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International Journal of Molecular... Sep 2023All known organisms encode 20 canonical amino acids by base triplets in the genetic code. The cellular translational machinery produces proteins consisting mainly of... (Review)
Review
All known organisms encode 20 canonical amino acids by base triplets in the genetic code. The cellular translational machinery produces proteins consisting mainly of these amino acids. Several hundred natural amino acids serve important functions in metabolism, as scaffold molecules, and in signal transduction. New side chains are generated mainly by post-translational modifications, while others have altered backbones, such as the β- or γ-amino acids, or they undergo stereochemical inversion, e.g., in the case of D-amino acids. In addition, the number of non-canonical amino acids has further increased by chemical syntheses. Since many of these non-canonical amino acids confer resistance to proteolytic degradation, they are potential protease inhibitors and tools for specificity profiling studies in substrate optimization and enzyme inhibition. Other applications include in vitro and in vivo studies of enzyme kinetics, molecular interactions and bioimaging, to name a few. Amino acids with bio-orthogonal labels are particularly attractive, enabling various cross-link and click reactions for structure-functional studies. Here, we cover the latest developments in protease research with non-canonical amino acids, which opens up a great potential, e.g., for novel prodrugs activated by proteases or for other pharmaceutical compounds, some of which have already reached the clinical trial stage.
Topics: Peptide Hydrolases; Amino Acids; Endopeptidases; Proteolysis; Antifibrinolytic Agents
PubMed: 37762340
DOI: 10.3390/ijms241814035 -
Journal of Cardiothoracic and Vascular... Dec 2023
Topics: Humans; Antifibrinolytic Agents; Meridians; Tranexamic Acid; Platelet Transfusion
PubMed: 37704490
DOI: 10.1053/j.jvca.2023.08.133 -
Arteriosclerosis, Thrombosis, and... Aug 2023Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver of disordered coagulation and inflammation in viral infections, may be... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver of disordered coagulation and inflammation in viral infections, may be a therapeutic target in COVID-19. The safety and efficacy of the novel TF inhibitor rNAPc2 (recombinant nematode anticoagulation protein c2) in COVID-19 are unknown.
METHODS
ASPEN-COVID-19 was an international, randomized, open-label, active comparator clinical trial with blinded end point adjudication. Hospitalized patients with COVID-19 and elevated D-dimer levels were randomized 1:1:2 to lower or higher dose rNAPc2 on days 1, 3, and 5 followed by heparin on day 8 or to heparin per local standard of care. In comparisons of the pooled rNAPc2 versus heparin groups, the primary safety end point was major or nonmajor clinically relevant International Society of Thrombosis and Haemostasis bleeding through day 8. The primary efficacy end point was proportional change in D-dimer concentration from baseline to day 8, or discharge if before day 8. Patients were followed for 30 days.
RESULTS
Among 160 randomized patients, median age was 54 years, 43.1% were female, and 38.8% had severe baseline COVID-19. There were no significant differences between rNAPc2 and heparin in bleeding or other safety events. Overall, median change in D-dimer was -16.8% (interquartile range, -45.7 to 36.8; =0.41) with rNAPc2 treatment and -11.2% (-36.0 to 34.4; =0.91) with heparin (=0.47). In prespecified analyses, in severely ill patients, D-dimer levels tended to increase more within the heparin (median, 29.0% [-14.9 to 145.2]; =0.02) than the rNAPc2 group (median, 25.9% [-49.1 to 136.4]; =0.14; =0.96); in mildly ill patients, D-dimer levels were reduced within each group with a numerically greater reduction with rNAPc2 versus heparin (rNAPc2 median, -32.7% [-44.7 to 4.3]; =0.007 and heparin median, -16.8% [-36.0 to 0.5]; =0.008, =0.34).
CONCLUSIONS
rNAPc2 treatment in hospitalized patients with COVID-19 was well tolerated without excess bleeding or serious adverse events but did not significantly reduce D-dimer more than heparin at day 8.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT04655586.
Topics: Female; Humans; Male; Middle Aged; Anticoagulants; Blood Coagulation Disorders; COVID-19; Hemorrhage; Heparin; Inflammation; Thromboplastin; Venous Thromboembolism; Fibrin Fibrinogen Degradation Products; Antifibrinolytic Agents
PubMed: 37381988
DOI: 10.1161/ATVBAHA.122.318748 -
Nephrology, Dialysis, Transplantation :... Sep 2023Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis.
METHODS
In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status.
RESULTS
After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023 g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants.
CONCLUSION
Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.
Topics: Humans; Bone Density; Vitamin K; Renal Dialysis; Absorptiometry, Photon; Vitamin K 2; Dietary Supplements; Double-Blind Method
PubMed: 36460034
DOI: 10.1093/ndt/gfac315 -
PeerJ 2024Ferroptosis is a form of cell death, , programmed cell death characterized by lipid peroxidation and iron dependence, which has unique morphological and biochemical... (Review)
Review
Ferroptosis is a form of cell death, , programmed cell death characterized by lipid peroxidation and iron dependence, which has unique morphological and biochemical properties. This unique mode of cell death is driven by iron-dependent phospholipid peroxidation and regulated by multiple cell metabolic pathways, including redox homeostasis, iron metabolism, mitochondrial activity, and the metabolism of amino acids, lipids, and sugars. Many organ injuries and degenerative pathologies are caused by ferroptosis. Ferroptosis is closely related to central nervous system injury diseases and is currently an important topic of research globally. This research examined the relationships between ferroptosis and the occurrence and treatment of central nervous system injury diseases. Additionally, ferroptosis was assessed from the aspect of theory proposal, mechanism of action, and related signaling pathways per recent research. This review provides a relevant theoretical basis for further research on this theory, the prospect of its development, and the prevention and treatment of such diseases.
Topics: Humans; Ferroptosis; Amino Acids; Antifibrinolytic Agents; Central Nervous System Diseases; Iron; Central Nervous System
PubMed: 38313006
DOI: 10.7717/peerj.16741 -
Journal of Shoulder and Elbow Surgery Feb 2024The effect of tranexamic acid (TXA) has been proven to be effective in reducing blood loss in lower limb arthroplasty. The aim of this study is to investigate the effect... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The effect of tranexamic acid (TXA) has been proven to be effective in reducing blood loss in lower limb arthroplasty. The aim of this study is to investigate the effect of TXA in shoulder surgery with the updated studies.
MATERIALS AND METHODS
A systematic review and meta-analysis of all the randomized controlled trials were conducted. We compared the outcomes of patients with and without TXA. The PubMed, MEDLINE, EMBASE, and CENTRAL databases were systematically searched for relevant studies.
RESULTS
A total of 14 studies, enrolling 1131 patients, were included for qualitative and quantitative analysis. Our results revealed that TXA was associated with a significant reduction in total volume blood loss (mean difference [MD]: -112.97, P = .0006), drain output (MD: -81.90, P < .00001), hemoglobin changes (MD: -0.55, P = .02), shorter operative time (MD: -6.19, P = .01), and lower risk of hematoma formation (odds ratio: -0.20, P = .01). The postoperative visual analog scale pain score was also significantly better in the TXA group (MD: -0.78, P < .00001). No significant difference was detected in length of hospital stay and incidence of thromboembolization.
CONCLUSION
The usage of TXA in shoulder surgery appeared to be safe and effective in reducing blood loss without any significant complication.
Topics: Humans; Antifibrinolytic Agents; Blood Loss, Surgical; Shoulder; Tranexamic Acid
PubMed: 37890768
DOI: 10.1016/j.jse.2023.09.024 -
The Journal of Trauma and Acute Care... Nov 2023In the Study of Tranexamic Acid During Air and Ground Prehospital Transport (STAAMP) Trial, prehospital tranexamic acid (TXA) was associated with lower mortality in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the Study of Tranexamic Acid During Air and Ground Prehospital Transport (STAAMP) Trial, prehospital tranexamic acid (TXA) was associated with lower mortality in specific patient subgroups. The underlying mechanisms responsible for a TXA benefit remain incompletely characterized. We hypothesized that TXA may mitigate endothelial injury and sought to assess whether TXA was associated with decreased endothelial or tissue damage markers among all patients enrolled in the STAAMP Trial.
METHODS
We collected blood samples from STAAMP Trial patients and measured markers of endothelial function and tissue damage including syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule-1 at hospital admission (0 hours) and 12 hours, 24 hours, and 72 hours after admission. We compared these marker values for patients in each treatment group during the first 72 hours, and modeled the relationship between TXA and marker concentration using regression analysis to control for potential confounding factors.
RESULTS
We analyzed samples from 766 patients: 383 placebo, 130 abbreviated dosing, 119 standard dosing, and 130 repeat dosing. Lower levels of syndecan-1, TM, and platelet endothelial cell adhesion molecule measured within the first 72 hours of hospital admission were associated with survival at 30 days ( p < 0.001). At hospital admission, syndecan-1 was lower in the TXA group (28.30 [20.05, 42.75] vs. 33.50 [23.00, 54.00] p = 0.001) even after controlling for patient, injury, and prehospital factors ( p = 0.001). For every 1 g increase in TXA administered over the first 8 hours of prehospital transport and hospital admission, there was a 4-ng/mL decrease in syndecan-1 at 12 hours controlling for patient, injury, and treatment factors ( p = 0.03).
CONCLUSION
Prehospital TXA was associated with decreased syndecan-1 at hospital admission. Syndecan-1 measured 12 hours after admission was inversely related to the dose of TXA received. Early prehospital and in-hospital TXA may decrease endothelial glycocalyx damage or upregulate vascular repair mechanisms in a dose-dependent fashion.
LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Topics: Humans; Tranexamic Acid; Antifibrinolytic Agents; Syndecan-1; Prospective Studies; Emergency Medical Services
PubMed: 37125811
DOI: 10.1097/TA.0000000000003955 -
Arthroscopy : the Journal of... Feb 2024To further clarify the role of tranexamic acid (TXA) in arthroscopic rotator cuff repair (ARCR), especially visual field clarity and operation time. (Meta-Analysis)
Meta-Analysis Review
Intravenous Tranexamic Acid Significantly Improved Visualization and Shortened the Operation Time in Arthroscopic Rotator Cuff Repair: A Systematic Review and Meta-analysis of Level I and II Studies.
PURPOSE
To further clarify the role of tranexamic acid (TXA) in arthroscopic rotator cuff repair (ARCR), especially visual field clarity and operation time.
METHODS
We searched the PubMed, Cochrane Library, and Embase databases to find prospective randomized controlled clinical trials (RCTs) examining the use of TXA in ARCR. All included RCTs were evaluated for methodological quality using the Cochrane Collaboration's risk of bias tool. We used Review Manager 5.3 for meta-analysis and calculated the weighted mean difference (WMD) and 95% confidence interval (CI) of the related outcome indicators. The GRADE system was used to evaluate the strength of the clinical evidence provided by the included studies.
RESULTS
Six RCTs (3 Level I, 3 Level II) from four countries or regions were included in this study: 2 studies used intra-articular (IA) TXA, and 4 studies used intravenous TXA. A total of 451 patients underwent ARCR, including 227 patients in the TXA group and 224 patients in the non-TXA group. In 2 RCTs evaluating good visualization, intravenous TXA achieved a better surgical field of view in ARCR compared to the control group (P =.036; P = .045). Meta-analysis showed that compared with non-TXA, intravenous TXA shortened the operation time (WMD = -12.87 min, 95% CI: -18.81 to -6.93). These two RCTs did not reveal a statistically significant difference in the impact of intravenous TXA and non-TXA on mean arterial pressure (MAP) (P = .306; P = .549). Compared with epinephrine (EPN), IA TXA had no significant effects on improving the visual field clarity under arthroscopy, shortening the operation time or reducing the total amount of irrigation fluid (P > .05). Compared with saline irrigation, IA TXA improved the surgical field of vision and shortened the operation time (P < .001). No adverse events were reported for either intravenous TXA or IA TXA.
CONCLUSIONS
Intravenous TXA can shorten the operation time of ARCR, and the conclusions of existing RCTs suggest that intravenous TXA can improve visual field clarity during ARCR, thus supporting the application of intravenous TXA in ARCR. Compared with EPN, IA TXA was not better at improving the visual field clarity under arthroscopy and shortening the operation time, but it was better than saline irrigation.
LEVEL OF EVIDENCE
Level II, systematic review and meta-analysis of Level I and II studies.
Topics: Humans; Tranexamic Acid; Antifibrinolytic Agents; Arthroscopy; Rotator Cuff; Arthroplasty; Epinephrine; Blood Loss, Surgical
PubMed: 37423470
DOI: 10.1016/j.arthro.2023.06.055 -
Plastic and Reconstructive Surgery Oct 2023Excess fluid accumulation (seroma/hematoma) around the breast implant after reconstruction can lead to significant complications. Topical administration of tranexamic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Excess fluid accumulation (seroma/hematoma) around the breast implant after reconstruction can lead to significant complications. Topical administration of tranexamic acid (TXA) may reduce fluid accumulation and reduce postoperative complications. This trial aims to investigate whether TXA-treated mastectomy pockets will exhibit less postoperative fluid production and complications.
METHODS
This paired, double-blind, randomized, controlled trial enrolled patients undergoing bilateral mastectomies with immediate direct-to-implant reconstruction. In each patient, one breast was randomized to receive 3 g of TXA (100 cc), and the other received 100 cc of normal saline. The blinded solutions were soaked in the mastectomy pocket for 5 minutes before implant placement. Postoperatively, daily drain outputs, complications, and baseline demographics were recorded.
RESULTS
Fifty-three eligible patients, representing 106 breasts, were enrolled. All patients underwent bilateral nipple-sparing mastectomies. After randomization, TXA was placed in the right breast in 30 patients (56.6%). The use of topical TXA resulted in a mean drain output reduction of 30.5% (range, -83.6% to 26.6%). Drains on the TXA-treated breast were eligible for removal 1.4 days (range, 0 to 4 days) sooner than the control side. The TXA-treated group had three complications (5.67%) versus 15 (28.3%) in the control group (OR, 0.1920; P = 0.0129). Specifically, for operative hematomas, the TXA group had none (0%), versus three in the control group (5.7%) (OR, 0.1348; P = 0.18).
CONCLUSIONS
Soaking the mastectomy bed with 3% topical TXA before implant insertion leads to a decrease in drain output and a decrease in complications. Topical administration of TXA represents an option to decrease complications in alloplastic breast reconstruction.
CLINICAL QUESTION/LEVEL OF EVIDENCE
Therapeutic, I.
Topics: Humans; Female; Tranexamic Acid; Antifibrinolytic Agents; Breast Neoplasms; Blood Loss, Surgical; Mastectomy; Blood Transfusion; Administration, Topical; Mammaplasty; Double-Blind Method; Hematoma
PubMed: 36827482
DOI: 10.1097/PRS.0000000000010322 -
Lasers in Medical Science Apr 2024Although patients with refractory melasma have been treated using various methods, there is still no precise definition or summary of the therapies. To define refractory... (Review)
Review
Although patients with refractory melasma have been treated using various methods, there is still no precise definition or summary of the therapies. To define refractory melasma and conduct a review of the treatments, we searched for relevant publications in PubMed, Web of Science, and the Cochrane Library, and a total of 35 references were obtained. Refractory melasma can be roughly defined as an ineffective treatment for melasma, including topical bleaching agents, chemical peels, laser therapy, microdermabrasion for more than six months, or chemical peels treated more than six times. Meanwhile, physicians should be careful when treating patients with darker skin and dermal or mixed types of melasma since these individuals do not respond well to treatment. Lasers combined with other methods, especially different types of lasers or topical agents, are considered more effective than monotherapy. Oral tranexamic acid (TXA) is a prospective cure for refractory melasma. Other methods include a combination of chemical peels, microneedling, or injections with additional therapies. In conclusion, we were able to provide a rough definition of refractory melasma and list the available therapies. According to the literature, the most prevalent treatment is laser combination therapy. However, laser treatment should be considered only after topical agents and chemical peeling have failed. Considering its side effects, efficacy, and safety, oral TXA may be a better option, but more research is needed to make a firm conclusion. Moreover, maintenance therapy is required after treatment.
Topics: Melanosis; Humans; Chemexfoliation; Tranexamic Acid; Laser Therapy; Low-Level Light Therapy; Combined Modality Therapy; Dermabrasion
PubMed: 38679674
DOI: 10.1007/s10103-024-04066-3