontic diseases, large periapical lesions and bone defect lesions. Guided tissue regeneration greatly im⁃ proves the success rate of endodontic surgery in treating these lesions. This article focuses on the application of various grafting materials, guided bone regeneration membranes and regulatory factors in endodontic surgery.

The aim of vital pulp therapy is to preserve vital, healthy pulp tissue through pulp capping or pulpotomy. Pulp ⁃ capping materials are applied to isolate infection, promote odontoblast differentiation and reparative dentine formation during the progress. Calcium silicon ⁃ based materials play significant roles in vital pulp therapy with their favorable mechanical properties, bioactivity and biocompatibility. The present paper will review current progress for these novel calcium silicon⁃based materials used in vital pulp therapy.

Objective To evaluate the antimicrobial properties of 2 different pulp capping materials (ProRoot MTA and iRoot BP Plus).Methods Modified direct contact test (DCT) was performed as follow. ProRoot MTA and iRoot BP Plus were set for 7 days, then crushed and immersed into deionized water at concentrations of 200 g·L -1 for another 7 days. PH values of the supernatants of the aqueous extracts were measured with a pH meter. The germfree supernatants were mixed with Streptococcus mutans suspensions and then incubated for 24 hours. The survival of bacteria was assessed by measuring the optical density (OD) at 600 nm with an automated microplate reader.Results PH values of the aqueous extracts of ProRoot MTA and iRoot BP Plus were between 12 and 13, and no statistically significant difference was found (t = 0.133, P = 0.899). Both ProRoot MTA and iRoot BP Plus demonstrated good antibacterial properties (P < 0.05), and iRoot BP Plus performed a better antibacterial effect (P < 0.05).Conclusion IRoot BP Plus performed a better antibacterial effect against Streptococcus mutans when compared to ProRoot MTA.

Enabled by a plethora of new technologies, research in membrane transporters has exploded in the past decade. The goal of this state-of-the-art article is to describe recent advances in research on membrane transporters that are particularly relevant to drug discovery and development. This review covers advances in basic, translational, and clinical research that has led to an increased understanding of membrane transporters at all levels. At the basic level, we describe the available crystal structures of membrane transporters in both the solute carrier (SLC) and ATP binding cassette superfamilies, which has been enabled by the development of cryogenic electron microscopy methods. Next, we describe new research on lysosomal and mitochondrial transporters as well as recently deorphaned transporters in the SLC superfamily. The translational section includes a summary of proteomic research, which has led to a quantitative understanding of transporter levels in various cell types and tissues and new methods to modulate transporter function, such as allosteric modulators and targeted protein degraders of transporters. The section ends with a review of the effect of the gut microbiome on modulation of transporter function followed by a presentation of 3D cell cultures, which may enable in vivo predictions of transporter function. In the clinical section, we describe new genomic and pharmacogenomic research, highlighting important polymorphisms in transporters that are clinically relevant to many drugs. Finally, we describe new clinical tools, which are becoming increasingly available to enable precision medicine, with the application of tissue-derived small extracellular vesicles and real-world biomarkers.

P-glycoprotein (P-gp) plays a critical role in drug oral bioavailability, and modulation of this transporter can alter the safety and/or efficacy profile of substrate drugs. Individual oral molecular excipients that inhibit P-gp function have been considered a mechanism for improving drug absorption, but a systematic evaluation of the interaction of excipients with P-gp is critical for informed selection of optimal formulations of proprietary and generic drug products. A library of 123 oral molecular excipients was screened for their ability to inhibit P-gp in two orthogonal cell-based assays. β-Cyclodextrin and light green SF yellowish were identified as modest inhibitors of P-gp with IC50 values of 168 μM (95% CI, 118-251 μM) and 204 μM (95% CI, 5.9-1745 μM), respectively. The lack of effect of most of the tested excipients on P-gp transport provides a wide selection of excipients for inclusion in oral formulations with minimal risk of influencing the oral bioavailability of P-gp substrates.

The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300 mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half-life (34.2 ± 12.2 h vs. 19.1 ± 1.42 h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1 mg/dl difference in serum creatinine. Real-world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously.

Numerous drugs are currently under accelerated clinical investigation for the treatment of coronavirus disease 2019 (COVID-19); however, well-established safety and efficacy data for these drugs are limited. The goal of this study was to predict the potential of 25 small molecule drugs in clinical trials for COVID-19 to cause clinically relevant drug-drug interactions (DDIs), which could lead to potential adverse drug reactions (ADRs) with the use of concomitant medications. We focused on 11 transporters, which are targets for DDIs. In vitro potency studies in membrane vesicles or HEK293 cells expressing the transporters coupled with DDI risk assessment methods revealed that 20 of the 25 drugs met the criteria from regulatory authorities to trigger consideration of a DDI clinical trial. Analyses of real-world data from electronic health records, including a database representing nearly 120,000 patients with COVID-19, were consistent with several of the drugs causing transporter-mediated DDIs (e.g., sildenafil, chloroquine, and hydroxychloroquine). This study suggests that patients with COVID-19, who are often older and on various concomitant medications, should be carefully monitored for ADRs. Future clinical studies are needed to determine whether the drugs that are predicted to inhibit transporters at clinically relevant concentrations, actually result in DDIs.

Human OAT1 and OAT3 play major roles in renal drug elimination and drug-drug interactions. However, there is little information on the interactions of drug metabolites with transporters. The goal of this study was to characterize the interactions of drug metabolites with OAT1 and OAT3 and compare their potencies of inhibition with those of their corresponding parent drugs. Using HEK293 cells stably transfected with OAT1 and OAT3, 25 drug metabolites and their corresponding parent drugs were screened for inhibitory effects on OAT1-and OAT3-mediated 6-carboxyfluorescein uptake at a screening concentration of 200 μM for all but 3 compounds. 20 and 24 drug metabolites were identified as inhibitors (inhibition > 50%) of OAT1 and OAT3, respectively. Seven drug metabolites were potent inhibitors of either or both OAT1 and OAT3 with Ki values less than 1 μM. 22 metabolites were more potent inhibitors of OAT3 than OAT1. Importantly, one drug and four metabolites were predicted to inhibit OAT3 at unbound plasma concentrations achieved clinically (Cmax,u/Ki values ≥ 0.1). In conclusion, our study highlights the potential interactions of drug metabolites with OAT1 and OAT3 at clinically relevant concentrations, suggesting that drug metabolites may modulate therapeutic and adverse drug response by inhibiting renal drug transporters.

The human solute carrier 22A (SLC22A) family consists of 23 members, representing one of the largest families in the human SLC superfamily. Despite their pharmacological and physiological importance in the absorption and disposition of a range of solutes, eight SLC22A family members remain classified as orphans. In this study, we used a multifaceted approach to identify ligands of orphan SLC22A15. Ligands of SLC22A15 were proposed based on phylogenetic analysis and comparative modeling. The putative ligands were then confirmed by metabolomic screening and uptake assays in SLC22A15 transfected HEK293 cells. Metabolomic studies and transporter assays revealed that SLC22A15 prefers zwitterionic compounds over cations and anions. We identified eight zwitterions, including ergothioneine, carnitine, carnosine, gabapentin, as well as four cations, including MPP+ , thiamine, and cimetidine, as substrates of SLC22A15. Carnosine was a specific substrate of SLC22A15 among the transporters in the SLC22A family. SLC22A15 transport of several substrates was sodium-dependent and exhibited a higher Km for ergothioneine, carnitine, and carnosine compared to previously identified transporters for these ligands. This is the first study to characterize the function of SLC22A15. Our studies demonstrate that SLC22A15 may play an important role in determining the systemic and tissue levels of ergothioneine, carnosine, and other zwitterions.

Requiring regional or in-country confirmatory clinical trials before approval of drugs already approved elsewhere delays access to medicines in low- and middle-income countries and raises drug costs. Here, we discuss the scientific and technological advances that may reduce the need for in-country or in-region clinical trials for drugs approved in other countries and limitations of these advances that could necessitate in-region clinical studies.

Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant K d values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R-N=N-R') dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.