An engineered monomer of CCL2 has anti-inflammatory properties emphasizing the importance of oligomerization for chemokine activity in vivo. | LitMetric
We demonstrated recently that P8A-CCL2, a monomeric variant of the chemokine CCL2/MCP-1, is unable to induce cellular recruitment in vivo, despite full activity in vitro. Here, we show that this variant is able to inhibit CCL2 and thioglycollate-mediated recruitment of leukocytes into the peritoneal cavity and recruitment of cells into lungs of OVA-sensitized mice. This anti-inflammatory activity translated into a reduction of clinical score in the more complex inflammatory model of murine experimental autoimmune encephalomyelitis. Several hypotheses for the mechanism of action of P8A-CCL2 were tested. Plasma exposure following s.c. injection is similar for P8A-CCL2 and wild-type (WT) CCL2, ruling out the hypothesis that P8A-CCL2 disrupts the chemokine gradient through systemic exposure. P8A-CCL2 and WT induce CCR2 internalization in vitro and in vivo; CCR2 then recycles to the cell surface, but the cells remain refractory to chemotaxis in vitro for several hours. Although the response to P8A-CCL2 is similar to WT, this finding is novel and suggests that despite the presence of the receptor on the cell surface, coupling to the signaling machinery is retarded. In contrast to CCL2, P8A-CCL2 does not oligomerize on glycosaminoglycans (GAGs). However, it retains the ability to bind GAGs and displaces endogenous JE (murine MCP-1) from endothelial surfaces. Intravital microscopy studies indicate that P8A-CCL2 prevents leukocyte adhesion, while CCL2 has no effect, and this phenomenon may be related to the mechanism. These results suggest that oligomerization-deficient chemokines can exhibit anti-inflammatory properties in vivo and may represent new therapeutic modalities.
Introduction: Hepatocellular carcinoma (HCC), the third leading cancer mortality worldwide, shows rising incidence. The mitochondria in HCC cells are prone to damage from metabolic stress and oxidative stress, necessitating heightened mitophagy for mitochondrial homeostasis and cell survival. Thus, mitophagy inhibition is a promising HCC therapy.
Purpose: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease that severely impairs patient's life quality and represents significant therapeutic challenge due to its pathophysiology arising from skin barrier dysfunction. Topical corticosteroids, the mainstay treatment for mild to moderate AD, are usually formulated into conventional dosage forms that are impeded by low drug permeation, resulting in high doses with consequent adverse effects, and also lack properties that would strengthen the skin barrier. Herein, we aimed to develop biomimetic lamellar lyotropic liquid crystals (LLCs), offering a novel alternative to conventional AD treatment.
Polyphenols, known for their potent antioxidant and anti-inflammatory properties, have emerged as promising, natural, and safe complementary treatment options for metabolic-associated steatotic liver disease (MASLD). Among these, curcumin, resveratrol, and silymarin are the most extensively studied; however, their differential effects on MASLD outcomes remain inconclusive. This systematic review and meta-analysis of RCTs aimed to evaluate the efficacy of curcumin, resveratrol, and silymarin in patients with MASLD.
Recent research indicates that the activation of the NLRP3 inflammasome is crucial in the development of diabetic kidney disease (DKD). Epigallocatechin-3-gallate (EGCG), the predominant catechin in green tea, has been noted for its anti-inflammatory properties in DKD. However, the specific mechanisms are not yet fully understood.
Betulin is a bioactive compound found in large quantities in birch bark and has a triterpene pentacyclic structure. Through the oxidation of betulin, betulinic acid is obtained, which is found in large quantities in nature. Betulin and betulinic acid have multiple pharmacological properties such as antiviral, anti-inflammatory, and anticancer properties.
