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Background and Aims: Liver fibrosis represents a global health burden, given the paucity of approved antifibrotic therapies. Liver sinusoidal endothelial cells (LSECs) play a major gatekeeping role in hepatic homeostasis and liver disease pathophysiology. In early tumorigenesis, runt-related transcription factor 3 (RUNX3) functions as a sentinel; however, its function in liver fibrosis in LSECs remains unclear. This study aimed to investigate the role of RUNX3 as an important regulator of the gatekeeping functions of LSECs and explore novel angiocrine regulators of liver fibrosis., Approach and Results: Mice with endothelial Runx3 deficiency develop gradual and spontaneous liver fibrosis secondary to LSEC dysfunction, thereby more prone to liver injury. Mechanistic studies in human immortalized LSECs and mouse primary LSECs revealed that IL-6/JAK/STAT3 pathway activation was associated with LSEC dysfunction in the absence of RUNX3. Single-cell RNA sequencing and quantitative RT-PCR revealed that leucine-rich alpha-2-glycoprotein 1 ( LRG1 ) was highly expressed in RUNX3-deficient and dysfunctional LSECs. In in vitro and coculture experiments, RUNX3-depleted LSECs secreted LRG1, which activated HSCs throughTGFBR1-SMAD2/3 signaling in a paracrine manner. Furthermore, circulating LRG1 levels were elevated in mouse models of liver fibrosis and in patients with fatty liver and cirrhosis., Conclusions: RUNX3 deficiency in the endothelium induces LSEC dysfunction, LRG1 secretion, and liver fibrosis progression. Therefore, endothelial RUNX3 is a crucial gatekeeping factor in LSECs, and profibrotic angiocrine LRG1 may be a novel target for combating liver fibrosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hypoxic responses have been implicated in critical pathologies, including inflammation, immunity, and tumorigenesis. Recently, efforts to identify effective natural remedies and health supplements are increasing. Previous studies have reported that the cell lysates and the cell wall-bound lipoteichoic acids of Lactiplantibacillus plantarum K8 (K8) exert anti-inflammatory and immunomodulative effects. However, the effect of K8 on cellular hypoxic responses remains unknown. In this study, we found that K8 lysates had a potent suppressive effect on gene expression under hypoxia. K8 lysates markedly downregulated hypoxia-induced HIF1α accumulation in the human bone marrow and lung cancer cell lines, SH-SY5Y and H460. Consequently, the transcription of known HIF1α target genes, such as p21, GLUT1, and ALDOC, was notably suppressed in the K8 lysate supplement and purified lipoteichoic acids of K8, upon hypoxic induction. Intriguingly, K8 lysates decreased the expression of PHD2 and VHL proteins, which are responsible for HIF1α destabilization under normoxic conditions, suggesting that K8 may regulate HIF1α stability in a non-canonical pathway. Overall, our results suggest that K8 lysates desensitize the cells to hypoxic stresses and suppress HIF1α-mediated hypoxic gene activation., (© 2024. The Author(s).)

A sensitive method for measuring cell surface and secreted protease activity utilizing 3H-labelled casein is described. The method is based upon proteolytic degradation of the casein substrate into trichloracetic acid soluble 3H-labelled peptides. Utilizing the radioassay we found that all cultured cell lines examined contain cell surface proteolytic activity which is not secreted into the media. The protease activity was found to be due to protease(s) other than plasminogen activator or plasmin. A comparison of surface protease activity of normal and transformed mouse epidermal cells indicated that the transformed cells contained approximately 3--1 times more proteolytic activity than the normal cells. Surface protease activity was also correlated with the doubling times of various cultured cells. The results indicated that cultured cells with doubling times of greater than three days possess less surface protease activity than cells with shorter doubling times. In order to determine changes in the levels of surface protease activity during the cell cycle several cell lines were synchronized. In synchronized rabbit aortic fibroblasts, mouse transformed epidermal cells and human melanoma cells, a marked increase in surface protease activity was observed during or before mitosis. The protease levels decreased following mitosis. The results suggest that in culture, cell surface protease(s) may be important factor in regulating the rate of cell growth.

Since estrogen has been shown to reduce aortic medial hypertrophy in hypertensive rats, a naturally occurring estrogen compound, estradiol, was studied for its ability to suppress the intimal hyperplasia which follows vessel transection and anastomosis. Suture lines and adjacent abdominal aortas were examined by light and electron microscopy 1 month after surgery, in 23 rabbits. Test animals were given 200 microgram of Depoestradiol I.M. weekly, starting 3 days preoperatively. Control animals were similarly manipulated but received no estrogen. Control animals showed striking intimal thickening over the sutures, in contrast to the estrogen-treated group in which there was significantly less growth of corresponding tissue (p less than 0.01).

We created permanent complete heart block (CHB) in 11 dogs without atriotomy by means of indirect cauterization of the atrioventricular (A-V) bundle with a partially insulated wire placed through a small puncture in the atrial wall and guided by palpation. In six acute studies and five chronic studies, all dogs exhibited permanent CHB. To test the block, isoproterenol increased both atrial and ventricular rates 200%-400% without affecting the block. Atropine had no effect on ventricular rate or block.

A 20-year-old female with congenital venous malformations in her left lower extremity had a self-limited, moderate consumption coagulopathy following angiographic studies. This episode was documented by both conventional coagulation studies and by 125l fibrinogen survival studies. It seems likely that venography triggered a local inflammation in the vascular malformations, which resulted in a localized consumption coagulopathy which abated as did the phlebitis in three weeks. We are aware of no prior reports of this complication of venography. Patients with venous malformations who undergo venography should have appropriate coagulation screening performed before and after the procedure so that any similar episode can be promptly diagnosed and treated, if treatment is deemed necessary.