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Experimental and Clinical... Apr 2024Splenectomy during liver transplant can affect platelet function. In this study, our primary aim was to assess the perioperative platelet function by rotational...
Effect of Splenectomy on Coagulation and Platelet Function in Adult Liver Transplant Recipients Assessed With Rotational Thromboelastometry and Standard Coagulation Tests.
OBJECTIVES
Splenectomy during liver transplant can affect platelet function. In this study, our primary aim was to assess the perioperative platelet function by rotational thromboelastometry and the effects of splenectomy on platelet function.
MATERIALS AND METHODS
We studied 40 consecutive liver transplant recipients with end-stage liver disease (50% as a result of hepatitis C). Patients with splenectomy were compared with patients without splenectomy (n = 20/group). Three platelet function parameters by rotational thromboelastometry were studied: platelet activation with arachidonic acid, platelet activation with adenosine diphosphate, and platelet activation with thrombin receptor-activating peptide 6. Patients were monitored perioperatively and until postoperative day 21. Heparin was infused for 2 days postoperatively (60-180 U/kg/day), followed by administration of subcutaneous low-molecular-weight heparin (40 mg/24 h) on postoperative days 2 and 3 and oral acetylsalicylic acid when platelet count was >50 × 103/μL.
RESULTS
Liver disease contributed to low perioperative platelet count and function. Patients showed significant improvement by postoperative day 14 and day 21, particularly after splenectomy. Platelet count was significantly correlated with the 3 platelet function parameters by rotational thromboelastometry (P < .001). Acetyl salicylic acid was required earlier (postoperative day 3) for patients with splenectomy (8/20) but only affected the platelet function represented by platelet activation with arachidonic acid, whereas other platelet activation pathways were less affected. Patients received no transfusions of platelet units.
CONCLUSIONS
End-stage liver disease significantly contributed to low platelet function and counts before transplant. Two weeks were required for recovery of patients posttransplant, with further enhancement by splenectomy. Some recipients showed recovery that exceeded the normal reference range, which warranted monitoring. Acetyl salicylic acid only affected 1 platelet activation receptor.
Topics: Humans; Thrombelastography; Liver Transplantation; Male; Female; Middle Aged; Splenectomy; Treatment Outcome; Blood Coagulation; Adult; End Stage Liver Disease; Time Factors; Blood Platelets; Predictive Value of Tests; Platelet Activation; Platelet Function Tests; Platelet Aggregation Inhibitors; Anticoagulants; Platelet Count; Blood Coagulation Tests; Aspirin; Prospective Studies
PubMed: 38742319
DOI: 10.6002/ect.2023.0329 -
Science Bulletin Apr 2024Ion channel activation upon ligand gating triggers a myriad of biological events and, therefore, evolution of ligand gating mechanism is of fundamental importance....
Ion channel activation upon ligand gating triggers a myriad of biological events and, therefore, evolution of ligand gating mechanism is of fundamental importance. TRPM2, a typical ancient ion channel, is activated by adenosine diphosphate ribose (ADPR) and calcium and its activation has evolved from a simple mode in invertebrates to a more complex one in vertebrates, but the evolutionary process is still unknown. Molecular evolutionary analysis of TRPM2s from more than 280 different animal species has revealed that, the C-terminal NUDT9-H domain has evolved from an enzyme to a ligand binding site for activation, while the N-terminal MHR domain maintains a conserved ligand binding site. Calcium gating pattern has also evolved, from one Ca-binding site as in sea anemones to three sites as in human. Importantly, we identified a new group represented by olTRPM2, which has a novel gating mode and fills the missing link of the channel gating evolution. We conclude that the TRPM2 ligand binding or activation mode evolved through at least three identifiable stages in the past billion years from simple to complicated and coordinated. Such findings benefit the evolutionary investigations of other channels and proteins.
PubMed: 38734586
DOI: 10.1016/j.scib.2024.04.052 -
Thrombosis Research Jun 2024Plaque erosion, a type of coronary atherothrombosis, involves superficial injury to smooth muscle cell (SMC)-rich plaques. Elevated levels of coagulation factor VIII...
BACKGROUND
Plaque erosion, a type of coronary atherothrombosis, involves superficial injury to smooth muscle cell (SMC)-rich plaques. Elevated levels of coagulation factor VIII (FVIII) correlate with an increased ischemic heart disease risk. FVIII may contribute to thrombus formation on eroded plaques.
AIMS
We aimed to elucidate the role of elevated FVIII in arterial thrombus formation within SMC-rich neointima in rabbits.
METHODS AND RESULTS
We assessed the effect of recombinant human FVIII (rFVIII) on blood coagulation in vitro and platelet aggregation ex vivo. An SMC-rich neointima was induced through balloon injury to the unilateral femoral artery. Three weeks after the first balloon injury, superficial erosive injury and thrombus formation were initiated with a second balloon injury of the bilateral femoral arteries 45 min after the administration of rFVIII (100 IU/kg) or saline. The thrombus area and contents were histologically measured 15 min after the second balloon injury. rFVIII administration reduced the activated partial thromboplastin time and augmented botrocetin-induced, but not collagen- or adenosine 5'-diphosphate-induced, platelet aggregation. While rFVIII did not influence platelet-thrombus formation in normal intima, it increased thrombus formation on SMC-rich neointima post-superficial erosive injury. Enhanced immunopositivity for glycoprotein IIb/IIIa and fibrin was observed in rFVIII-administered SMC-rich neointima. Neutrophil count in the arterial thrombus on the SMC-rich neointima correlated positively with thrombus size in the control group, unlike the rFVIII group.
CONCLUSIONS
Increased FVIII contributes to thrombus propagation within erosive SMC-rich neointima, highlighting FVIII's potential role in plaque erosion-related atherothrombosis.
Topics: Rabbits; Animals; Factor VIII; Neointima; Thrombosis; Male; Myocytes, Smooth Muscle; Tunica Intima; Humans; Platelet Aggregation; Femoral Artery
PubMed: 38729030
DOI: 10.1016/j.thromres.2024.04.025 -
Nature Communications May 2024The K uptake system KtrAB is essential for bacterial survival in low K environments. The activity of KtrAB is regulated by nucleotides and Na. Previous studies proposed...
The K uptake system KtrAB is essential for bacterial survival in low K environments. The activity of KtrAB is regulated by nucleotides and Na. Previous studies proposed a putative gating mechanism of KtrB regulated by KtrA upon binding to ATP or ADP. However, how Na activates KtrAB and the Na binding site remain unknown. Here we present the cryo-EM structures of ATP- and ADP-bound KtrAB from Bacillus subtilis (BsKtrAB) both solved at 2.8 Å. A cryo-EM density at the intra-dimer interface of ATP-KtrA was identified as Na, as supported by X-ray crystallography and ICP-MS. Thermostability assays and functional studies demonstrated that Na binding stabilizes the ATP-bound BsKtrAB complex and enhances its K flux activity. Comparing ATP- and ADP-BsKtrAB structures suggests that BsKtrB Arg417 and Phe91 serve as a channel gate. The synergism of ATP and Na in activating BsKtrAB is likely applicable to Na-activated K channels in central nervous system.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Bacillus subtilis; Bacterial Proteins; Binding Sites; Cation Transport Proteins; Cryoelectron Microscopy; Crystallography, X-Ray; Models, Molecular; Potassium; Protein Binding; Sodium
PubMed: 38719864
DOI: 10.1038/s41467-024-48057-y -
Nature Structural & Molecular Biology May 2024The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, epigenetics and...
The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, epigenetics and immunity. Yet, it remains unknown whether DNA ADP-ribosylation (DNA-ADPr) promotes genome stability and how it is regulated. Here, we show that telomeres are subject to DNA-ADPr catalyzed by PARP1 and removed by TARG1. Mechanistically, we show that DNA-ADPr is coupled to lagging telomere DNA strand synthesis, forming at single-stranded DNA present at unligated Okazaki fragments and on the 3' single-stranded telomere overhang. Persistent DNA-linked ADPr, due to TARG1 deficiency, eventually leads to telomere shortening. Furthermore, using the bacterial DNA ADP-ribosyl-transferase toxin to modify DNA at telomeres directly, we demonstrate that unhydrolyzed DNA-linked ADP-ribose compromises telomere replication and telomere integrity. Thus, by identifying telomeres as chromosomal targets of PARP1 and TARG1-regulated DNA-ADPr, whose deregulation compromises telomere replication and integrity, our study highlights and establishes the critical importance of controlling DNA-ADPr turnover for sustained genome stability.
Topics: Telomere; ADP-Ribosylation; DNA Replication; Poly (ADP-Ribose) Polymerase-1; Humans; DNA; Animals; Mice; Adenosine Diphosphate Ribose; Genomic Instability; Telomere Shortening
PubMed: 38714889
DOI: 10.1038/s41594-024-01279-6 -
Journal of Food Protection Jul 2024Given its presence in a wide spectrum of soils relevant to food process hygiene, the biological metabolite adenosine triphosphate (ATP) is used as a target for surface...
Given its presence in a wide spectrum of soils relevant to food process hygiene, the biological metabolite adenosine triphosphate (ATP) is used as a target for surface hygiene assessments in food processing facilities. Yet, ample evidence demonstrates that ATP is depleted into adenosine di- (ADP) and monophosphate (AMP) homologs resulting in a loss of sensitivity for ATP-based hygiene assays. Yet, there are few studies that denote the degree of these shifts under routine processing conditions such as those encountered during various meat processing steps that may likely alter redox potential and adenosine profiles (e.g., tissue/cellular disruption, application of reducing additives, fermentation, or thermal treatment steps). In this study, meat samples were collected from homogenized beef tissue treated with nonmeat ingredients (sodium chloride, sodium nitrite, sodium erythorbate, natural smoke condensate, and sodium acid pyrophosphate) during manufacture at predetermined steps, and from retail meat products purchased from local markets. Concentrations of ATP, ADP, AMP, and AXP (sum concentration of all homologs) in a lab setting and in situ meat processing venues were determined and compared. Greater differences in AXP were seen during manufacture, where ADP generally comprised ∼90% as a mole fraction of AXP across all treatments, with the exception of the final cook step where AMP predominated. ATP concentrations averaged 2 log values lower than ADP and AMP. Adenosine profiles in retail samples followed similar trends with minimal ATP concentrations with ADP predominant in uncooked samples and AMP predominant in cooked samples. Resultingly, meat processing steps during product manufacture will alter AXP-reliant test sensitivities which should be considered when such technologies are utilized for hygiene verification in meat processing.
Topics: Adenosine Triphosphate; Food Handling; Animals; Meat; Adenosine Diphosphate; Adenosine Monophosphate; Food Contamination; Cattle; Humans; Meat Products
PubMed: 38697482
DOI: 10.1016/j.jfp.2024.100287 -
Journal of Nanobiotechnology Apr 2024Combination of tumor immunotherapy with photothermal therapy (PTT) is a feasible tactic to overcome the drawback of immunotherapy such as poor immune response. Via...
Combination of tumor immunotherapy with photothermal therapy (PTT) is a feasible tactic to overcome the drawback of immunotherapy such as poor immune response. Via triggering the immunogenic cells death (ICD), PTT can stimulate the activity of immune cells, but meanwhile, the level of adenosine is elevated via the CD73-induced decomposition of ATP which is overexpressed accompanying with the PTT process, resulting in negative feedback to impair the immune stimulation. Herein, we developed a novel biomimetic photothermal nanodrug to specifically block CD73 for inhibition of adenosine production and more efficient priming of the suppressive immune microenvironments. The nanodrug, named as AptEM@CBA, is constructed by encapsulation of photothermal agent black phosphorus quantum dots (BPQDs) and selective CD73 inhibitor α, β-Methyleneadenosine 5'-diphosphate (AMPCP) in chitosan nanogels, which are further covered with aptamer AS1411 modified erythrocyte membrane (EM) for biomimetic camouflage. With AS1411 induced active targeting and EM induced long blood circulation time, the enrichment of the nanodrug tumor sites is promoted. The photothermal treatment promotes the maturation of dendritic cells. Meanwhile, the release of AMPCP suppress the adenosine generation via CD73 blockade, alleviating the impairment of adenosine to dendritic cells and suppressing regulatory T cells, synergically stimulate the activity of T cells. The combination of CD73 blockade with PTT, not only suppresses the growth of primary implanted tumors, but also boosts strong antitumor immunity to inhibit the growth of distal tumors, providing good potential for tumor photoimmunotherapy.
Topics: Animals; Humans; Mice; 5'-Nucleotidase; Adenosine; Adenosine Diphosphate; Biomimetic Materials; Biomimetics; Cell Line, Tumor; Dendritic Cells; Immunotherapy; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Photothermal Therapy; Quantum Dots; Tumor Microenvironment; Male
PubMed: 38689291
DOI: 10.1186/s12951-024-02487-4 -
Poultry Science Jun 2024We aimed to determine the onset time of hypophosphatemic rickets and investigate the mechanism of motility impairment through adenosine triphosphate (ATP) production in...
Early manifestation of hypophosphatemic rickets in goslings: a potential role of insufficient muscular adenosine triphosphate in motility impairment of early P-deficient geese.
We aimed to determine the onset time of hypophosphatemic rickets and investigate the mechanism of motility impairment through adenosine triphosphate (ATP) production in goslings. Two hundred and sixteen 1-day-old male Jiangnan white geese were randomly divided into 3 groups, with 6 replicates and 12 geese per replicate. Birds were fed on 3 diets: a control diet (nonphytic phosphorus, NPP, 0.38%), a P-deficient diet (PD; NPP, 0.08%), and a high P diet (HP; NPP, 0.80%) for 14 d. Subsequently, all birds were shifted to the control diet for an additional 14 d. The cumulative incidence of lameness increased significantly (P < 0.01) starting on d 4, reaching over 80% on d 7 and 100% on d 12 in the PD group. Drinking and eating frequency decreased from d 4 and d 5, respectively, in the PD group compared to the other groups (most P < 0.01). The PD group exhibited shorter and narrower beaks, higher (worse) curvature scores of the beak and costochondral junctions, swelling caput costae, and dirtier feathers since d 4, in contrast to the control and HP groups (most P < 0.01). The HP had bigger (P < 0.05) beak and sternum sizes than the control groups on d 4 to 11. Leg muscle ATP levels were lower (P < 0.01 or 0.05) on d 4 to 11; in contrast, adenosine diphosphate (d 7-11) was higher in PD compared to the control (P < 0.05). Leg muscle ATP level had positive linear (R > 0.40) correlations (r > 0.60) with eating and drinking frequencies on d 7 and 11 (P < 0.01). Bone stiffness, feather cleanliness, and ATP levels recovered (P > 0.05) to the control level, whereas bone size did not recover (P < 0.05) in PD and HP after eating the control diet for 2 wk. The onset time of hypophosphatemic rickets was around 4 d in goslings, and insufficient leg muscle ATP was related to the impaired motility observed in early P-deficient geese.
Topics: Animals; Male; Adenosine Triphosphate; Geese; Diet; Poultry Diseases; Animal Feed; Random Allocation; Muscle, Skeletal; Phosphorus, Dietary; Rickets; Phosphorus
PubMed: 38677064
DOI: 10.1016/j.psj.2024.103736 -
Journal of Cardiovascular Development... Mar 2024The impact of non-vitamin K antagonist oral anticoagulants (NOACs) on platelet function is still unclear. We conducted a comprehensive ex vivo study aimed at assessing...
BACKGROUND
The impact of non-vitamin K antagonist oral anticoagulants (NOACs) on platelet function is still unclear. We conducted a comprehensive ex vivo study aimed at assessing the effect of the four currently marketed NOACs on platelet function.
METHODS
We incubated blood samples from healthy donors with concentrations of NOACs (50, 150 and 250 ng/mL), in the range of those achieved in the plasma of patients during therapy. We evaluated generation of thrombin; light transmittance platelet aggregation (LTA) in response to adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), human γ-thrombin (THR) and tissue factor (TF); generation of thromboxane (TX)B; and expression of protease-activated receptor (PAR)-1 and P-selectin on the platelet surface.
RESULTS
All NOACs concentration-dependently reduced thrombin generation compared with control. THR-induced LTA was suppressed by the addition of dabigatran at any concentration, while TF-induced LTA was reduced by factor-Xa inhibitors. ADP- and TRAP-induced LTA was not modified by NOACs. TXB generation was reduced by all NOACs, particularly at the highest concentrations. We found a concentration-dependent increase in PAR-1 expression after incubation with dabigatran, mainly at the highest concentrations, but not with FXa inhibitors; P-selectin expression was not changed by any drugs.
CONCLUSIONS
Treatment with the NOACs is associated with measurable ex vivo changes in platelet function, arguing for antiplatelet effects beyond the well-known anticoagulant activities of these drugs. There are differences, however, among the NOACs, especially between dabigatran and the FXa inhibitors.
PubMed: 38667729
DOI: 10.3390/jcdd11040111