STNN-DDI: a Substructure-aware Tensor Neural Network to predict Drug-Drug Interactions.

Computational prediction of multiple-type drug-drug interaction (DDI) helps reduce unexpected side effects in poly-drug treatments. Although existing computational approaches achieve inspiring results, they ignore to study which local structures of drugs cause DDIs, and their interpretability is still weak. In this paper, by supposing that the interactions between two given drugs are caused by their local chemical structures (substructures) and their DDI types are determined by the linkages between different substructure sets, we design a novel Substructure-aware Tensor Neural Network model for DDI prediction (STNN-DDI). The proposed model learns a 3-D tensor of $\langle $  substructure, substructure, interaction type  $\rangle $ triplets, which characterizes a substructure-substructure interaction (SSI) space. According to a list of predefined substructures with specific chemical meanings, the mapping of drugs into this SSI space enables STNN-DDI to perform the multiple-type DDI prediction in both transductive and inductive scenarios in a unified form with an explicable manner. The comparison with deep learning-based state-of-the-art baselines demonstrates the superiority of STNN-DDI with the significant improvement of AUC, AUPR, Accuracy and Precision. More importantly, case studies illustrate its interpretability by both revealing an important substructure pair across drugs regarding a DDI type of interest and uncovering interaction type-specific substructure pairs in a given DDI. In summary, STNN-DDI provides an effective approach to predicting DDIs as well as explaining the interaction mechanisms among drugs. Source code is freely available at https://github.com/zsy-9/STNN-DDI.

Keguizhuia sedimenti gen. nov., sp. nov., isolated from river sediment represents a novel genus of the family Oxalobacteraceae.

A Gram-stain-negative bacterium, designated as R-40T, was isolated from sediment of the Mulong river in Mianyang city, Sichuan province, PR China. The cells of strain R-40T were aerobic non-motile and formed translucent white colonies on R2A agar. Growth occurred at 15-37 °C (optimum 30 °C), pH 5.0-9.0 (optimum 7.0) and salinities of 0-3.0 % (w/v, optimum 0 %). R-40T showed 95.2-96.6 % 16S rRNA gene sequence similarities with the type strains of species of the genera Oxalicibacterium, Herminiimonas, Lacisediminimonas, Paucimonas, Herbaspirillum and Noviherbaspirillum in the family Oxalobacteraceae. The results of phylogenetic analysis based on genome sequences indicated that the strain was clustered with type strains of species of the genera Oxalicibacterium and Herminiimonas in the family Oxalobacteraceae but formed a distinct lineage. The average nucleotide identity (ANI), digital DNA-DNA hybridization (dDDH) and average amino acid identity (AAI) values between R-40T and type strains of species of the genera Oxalicibacterium, Herminiimonas, Lacisediminimonas, Paucimonas, Herbaspirillum and Noviherbaspirillum ranged from 69.3 to 74.1 %, from 18.2 to 21.4 % and from 60.1 to 67.4 %, respectively. The major cellular fatty acids were C16 : 0, C17 : 0 cyclo and summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c). The major quinone was ubiquinone-8 (Q-8). The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phospholipid and small amounts of glycophospholipids. The genome size of R-40T was 5.1 Mbp with 54.0 % DNA G+C content. On the basis of the evidence presented in this study, strain R-40T represents a novel species of a novel genus in the family Oxalobacteraceae, for which the name Keguizhuia sedimenti gen. nov., sp. nov. (type strain R-40T=MCCC 1K08818T=KCTC 8137T) is proposed.

Discovery of first-in-class highly selective TRPV1 antagonists with dual analgesic and hypoglycemic effects.

Analgesia and blood sugar control are considered as two main unmet clinical needs for diabetes related neuropathic pain patients. Transient receptor potential vanilloid type-1 (TRPV1) channel is a highly validated target for pain perception, while no TRPV1 antagonists have been approved due to hyperthermia side effects. Herein, two series of new TRPV1 antagonists with flavonoid skeleton were designed by the structure-based drug design (SBDD) strategy. After comprehensive evaluation, compound CX-3 was identified as a promising TRPV1 antagonist. CX-3 exhibited equivalent TRPV1 antagonistic activity with classical TRPV1 antagonist BCTC in vitro, and exerted better analgesic activity in vivo than that of BCTC in the formalin induced inflammatory pain model without hyperthermia risk. Moreover, CX-3 exhibited robust glucose-lowering effects and showed high selectivity over other ion channels. Overall, these findings identified a first-in-class highly selective TRPV1 antagonist CX-3, which is a promising candidate to target the pathogenesis of diabetes related neuropathic pain.

Degradation of Atrazine by an Anaerobic Microbial Consortium Enriched from Soil of an Herbicide-Manufacturing Plant.

Atrazine is an important herbicide that has been widely used for weed control in recent decades. However, with the extensive use of atrazine, its residue seriously pollutes the environment. Therefore, the microbial degradation and detoxification of atrazine have received extensive attention. To date, the aerobic degradation pathway of atrazine has been well studied; however, little is known about its anaerobic degradation in the environment. In this study, an anaerobic microbial consortium capable of efficiently degrading atrazine was enriched from soil collected from an herbicide-manufacturing plant. Six metabolites including hydroxyatrazine, deethylatrazine, N-isopropylammelide, deisopropylatrazine, cyanuric acid, and the novel metabolite 4-ethylamino-6-isopropylamino-1,3,5-triazine (EIPAT) were identified, and two putative anaerobic degradation pathways of atrazine were proposed: a hydrolytic dechlorination pathway is similar to that seen in aerobic degradation, and a novel pathway initiated by reductive dechlorination. During enrichment, Denitratisoma, Thiobacillus, Rhodocyclaceae_unclassified, Azospirillum, and Anaerolinea abundances significantly increased, dominating the enriched consortium, indicating that they may be involved in atrazine degradation. These findings provide valuable evidence for elucidating the anaerobic catabolism of atrazine and facilitating anaerobic remediation of residual atrazine pollution.

A nomogram based on radiomics and clinical information to predict prognosis in percutaneous balloon compression for the treatment of trigeminal neuralgia.

OBJECTIVE: To develop a clinical-radiomics nomogram based on clinical information and radiomics features to predict the prognosis of percutaneous balloon compression (PBC) for the treatment of trigeminal neuralgia (TN). METHODS: The retrospective study involved clinical data from 149 TN patients undergoing PBC at Zhongnan Hospital, Wuhan University from January 2018 to January 2022. The free open-source software 3D Slicer was used to extract all radiomic features from the intraoperative X-ray balloon region. The relationship between clinical information and TN prognosis was analyzed by univariate logistic analysis and multivariate logistic analysis. Using R software, the optimal radiomics features were selected using the least absolute shrinkage and selection operator (Lasso) algorithm. A prediction model was constructed based on the clinical information and radiomic features, and a nomogram was visualized. The performance of the clinical radiomics nomogram in predicting the prognosis of PBC in TN treatment was evaluated using the area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA). RESULTS: A total of 149 patients were eventually included. The clinical factors influencing the prognosis of TN in univariate analysis were compression severity score and TN type. The lasso algorithm Max-Relevance and Min-Redundancy(mRMR) was used to select two predictors from 13 morphology-related radiomics features, including elongation and surface-volume ratio. A total of 4 predictors were used to construct a prediction model and nomogram. The AUC was 0.886(95% confidence interval (CI), 0.75 to 0.96), indicating that the model's good predictive ability. DCA demonstrated the nomogram's high clinical applicability. CONCLUSION: Clinical-radiomics nomogram constructed by combining clinical information and morphology-related radiomics features have good potential in predicting the prognosis of TN for PBC treatment. However, this needs to be further studied and validated in several independent external patient populations.

Research on the Sensing Characteristics of an Integrated Grid-like Sensor Based on a Triboelectric Nanogenerator.

With the development of the integration and miniaturization of sensing devices, the concept of self-sensing devices has been proposed. A motion state is self-sensed via the structure or integration of an actuator in the construction of a sensing unit. This device is then used to capture the perception and measurement of states such as position, displacement, and speed. A triboelectric nanogenerator converts mechanical energy into electrical energy through the coupling effect of contact generation and electrostatic induction, which represents one of the reliable ways through which to realize integrated sensing. In this world, the power generation technology of the TENG is applied to a sensing device. The sensing characteristics of a grid-like TENG are designed and analyzed in freestanding triboelectric mode. Firstly, a relation model of displacement, velocity, voltage, and charge is established. The charge-transfer increment and current amounts are linearly related to the velocity. The open-circuit voltage has a positive relationship with the displacement. The maximum open-circuit voltage and the maximum charge transfer are fixed values, and they are only related to the inherent parameters of a triboelectric nanogenerator. Next, the sensor model is constructed using COMSOL Multiphysics 6.0. The simulation results show that the relationships between output voltage and charge transfer, as well as those between the increments of charge transfer, velocity, and displacement, are consistent with the results derived from the formula. Finally, a performance test of the designed sensor is carried out, and the results are consistent with the theoretical deduction and simulation. After analysis and processing of the output electrical signal by the host computer, it can feedback the frequency and speed value of the measured object. In addition, the output signal is stable, and there is no large fluctuation or attenuation during the 521-s vibration test. Because the working unit of the sensor is thin filmed, it is small in size, easy to integrate, and has no external power supply; moreover, it can be integrated into a device to realize the self-sensing of a motion state.

Dual-function tunable metasurface for polarization-insensitive electromagnetic induction transparency and dual-band absorption.

In this paper, we propose a dual-operating mode metasurface based on graphene and vanadium dioxide (VO2), which can switch operating modes by changing the temperature. At room temperature (25 °C), the metasurface can generates a polarization-insensitive electromagnetically induced transparency (EIT)-like effect that can be modulated by changing the Fermi energy level (EF) of graphene (through adding external voltage). In addition, the theoretical results derived from the two-particle model are in good agreement with the simulation results based on the finite element method. At high temperature (68 °C), the metasurface mode of operation can be changed to a dual-band absorber, providing absorption of 78.6% and 99.9% at 1.13 THz and 2.16 THz, respectively. Both absorption peaks can be dynamically tuned by changing theEFof graphene. The metasurface is also simultaneously polarization insensitive and has a wide incidence angle. The proposed metasurface can be used as a slow light device with a maximum group delay of 0.5 ps at room temperature and as a refractive index sensor with a maximum sensitivity of 0.5 THz/RIU at high temperature. The designed metasurface offers a new way for designing multifunctional terahertz devices, slow light devices, and refractive index sensors.

Anaerobic biodegradation and detoxification of chloroacetamide herbicides by a novel Proteiniclasticum sediminis BAD-10T.

Chloroacetamide herbicides (CAAHs) are important herbicides that were widely used to control agricultural weeds. However, their mass applications have seriously contaminated environment, and they are toxic to living beings. CAAHs are easy to enter anoxic environments such as subsoil, wetland sediment, and groundwater, where CAAHs are mainly degraded by anaerobic organisms. To date, there are no research on the anaerobic degradation of CAAHs by pure isolate and toxicity of anaerobic metabolites of CAAHs. In this study, the anaerobic degradation kinetics and metabolites of CAAHs by an anaerobic isolate BAD-10T and the toxicity of anaerobic metabolites were studied. Isolate BAD-10T could degrade alachlor, acetochlor, propisochlor, butachlor, pretilachlor and metolachlor with the degradation kinetics fitting the pseudo-first-order kinetics equation. The degradation rates of CAAHs were significantly affected by the length of N-alkoxyalkyl groups, the shorter the N-alkoxyalkyl groups, the higher the degradation rates. Four metabolites 2-ethyl-6-methyl-N-(ethoxymethyl)-acetanilide (EMEMA), N-(2-methyl-6-ethylphenyl)-acetamide (MEPA), N-2-ethylphenyl acetamide and 2-ethyl-N-carboxyl aniline were identified during acetochlor degradation, and an anaerobic catabolic pathway of acetochlor was proposed. The toxicity of EMEMA and EMPA for zebrafish, Arabidopsis and Chlorella ellipsoidea were obviously lower than that of acetochlor, indicating that the anaerobic degradation of acetochlor by isolate BAD-10T is a detoxification process. The work reveals the anaerobic degradation kinetics and catabolic pathway of CAAHs and highlights a potential application of Proteiniclasticum sediminis BAD-10T for bioremediation of CAAHs residue-contaminated environment.

A 12-week personalised physical activity and dietary protein intervention for older adults undergoing peritoneal dialysis: A feasibility study.

This single-arm observational study explored the feasibility and efficacy of a 12-week personalised physical activity and dietary protein intervention programme for older adults undergoing peritoneal dialysis. Older adults undergoing peritoneal dialysis received eight individualised nutrition and physical activity advice sessions provided by trained nurses. Protein intake and physical activity were regarded as primary outcomes. All data were collected at baseline and at week 12. The enrolment rate was 78.4%. Twenty-nine patients participated in the study. Of these, 86.2% (25/29) completed the intervention. There was a significant increase in protein intake (t = -4.453, P< 0.001) and physical activity levels (Z = -2.929, P = 0.004). Of the participants, 56.0% achieved the targeted protein goal, and 41.4% met the physical activity goal. The timed up-and-go performance (t = 4.135, P = 0.001) increased after intervention. Trained nurses can successfully implement personalised diet and physical activity advice, and achieve promising patient outcomes.

Health study of 11,800 workers under occupational noise in Xinjiang.

BACKGROUND: We investigated the health status of some workers exposed to occupational noise in Xinjiang, and explored the influencing factors of their health level. We aimed to determine the key protection groups of occupational noise hazards, which might provide the basis for the development of targeted noise prevention measures. METHODS: We used descriptive analysis to investigate a total of 11,800 participants who underwent occupational health examination in Xinjiang Occupational Disease Prevention Hospital. RESULTS: The hearing abnormality rate of noise exposure participants was 8.03%, which was higher in males than females (χ2 = 54.507, p < 0.05). The abnormal rate of high-frequency hearing threshold in Xinjiang minorities was lower than in Han nationality (χ2 = 11.780, p < 0.05), while the results of the electrocardiogram were reversed (χ2 = 9.128, p < 0.05). Differences in abnormal rates of blood pressure (χ2 = 149.734, p < 0.05), hearing (χ2 = 231.203, p < 0.05), and physical examination (χ2 = 360.609, p < 0.05) are statistically significant in different industries. The abnormal rates of blood pressure (χ2 = 67.416, p < 0.05) and hearing (χ2 = 49.535, p < 0.05) gradually decrease with the expansion of the enterprise scale. Logistic regression analysis showed that gender, nationality, age, enterprise size, and industry were closely related to pure tone audiometry examination abnormal rate. CONCLUSION: Workers of male, elder, in mine and small/medium enterprises should be the key populations to prevent occupational noise hazard. It is necessary to standardize occupational health management in enterprises, which helps to improve workers' self-protection awareness and quality of life.

Anti-Inflammatory, Antioxidant, and Antifibrotic Effects of Gingival-Derived MSCs on Bleomycin-Induced Pulmonary Fibrosis in Mice.

BACKGROUND: Mesenchymal stem cell (MSC) intervention has been associated with lung protection. We attempted to determine whether mouse gingival-derived mesenchymal stem cells (GMSCs) could protect against bleomycin-induced pulmonary fibrosis. METHODS: Mice were divided into three groups: control (Con), bleomycin (Bl), and bleomycin + MSCs (Bl + MSCs). Mice were treated with 5 mg/kg bleomycin via transtracheal instillation to induce pulmonary fibrosis. We assessed the following parameters: histopathological severity of injury in the lung, liver, kidney, and aortic tissues; the degree of pulmonary fibrosis; pulmonary inflammation; pulmonary oedema; profibrotic factor levels in bronchoalveolar lavage fluid (BALF) and lung tissue; oxidative stress-related indicators and apoptotic index in lung tissue; and gene expression levels of IL-1ß, IL-8, TNF-α, lysophosphatidic acid (LPA), lysophosphatidic acid receptor 1 (LPA1), TGF-ß, matrix metalloproteinase 9 (MMP-9), neutrophil elastase (NE), MPO, and IL-10 in lung tissue. RESULTS: GMSC intervention attenuated bleomycin-induced pulmonary fibrosis, pulmonary inflammation, pulmonary oedema, and apoptosis. Bleomycin instillation notably increased expression levels of the IL-1ß, IL-8, TNF-α, LPA, LPA1, TGF-ß, MMP-9, NE, and MPO genes and attenuated expression levels of the IL-10 gene in lung tissue, and these effects were reversed by GMSC intervention. Bleomycin instillation notably upregulated MDA and MPO levels and downregulated GSH and SOD levels in lung tissue, and these effects were reversed by GMSC intervention. GMSC intervention prevented upregulation of neutrophil content in the lung, liver, and kidney tissues and the apoptotic index in lung tissue. CONCLUSIONS: GMSC intervention exhibits anti-inflammatory and antioxidant capacities. Deleterious accumulation of neutrophils, which is reduced by GMSC intervention, is a key component of bleomycin-induced pulmonary fibrosis. GMSC intervention impairs bleomycin-induced NE, MMP-9, LPA, APL1, and TGF-ß release.

A novel tigecycline resistance gene, tet(X6), on an SXT/R391 integrative and conjugative element in a Proteus genomospecies 6 isolate of retail meat origin.

OBJECTIVES: To characterize a novel tigecycline resistance gene, tet(X6), and a novel SXT-related integrative and conjugative element (ICE), ICEPgs6Chn1, found in a tigecycline-resistant Proteus genomospecies 6 strain, T60. METHODS: Strain T60 was identified by the VITEK 2 system, biochemical reactions and an SNP-based approach. The genetic profile of strain T60 was determined by WGS analysis. ICEPgs6Chn1 was analysed by PCR, conjugation experiments and bioinformatics tools. tet(X6) was characterized by cloning and protein structure prediction. RESULTS: Strain T60 was resistant to ampicillin, tetracycline, tigecycline, florfenicol, colistin and kanamycin, but susceptible to cefotaxime; it also exhibited high MICs of eravacycline (32 mg/L) and omadacycline (>64 mg/L). Only one chromosome was identified and tet(X6) was located in chromosomal ICEPgs6Chn1, a member of the SXT/R391 ICE family, of 114 368 bp and encoding the antimicrobial resistance genes floR, strB, strA, aph(3')-Ia, aac(3)-IV, aph(4)-Ia, tet(X6) and sul2. The circular intermediate of ICEPgs6Chn1 was detected by PCR and sequencing, but conjugation experiments showed that it was not self-transmissible. Cloning of the novel gene tet(X6) and protein structure prediction revealed that Tet(X6) confers tigecycline resistance. CONCLUSIONS: To our knowledge, this is the first report of a novel SXT/R391 ICE in a Proteus genomospecies 6 strain. Importantly, a novel high-level tigecycline resistance gene, tet(X6), emerged for the first time in the SXT/R391 element of Proteus genomospecies 6, revealing that ICEs may serve as an important platform for the accumulation of antibiotic resistance genes.

Multi-platform analysis of methylation-regulated genes in human lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most frequent pathological type of lung cancer that has a poor prognosis and high mortality rate. DNA methylation plays a critical role in various biological processes during development, while dysregulation results in pathological consequences. Thus, this study aimed to identify DNA methylation-regulated genes involved in LUAD occurrence. Initially, 300 downregulated and 168 upregulated mRNA expression levels were identified in two databases: Gene Expression Omnibus (GEO) and The Cancer Genome Atlas. In addition, GEO was utilized to detect 243 DNA hyper-methylated sites. Based on our observations, it was possible to correlate downregulation of mRNA expression and DNA hyper-methylation of six genes (ABCA3, COX7A1, HOXA5, SLIT3, SOX17, and SPARCL1). Functional analysis of the six genes indicated that these genes are predominantly enriched in cancer-related pathways and may promote carcinogenesis by regulating epithelialmesenchymal transition processes. In conclusion, our study identified a panel of DNA methylation-regulated genes involved in LUAD and may serve as potential epigenetic markers for this type of carcinoma.

Determination of adenosine triphosphate based on the use of fluorescent terbium(III) organic frameworks and aptamer modified gold nanoparticles.

A thiol-labeled adenosine triphosphate (ATP) binding aptamer is covalently linked on the surface of gold nanoparticles (AuNPs). This warrants protection of the red AuNPs from aggregation in high salt condition. The dispersed AuNPs can quench the fluorescence of the Tb(III)-MOFs at 547 nm with the excitation wavelength of 290 nm. This is ascribed to the combined action of inner filter effect, dynamic quenching and fluorescence resonance energy transfer. If the aptamer binds ATP to form folded structures, the AuNPs aggregate in high salt medium and the green fluorescence of the Tb(III)-MOFs is recovered. This method shows good sensitivity and selectivity for ATP, and the linear range is from 0.5 to 10 µM of ATP with the detection limitat of 0.32 µM. It was applied to the determination of ATP in (spiked) human plasma with satisfactory recoveries (from 93.2% to 106.3%). Oppositely, when the unlabeled aptamer is used instead of thiol-labeled aptamer in this process, the ATP-aptamer complexes rather than unlabeled aptamer provide greater protection for AuNPs against salt-induced aggregation. It is found that when the aptamer covalently binds to AuNPs, the steric hindrance is dominant for the stabilization of AuNPs; for unlabeled aptamer, the electrostatic repulsion is responsible for their stability, irrespective of whether ATP is present or not. These two different forces lead to the aggregation or dispersion of AuNPs with addition of target in salt solution. Graphical abstractThe impact of two repulsive forces (electrostatic repulsion and steric repulsion) on the stabilization of gold nanoparticles, and its application in fluorescent terbium metal-organic frameworks as a nanoprobe for adenosine triphosphate.

Characterization of Streptococcus pluranimalium from a cattle with mastitis by whole genome sequencing and functional validation.

BACKGROUND: Streptococcus pluranimalium is a new member of the Streptococcus genus isolated from multiple different animal hosts. It has been identified as a pathogen associated with subclinical mastitis, valvular endocarditis and septicaemia in animals. Moreover, this bacterium has emerged as a new pathogen for human infective endocarditis and brain abscess. However, the patho-biological properties of S. pluranimalium remain virtually unknown. The aim of this study was to determine the complete genome sequence of S. pluranimalium strain TH11417 isolated from a cattle with mastitis, and to characterize its antimicrobial resistance, virulence, and carbon catabolism. RESULTS: The genome of S. pluranimalium TH11417, determined by single-molecule real-time (SMRT) sequencing, consists of 2,065,522 base pair (bp) with a G + C content of 38.65%, 2,007 predicted coding sequence (CDS), 58 transfer RNA (tRNA) genes and five ribosome RNA (rRNA) operons. It contains a novel ISSpl1 element (a memeber of the IS3 family) and a Ф11417.1 prophage that carries the mef(A), msr(D) and lnu(C) genes. Consistently, our antimicrobial susceptibility test confirmed that S. pluranimalium TH11417 was resistant to erythromycin and lincomycin. However, this strain did not show virulence in murine pneumonia (intranasal inoculation, 107 colony forming unit - CFU) and sepsis (intraperitoneal inoculation, 107 CFU) models. Additionally, this strain is able to grow with glucose, lactose or galactose as the sole carbon source, and possesses a lactose-specific phosphoenolpyruvate-dependent phosphotransferase system (PTS). CONCLUSIONS: We reported the first whole genome sequence of S. pluranimalium isolated from a cattle with mastitis. It harbors a prophage carrying the mef(A), msr(D) and lnu(C) genes, and is avirulent in the murine infection model.

Superparamagnetic iron oxide magnetic nanomaterial-labeled bone marrow mesenchymal stem cells for rat liver repair after hepatectomy.

BACKGROUND: Superparamagnetic iron oxide magnetic nanomaterials (SPIO) are tracers used for treatment of central nervous and cardiovascular system complications in animal models. The present study investigated survival and proliferation of SPIO-labeled bone marrow mesenchymal stem cells (BMSCs) to determine their potential therapeutic value in liver repair. METHODS: Surface antigens of BMSCs were measured using flow cytometry. BMSCs viability, growth curve, and SPIO (0-100 µg/mL) labeling rate were evaluated using trypan blue staining, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and Prussian blue staining, respectively. SPIO-labeled BMSCs were transplanted via liver or spleen injection in rats undergoing 70% hepatectomy. Distribution of SPIO-labeled BMSCs in liver and spleen, and liver repair were evaluated by magnetic resonance imaging (MRI), and serum alanine aminotransferase, aspartate aminotransferase, albumin, and total bilirubin levels. RESULTS: CD29(+)/CD90(+)/CD45(-) BMSCs were successfully isolated from rats. Labeling rate of SPIO in 25 µg/mL was 94.9%. SPIO labeling did not affect BMSCs survival and proliferation. MRI showed that BMSCs colonized in the liver, whether via spleen or liver injection. Serum levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin in the transplanted rats were significantly lower than in the hepatectomy group at days 1, 3, and 7 after hepatectomy (all P < 0.05), whereas serum albumin levels were significantly higher in the transplanted rats on posthepatectomy day 3 (both P < 0.05). These indicators were not significantly different between the spleen and liver injection approaches. CONCLUSIONS: BMSCs transplantation via liver or spleen injection could significantly accelerate liver healing. In vivo MRI of SPIO-labeled BMSCs can be used to trace real-time liver healing during clinical treatment after hepatectomy.

Transient receptor potential vanilloid-1 (TRPV1) channels act as suppressors of the growth of glioma.

The aim of this study was to investigate the expression and function of the transient receptor potential vanilloid 1 (TRPV1) in glioma. We found that the expression of TRPV1 mRNA and protein were upregulated in glioma compared with normal brain by qPCR and western blot analysis. In order to investigate the function of TRPV1 in glioma, short hairpin RNA (shRNA) and the inhibitor of TRPV1 were used. In vitro, the activation of TRPV1 induced cell apoptosis with decreased migration capability and inhibited proliferation, which was abolished upon TRPV1 pharmacological inhibition and silencing. Mechanistically, TRPV1 modulated glioma proliferation through the protein kinase B (Akt) signaling pathway. More importantly, in immunodeficient (NOD-SCID) mouse xenograft models, tumor size was significantly increased when TRPV1 expression was disrupted by a shRNA knockdown approach in vivo. Altogether, our findings indicate that TRPV1 negatively controls glioma cell proliferation in an Akt-dependent manner, which suggests that targeting TRPV1 may be a potential therapeutic strategy for glioma.

Vitamin D and major chronic diseases.

Numerous observational studies have demonstrated a significant inverse association between vitamin D status and the risk of major chronic disease, including type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer. However, findings from Mendelian randomization (MR) studies and randomized controlled trials (RCTs) suggest minimal or no benefit of increased vitamin D levels. We provide an overview of recent literature linking vitamin D to major chronic diseases. Because emerging evidence indicates a potential threshold effect of vitamin D, future well-designed studies focused on diverse populations with vitamin D deficiency or insufficiency are warranted for a more comprehensive understanding of the effect of maintaining sufficient vitamin D status on the prevention of major chronic diseases.

Identification of the human Cytochrome P450 enzymes (P450s) responsible for metabolizing infigratinib to its pharmacologically active Metabolites, BHS697, and CQM157, and assessment of their in vitro inhibition of P450s and UDP-glucuronosyltransferases (UGTs).

Infigratinib, an oral FGFR inhibitor for advanced cholangiocarcinoma, yielded two active metabolites, BHS697 and CQM157, with similar receptor affinity. Our study characterized P450s that are responsible for the metabolism of infigratinib to its two major active metabolites, BHS697 and CQM157. In vitro inhibition of P450s and UGTs by infigratinib, BHS697 or CQM157 was further investigated. The unbound apparent Km values for metabolism of infigratinib to BHS697 by HLM, human recombinant CYP2C8, CYP2C19, CYP2D6 and CYP3A4 enzymes are 4.47, 0.65, 2.50, 30.6 and 2.08 µM, while Vmax values are 90.0 pmol/min/mg protein, 0.13, 0.027, 0.81, and 0.56 pmol/min/pmol protein, respectively. The unbound apparent Km value for metabolism of infigratinib to CQM157 by HLM is 0.049 µM, while the Vmax value is 0.32 pmol/min/mg protein respectively. In HLM, infigratinib displayed moderate inhibition of CYP3A4 and CYP2C19 and weak or negligible inhibition of other P450 isoforms. BHS697 exhibited weak inhibition of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, and no inhibition of CYP2C8 and CYP2D6. CQM157 moderately inhibited CYP2C9 and CYP3A4, and weakly or negligibly inhibited other P450 isoforms. Regarding UGTs, infigratinib moderately inhibited UGT1A4 and weakly inhibited UGT1A1, respectively. BHS697 weakly inhibited UGT1A1. In contrast, CQM157 moderately inhibited both UGT1A1 and UGT1A4. Our findings provide novel insights into the metabolism of and potential DDIs implicating infigratinib.

Impact of CYP2C19, CYP2C9, CYP3A4, and FMO3 Genetic Polymorphisms and Sex on the Pharmacokinetics of Voriconazole after Single and Multiple Doses in Healthy Chinese Subjects.

Voriconazole is the first-line treatment for invasive aspergillosis. Its pharmacokinetics exhibit considerable inter- and intra-individual variability. The purpose of this study was to investigate the effects of CYP2C19, CYP2C9, CYP3A4, and FMO3 genetic polymorphisms and sex on the pharmacokinetics of voriconazole in healthy Chinese adults receiving single-dose and multiple-dose voriconazole, to provide a reference for its clinical individualized treatment. A total of 123 healthy adults were enrolled in the study, with 108 individuals and 15 individuals in the single-dose and multiple-dose doses, respectively. Plasma voriconazole concentrations were measured using a validated LC-MS/MS method, and pharmacokinetics parameters were calculated using the non-compartmental method with WinNonlin 8.2. CYP2C19, CYP2C9, CYP3A4, and FMO3 single-nucleotide polymorphisms were sequenced using the Illumina Hiseq X-Ten platform. The results suggested that CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of voriconazole at single doses of 4, 6, and 8 mg/kg and multiple doses of voriconazole. CYP3A4 rs2242480 had a significant effect on AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity) and MRT (mean residence time) of voriconazole at a single dose of 4 mg/kg in CYP2C19 extensive metabolizer. Regardless of the CYP2C19 genotype, CYP2C9 rs1057910 and FMO3 rs2266780 were not associated with the pharmacokinetics of voriconazole at three single-dose levels or multiple doses. No significant differences in most voriconazole pharmacokinetics parameters were noted between male and female participants after single and multiple dosing. For patients receiving voriconazole treatment, CYP2C19 genetic polymorphisms should be genotyped for its precision administration. In contrast, based on our study of healthy Chinese adults, it seems unnecessary to consider the effects of CYP2C9, CYP3A4, and FMO3 genetic polymorphisms on voriconazole pharmacokinetics.