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International Journal of Molecular... Jun 2024Aneurysms pose life-threatening risks due to the dilatation of the arteries and carry a high risk of rupture. Despite continuous research efforts, there are still no...
Aneurysms pose life-threatening risks due to the dilatation of the arteries and carry a high risk of rupture. Despite continuous research efforts, there are still no satisfactory or clinically effective pharmaceutical treatments for this condition. Accelerated inflammatory processes during aneurysm development lead to increased levels of matrix metalloproteinases (MMPs) and destabilization of the vessel wall through the degradation of the structural components of the extracellular matrix (ECM), mainly collagen and elastin. Tissue inhibitors of metalloproteinases (TIMPs) directly regulate MMP activity and consequently inhibit ECM proteolysis. In this work, the synthesis of TIMP-1 protein was increased by the exogenous delivery of synthetic TIMP-1 encoding mRNA into aortic vessel tissue in an attempt to inhibit MMP-9. In vitro, TIMP-1 mRNA transfection resulted in significantly increased TIMP-1 protein expression in various cells. The functionality of the expressed protein was evaluated in an appropriate ex vivo aortic vessel model. Decreased MMP-9 activity was detected using in situ zymography 24 h and 48 h post microinjection of 5 µg TIMP-1 mRNA into the aortic vessel wall. These results suggest that TIMP-1 mRNA administration is a promising approach for the treatment of aneurysms.
Topics: Tissue Inhibitor of Metalloproteinase-1; Matrix Metalloproteinase 9; RNA, Messenger; Animals; Humans; Rats; Aneurysm; Aorta; Male; Arteries; Matrix Metalloproteinase Inhibitors
PubMed: 38928311
DOI: 10.3390/ijms25126599 -
Bioengineering (Basel, Switzerland) Jun 2024Autologous-engineered artificial tissues constitute an ideal alternative for radical surgery in terms of natural anticoagulation, self-repair, tissue regeneration, and... (Review)
Review
Autologous-engineered artificial tissues constitute an ideal alternative for radical surgery in terms of natural anticoagulation, self-repair, tissue regeneration, and the possibility of growth. Previously, we focused on the development and practical application of artificial tissues using "in-body tissue architecture (iBTA)", a technique that uses living bodies as bioreactors. This study aimed to further develop iBTA by fabricating tissues with diverse shapes and evaluating their physical properties. Although the breaking strength increased with tissue thickness, the nominal breaking stress increased with thinner tissues. By carving narrow grooves on the outer periphery of an inner core with narrow grooves, we fabricated approximately 2.2 m long cord-shaped tissues and net-shaped tissues with various designs. By assembling the two inner cores inside the branched stainless-steel pipes, a large graft with branching was successfully fabricated, and its aortic arch replacement was conducted in a donor goat without causing damage. In conclusion, by applying iBTA technology, we have made it possible, for the first time, to create tissues of various shapes and designs that are difficult using existing tissue-engineering techniques. Thicker iBTA-induced tissues exhibited higher rupture strength; however, rupture stress was inversely proportional to thickness. These findings broaden the range of iBTA-induced tissue applications.
PubMed: 38927834
DOI: 10.3390/bioengineering11060598 -
Biomedicines Jun 2024Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients.... (Review)
Review
Arteriovenous malformations (AVMs) are vascular malformations that are prone to rupturing and can cause significant morbidity and mortality in relatively young patients. Conventional treatment options such as surgery and endovascular therapy often are insufficient for cure. There is a growing body of knowledge on the genetic and molecular underpinnings of AVM development and maintenance, making the future of precision medicine a real possibility for AVM management. Here, we review the pathophysiology of AVM development across various cell types, with a focus on current and potential druggable targets and their therapeutic potentials in both sporadic and familial AVM populations.
PubMed: 38927496
DOI: 10.3390/biomedicines12061289 -
Biomedicines Jun 2024The aim of our study was to evaluate the early and long-term clinical and morphological outcomes of the endovascular treatment of ruptured and non-ruptured intracranial...
The aim of our study was to evaluate the early and long-term clinical and morphological outcomes of the endovascular treatment of ruptured and non-ruptured intracranial aneurysms in a cohort of patients from a single centre. We retrospectively analysed the treatment outcomes of 402 endovascularly treated intracranial aneurysms with an average follow-up of 5.5 years. All included patients were treated with endovascular techniques (coil, stent or both). We analysed patient demographics, risk factors for an aneurysm rupture, aneurysm characteristics, and clinical and angiographic complications and outcomes. We analysed and compared the data from the two groups, ruptured aneurysms (RAs) and unruptured aneurysms (UAs), separately. Out of the 318 patients included, a good early clinical outcome was achieved in 78.5% of RAs and in 95.3% of UAs. No complications occurred in 87.71% of patients with UAs and in 80.45% with RAs. The periprocedural rupture rate for UAs and RAs was 0.8% and 2.2%, respectively. The rate of thromboembolic events was 4.8 and 8% for UAs and RAs, respectively. A retreatment due to the recanalisation was required in 9.21% of patients with UAs and in 16.66% of patients with RAs. The results from our centre showed an overall favourable clinical outcome with acceptable periprocedural complications for both RAs and UR aneurysms and proved the endovascular method as safe and effective in the treatment of intracranial aneurysms.
PubMed: 38927438
DOI: 10.3390/biomedicines12061231 -
Biology May 2024Basement membranes (BMs) are thin layers of extracellular matrix that separate epithelia, endothelia, muscle cells, and nerve cells from adjacent interstitial connective... (Review)
Review
Basement membranes (BMs) are thin layers of extracellular matrix that separate epithelia, endothelia, muscle cells, and nerve cells from adjacent interstitial connective tissue. BMs are ubiquitous in almost all multicellular animals, and their composition is highly conserved across the Metazoa. There is increasing interest in the mechanical functioning of BMs, including the involvement of altered BM stiffness in development and pathology, particularly cancer metastasis, which can be facilitated by BM destabilization. Such BM weakening has been assumed to occur primarily through enzymatic degradation by matrix metalloproteinases. However, emerging evidence indicates that non-enzymatic mechanisms may also contribute. In brittlestars (Echinodermata, Ophiuroidea), the tendons linking the musculature to the endoskeleton consist of extensions of muscle cell BMs. During the process of brittlestar autotomy, in which arms are detached for the purpose of self-defense, muscles break away from the endoskeleton as a consequence of the rapid destabilization and rupture of their BM-derived tendons. This contribution provides a broad overview of current knowledge of the structural organization and biomechanics of non-echinoderm BMs, compares this with the equivalent information on brittlestar tendons, and discusses the possible relationship between the weakening phenomena exhibited by BMs and brittlestar tendons, and the potential translational value of the latter as a model system of BM destabilization.
PubMed: 38927255
DOI: 10.3390/biology13060375 -
Biomolecules Jun 2024De-differentiation and subsequent increased proliferation and inflammation of vascular smooth muscle cells (VSMCs) is one of the mechanisms of atherogenesis. Maintaining...
De-differentiation and subsequent increased proliferation and inflammation of vascular smooth muscle cells (VSMCs) is one of the mechanisms of atherogenesis. Maintaining VSMCs in a contractile differentiated state is therefore a promising therapeutic strategy for atherosclerosis. We have reported the 18-base myogenetic oligodeoxynucleotide, iSN04, which serves as an anti-nucleolin aptamer and promotes skeletal and myocardial differentiation. The present study investigated the effect of iSN04 on VSMCs because nucleolin has been reported to contribute to VSMC de-differentiation under pathophysiological conditions. Nucleolin is localized in the nucleoplasm and nucleoli of both rat and human VSMCs. iSN04 without a carrier was spontaneously incorporated into VSMCs, indicating that iSN04 would serve as an anti-nucleolin aptamer. iSN04 treatment decreased the ratio of 5-ethynyl-2'-deoxyuridine (EdU)-positive proliferating VSMCs and increased the expression of α-smooth muscle actin, a contractile marker of VSMCs. iSN04 also suppressed angiogenesis of mouse aortic rings ex vivo, which is a model of pathological angiogenesis involved in plaque formation, growth, and rupture. These results demonstrate that antagonizing nucleolin with iSN04 preserves VSMC differentiation, providing a nucleic acid drug candidate for the treatment of vascular disease.
Topics: Nucleolin; Animals; RNA-Binding Proteins; Muscle, Smooth, Vascular; Aptamers, Nucleotide; Cell Proliferation; Phosphoproteins; Cell Differentiation; Humans; Rats; Myocytes, Smooth Muscle; Mice; Cells, Cultured; Oligodeoxyribonucleotides; Male; Rats, Sprague-Dawley; Mice, Inbred C57BL
PubMed: 38927112
DOI: 10.3390/biom14060709 -
Biomolecules Jun 2024Abdominal aortic aneurysm (AAA) is a progressive dilatation of the aorta that can lead to aortic rupture. The pathophysiology of the disease is not well characterized... (Review)
Review
Abdominal aortic aneurysm (AAA) is a progressive dilatation of the aorta that can lead to aortic rupture. The pathophysiology of the disease is not well characterized but is known to be caused by the general breakdown of the extracellular matrix within the aortic wall. In this comprehensive literature review, all current research on proteins that have been investigated for their potential prognostic capabilities in patients with AAA was included. A total of 45 proteins were found to be potential prognostic biomarkers for AAA, predicting incidence of AAA, AAA rupture, AAA growth, endoleak, and post-surgical mortality. The 45 proteins fell into the following seven general categories based on their primary function: (1) cardiovascular health, (2) hemostasis, (3) transport proteins, (4) inflammation and immunity, (5) kidney function, (6) cellular structure, (7) and hormones and growth factors. This is the most up-to-date literature review on current prognostic markers for AAA and their functions. This review outlines the wide pathophysiological processes that are implicated in AAA disease progression.
Topics: Aortic Aneurysm, Abdominal; Humans; Biomarkers; Prognosis
PubMed: 38927064
DOI: 10.3390/biom14060661 -
Journal of Cardiothoracic Surgery Jun 2024Following an acute myocardial infarction (AMI), surgery for left ventricular free wall rupture (LVFWR) and ventricular septal rupture (VSR) has a high in-hospital...
BACKGROUND
Following an acute myocardial infarction (AMI), surgery for left ventricular free wall rupture (LVFWR) and ventricular septal rupture (VSR) has a high in-hospital mortality rate, which has not improved significantly over time. Unloading the LV is critical to preventing excessive stress on the repair site and avoiding problems such as bleeding, leaks, patch dehiscence, and recurrence of LVFWR and VSR because the tissue is so fragile. We present two cases of patients who used Impella 5.5 for LV unloading following emergency surgery for AMI mechanical complications.
CASE PRESENTATION
A 76-year-old male STEMI patient underwent fibrinolysis of the distal right coronary artery. Three days later, he passed out and went into shock. Echocardiography revealed a cardiac tamponade. We found an oozing-type LVFWR on the posterolateral wall and treated it with a non-suture technique using TachoSil. Before the patient was taken off CPB, Impella 5.5 was inserted into the LV via a 10 mm synthetic graft connected to the right axillary artery. We kept the flow rate above 4.0 to 4.5 L/min until POD 3 to reduce LV wall tension while minimizing pulsatility. On POD 6, we weaned the patient from Impella 5.5. A postoperative cardiac CT scan showed no contrast leakage from the LV. However, a cerebral hemorrhage on POD 4 during heparin administration complicated his hospitalization. Case 2: A diagnosis of cardiogenic shock caused by STEMI occurred in an 84-year-old male patient, who underwent PCI of the LAD with IABP support. Three days after PCI, echocardiography revealed VSR, and the patient underwent emergency VSR repair with two separate patches and BioGlue applied to the suture line between them. Before weaning from CPB, we implanted Impella 5.5 in the LV and added venoarterial extracorporeal membrane oxygenation (VA-ECMO) support for right heart failure. The postoperative echocardiography revealed no residual shunt.
CONCLUSIONS
Patients undergoing emergency surgery for mechanical complications of AMI may find Impella 5.5 to be an effective tool for LV unloading. The use of VA-ECMO in conjunction with Impella may be an effective strategy for managing VSR associated with concurrent right-sided heart failure.
Topics: Humans; Male; Aged; Heart-Assist Devices; Myocardial Infarction; Heart Ventricles; Heart Rupture, Post-Infarction; Ventricular Septal Rupture; Echocardiography; Postoperative Complications
PubMed: 38926884
DOI: 10.1186/s13019-024-02879-5 -
Scientific Reports Jun 2024During metastatic dissemination, circulating tumour cells (CTCs) enter capillary beds, where they experience mechanical constriction forces. The transient and persistent...
During metastatic dissemination, circulating tumour cells (CTCs) enter capillary beds, where they experience mechanical constriction forces. The transient and persistent effects of these forces on CTCs behaviour remain poorly understood. Here, we developed a high-throughput microfluidic platform mimicking human capillaries to investigate the impact of mechanical constriction forces on malignant and normal breast cell lines. We observed that capillary constrictions induced nuclear envelope rupture in both cancer and normal cells, leading to transient changes in nuclear and cytoplasmic area. Constriction forces transiently activated cGAS/STING and pathways involved in inflammation (NF-κB, STAT and IRF3), especially in the non-malignant cell line. Furthermore, the non-malignant cell line experienced transcriptional changes, particularly downregulation of epithelial markers, while the metastatic cell lines showed minimal alterations. These findings suggest that mechanical constriction forces within capillaries may promote differential effects in malignant and normal cell lines.
Topics: Humans; Breast Neoplasms; Female; Neoplastic Cells, Circulating; Cell Line, Tumor; Capillaries; Cell Nucleus; Neoplasm Metastasis; Nuclear Envelope
PubMed: 38926422
DOI: 10.1038/s41598-024-64733-x -
Journal of Biomechanics Jun 2024Lumbrical muscles originate on the flexor digitorum profundus (FDP) tendons and, during fist making, they move in the same direction when FDP muscle produces maximal...
Lumbrical muscles originate on the flexor digitorum profundus (FDP) tendons and, during fist making, they move in the same direction when FDP muscle produces maximal proximal tendon gliding. Injuries of the bipennate lumbricals have been described when a shear force acts between the origins on adjacent tendons of the FDP, as they glide in opposite directions in asymmetric hand postures. Other structures of the deep flexors complex can be affected during this injury mechanism, due to the so-called quadriga effect, which can commonly occur during sport climbing practise. Biomechanical studies are needed to better understand the pathomechanism. A cadaveric study was designed to analyse the effects of load during the fourth lumbrical muscle injury mechanism. The amount of FDP tendon gliding and metacarpophalangeal (MCP) joint flexion of the 5th finger were calculated. Ten fresh-frozen cadaveric specimens (ten non-paired forearms and hands) were used. The specimens were placed on a custom-made loading apparatus. The FDP of the 5th finger was loaded, inducing isolated flexion of the 5th finger, until rupture. The rupture occurred in all specimens, under a load of 11 kg (SD 4.94), at 9.23 mm of proximal tendon gliding (SD 3.55) and at 21.4° (SD 28.91) of MCP joint flexion. Lumbrical muscle detachment from the 4th FDP was observed, from distal to proximal, and changes in FDP tendons at the distal forearm level too. The quadriga effect can lead to injury of the bipennate lumbrical muscles and the deep flexors complex in the hand and forearm.
PubMed: 38924964
DOI: 10.1016/j.jbiomech.2024.112196