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Keywords = P-m-TAT

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20 pages, 941 KiB  
Review
HIV-1 Tat: Molecular Switch in Viral Persistence and Emerging Technologies for Functional Cure
by Kaixin Yu, Hanxin Liu and Ting Pan
Int. J. Mol. Sci. 2025, 26(13), 6311; https://doi.org/10.3390/ijms26136311 - 30 Jun 2025
Viewed by 713
Abstract
HIV-1 Tat acts as a central molecular switch governing the transition between viral latency and active replication, making it a pivotal target for HIV-1 functional cure strategies. By binding to the viral long terminal repeat (LTR) and hijacking host transcriptional machinery, Tat dynamically [...] Read more.
HIV-1 Tat acts as a central molecular switch governing the transition between viral latency and active replication, making it a pivotal target for HIV-1 functional cure strategies. By binding to the viral long terminal repeat (LTR) and hijacking host transcriptional machinery, Tat dynamically regulates RNA polymerase II processivity to alter viral transcription states. Recent studies reveal its context-dependent variability: while Tat recruits chromatin modifiers and scaffolds non-coding RNAs to stabilize epigenetic silencing in latently infected cells, it also triggers rapid transcriptional amplification upon cellular activation. This review systematically analyzes the bistable regulatory mechanism of Tat and investigates advanced technologies for reprogramming this switch to eliminateviral reservoirs and achieve functional cures. Conventional approaches targeting Tat are limited by compensatory viral evolution and poor bioavailability. Next-generation interventions will employ precision-engineered tools, such as AI-optimized small molecules blocking Tat-P-TEFb interfaces and CRISPR-dCas9/Tat chimeric systems, for locus-specific LTR silencing or reactivation (“block and lock” or “shock and kill”). Advanced delivery platforms, including brain-penetrant lipid nanoparticles (LNPs), enable the targeted delivery of Tat-editing mRNA or base editors to microglial reservoirs. Single-cell multiomics elucidates Tat-mediated clonal heterogeneity, identifying “switchable” subpopulations for timed interventions. By integrating systems-level Tat interactomics, epigenetic engineering, and spatiotemporally controlled delivery, this review proposes a roadmap to disrupt HIV-1 persistence by hijacking the Tat switch, ultimately bridging mechanistic insights to clinical applications. Full article
(This article belongs to the Section Molecular Microbiology)
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18 pages, 2142 KiB  
Article
Towards DFO*12—Preliminary Results of a New Chelator for the Complexation of Actinium-225
by Irene V. J. Feiner, Dennis Svatunek, Martin Pressler, Tori Demuth, Xabier Guarrochena, Johannes H. Sterba, Susanne Dorudi, Clemens Pichler, Christoph Denk and Thomas L. Mindt
Pharmaceutics 2025, 17(3), 320; https://doi.org/10.3390/pharmaceutics17030320 - 1 Mar 2025
Viewed by 1411
Abstract
Background: Actinium-225 (225Ac) has gained interest in nuclear medicine for use in targeted alpha therapy (TAT) for the treatment of cancer. However, the number of suitable chelators for the stable complexation of 225Ac3+ is limited. The promising physical [...] Read more.
Background: Actinium-225 (225Ac) has gained interest in nuclear medicine for use in targeted alpha therapy (TAT) for the treatment of cancer. However, the number of suitable chelators for the stable complexation of 225Ac3+ is limited. The promising physical properties of 225Ac result in an increased demand for the radioisotope that is not matched by its current supply. To expand the possibilities for the development of 225Ac-based TAT therapeutics, a new hydroxamate-based chelator, DFO*12, is described. We report the DFT-guided design of dodecadentate DFO*12 and an efficient and convenient automated solid-phase synthesis for its preparation. To address the limited availability of 225Ac, a small-scale 229Th/225Ac generator was constructed in-house to provide [225Ac]AcCl3 for research. Methods: DFT calculations were performed in ORCA 5.0.1 using the BP86 functional with empirical dispersion correction D3 and Becke–Johnson damping (D3BJ). The monomer synthesis over three steps enabled the solid-phase synthesis of DFO*12. The small-scale 229Th/225Ac generator was realized by extracting 229Th from aged 233U material. Radiolabeling of DFO*12 with 225Ac was performed in 1 M TRIS pH 8.5 or 1.5 M NaOAc pH 4.5 for 30 min at 37 °C. Results: DFT calculations directed the design of a dodecadentate chelator. The automated synthesis of the chelator DFO*12 and the development of a small-scale 229Th/225Ac generator allowed for the radiolabeling of DFO*12 with 225Ac quantitatively at 37 °C within 30 min. The complex [225Ac]Ac-DFO*12 indicated good stability in different media for 20 h. Conclusions: The novel hydroxamate-based dodecadentate chelator DFO*12, together with the developed 229Th/225Ac generator, provide new opportunities for 225Ac research for future radiopharmaceutical development and applications in TAT. Full article
(This article belongs to the Special Issue Advances in Radiopharmaceuticals for Disease Diagnoses and Therapy)
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12 pages, 626 KiB  
Article
Superior Biological Healing of Hamstring Autografts Compared with Tibialis Allografts after Anterior Cruciate Ligament Reconstruction: A Propensity Score Matching Analysis Based on Second-Look Arthroscopy
by Seo-Jun Lee, Jun-Gu Park, Seung-Beom Han, Ji-Hoon Bae and Ki-Mo Jang
Medicina 2024, 60(10), 1631; https://doi.org/10.3390/medicina60101631 - 6 Oct 2024
Viewed by 1461
Abstract
Background and Objectives: Remodeling and healing of the graft are crucial processes for long-term graft survival after anterior cruciate ligament reconstruction (ACLR). However, few studies have objectively evaluated the differences in graft healing between autografts and allografts. This study aimed to compare the [...] Read more.
Background and Objectives: Remodeling and healing of the graft are crucial processes for long-term graft survival after anterior cruciate ligament reconstruction (ACLR). However, few studies have objectively evaluated the differences in graft healing between autografts and allografts. This study aimed to compare the status of the anterior cruciate ligament (ACL) grafts between hamstring tendon (HT) autografts and tibialis anterior tendon (TAT) allografts using second-look arthroscopy. Materials and Methods: The outcomes of 193 consecutive patients (153 males and 40 females, with an average age of 30.38 and BMI of 25.43 kg/m2) who underwent second-look arthroscopy following primary ACLR were retrospectively reviewed. Prior to participating in this study, all patients provided written informed consent. The patients were divided into two groups: those with HT autografts and those with TAT allografts. Confounding factors were matched between the two groups using propensity score matching (PSM). ACL graft status was assessed during second-look arthroscopy using a numeric scale system based on the degree of four parameters: graft tension, continuity, synovium coverage, and vascular marking. Clinical outcomes were assessed using the Lysholm and International Knee Documentation Committee (IKDC) scores. Graft status and clinical outcomes were compared between the two groups. Additionally, a subgroup analysis based on the timing of the second-look arthroscopy (12–24 months vs. >24 months after the initial ACLR) was conducted. Results: After PSM, 62 patients were included in each group. The second-look arthroscopy was conducted at 23.6 ± 6.6 months for the HT group and at 24.0 ± 7.9 months for the TAT group (p = 0.749). The continuity and tension of the ACL graft were not significantly different between the two groups (p = 0.146 and 0.075, respectively). However, the TAT group exhibited significantly inferior synovial coverage and vascular marking of the ACL graft compared with the HT group (p = 0.021 and 0.007, respectively). These findings were consistent regardless of the timing of the second-look arthroscopy. Clinical outcomes, according to the Lysholm and IKDC scores, significantly improved in both groups with no significant differences (p = 0.386 and 0.733, respectively). Conclusions: Although there were no differences in graft tension and continuity between HT autografts and TAT allografts, the biological healing of ACL grafts, in terms of synovialization and vascularization, was superior in HT autografts compared to TAT allografts. Full article
(This article belongs to the Special Issue Diagnosis and Treatment of Injuries to the Knee Ligaments)
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14 pages, 4143 KiB  
Article
HIV-1 Tat-Mediated Human Müller Glial Cell Senescence Involves Endoplasmic Reticulum Stress and Dysregulated Autophagy
by Uma Maheswari Deshetty, Nivedita Chatterjee, Shilpa Buch and Palsamy Periyasamy
Viruses 2024, 16(6), 903; https://doi.org/10.3390/v16060903 - 3 Jun 2024
Cited by 1 | Viewed by 1687
Abstract
Antiretroviral treatments have notably extended the lives of individuals with HIV and reduced the occurrence of comorbidities, including ocular manifestations. The involvement of endoplasmic reticulum (ER) stress in HIV-1 pathogenesis raises questions about its correlation with cellular senescence or its role in initiating [...] Read more.
Antiretroviral treatments have notably extended the lives of individuals with HIV and reduced the occurrence of comorbidities, including ocular manifestations. The involvement of endoplasmic reticulum (ER) stress in HIV-1 pathogenesis raises questions about its correlation with cellular senescence or its role in initiating senescent traits. This study investigated how ER stress and dysregulated autophagy impact cellular senescence triggered by HIV-1 Tat in the MIO-M1 cell line (human Müller glial cells). Cells exposed to HIV-1 Tat exhibited increased vimentin expression combined with markers of ER stress (BiP, p-eIF2α), autophagy (LC3, Beclin-1, p62), and the senescence marker p21 compared to control cells. Western blotting and staining techniques like SA-β-gal were employed to examine these markers. Additionally, treatments with ER stress inhibitor 4-PBA before HIV-1 Tat exposure led to a decreased expression of ER stress, senescence, and autophagy markers. Conversely, pre-treatment with the autophagy inhibitor 3-MA resulted in reduced autophagy and senescence markers but did not alter ER stress markers compared to control cells. The findings suggest a link between ER stress, dysregulated autophagy, and the initiation of a senescence phenotype in MIO-M1 cells induced by HIV-1 Tat exposure. Full article
(This article belongs to the Special Issue HIV and Drugs of Abuse, 3rd Edition)
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10 pages, 215 KiB  
Article
QMAC-DST for Rapid Detection of Drug Resistance in Pulmonary Tuberculosis Patients: A Multicenter Pre–Post Comparative Study
by Nakwon Kwak, Sangyeop Lee, Suyeoun Kim, Eunbee Song, Jae-Joon Yim, Tae Sun Shim, Doosoo Jeon, Byung Woo Jhun, Kwang-Hyuk Seok, Saerom Kim, Sunghoon Kwon and Jeongha Mok
J. Clin. Med. 2024, 13(10), 2941; https://doi.org/10.3390/jcm13102941 - 16 May 2024
Viewed by 1555
Abstract
Background/Objectives: This study explores the impact of QMAC-DST, a rapid, fully automated phenotypic drug susceptibility test (pDST), on the treatment of tuberculosis (TB) patients. Methods: This pre–post comparative study, respectively, included pulmonary TB patients who began TB treatment between 1 December 2020 and [...] Read more.
Background/Objectives: This study explores the impact of QMAC-DST, a rapid, fully automated phenotypic drug susceptibility test (pDST), on the treatment of tuberculosis (TB) patients. Methods: This pre–post comparative study, respectively, included pulmonary TB patients who began TB treatment between 1 December 2020 and 31 October 2021 (pre-period; pDST using the Löwenstein–Jensen (LJ) DST (M-kit DST)) and between 1 November 2021 and 30 September 2022 (post-period; pDST using the QMAC-DST) in five university-affiliated tertiary care hospitals in South Korea. We compared the turnaround times (TATs) of pDSTs and the time to appropriate treatment for patients whose anti-TB drugs were changed based on these tests between the groups. All patients were permitted to use molecular DSTs (mDSTs). Results: A total of 182 patients (135 in the M-kit DST group and 47 in the QMAC-DST group) were included. The median TAT was 36 days for M-kit DST (interquartile range (IQR), 30–39) and 12 days for QMAC-DST (IQR, 9–15), with the latter being significantly shorter (p < 0.001). Of the total patients, 10 (5.5%) changed their anti-TB drugs based on the mDST or pDST results after initiating TB treatment (8 in the M-kit DST group and 2 in the QMAC-DST group). In the M-kit DST group, three (37.5%) patients changed anti-TB drugs based on the pDST results. In the QMAC-DST group, all changes were due to mDST results; therefore, calculating the time to appropriate treatment for patients whose anti-TB drugs were changed based on pDST results was not feasible. In the QMAC-DST group, 46.8% of patients underwent the first-line line probe assay compared to 100.0% in the M-kit DST group (p < 0.001), indicating that rapid QMAC-DST results provide quicker assurance of the ongoing treatment by confirming susceptibility to the current anti-TB drugs. Conclusions: QMAC-DST delivers pDST results more rapidly than LJ-DST, ensuring faster confirmation for the current treatment regimen. Full article
(This article belongs to the Section Respiratory Medicine)
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10 pages, 945 KiB  
Perspective
Viral–Bacterial Interactions That Impact Viral Thermostability and Transmission
by Lorimar Robledo Gonzalez, Rachel P. Tat, Justin C. Greaves and Christopher M. Robinson
Viruses 2023, 15(12), 2415; https://doi.org/10.3390/v15122415 - 13 Dec 2023
Cited by 2 | Viewed by 2151
Abstract
Enteric viruses are significant human pathogens that commonly cause foodborne illnesses worldwide. These viruses initiate infection in the gastrointestinal tract, home to a diverse population of intestinal bacteria. In a novel paradigm, data indicate that enteric viruses utilize intestinal bacteria to promote viral [...] Read more.
Enteric viruses are significant human pathogens that commonly cause foodborne illnesses worldwide. These viruses initiate infection in the gastrointestinal tract, home to a diverse population of intestinal bacteria. In a novel paradigm, data indicate that enteric viruses utilize intestinal bacteria to promote viral replication and pathogenesis. While mechanisms underlying these observations are not fully understood, data suggest that some enteric viruses bind directly to bacteria, stabilizing the virion to retain infectivity. Here, we discuss the current knowledge of these viral–bacterial interactions and examine the impact of these interactions on viral transmission. Full article
(This article belongs to the Section Human Virology and Viral Diseases)
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19 pages, 3450 KiB  
Article
Enhancing the Antimicrobial Properties of Peptides through Cell-Penetrating Peptide Conjugation: A Comprehensive Assessment
by Sergey V. Kravchenko, Pavel A. Domnin, Sergei Y. Grishin, Nikita A. Vershinin, Elena V. Gurina, Anastasiia A. Zakharova, Viacheslav N. Azev, Leila G. Mustaeva, Elena Y. Gorbunova, Margarita I. Kobyakova, Alexey K. Surin, Roman S. Fadeev, Olga S. Ostroumova, Svetlana A. Ermolaeva and Oxana V. Galzitskaya
Int. J. Mol. Sci. 2023, 24(23), 16723; https://doi.org/10.3390/ijms242316723 - 24 Nov 2023
Cited by 14 | Viewed by 2985
Abstract
Combining antimicrobial peptides (AMPs) with cell-penetrating peptides (CPPs) has shown promise in boosting antimicrobial potency, especially against Gram-negative bacteria. We examined the CPP-AMP interaction with distinct bacterial types based on cell wall differences. Our investigation focused on AMPs incorporating penetratin CPP and dihybrid [...] Read more.
Combining antimicrobial peptides (AMPs) with cell-penetrating peptides (CPPs) has shown promise in boosting antimicrobial potency, especially against Gram-negative bacteria. We examined the CPP-AMP interaction with distinct bacterial types based on cell wall differences. Our investigation focused on AMPs incorporating penetratin CPP and dihybrid peptides containing both cell-penetrating TAT protein fragments from the human immunodeficiency virus and Antennapedia peptide (Antp). Assessment of the peptides TAT-AMP, AMP-Antp, and TAT-AMP-Antp revealed their potential against Gram-positive strains (Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), and Bacillus cereus). Peptides TAT-AMP and AMP-Antp using an amyloidogenic AMP from S1 ribosomal protein Thermus thermophilus, at concentrations ranging from 3 to 12 μM, exhibited enhanced antimicrobial activity against B. cereus. TAT-AMP and TAT-AMP-Antp, using an amyloidogenic AMP from the S1 ribosomal protein Pseudomonas aeruginosa, at a concentration of 12 µM, demonstrated potent antimicrobial activity against S. aureus and MRSA. Notably, the TAT-AMP, at a concentration of 12 µM, effectively inhibited Escherichia coli (E. coli) growth and displayed antimicrobial effects similar to gentamicin after 15 h of incubation. Peptide characteristics determined antimicrobial activity against diverse strains. The study highlights the intricate relationship between peptide properties and antimicrobial potential. Mechanisms of AMP action are closely tied to bacterial cell wall attributes. Peptides with the TAT fragment exhibited enhanced antimicrobial activity against S. aureus, MRSA, and P. aeruginosa. Peptides containing only the Antp fragment displayed lower activity. None of the investigated peptides demonstrated cytotoxic or cytostatic effects on either BT-474 cells or human skin fibroblasts. In conclusion, CPP-AMPs offer promise against various bacterial strains, offering insights for targeted antimicrobial development. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Newer Antimicrobial Agents)
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18 pages, 2961 KiB  
Article
Long-Term Effects of Suramin on Renal Function in Streptozotocin-Induced Diabetes in Rats
by Gabriela Chyła-Danił, Kornelia Sałaga-Zaleska, Ewelina Kreft, Olaf Stumski, Aleksandra Krzesińska, Monika Sakowicz-Burkiewicz, Agnieszka Kuchta and Maciej Jankowski
Int. J. Mol. Sci. 2023, 24(19), 14671; https://doi.org/10.3390/ijms241914671 - 28 Sep 2023
Viewed by 1602
Abstract
In short-term diabetes (3 weeks), suramin, a drug used clinically, affects renal function and the expression of vascular endothelial growth factor A (VEGF-A), which may be involved in the pathogenesis of diabetic nephropathy, the main cause of end-stage renal disease. In the present [...] Read more.
In short-term diabetes (3 weeks), suramin, a drug used clinically, affects renal function and the expression of vascular endothelial growth factor A (VEGF-A), which may be involved in the pathogenesis of diabetic nephropathy, the main cause of end-stage renal disease. In the present study, we evaluated the long-term (11 weeks) effects of suramin (10 mg/kg, i.p., once-weekly) in diabetic rats. Concentrations of VEGF-A, albumin, soluble adhesive molecules (sICAM-1, sVCAM-1), nucleosomes, and thrombin–antithrombin complex (TAT) were measured by ELISA, total protein was measured using a biuret reagent. Glomerular expression of VEGF-A was evaluated by Western blot, mRNA for VEGF-A receptors in the renal cortex by RT-PCR. The vasoreactivity of the interlobar arteries to acetylcholine was assessed by wire myography. Long-term diabetes led to an increased concentration of VEGF-A, TAT, and urinary excretion of total protein and albumin, and a decrease in the concentration of sVCAM-1. We have shown that suramin in diabetes reduces total urinary protein excretion and restores the relaxing properties of acetylcholine relaxation properties to non-diabetic levels. Suramin had no effect on glomerular expression VEGF-A expression and specific receptors, and on sICAM-1 and nucleosomes concentrations in diabetic rats. In conclusion, the long-term effect of suramin on the kidneys in diabetes, expressed in the reduction of proteinuria and the restoration of endothelium-dependent relaxation of the renal arteries, can be considered as potentially contributing to the reduction/slowing down of the development of diabetic nephropathy. Full article
(This article belongs to the Special Issue Kidney Diseases: From Molecular Basis to Therapy)
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14 pages, 2370 KiB  
Article
A Network Comprised of miR-15b and miR-29a Is Involved in Vascular Endothelial Growth Factor Pathway Regulation in Thymus Adipose Tissue from Elderly Ischemic Cardiomyopathy Subjects
by Adriana Mariel Gentile, Said Lhamyani, María Mengual Mesa, Francisco Javier Pavón-Morón, John R. Pearson, Julián Salas, Mercedes Clemente-Postigo, Lucía Pérez Costillas, Gabriel Olveira Fuster and Rajaa El Bekay Rizky
Int. J. Mol. Sci. 2023, 24(19), 14456; https://doi.org/10.3390/ijms241914456 - 22 Sep 2023
Cited by 3 | Viewed by 2053
Abstract
As the human thymus ages, it undergoes a transformation into adipose tissue known as TAT. Interestingly, in previous research, we observed elevated levels of vascular endothelial growth factor A (VEGFA) in TAT from patients with ischemic cardiomyopathy (IC), particularly in those over 70 [...] Read more.
As the human thymus ages, it undergoes a transformation into adipose tissue known as TAT. Interestingly, in previous research, we observed elevated levels of vascular endothelial growth factor A (VEGFA) in TAT from patients with ischemic cardiomyopathy (IC), particularly in those over 70 years old. Moreover, in contrast to subcutaneous adipose tissue (SAT), TAT in elderly individuals exhibits enhanced angiogenic properties and the ability to stimulate tube formation. This makes TAT a promising candidate for angiogenic therapies and the regeneration of ischemic tissues following coronary surgery. MicroRNAs (miRNAs) have emerged as attractive therapeutic targets, especially those that regulate angiogenic processes. The study’s purpose is to determine the miRNA network associated with both the VEGFA pathway regulation and the enrichment of age-linked angiogenesis in the TAT. RT-PCR was used to analyze angiogenic miRNAs and the expression levels of their predicted target genes in both TAT and SAT from elderly and middle-aged patients treated with coronary artery bypass graft surgery. miRTargetLink Human was used to search for miRNAs and their target genes. PANTHER was used to annotate the biological processes of the predicted targets. The expression of miR-15b-5p and miR-29a-3p was significantly upregulated in the TAT of elderly compared with middle-aged patients. Interestingly, VEGFA and other angiogenic targets were significantly upregulated in the TAT of elderly patients. Specifically: JAG1, PDGFC, VEGFA, FGF2, KDR, NOTCH2, FOS, PDGFRA, PDGFRB, and RHOB were upregulated, while PIK3CG and WNT7A were downregulated. Our results provide strong evidence of a miRNA/mRNA interaction network linked with age-associated TAT angiogenic enrichment in patients with IC. Full article
(This article belongs to the Special Issue Advances in Ageing: From Molecular Mechanism to Strategies)
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14 pages, 1296 KiB  
Article
Circulating Syndecan-1 Levels Are Associated with Chronological Coagulofibrinolytic Responses and the Development of Disseminated Intravascular Coagulation (DIC) after Trauma: A Retrospective Observational Study
by Hironori Matsumoto, Suguru Annen, Naoki Mukai, Muneaki Ohshita, Satoru Murata, Yutaka Harima, Shirou Ogawa, Mitsuo Okita, Yuki Nakabayashi, Satoshi Kikuchi, Jun Takeba and Norio Sato
J. Clin. Med. 2023, 12(13), 4386; https://doi.org/10.3390/jcm12134386 - 29 Jun 2023
Cited by 5 | Viewed by 1555
Abstract
Background: The purpose of this study was to evaluate the association between endotheliopathy represented by high levels of circulating syndecan-1 (SDC-1) and coagulofibrinolytic responses due to trauma, which can lead to disseminated intravascular coagulation (DIC). Methods: We retrospectively evaluated 48 eligible trauma patients [...] Read more.
Background: The purpose of this study was to evaluate the association between endotheliopathy represented by high levels of circulating syndecan-1 (SDC-1) and coagulofibrinolytic responses due to trauma, which can lead to disseminated intravascular coagulation (DIC). Methods: We retrospectively evaluated 48 eligible trauma patients immediately admitted to our hospital and assessed SDC-1 and coagulofibrinolytic parameters for 7 days after admission. We compared the longitudinal changes of coagulofibrinolytic parameters and SDC-1 levels between two groups (high and low SDC-1) according to median SDC-1 value on admission. Results: The median circulating SDC-1 level was 99.6 (61.1–214.3) ng/mL on admission, and levels remained high until 7 days after admission. Coagulofibrinolytic responses assessed by biomarkers immediately after trauma were correlated with SDC-1 elevation (thrombin–antithrombin complex, TAT: r = 0.352, p = 0.001; antithrombin, AT: r = −0.301, p < 0.001; plasmin-α2-plasmin inhibitor complex, PIC: r = 0.503, p = 0.035; tissue plasminogen activator, tPA: r = 0.630, p < 0.001). Sustained SDC-1 elevation was associated with intense and prolonged coagulation activation, impairment of anticoagulation, and fibrinolytic activation followed by inhibition of fibrinolysis, which are the primary responses associated with development of DIC in the acute phase of trauma. Elevation of circulating SDC-1 level was also associated with consumption coagulopathy and the need for transfusion, which revealed a significant association between high SDC-1 levels and the development of DIC after trauma (area under the curve, AUC = 0.845, cut-off value = 130.38 ng/mL, p = 0.001). Conclusions: High circulating levels of syndecan-1 were associated with intense and prolonged coagulation activation, impairment of anticoagulation, fibrinolytic activation, and consumption coagulopathy after trauma. Endotheliopathy represented by SDC-1 elevation was associated with trauma induced coagulopathy, which can lead to the development of DIC. Full article
(This article belongs to the Section Emergency Medicine)
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10 pages, 645 KiB  
Article
Vascular Function, Systemic Inflammation, and Coagulation Activation 18 Months after COVID-19 Infection: An Observational Cohort Study
by Loes H. Willems, Lotte M. C. Jacobs, Laszlo A. Groh, Hugo ten Cate, Henri M. H. Spronk, Boden Wilson-Storey, Gerjon Hannink, Sander M. J. van Kuijk, Chahinda Ghossein-Doha, Magdi Nagy, Dick H. J. Thijssen, André S. van Petersen and Michiel C. Warlé
J. Clin. Med. 2023, 12(4), 1413; https://doi.org/10.3390/jcm12041413 - 10 Feb 2023
Cited by 7 | Viewed by 3656
Abstract
Introduction: Among its effect on virtually all other organs, COVID-19 affects the cardiovascular system, potentially jeopardizing the cardiovascular health of millions. Previous research has shown no indication of macrovascular dysfunction as reflected by carotid artery reactivity, but has shown sustained microvascular dysfunction, systemic [...] Read more.
Introduction: Among its effect on virtually all other organs, COVID-19 affects the cardiovascular system, potentially jeopardizing the cardiovascular health of millions. Previous research has shown no indication of macrovascular dysfunction as reflected by carotid artery reactivity, but has shown sustained microvascular dysfunction, systemic inflammation, and coagulation activation at 3 months after acute COVID-19. The long-term effects of COVID-19 on vascular function remain unknown. Materials and Methods: This cohort study involved 167 patients who participated in the COVAS trial. At 3 months and 18 months after acute COVID-19, macrovascular dysfunction was evaluated by measuring the carotid artery diameter in response to cold pressor testing. Additionally, plasma endothelin-1, von Willebrand factor, Interleukin(IL)-1ra, IL-6, IL-18, and coagulation factor complexes were measured using ELISA techniques. Results: The prevalence of macrovascular dysfunction did not differ between 3 months (14.5%) and 18 months (11.7%) after COVID-19 infection (p = 0.585). However, there was a significant decrease in absolute carotid artery diameter change, 3.5% ± 4.7 vs. 2.7% ± 2.5, p—0.001, respectively. Additionally, levels of vWF:Ag were persistently high in 80% of COVID-19 survivors, reflecting endothelial cell damage and possibly attenuated endothelial function. Furthermore, while levels of the inflammatory cytokines interleukin(IL)-1RA and IL-18 were normalized and evidence of contact pathway activation was no longer present, the concentrations of IL-6 and thrombin:antithrombin complexes were further increased at 18 months versus 3 months (2.5 pg/mL ± 2.6 vs. 4.0 pg/mL ± 4.6, p = 0.006 and 4.9 μg/L ± 4.4 vs. 18.2 μg/L ± 11.4, p < 0.001, respectively). Discussion: This study shows that 18 months after COVID-19 infection, the incidence of macrovascular dysfunction as defined by a constrictive response during carotid artery reactivity testing is not increased. Nonetheless, plasma biomarkers indicate sustained endothelial cell activation (vWF), systemic inflammation (IL-6), and extrinsic/common pathway coagulation activation (FVII:AT, TAT) 18 months after COVID-19 infection. Full article
(This article belongs to the Section Cardiovascular Medicine)
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17 pages, 3430 KiB  
Article
Comprehensive Analysis of Whole-Transcriptome Profiles in Response to Acute Hypersaline Challenge in Chinese Razor Clam Sinonovacula constricta
by Wei Cao, Yinghui Dong, Yusong Geng, Siqi Bi, Zhihong Liu, Liqing Zhou, Xiujun Sun, Sudong Xia, Changfeng Chi and Biao Wu
Biology 2023, 12(1), 106; https://doi.org/10.3390/biology12010106 - 10 Jan 2023
Cited by 10 | Viewed by 2720
Abstract
The Chinese razor clam (Sinonovacula constricta) is an important for Chinese aquaculture marine bivalve that naturally occurs across intertidal and estuarine areas subjected to significant changes in salinity level. However, the information on the molecular mechanisms related to high salinity stress [...] Read more.
The Chinese razor clam (Sinonovacula constricta) is an important for Chinese aquaculture marine bivalve that naturally occurs across intertidal and estuarine areas subjected to significant changes in salinity level. However, the information on the molecular mechanisms related to high salinity stress in the species remain limited. In this study, nine gill samples of S. constricta treated with 20, 30, and 40 ppt salinity for 24 h were used for whole-transcriptome RNA sequencing, and a regulatory network of competing endogenous RNAs (ceRNAs) was constructed to better understand the mechanisms responsible for adaptation of the species to high salinity. A total of 83,262 lncRNAs, 52,422 mRNAs, 2890 circRNAs, and 498 miRNAs were identified, and 4175 of them displayed differential expression pattern among the three groups examined. The KEGG analyses of differentially expressed RNAs evidenced that amino acid synthesis and membrane transport were the dominant factors involved in the adaptation of the Chinese razor clam to acute salinity increase, while lipid metabolism and signaling played only a supporting role. In addition, lncRNA/circRNA-miRNA-mRNA regulatory networks (ceRNA network) showed clearly regulatory relationships among different RNAs. Moreover, the expression of four candidate genes, including tyrosine aminotransferase (TAT), hyaluronidase 4 (HYAL4), cysteine sulfinic acid decarboxylase (CSAD), and ∆1-pyrroline-5-carboxylate synthase (P5CS) at different challenge time were detected by qRT-PCR. The expression trend of TAT and HYAL4 was consistent with that of the ceRNA network, supporting the reliability of established network. The expression of TAT, CSAD, and P5CS were upregulated in response to increased salinity. This might be associated with increased amino acid synthesis rate, which seems to play an essential role in adaptation of the species to high salinity stress. In contrast, the expression level of HYAL4 gene decreased in response to elevated salinity level, which is associated with reduction Hyaluronan hydrolysis to help maintain water in the cell. Our findings provide a very rich reference for understanding the important role of ncRNAs in the salinity adaptation of shellfish. Moreover, the acquired information may be useful for optimization of the artificial breeding of the Chinese razor clam under aquaculture conditions. Full article
(This article belongs to the Special Issue Omics Technologies Applied to Aquaculture Research)
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24 pages, 10901 KiB  
Article
Metabolomics and Lipidomics Screening Reveal Reprogrammed Signaling Pathways toward Cancer Development in Non-Alcoholic Steatohepatitis
by Eman A. Ahmed, Marwa O. El-Derany, Ali Mostafa Anwar, Essa M. Saied and Sameh Magdeldin
Int. J. Mol. Sci. 2023, 24(1), 210; https://doi.org/10.3390/ijms24010210 - 22 Dec 2022
Cited by 27 | Viewed by 6412
Abstract
With the rising incidence of hepatocellular carcinoma (HCC) from non-alcoholic steatohepatitis (NASH), identifying new metabolic readouts that function in metabolic pathway perpetuation is still a demand. The study aimed to compare the metabolic signature between NASH and NASH-HCC patients to explore novel reprogrammed [...] Read more.
With the rising incidence of hepatocellular carcinoma (HCC) from non-alcoholic steatohepatitis (NASH), identifying new metabolic readouts that function in metabolic pathway perpetuation is still a demand. The study aimed to compare the metabolic signature between NASH and NASH-HCC patients to explore novel reprogrammed metabolic pathways that might modulate cancer progression in NASH patients. NASH and NASH-HCC patients were recruited and screened for metabolomics, and isotope-labeled lipidomics were targeted and profiled using the EXION-LCTM system equipped with a Triple-TOFTM 5600+ system. Results demonstrated significantly (p ≤ 0.05) higher levels of triacylglycerol, AFP, AST, and cancer antigen 19-9 in NASH-HCC than in NASH patients, while prothrombin time, platelet count, and total leukocyte count were decreased significantly (p ≤ 0.05). Serum metabolic profiling showed a panel of twenty metabolites with 10% FDR and p ≤ 0.05 in both targeted and non-targeted analysis that could segregate NASH-HCC from NASH patients. Pathway analysis revealed that the metabolites are implicated in the down-regulation of necroptosis, amino acid metabolism, and regulation of lipid metabolism by PPAR-α, biogenic amine synthesis, fatty acid metabolism, and the mTOR signaling pathway. Cholesterol metabolism, DNA repair, methylation pathway, bile acid, and salts metabolism were significantly upregulated in NASH-HCC compared to the NASH group. Metabolite–protein interactions network analysis clarified a set of well-known protein encoding genes that play crucial roles in cancer, including PEMT, IL4I1, BAAT, TAT, CDKAL1, NNMT, PNP, NOS1, and AHCYL. Taken together, reliable metabolite fingerprints are presented and illustrated in a detailed map for the most predominant reprogrammed metabolic pathways that target HCC development from NASH. Full article
(This article belongs to the Special Issue Proteomics and Metabolomics Approaches on Cancer Research)
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14 pages, 3524 KiB  
Article
Transcriptome Analysis Reveals the Complex Regulatory Pathway of Background Color in Juvenile Plectropomus leopardus Skin Color Variation
by Feibiao Song, Lei Wang, Zihang Yang, Liping Shi, Da Zheng, Kaixi Zhang, Junlong Sun and Jian Luo
Int. J. Mol. Sci. 2022, 23(19), 11186; https://doi.org/10.3390/ijms231911186 - 23 Sep 2022
Cited by 14 | Viewed by 3024
Abstract
Fish skin color is often strongly affected by background color. We hypothesized that the regulatory mechanism of variations in skin color in P. leopardus is linked to the background color. In this study, we conducted transcriptome analysis of Plectropomus leopardus cultured under different [...] Read more.
Fish skin color is often strongly affected by background color. We hypothesized that the regulatory mechanism of variations in skin color in P. leopardus is linked to the background color. In this study, we conducted transcriptome analysis of Plectropomus leopardus cultured under different background colors to compare gene expression levels and the important signaling pathways. The RNA-seq analysis yielded 26,675 known mRNAs, 3278 novel mRNAs, and 3179 differentially expressed genes (DEGs). The DEGs related to melanin synthesis were screened out. Some key melanin-related genes were identified, specifically tyr, slc7a11, mc1r, ednrb, dct, tat, and wnt1. These DEGs were mainly involved in melanogenesis, including tyrosine metabolism, the Wnt signaling pathway, and the cAMP signaling pathway. The expression levels of some key genes were upregulated when background color deepened, such as α-msh, wnt, and gf. The α-MSH/cAMP-dependent, Wnt/β-catenin, and PI3K/Akt signaling pathways were activated, resulting in the accumulation of intracellular mitf. mitf promoted melanin production by binding to the tyr/tyrp1/dct promoter region. In the present study, we explored the molecular mechanism underlying the darkened skin color pattern of P. leopardus, providing a theoretical basis for the molecular mechanism underlying pigmentation in P. leopardus. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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40 pages, 5122 KiB  
Article
Identification, Quantification, and Characterization of HIV-1 Reservoirs in the Human Brain
by Maribel Donoso, Daniela D’Amico, Silvana Valdebenito, Cristian A. Hernandez, Brendan Prideaux and Eliseo A. Eugenin
Cells 2022, 11(15), 2379; https://doi.org/10.3390/cells11152379 - 2 Aug 2022
Cited by 30 | Viewed by 4752
Abstract
The major barrier to cure HIV infection is the early generation and extended survival of HIV reservoirs in the circulation and tissues. Currently, the techniques used to detect and quantify HIV reservoirs are mostly based on blood-based assays; however, it has become evident [...] Read more.
The major barrier to cure HIV infection is the early generation and extended survival of HIV reservoirs in the circulation and tissues. Currently, the techniques used to detect and quantify HIV reservoirs are mostly based on blood-based assays; however, it has become evident that viral reservoirs remain in tissues. Our study describes a novel multi-component imaging method (HIV DNA, mRNA, and viral proteins in the same assay) to identify, quantify, and characterize viral reservoirs in tissues and blood products obtained from HIV-infected individuals even when systemic replication is undetectable. In the human brains of HIV-infected individuals under ART, we identified that microglia/macrophages and a small population of astrocytes are the main cells with integrated HIV DNA. Only half of the cells with integrated HIV DNA expressed viral mRNA, and one-third expressed viral proteins. Surprisingly, we identified residual HIV-p24, gp120, nef, vpr, and tat protein expression and accumulation in uninfected cells around HIV-infected cells suggesting local synthesis, secretion, and bystander uptake. In conclusion, our data show that ART reduces the size of the brain’s HIV reservoirs; however, local/chronic viral protein secretion still occurs, indicating that the brain is still a major anatomical target to cure HIV infection. Full article
(This article belongs to the Special Issue The Past, Present and Future of NeuroHIV: A Perspective to A Cure)
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