Circulating LPS from gut microbiota leverages stenosis-induced deep vein thrombosis in mice.

Objective And Design: An accumulating body of evidence has shown that gut microbiota is involved in regulating inflammation; however, it remains undetermined if and how gut microbiota plays an important role in modulating deep venous thrombosis (DVT), which is an inflammation-involved thrombotic event.

Subjects: Mice under different treatments were used in this study.

Methods And Treatment: We induced stenosis DVT in mice by partially ligating the inferior vena cava.

Kindlin-3 in Immune Cells Is Required to Suppress Prostate Cancer Tumor Growth in Mice.

Background/aim: Kindlins are essential integrin activators. Kindlin-1 and kindlin-2 are often concomitantly expressed in epithelial tumor cells and participate in regulating tumor malignancy. However, it remains unclear whether kindlin-3, the one expressed in immune cells, also plays a role in regulating tumor malignancy.

Paxillin binding to the PH domain of kindlin-3 in platelets is required to support integrin αIIbβ3 outside-in signaling.

Background: Kindlin-3 is essential for supporting the bidirectional signaling of integrin αIIbβ3 in platelets by bridging the crosstalk between integrin αIIbβ3 and the cytoplasmic signaling adaptors.

Objective: In this study, we identified a previously unrecognized paxillin binding site in the pleckstrin homology (PH) domain of kindlin-3 and verified its functional significance.

Methods: Structure-based approaches were employed to identify the paxillin binding site in the PH domain of kindlin-3.

Structure basis of the FERM domain of kindlin-3 in supporting integrin αIIbβ3 activation in platelets.

Kindlin-3, a protein 4.1, ezrin, radixin, and moesin (FERM) domain-containing adaptor in hematopoietic cells, is essentially required for supporting the bidirectional integrin αIIbβ3 signaling in platelets by binding to the integrin β3 cytoplasmic tail. However, the structural details of kindlin-3's FERM domain remain unknown.

Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from -Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message-Address Concept.

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of -cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound , SLL-039) as a highly selective and potent κ opioid agonist (κ, = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays and antinociceptive assays .

Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice.

Platelets and myeloid cells cooperate to promote deep vein thrombosis (DVT). Here we evaluated the role of kindlin-3, a key integrin activator in these cells, in regulating stenosis-induced DVT in mice. DVT was significantly suppressed in mice that express a kindlin-3 mutant defective for integrin binding, showing that kindlin-3-mediated integrin signaling in blood cells is required for DVT.

Sharpin suppresses β1-integrin activation by complexing with the β1 tail and kindlin-1.

Background: Previously sharpin has been identified as an endogenous inhibitor of β1-integrin activation by directly binding to a conserved region in the cytoplasmic tails (CTs) of the integrin β1-associated α subunits.

Methods: Here we employed biochemical approaches and cellular analyses to evaluate the function and molecular mechanism of the sharpin-kindlin-1 complex in regulating β1-integrin activation.

Results: In this study, we found that although the inhibition of sharpin on β1-integrin activation could be confirmed, sharpin had no apparent effect on integrin αIIbβ3 activation in CHO cell system.

Kindlin-3 negatively regulates the release of neutrophil extracellular traps.

Neutrophils fight infections by generating reactive oxygen species (ROS) and extracellular traps (NETs). However, how neutrophils modulate ROS/NET generation is mechanistically unclear. Kindlin-3, an essential integrin activator expressed in hematopoietic cells, is required to support integrin-mediated neutrophil recruitment during inflammation.

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin.

Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbβ3 activation. An exposed loop in the N-terminal F subdomain of kindlins was involved in mediating the interaction.

Two di-leucine motifs regulate trafficking and function of mouse ASIC2a.

Background: Acid-sensing ion channels (ASICs) are proton-gated cation channels that mediate acid-induced responses in neurons. ASICs are important for mechanosensation, learning and memory, fear, pain, and neuronal injury. ASIC2a is widely expressed in the nervous system and modulates ASIC channel trafficking and activity in both central and peripheral systems.

Interaction of kindlin-3 and β2-integrins differentially regulates neutrophil recruitment and NET release in mice.

Kindlin-3 essentially supports integrin activation in blood cells. Absence of kindlin-3 in humans causes leukocyte adhesion deficiency-III characterized with severe bleeding disorder and recurrent infections. Previously, we generated kindlin-3 knock-in (K3KI) mice carrying an integrin-interaction disrupting mutation in kindlin-3 and verified the functional significance of the binding of kindlin-3 to integrin αIIbβ3 in platelets.

Direct interaction of kindlin-3 with integrin αIIbβ3 in platelets is required for supporting arterial thrombosis in mice.

Objective: Kindlin-3 is a critical supporter of integrin function in platelets. Lack of expression of kindlin-3 protein in patients impairs integrin αIIbβ3-mediated platelet aggregation. Although kindlin-3 has been categorized as an integrin-binding partner, the functional significance of the direct interaction of kindlin-3 with integrin αIIbβ3 in platelets has not been established.