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1.
JACS Au ; 3(1): 143-153, 2023 Jan 23.
Article in English | MEDLINE | ID: mdl-36711102

ABSTRACT

The aldehyde hydrogenation for stabilizing and upgrading biomass is typically performed in aqueous phase with supported metal catalysts. By combining density functional theory calculations and ab initio molecular dynamics simulations, the model reaction of formaldehyde hydrogenation with a Pt/TiO2 catalyst is investigated with explicit solvent water molecules. In aqueous phase, both the O vacancy (Ov) on support and solvent molecules could donate charges to a Pt cluster, where the Ov could dominantly reduce the Pt cluster from positive to negative. During the formaldehyde hydrogenation, the water molecules could spontaneously protonate the O in the aldehyde group by acid/base exchange, generating the OH* at the metal-support interface by long-range proton transfer. By comparing the stoichiometric and reduced TiO2 support, it is found that the further hydrogenation of OH* is hard on the positively charged Pt cluster over stoichiometric TiO2. However, with the presence of Ov on reduced support, the OH* hydrogenation could become not only exergonic but also kinetically more facile, which prohibits the catalyst from poisoning. This mechanism suggests that both the proton transfer from solvent water molecules and the easier OH* hydrogenation from Ov could synergistically promote aldehyde hydrogenation. That means, even for such simple hydrogenation in water, the catalytic mechanism could explicitly relate to all of the metal cluster, oxide support, and solvent waters. Considering the ubiquitous Ov defects in reducible oxide supports and the common aqueous environment, this synergistic effect may not be exclusive to Pt/TiO2, which can be crucial for supported metal catalysts in biomass conversion.

2.
Front Surg ; 9: 1089697, 2022.
Article in English | MEDLINE | ID: mdl-36713676

ABSTRACT

Objective: To evaluate the clinical effects of the posterior unilateral approach with 270° spinal canal decompression and three-column reconstruction using double titanium mesh cage (TMC) for thoracic and lumbar burst fractures. Materials and methods: From May 2013 to May 2018, 27 patients with single-level thoracic and lumbar burst fractures were enrolled. Every patient was followed for at least 18 months. Demographic data, neurologic status, back pain, canal compromise, anterior body compression, operative time, estimated blood loss and surgical-related complications were evaluated. Radiographs were reviewed to assess deformity correction, anterior body height correction, bony fusion and TMC subsidence. Results: The average preoperative percentages of canal compromise and anterior body height compression were 58.4% and 50.5%, respectively. All surgeries were successfully completed in one phase, the operative time was 151.5 ± 25.5 min (range: 115-220 min), the estimated blood loss was 590.7 ± 169.9 ml (range: 400-1,000 ml). Neurological function recovery was significantly improved except for 3 grade A patients. The preoperative visual analog scale (VAS) scores for back pain were significantly decreased compared with the values at the last follow-up (P = 0.000). The correct deformity angle was 12.4 ± 4.7° (range: 3.9-23.3°), and the anterior body height recovery was 96.7%. The TMC subsidence at the last follow-up was 1.3 ± 0.7 mm (range: 0.3-3.1 mm). Bony fusion was achieved in all patients. Conclusion: The posterior unilateral approach with 270° spinal canal decompression and three-column reconstruction using double TMC is a clinically feasible, safe and alternative treatment for thoracic and lumbar burst fractures.

3.
Biomacromolecules ; 2023 Jan 30.
Article in English | MEDLINE | ID: mdl-36716207

ABSTRACT

Wood has been used in a variety of applications in our daily lives and military industry. Nevertheless, its flammability causes potential fire risks and hazards. Improving the flame retardancy of wood is a challenging task. Herein, a phytic acid-based flame retardant (referred to as AMPA) was synthesized based on supramolecular reactions between melamine and p-amino-benzene sulfonic acid followed by a reaction with phytic acid using deionized water as the solvent. A composite wood was prepared by removing lignin to tailor the unique mesoporous structure of the material, followed by coating AMPA on the surfaces of wood microchannels. The limiting oxygen index of wood has been improved to 52.5% with the addition of 5.6 wt % AMPA. The peak heat release rate for the prepared composite wood was reduced by 81% compared to that for delignified wood, which demonstrates the excellent flame-retardant performance of the prepared composite wood. Furthermore, AMPA and mesoporous structures endow antimicrobial and thermal insulation functions. Hence, this work provides a feasible method for preparing flame-retardant wood-based materials for diversified applications.

4.
ACS Appl Mater Interfaces ; 2023 Jan 28.
Article in English | MEDLINE | ID: mdl-36708351

ABSTRACT

Protein bioassay is a critical tool for the screening and detection of protein biomarkers in disease diagnostics and biological applications. However, the detection sensitivity and system automation of current immunoassays do not meet the emerging demands of clinical applications. Here, we developed a dissolution-enhanced luminescence-enhanced digital microfluidics immunoassay (DEL-DMF), which significantly improves the sensitivity and automation of the protein bioassay. In DEL-DMF, the sample and reagent droplets are controlled to complete the processes of sample transport, immunoreaction, and buffer washing, which not only minimizes sample consumption to 2 µL and enhances the binding efficiency of immunoreaction but also streamlines all the procedures and simplifies the process of immunoassay. Moreover, dissolution-enhanced luminescence using NaEuF4 NPs as nanoprobes boosts the fluorescence and increases the sensitivity of the bioassay. We demonstrate the enhanced analytical performance of our DEL-DMF immunoassay to detect H5N1 hemagglutinin in human serum and saliva. A limit of detection of 1.16 pM was achieved in less than 0.5 h with only 2 µL sample consumption. Overall, our DEL-DMF immunoassay combines the merits of the microfluidics platform and dissolution-enhanced luminescence, thus affording superior detection sensitivity and system automation for protein biomarkers. This novel immunoassay microsystem holds great potential in clinical and biological applications.

5.
Front Endocrinol (Lausanne) ; 13: 1013894, 2022.
Article in English | MEDLINE | ID: mdl-36704038

ABSTRACT

Primary ovarian insufficiency (POI) is among the foremost causes of women infertility due to premature partial or total loss of ovarian function. Resistant ovary syndrome (ROS) is a subtype of POI manifested as normal ovarian reserve but insensitive to gonadotropin stimulation. Inactivating variants of follicle-stimulating hormone receptor (FSHR), a class A G-protein coupled receptor, have been associated with POI and are inherited via an autosomal recessive pattern. In this study, we investigated the genetic causes of a primary infertility patient manifested as POI with ROS, and elucidated the structural and functional impact of variants of uncertain significance. Next-generation sequencing (NGS) combined with Sanger sequencing revealed novel compound heterozygous FSHR variants: c.1384G>C/p.Ala462Pro and c.1862C>T/p.Ala621Val, inherited from her father and mother, respectively. The two altered amino acid sequences, localized in the third and seventh transmembrane helix of FSHR, were predicted as deleterious by in silico prediction. In vitro experiments revealed that the p.Ala462Pro variant resulted in barely detectable levels of intracellular signaling both in cAMP-dependent CRE-reporter activity and ERK activation and displayed a severely reduced plasma membrane receptor expression. In contrast, the p.Ala621Val variant resulted in partial loss of receptor activation without disruption of cell surface expression. In conclusion, two unreported inactivating FSHR variants potentially responsible for POI with ROS were first identified. This study expands the current phenotypic and genotypic spectrum of POI.


Subject(s)
Infertility, Female , Primary Ovarian Insufficiency , Humans , Female , Primary Ovarian Insufficiency/genetics , Primary Ovarian Insufficiency/metabolism , Receptors, FSH/genetics , Receptors, FSH/metabolism , Reactive Oxygen Species , Genotype
6.
Bioengineered ; 13(5): 13366-13383, 2022 May.
Article in English | MEDLINE | ID: mdl-36700466

ABSTRACT

Myocardial ischemia-reperfusion injury (MIRI) represents a coronary artery disease, accompanied by high morbidity and mortality. Sevoflurane post-conditioning (SPC) is importantly reported in myocardial disease. Accordingly, the current study sought to evaluate the role of Sevo in MI/RI. Firstly, MI/RI models were established and subjected to SPC. Subsequently, pathological injury in the myocardium, myocardial infarction areas, H9c2 cell viability, apoptosis, and levels of creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH) were all measured. Ubiquitin-specific peptidase (22USP22), lysine-specific demethylase 3A (KDM3A), and Yes1 associated transcriptional regulator (YAP1) were down-regulated in H9c2 cells using cell transfection to verify their roles. The interaction between USP22 and KDM3A and between KDM3A and YAP1 was further validated. USP 22, KDM3A, and YAP1 were found to be down-regulated in MI/RI and SPC protected MI/RI rats, as evidenced by up-regulated expressions of USP22, KDM3A, and YAP1, reduced pathological injury in the myocardium, myocardial infarction areas, apoptosis, and levels of CK-MB, cTnI, and LDH, and enhanced H9c2 cell viability; while the protective effects of Sevo were counteracted by silencing of USP22, KDM3A, and SPC upregulated USP22, which stabilized KDM3A protein levels via deubiquitination, and KDM3A inhibited histone 3 lysine 9 di-methylation (H3K9me2) levels in the YAP1 promoter to encourage YAP1 transcription, to reduce MI/RI.


Subject(s)
Myocardial Infarction , Myocardial Reperfusion Injury , Rats , Animals , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/metabolism , Sevoflurane/pharmacology , Lysine/pharmacology , Rats, Sprague-Dawley , Apoptosis , Myocytes, Cardiac/metabolism
7.
Neurosurgery ; 2022 Dec 29.
Article in English | MEDLINE | ID: mdl-36700744

ABSTRACT

BACKGROUND: Pipeline embolization devices (PEDs) have been increasingly used for the treatment of posterior circulation aneurysms. OBJECTIVE: To investigate the safety and efficacy of PED in the treatment of small to medium unruptured vertebral artery intracranial aneurysms (VAIAs). METHODS: Data from 76 patients with 78 unruptured small and medium (≤12 mm) VAIAs were analyzed. Data for this study come from the PLUS study, which was conducted at 14 centers in China from 2014 to 2019. Univariate analyses were performed to evaluate predictors of the occlusion and complication. RESULTS: Seventy-eight aneurysms in 76 patients were treated with PED. The mean aneurysm size was 8.28 ± 2.13 mm, and all PEDs were successfully placed. The median follow-up was 7 months and available for 67 (85.9%) aneurysms. Complete occlusion was seen in 60 (89.6%) aneurysms, which 86.6% met the primary efficacy outcome. All patients received clinical follow-up, the combined major morbidity and mortality was 2.6%, and 98.7% of patients had a good prognosis. Ischemic stroke occurred in 10.5% of patients, and adjuvant coil and successful after adjustment were predictors of ischemic stroke in the early postoperative and follow-up, respectively. There was no significant difference in the occlusion rate of aneurysm involving posterior inferior cerebellar artery (P = .78). In cases where posterior inferior cerebellar artery was covered by PED, there was no significant difference in ischemic stroke. CONCLUSION: In the treatment of unruptured ≤12 mm VAIAs, PED has a high surgical success rate, a high degree of occlusion, and low morbidity and mortality. PED may be a promising endovascular technique.

8.
Plast Reconstr Surg ; 151(2): 293-302, 2023 Feb 01.
Article in English | MEDLINE | ID: mdl-36696310

ABSTRACT

BACKGROUND: Although widely accepted as an optimal procedure in thigh contouring, liposuction can result in complications, such as skin irregularity or aspiration inadequacy. A main cause might be insufficient knowledge of the superficial fascial system (SFS). The authors aimed to explore the characteristics of the SFS in the thigh and propose anatomical guidelines and new zoning for liposuction-assisted thigh contouring. METHODS: A total of 20 fresh female thighs were dissected from the skin to deep fascia to observe and compare changes in the SFS from the medial to the lateral side and from the proximal to the distal end. RESULTS: The thigh was divided into four units, namely, the medial (three subunits: upper, middle, and lower), anterior, posterior (three subunits: upper medial, upper lateral, and middle lower parts), and lateral thigh. The authors found that the form of the SFS has regional variations. Therefore, based on these varied features, four anatomical scenarios (degrees I to IV) and one functional section (hip-contour support) were devised from the eight subunits. Five different liposuction methods were formulated to manage these subunits: all-layer mass liposuction, normal aspiration, border feather-out, restricted lipoplasty, and anchor. CONCLUSIONS: The SFS of the thigh showed a regional variation pattern, based on which the authors proposed a series of new anatomy-based liposuction approaches. A well-sculpted thigh with its different sections presented in harmony can be safely obtained using these approaches.


Subject(s)
Lipectomy , Thigh , Humans , Female , Thigh/surgery , Lipectomy/methods , Skin , Dissection , Cadaver
9.
Acta Pharmacol Sin ; 2023 Jan 25.
Article in English | MEDLINE | ID: mdl-36697976

ABSTRACT

The inflammatory responses involving infiltration and activation of liver macrophages play a vital role in acute liver failure (ALF). In the liver of ALF mice, cannabinoid receptor 2 (CB2R) is significantly upregulated on macrophages, while CB2R agonist GW405833 (GW) could protect against cell death in acute liver damage. In this study, we investigated the molecular mechanisms underlying the protective effects of GW against ALF in vivo and in vitro from a perspective of macrophage glycometabolism. Mice were pretreated with GW (10 mg/kg, i.p.), then were injected with D-GalN (750 mg/kg, i.p.) and LPS (10 mg/kg, i.p.) to induce ALF. We verified the protective effects of GW pretreatment in ALF mice. Furthermore, GW pretreatment significantly reduced liver macrophage infiltration and M1 polarization, and inhibited the release of inflammatory factors TNF-α and IL-1ß in ALF mice. These protective effects were eliminated by CB2R antagonist SR144528 or in CB2R-/- ALF mice. We used LPS-stimulated RAW264.7 cells as an in vitro M1 macrophage-centered model of inflammatory response, and demonstrated that pretreatment with GW (10 µM) significantly reduced glucose metabolism by inhibiting glycolysis, which inhibited LPS-induced macrophage proliferation and inflammatory cytokines release. We verified these results in a stable CB2R-/- RAW264.7 cell line. Moreover, we found that GW significantly inhibited the expression of hypoxia inducible factor 1α (HIF-1α). Using a stable HIF-1α-/- RAW264.7 cell line, we confirmed that GW reduced the release of inflammatory cytokines from macrophages and inhibited glycolysis by downregulating HIF-1α expression. In conclusion, activation of CB2Rs inhibits the proliferation of hepatic macrophages and release of inflammatory factors in ALF mice through downregulating HIF-1α to inhibit glycolysis.

10.
ACS Nano ; 2023 Jan 25.
Article in English | MEDLINE | ID: mdl-36695402

ABSTRACT

To address the issue posed by drug-resistant bacteria and inspired by natural antimicrobial enzymes, we report the atomically doped copper on guanine-derived nanosheets (G-Cu) that possess the integrated catalytic cascade property of glucose oxidase and peroxidase, yielding free radicals to eliminate drug-resistant bacteria upon light irradiation. Density functional theory calculations demonstrate that copper could notably promote oxygen activation and H2O2 splitting on the G-Cu complexes. Further all-atom simulation and experimental data indicate that the lysis of bacteria is mainly induced by cell membrane damage and the elevation of intracellular reactive oxygen species. Lastly, the G-Cu complexes efficiently eliminate the staphylococci in the infected wounds and accelerate their closure in a murine model, with negligible side effects on the normal tissues. Therefore, our G-Cu complexes may provide an efficient nonantibiotic alternative to the current treatments for bacterial infections.

11.
Reprod Sci ; 2023 Jan 24.
Article in English | MEDLINE | ID: mdl-36694081

ABSTRACT

Embryo implantation and decidualization are key steps in establishing a successful pregnancy. Defects in embryo implantation and decidualization can cause a series of adverse chain reactions which can contribute to harmful pregnancy outcomes, such as embryo growth retardation, preeclampsia, miscarriage, premature birth, and so on. Approximately 75% of failed pregnancies are considered to be due to embryo implantation failure or defects. Decidualization, characterized by proliferation and differentiation of uterine stromal cells, is one of the essential conditions for blastocyst implantation, placental formation, and maintenance of pregnancy and is indispensable for the establishment of pregnancy in many species. Embryo implantation and decidualization are closely regulated by estrogen and progesterone secreted by the ovaries. Many cellular events and molecular signaling network pathways are involved in this process. This article reviews the recent advances in the molecular mechanisms of estrogen- and progesterone-regulating uterine receptivity establishment, blastocyst implantation, and decidualization, in order to better understand the underlying molecular mechanisms of hormonal regulation of embryo implantation and to develop new strategies for preventing or treating embryo implantation defects and improving the pregnancy rate of women.

12.
Bioeng Transl Med ; 8(1): e10334, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36684075

ABSTRACT

Cell aggregates that mimic in vivo cell-cell interactions are promising and powerful tools for tissue engineering. This study isolated a new, easily obtained, population of mesenchymal stem cells (MSCs) from rat hard palates named hard palatal-derived mesenchymal stem cells (PMSCs). The PMSCs were positive for CD90, CD44, and CD29 and negative for CD34, CD45, and CD146. They exhibited clonogenicity, self-renewal, migration, and multipotent differentiation capacities. Furthermore, this study fabricated scaffold-free 3D aggregates using light-controlled cell sheet technology and a serum-free method. PMSC aggregates were successfully constructed with good viability. Transplantation of the PMSC aggregates and the PMSC aggregate-implant complexes significantly enhanced bone formation and implant osseointegration in vivo, respectively. This new cell resource is easy to obtain and provides an alternative strategy for tissue engineering and regenerative medicine.

13.
Stem Cells Int ; 2023: 2915826, 2023.
Article in English | MEDLINE | ID: mdl-36684388

ABSTRACT

Background: Tendon injuries are common clinical disorders. Due to the limited regeneration ability of tendons, tissue engineering technology is often used as an adjuvant treatment. This study explored the molecular pathways underlying micropattern SF film-regulated TSPC propensity and their repairing effects to highlight the application value of micropattern SF films. Methods: First, we characterized the physical properties of the micropattern SF films and explored their repairing effects on the injured tendons in vivo. Then, we seeded TSPCs on SF films in vitro and determined the micropattern SF film-induced gene expression and activation of signaling pathways in TSPCs through high-throughput RNA sequencing and proteomics assays. Results: The results of in vivo studies suggested that micropattern SF films can promote remodeling of the injured tendon. In addition, immunohistochemistry (IHC) results showed that tendon marker genes were significantly increased in the micropattern SF film repair group. Transcriptomic and proteomic analyses demonstrated that micropattern SF film-induced genes and proteins in TSPCs were mainly enriched in the focal adhesion kinase (FAK)/actin and phosphoinositide 3-kinase (PI3K)/AKT pathways. Western blot analysis showed that the expression of integrins α2ß1, tenascin-C (TNC), and tenomodulin (TNMD) and the phosphorylation of AKT were significantly increased in the micropattern SF film group, which could be abrogated by applying PI3K/AKT inhibitors. Conclusion: Micropattern SF films modified by water annealing can promote remodeling of the injured tendon in vivo and regulate the tendon differentiation of TSPCs through the α2ß1/FAK/PI3K/AKT signaling pathway in vitro. Therefore, they have great medical value in tendon repair.

14.
World J Clin Cases ; 11(2): 464-471, 2023 Jan 16.
Article in English | MEDLINE | ID: mdl-36686343

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations have been administered worldwide, with occasional reports of associated neurological complications. Specifically, the impact of vaccinations on individuals with X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is unclear. Patients with CMTX1 can have stroke-like episodes with posterior reversible encephalopathy syndrome on magnetic resonance imaging (MRI), although this is rare. CASE SUMMARY: A 39-year-old man was admitted with episodic aphasia and dysphagia for 2 d. He received SARS-CoV-2 vaccination 39 d before admission. Physical examination showed pes cavus and reduced tendon reflexes. Brain MRI showed bilateral, symmetrical, restricted diffusion with T2 hyperintensities in the cerebral hemispheres. Nerve conduction studies revealed peripheral nerve damage. He was diagnosed with Charcot-Marie-Tooth disease, and a hemizygous mutation in the GJB1 gene on the X chromosome, known to be pathogenic for CMTX1, was identified. Initially, we suspected transient ischemic attack or demyelinating leukoencephalopathy. We initiated treatment with antithrombotic therapy and immunotherapy. At 1.5 mo after discharge, brain MRI showed complete resolution of lesions, with no recurrence. CONCLUSION: SARS-CoV-2 vaccination could be a predisposing factor for CMTX1 and trigger a sudden presentation.

15.
Clin Cosmet Investig Dermatol ; 16: 103-110, 2023.
Article in English | MEDLINE | ID: mdl-36686607

ABSTRACT

Purpose: Madelung's disease (MD) is a rare condition of massive deposits of fat accumulations between superficial and deep fascia at typical locations. There is an absence of systematic studies related to MD in the Chinese cohort. Thus, the objective of the study was to investigate the clinical features of the MD cases in our institution and to explore the clinical variables associated with postoperative recurrence. Materials and Methods: We retrospectively analyzed the clinical information of 21 individuals with MD from 2013 to 2021 enrolled in our institution. The paired t-test and χ 2 test were, respectively, used to determine the difference between continuous and classified variables. The univariate Kaplan-Meier analysis by log-rank and multivariate stepwise Cox regression analysis were used to explore variables possibly associated with postoperative recurrence in MD individuals. Results: In the current study, 90.48% of the studied patients were male with a mean age of 48.76 years old. About 61.90% exhibited type I MD. MD patients who experienced postoperative recurrence had a higher age, BMI, incidence of chronic complications, and prevalence of alcoholism than the other MD patients without recurrence (P < 0.05). The univariate Kaplan-Meier analysis by log-rank identified that age, BMI, alcoholism, and comorbidities were influencing factors related with postoperative recurrence (P < 0.05). Conclusion: Demographic characteristics of the 21 studied Chinese cases with MD were generally in accordance with previously published data of other foreign populations. The factors possibly influencing the postoperative recurrence for patients with MD were age, BMI, alcoholism, and a combination of comorbidities. This is the first time that a summarization of clinical characteristics and postoperative recurrence variables of Chinese patients with MD has been reported.

16.
ACS Omega ; 8(2): 2306-2314, 2023 Jan 17.
Article in English | MEDLINE | ID: mdl-36687021

ABSTRACT

The extract of Tribulus terrestris (TT) has been used as a component of several nutritional supplements for enhancing human vitality. However, its protective effect on ischemic stroke has yet to be fully investigated. In this study, the middle cerebral artery occlusion (MCAO) rat model was established and treated with gross saponin of TT fruit (GSTTF) by gavage to explore its anti-ischemic stroke efficacy. Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was applied to profile the brain tissue metabolite changes and further obtain the metabolic pathways that were greatly involved in the efficacy of GSTTF. Subsequent molecular biology experiments were applied to validate the findings from metabolomics analysis. The results showed that GSTTF administration remarkably decreased the infarction volume of brain tissue and improved the neurobehavioral scores of MCAO rats. Metabolomics analysis revealed that pathways, including glycerophospholipid metabolism, sphingolipid metabolism, and arachidonic acid metabolism, were considered associated with the protective effect of GSTTF against MCAO, which were greatly involved in the inflammatory responses. The results of the biochemistry analysis showed that GSTTF treatment significantly reduced the levels of TNF-α and IL-6 in brain tissue after MCAO. The anti-inflammatory mechanism of GSTTF was further investigated, which revealed that GSTTF could inhibit the TLR4/MyD88/NF-κB signaling pathway to exert protective effects on MCAO. This study provides the underlying anti-inflammatory mechanism of GSTTF for ischemic stroke protection, which has important implications for the development of GSTTF-related functional foods or food supplements.

17.
Biomark Res ; 11(1): 8, 2023 Jan 24.
Article in English | MEDLINE | ID: mdl-36691065

ABSTRACT

BACKGROUND: Gilteritinib is the only drug approved as monotherapy for acute myeloid leukemia (AML) patients harboring FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation throughout the world. However, drug resistance inevitably develops in clinical. Sitravatinib is a multi-kinase inhibitor under evaluation in clinical trials of various solid tumors. In this study, we explored the antitumor activity of sitravatinib against FLT3-ITD and clinically-relevant drug resistance in FLT3 mutant AML. METHODS: Growth inhibitory assays were performed in AML cell lines and BaF3 cells expressing various FLT3 mutants to evaluate the antitumor activity of sitravatinib in vitro. Immunoblotting was used to examine the activity of FLT3 and its downstream pathways. Molecular docking was performed to predict the binding sites of FLT3 to sitravatinib. The survival benefit of sitravatinib in vivo was assessed in MOLM13 xenograft mouse models and mouse models of transformed BaF3 cells harboring different FLT3 mutants. Primary patient samples and a patient-derived xenograft (PDX) model were also used to determine the efficacy of sitravatinib. RESULTS: Sitravatinib inhibited cell proliferation, induced cell cycle arrest and apoptosis in FLT3-ITD AML cell lines. In vivo studies showed that sitravatinib exhibited a better therapeutic effect than gilteritinib in MOLM13 xenograft model and BaF3-FLT3-ITD model. Unlike gilteritinib, the predicted binding sites of sitravatinib to FLT3 did not include F691 residue. Sitravatinib displayed a potent inhibitory effect on FLT3-ITD-F691L mutation which conferred resistance to gilteritinib and all other FLT3 inhibitors available, both in vitro and in vivo. Compared with gilteritinib, sitravatinib retained effective activity against FLT3 mutation in the presence of cytokines through the more potent and steady inhibition of p-ERK and p-AKT. Furthermore, patient blasts harboring FLT3-ITD were more sensitive to sitravatinib than to gilteritinib in vitro and in the PDX model. CONCLUSIONS: Our study reveals the potential therapeutic role of sitravatinib in FLT3 mutant AML and provides an alternative inhibitor for the treatment of AML patients who are resistant to current FLT3 inhibitors.

18.
Sci Total Environ ; : 161711, 2023 Jan 19.
Article in English | MEDLINE | ID: mdl-36682563

ABSTRACT

The frequency of extreme drought events has been rising worldwide, but due to its unpredictability, how plants will respond remains poorly understood. Here, we aimed to characterize how the hydraulics and photosynthesis of savanna plants respond to extreme drought, and tested whether they can subsequently recover photosynthesis after drought. There was an extreme drought in 2019 in Southwest (SW) China. We investigated photosynthetic gas exchange, leaf-, stem-, and whole-shoot hydraulic conductance of 18 plant species with diverse leaf habits (deciduous, semi-deciduous and evergreen) and growth forms (tree and shrub) from a dry-hot valley savanna in SW China for three rainy seasons from 2019 to 2021. We also compared photosynthetic gas exchange to those of a regular year (2014). We found that leaf stomatal and hydraulic conductance and maximum photosynthetic rate were significantly lower during the drought in 2019 than in the wetter years. In 2019, all studied plants maintained stomatal conductance at their minimum level observed, which could be related to high vapor pressure deficits (VPD, >2 kPa). However, no significant difference in stem and shoot hydraulic conductance was detected across years. The reductions in leaf hydraulic conductance and stomatal regulation under extreme drought might help keep the stem hydraulic function. Stomatal conductance and photosynthesis after drought (2020 and 2021) showed comparable or even higher values compared to that of 2014, suggesting high recovery of photosynthetic gas exchange. In addition, the response of hydraulic and photosynthetic traits to extreme drought was convergent across leaf habits and growth forms. Our results will help better understand the physiological mechanism underlying the response of savanna ecosystems to climate change.

20.
J Hepatol ; 2023 Jan 18.
Article in English | MEDLINE | ID: mdl-36681162

ABSTRACT

BACKGROUND & AIMS: Hepatocyte growth and proliferation depends on membrane phospholipid biosynthesis. Short chain fatty acids (SCFA) generated by bacterial fermentation, delivered through the gut-liver axis, significantly contribute to lipid biosynthesis. We therefore hypothesized that dysbiotic insults like antibiotics treatment not only affect gut microbiota, but also impair hepatic lipid synthesis and liver regeneration. METHODS: Stable isotope labelling and 70% partial hepatectomy (PHx) was carried out in C57 B l/6 J wildtype mice, in mice treated with broad-spectrum antibiotics, in germfree mice and mice colonized with minimal microbiota. Microbiome was analysed by 16 S rRNA gene sequencing and microbial culture. Gut content, liver, blood and primary hepatocyte organoids were tested by lipidomics mass spectrometry, qRT-PCR, immunoblot and immunohistochemistry for expression of proliferative and lipogenic markers. Matched biopsies from hyperplastic and hypoplastic liver tissue of human patients subjected to portal vein embolization were analysed by qRT-PCR for lipogenic enzymes. RESULTS: Three days of antibiotics treatment induced persistent dysbiosis with significantly decreased beta-diversity and richness, but massive increase of Proteobacteria, accompanied by decreased colonic SCFA. After PHx, antibiotics-treated mice showed delayed liver regeneration, increased mortality, impaired hepatocyte proliferation and decreased hepatic phospholipid synthesis. Expression of the lipogenic enzyme SCD1 was upregulated after PHx, but delayed by antibiotics-treatment. Germfree mice essentially recapitulated the phenotype of antibiotics-treatment. Phospholipid biosynthesis, hepatocyte proliferation, liver regeneration and survival were rescued in gnotobiotic mice colonized with a minimal SCFA-producing microbial community. SCFA induced the growth of murine hepatocyte organoids and hepatic SCD1 expression in mice. Further, SCD1 was required for proliferation of human hepatoma cells and associated with liver regeneration in human patients. CONCLUSION: Gut microbiota are pivotal for hepatic membrane phospholipid biosynthesis and liver regeneration. IMPACT AND IMPLICATIONS: Gut microbiota affect the hepatic lipid metabolism through the gut-liver axis, but the underlying mechanisms are poorly understood. Perturbations of the gut microbiome, e.g., by antibiotics, impair the production of bacterial metabolites, which normally serve as building blocks for membrane lipids in liver cells. As a consequence, liver regeneration and survival after liver surgery is severely impaired. Even though this study is preclinical, its results might allow physicians in the future to improve patient's outcome after liver surgery, by modulation of the gut microbiota or their metabolites.

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