Aim
Novel long‐acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin‐4‐IgG4‐Fc (E4F4) is a long‐acting glucagon‐like peptide‐1 receptor agonist. ...This first‐in‐human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects.
Methods
This single‐centre, randomized, double‐blind, placebo‐controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level.
Results
E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose‐dependent relationship between frequency, severity or causality of treatment‐emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45‐14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose‐dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose‐response relationship in the 1.8‐10.35 mg dose range, with an increased response at the higher doses.
Conclusion
E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5‐10.35 mg once every 2 weeks.
Summary
Indole is well known as an interspecies signalling molecule to modulate bacterial physiology; however, it is not clear how the indole signal is perceived and responded to by plant growth ...promoting rhizobacteria (PGPR) in the rhizosphere. Here, we demonstrated that indole enhanced the antibiotic tolerance of Pseudomonas fluorescens 2P24, a PGPR well known for its biocontrol capacity. Proteomic analysis revealed that indole influenced the expression of multiple genes including the emhABC operon encoding a major multidrug efflux pump. The expression of emhABC was regulated by a TetR‐family transcription factor EmhR, which was demonstrated to be an indole‐responsive regulator. Molecular dynamics simulation showed that indole allosterically affected the distance between the two DNA‐recognizing helices within the EmhR dimer, leading to diminished EmhR–DNA interaction. It was further revealed the EmhR ortholog in Pseudomonas syringae was also responsible for indole‐induced antibiotic tolerance, suggesting this EmhR‐dependent, indole‐induced antibiotic tolerance is likely to be conserved among Pseudomonas species. Taken together, our results elucidated the molecular mechanism of indole‐induced antibiotic tolerance in Pseudomonas species and had important implications on how rhizobacteria sense and respond to indole in the rhizosphere.
Granulocyte colony‐stimulating factor (G‐CSF) has been widely used in the field of allogeneic haematopoietic stem cell transplantation (allo‐HSCT) for priming donor stem cells from the bone marrow ...(BM) to peripheral blood (PB) to collect stem cells more conveniently. Donor‐derived natural killer (NK) cells have important antitumour functions and immune regulatory roles post‐allo‐HSCT. The aim of this study was to evaluate the effect of G‐CSF on donors' NK cells in BM and PB. The percentage of NK cells among nuclear cells and lymphocyte was significantly decreased and led to increased ratio of T and NK cells in BM and PB post‐G‐CSF in vivo application. Relative expansion of CD56bri NK cells led to a decreased ratio of CD56dim and CD56bri NK subsets in BM and PB post‐G‐CSF in vivo application. The expression of CD62L, CD54, CD94, NKP30 and CXCR4 on NK cells was significantly increased in PB after G‐CSF treatment. G‐CSF treatment decreased the IFN‐γ‐secreting NK population (NK1) dramatically in BM and PB, but increased the IL‐13‐secreting NK (NK2), TGF‐β‐secreting NK (NK3) and IL‐10‐secreting NK (NKr) populations significantly in BM. Clinical data demonstrated that higher doses of NK1 infused into the allograft correlated with an increased incidence of chronic graft‐vs‐host disease post‐transplantation. Taken together, our results show that the in vivo application of G‐CSF can modulate NK subpopulations, leading to an increased ratio of T and NK cells and decreased ratio of CD56dim and CD56bri NK cells as well as decreased NK1 populations in both PB and BM.
Rose is a highly significant ornamental plant with substantial edible and medicinal value, cultivated worldwide primarily for perfume production. Recently, Rosa yangii, a new species found in ...northwestern Yunnan, China, has drawn attention due to its strong sweet scented flowers. In this study, the floral components of R. yangii were extracted at different flowering stages using solid phase micro extraction (SPME) and analyzed through gas chromatography–mass spectrometry (GC–MS). A total of 131 volatile organic compounds (VOCs) were detected from R. yangii, including 69 odor compounds. The production and release of floral VOCs were the highest during the initial-open stage, making it the most suitable time for harvesting as a significant number of floral components were synthesized and preserved. The analysis of the odor activity values (OAV) highlighted several key aromatic ingredients of R. yangii, such as eugenol, methyleugenol, benzeneacetaldehyde and phenylethylalcohol, heptanal, decanal, (E)-2-hexen-1-yl acetate, caryophyllene, and others. Metabolome and time-order gene co-expression networks (TO-GCN) revealed that VOCs and benzenoids/phenylpropanoids, along with associated genes, played a pivotal role in the overall floral regulatory network of R. yangii. MYB and bHLH were identified as the essential regulatory factors governing the regulation of eugenol synthase (EGS) and isoeugenol synthase (IGS), consequently influencing the sweet scent of R. yangii. The findings of this study provide a scientific foundation for enhancing fragrance through molecular breeding of ornamental plants. Furthermore, the study facilitated the development and utilization of this new plant’s essential oil material in various industries, including food storage, aromatherapy, cosmetic, and perfumery.
The proinflammatory property of cisplatin is potentially destructive and contributes to the pathogenesis of acute kidney injury (AKI). The role and upstream regulatory mechanism of histone ...acetyltransferase 1 (HAT1) in acute kidney inflammation are still unknown. We performed RNA sequencing to filter differentially expressed microRNAs (miRNAs) in the kidney tissue of mice with AKI induced by cisplatin and ischemia‐reperfusion. Here, we found that miR‐486‐5p was upregulated and that the expression of HAT1 was reduced in AKI mouse models and injured human renal proximal tubular epithelial cell (HK‐2) model induced by cisplatin. miR‐486‐5p is implicated in cisplatin‐induced kidney damage in vivo. Bioinformatics analysis predicted a potential binding site between miR‐486‐5p and HAT1. The Luciferase reporter assay and Western blot confirmed that miR‐486‐5p directly targeted the 3′‐untranslated region of HAT1 mRNA and inhibited its expression in the cytoplasm of HK‐2 cells. In the in vitro study, inhibiting miR‐486‐5p reduced apoptosis, and the expression of proinflammatory mediators was induced by cisplatin in HK‐2 cells. Simultaneously, the downregulation of miR‐486‐5p inhibited the activation of the toll‐like receptor 4 (TLR4) and nuclear factor‐kappa B (NF‐κB). We further found that HAT1 could inhibit apoptosis and the activation of cisplatin on the TLR4/NF‐κB pathway and that the upregulation of miR‐486‐5p reversed this effect. Therefore, the upregulation of miR‐486‐5p targeting HAT1 promoted the cisplatin‐induced apoptosis and acute inflammation response of renal tubular epithelial cells by activating the TLR4/NF‐κB pathway, providing a new basis to highlight the potential intervention of regulating the miR‐486‐5p/HAT1 axis.
Both continuous oxidative stress and poly (ADP-ribose) polymerase 1 (PARP-1) activation occur in neurodegenerative diseases such as Parkinson's disease. PARP-1 inhibition can reverse mitochondrial ...damage and has a neuroprotective effect. In a previous study, we synthesized melatonin derivative 6a (MD6a) and reported that it has excellent antioxidant activity and significantly reduces α-synuclein aggregation in
; however, the underlying mechanism is largely unknown. In the present study, we revealed that MD6a is a potential PARP-1 inhibitor, leading to mammalian targe of rapamycin/heat shock factor 1 signaling downregulation and reducing heat shock protein 4 and 6 expression, thus helping to maintain protein homeostasis and improve mitochondrial function. Together, these findings suggest that MD6a might be a viable candidate for the prevention and treatment of Parkinson's disease.
Like the coronavirus disease 2019, the hepatitis B virus is also wreaking havoc worldwide, which has infected over 2 billion people globally. Using an experimental animal model, our previous research ...observed that the hepatitis B virus genes integrated into human spermatozoa can replicate and express after being transmitted to embryos. However, as of now, this phenomenon has not been confirmed in clinical data from patients.
To explore the integration of the hepatitis B virus into patients' sperm genome and its potential clinical risks.
Forty-eight patients with chronic hepatitis B virus infection were categorized into two groups: Test Group-1 comprised 23 patients without integration of hepatitis B virus DNA within the sperm genome. Test Group-2 comprised 25 patients with integration of hepatitis B virus DNA within the sperm genome. Forty-eight healthy male donors were included as control. The standard semen parameter analysis, real-time polymerase chain reaction, quantitative real-time polymerase chain reaction, sperm chromatin structure assay, fluorescence in situ hybridization, and immunofluorescence assays were utilized.
The difference in the median copy number of hepatitis B virus DNA per mL of sera between Test Group-1 and Group-2 was not statistically significant. In Test Group-2, the integration rate of hepatitis B virus DNA was 0.109%, which showed a significant correlation with the median copy number of hepatitis B virus DNA in motile spermatozoa (1.18 × 10
/mL). Abnormal semen parameters were found in almost all these 25 patients. The integrated hepatitis B virus S, C, X, and P genes were detected to be introduced into sperm-derived embryos through fertilization and retained their function in replication, transcription, and translation.
Our findings suggest that hepatitis B virus infection can lead to sperm quality deterioration and reduced fertilization capacity. Furthermore, viral integration causes instability in the sperm genome, increasing the potential risk of termination, miscarriage, and stillbirth. This study identified an unconventional mode of hepatitis B virus transmission through genes rather than virions. The presence of viral sequences in the embryonic genome poses a risk of liver inflammation and cancer.
Current organic memristive devices have been suffering from unstable performance, ambiguous mechanism, and poor NIR response, thus restricting their commercial translation. Here, a ...near‐infrared‐sensitive (NIR) organic memristive device with high stability based on solution‐processed copper phthalocyanine nanowires (N‐CuMe2Pc NWs) is first reported. Compared with uneven thermal evaporated N‐CuMe2Pc film, the N‐CuMe2Pc NWs film possesses a uniform 3D mesh structure, which attribute to the localized cationic migration, robust formation/rupture of conductive filament and subsequent improvement of reproducibility, thermal stability, and retention characteristics. Furthermore, operating voltage and OFF current can be readily regulated by NIR illumination due to strong NIR absorption of the well‐aligned edge‐to‐edge interconnected N‐CuMe2Pc NWs and tunable potential barrier formed between active layer and Ag electrode, which are further verified by absorption spectrum and Kelvin probe force microscope analysis, respectively. This study provides a generalized method for optimizing device performance and attaching phototunable properties of organic memristive memories. In addition, compared with pristine CuPc molecules with low solubility, limitation of thermal evaporation approach that is incompatible with scaling up is expected to overcome by the solution‐processed N‐CuMe2Pc NWs.
The organic memristor based on solution‐proceesed N‐CuMe2Pc nanowires is demonstrated. The device exhibits high reproducibility, thermal stability, endurance due to well‐manipulated Ag+ cation injection path in mesh‐structural nanowire film through nanoconfinement of the molecules into well‐aligned edge‐to‐edge interconnected nanowires. Furthermore, the solution‐processed N‐CuMe2Pc NWs exhibit strong extinction at wavelength of 788 nm, which ensures the NIR light‐controlled resistive switching.
An active mechanism for controlling ambipolar charge transport is developed based on self‐assembled monolayers of gold nanoparticles. Electron and hole currents are manipulated by controlling the ...gate bias in order to overcome the intrinsic material limitations. The endurance and retention measurements confirm that this method exhibits good electrical reliability and stability. This solution process approach has potential for applications in large‐area printed electronic devices.
Summary
Licensed natural killer (NK) cells have been demonstrated to have anti‐cytomegalovirus (CMV) activity. We prospectively analysed the human leucocyte antigen typing of donor‐recipient pairs ...and the killer cell immunoglobulin–like receptor (KIR) typing of donors for 180 leukaemia patients to assess the predictive roles of licensed NK cells on CMV reactivation post‐T‐cell‐replete haploidentical stem cell transplantation. Multivariate analysis showed that donor‐recipient KIR ligand graft‐versus‐host or host‐versus‐graft direction mismatch was associated with increased refractory CMV infection (Hazard ratio = 2·556, 95% confidence interval, 1·377–4·744, P = 0·003) post‐transplantation. Donor‐recipient KIR ligand matching decreased CMV reactivation 51·65% (46·67, 56·62%) vs. 75·28% (70·87, 79·69%), P = 0·012, refractory CMV infection 17·58% (13·77, 21·40%) vs. 35·96% (31·09, 40·82%), P = 0·004 and CMV disease 3·30% (1·51, 5·08%) vs. 11·24% (8·04, 14·43%), P = 0·024 by day 100 post‐transplantation. In addition, the percentage of γ‐interferon expression on donor‐derived NK cells was significantly higher in the recipients among the recipient‐donor pairs with a KIR ligand match compared with that in the recipients among the pairs with a KIR ligand graft‐versus‐host or host‐versus‐graft direction mismatch on days 30 and 100 post‐transplantation (P = 0·036 and 0·047, respectively). These findings have suggested that donor‐recipient KIR ligand matching might promote the NK cell licensing process, thereby increasing NK cell‐mediated protection against CMV reactivation.
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