Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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Anti-aging effect of magnesium lithospermate ? from Salvia miltiorrhiza Bunge on skin
Get PDFMagnesium lithospermate B (MLB, also called salvianolic acid B), one of the hydrophilic phenolic compounds of Salvia miltiorrhiza Bunge has been reported to possess numerous health benefits, but a role for MLB in the prevention of skin aging has not been fully explored. In a recent publication, we reported that the skin anti-aging action of MLB depends on its ability to suppress collagen degradation via its anti-oxidant activity, and subsequently, to increase the expressions of type I and III collagen genes through PPARb/d activation. For this research highlight, we describe the salient findings from our recent study on the anti-wrinkle effect of MLB and the molecular mechanism underlying its skin anti-aging action
New mechanism leading to alleviation of salt-sensitive hypertension by a powerful angiotensin receptor blocker, azilsartan
Get PDFHypertension is one of the most life-threatening health problems in the modern world. Particularly, salt-sensitive hypertension is often associated with cardiovascular disease and defects in the circadian rhythm of the blood pressure. To date, the effects of angiotensin receptor blocker (ARB) against salt sensitivity and the blood pressure’s circadian rhythm have been obscure. A strong ARB, azilsartan, was previously reported to improve the circadian rhythm of blood pressure in hypertensive patients. In a recently published study, we investigated the mechanism by which azilsartan brought about this reaction. We speculated that azilsartan modulated sodium transporters located in the renal tubules because the circadian rhythm of blood pressure is linked to salt handling in the kidney. We discovered that one sodium transporter, NHE3 protein, in the proximal tubules was greatly attenuated in the kidneys of 5/6 nephrectomized mice that had been treated with azilsartan, although the expression of other sodium transporter proteins remained unchanged. The genetic expression of NHE3, however, was not changed by azilsartan. In a subsequent in vitro study using OKP cells, we found that NHE3 protein reduction was induced by enhanced protein degradation by proteasomes, not lysosomes, leading to enhanced sodium excretion. It is suggested that diminished salt sensitivity in the 5/6 nephrectomized mice treated with azilsartan was due to a change in sodium handling induced by the reduction of NHE3 protein in the proximal tubules. These mechanisms underlying the decreased salt sensitivity by azilsartan treatment may lead to totally new drug discoveries
Dectin-1 in the control of Th2-type T cell responses
Get PDFDendritic cells (DCs) are major antigen-presenting cells (APCs) that can induce and control host immune responses. DCs express pattern recognition receptors (PRRs), which can translate external and internal triggers into different types of T cell responses. The types of CD4+ T cell responses elicited by DCs (e.g., Th1, Th2, Th17, Th21, Th22 and regulatory T cells (Tregs)) are associated with either host immunity or inflammatory diseases, including allergic diseases and autoimmune diseases. In particular, the pathogenic functions of Th2-type T cells in allergic immune disorders have been well documented, although Th2-type T cell responses are crucial for immunity against certain parasite infections. Recent evidence also indicates that the inflammatory Th2 signatures in cancers, including breast and pancreatic cancers, are highly associated with poor clinical outcomes in patients. It is thus important to find cellular/molecular targets expressed in DCs that control such inflammatory Th2-type T cell responses. In a recent paper published in The Journal of Immunology, we demonstrated that Dectin-1 expressed on the two major human DC subsets, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), has opposing roles in the control of Th2-type CD4+ T cell responses. Dectin-1 expressed on mDCs decreases Th2-type CD4+ T cell responses, while Dectin-1 expressed on pDCs favors Th2-type CD4+ T cell responses. This finding expands our understanding of the roles of DCs and Dectin-1 expressed on DCs in the pathogenesis of Th2-associated diseases and in host immunity to microbial infections and cancers
Promiscuous signaling of ligands via mutant ALK2 in fibrodysplasia ossificans progressiva
Get PDFFibrodysplasia ossificans progressiva (FOP) is a rare hereditary disorder characterized by successive heterotopic bone formation, for which at present there is no therapy. Mutations in the bone morphogenetic protein (BMP) type I receptor Activin receptor-like kinase 2 (ACVR1/ALK2) are the main trigger for FOP and inflammation is thought to be the secondary hit. The single nucleotide mutation at position 617 in the cDNA ALK2 sequence, which is found in 98% of FOP patients, results in a R206H change in the intracellular juxtamembrane region of ALK2. Previous studies had revealed that this mutation perturbs the interaction with the negative regulator FKBP12, thereby sensitising cells expressing this mutant receptor to BMPs, which are potent inducers of cartilage and bone formation. Recently, however, a twist in the underlying mechanism of FOP was revealed. Mutant ALK2 was found to respond to Activin-A, whereas wild type ALK2 function is inhibited by Activin-A. The latter cytokine is induced locally upon tissue damage and inflammation. Moreover, therapeutic targeting of Activin-A was found to inhibit heterotopic ossification in a mutant ALK2 knock-in mouse model that is highly reminiscent to human FOP. This review will focus on these latest surprising findings and discuss the implication for treatment of FOP patients
Pioglitazone improves pelvic ganglion neuronal survival
Get PDFCavernosal nerve injury is a common complication after radical prostatectomy and causes erectile dysfunction (ED). Our recent publication established that pioglitazone (PGZ) improves cavernosal nerve function after crush injury in the rat model by both neural protection and neuroregeneration. This result is clinically significant for the many men who undergo treatment for localized prostate cancer. A better understanding of the effects of PGZ on pelvic ganglion neurons after cavernosal nerve injury is warranted. In this Research Highlight, we discuss the implications of our investigation from a molecular and clinical perspective
Wnt signaling in idiopathic carpal tunnel syndrome
Get PDFCarpal tunnel syndrome (CTS) is the most frequently reported entrapment neuropathy; however, the exact pathological mechanism of CTS remains unknown. In a recent paper published in the Journal of Orthopaedic Research, we investigated the associations between Wnt signaling and the etiology of idiopathic CTS (ICTS). We compared the expression levels of genes encoding Wnt1, 2, 3, 4, 5a, 5b, 6, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11, and 16 in the flexor tenosynovium between ICTS patients and controls, and we also evaluated whether an association exists between Wnt signaling and cell proliferation factors, such as estrogen-responsive finger protein, epidermal growth factor receptor, heparin binding-epidermal growth factor-like growth factor, insulin-like growth factor-1, and vascular endothelial growth factor (VEGF). To compare the cell proliferation potency, expression levels of MIB-1 protein were also measured. We found that Wnt9a gene expression in the flexor tenosynovium is more prominent in ICTS patients. A positive correlation was observed in only ICTS patient group for the gene expression of Wnt9a and VEGF in the flexor tenosynovium. There were no relationships between the expression levels of Wnt9a and fibroblast proliferation in either group. These results indicate that Wnt9a may be involved in the expression of VEGF in ICTS
Microbial DNA regulates intestinal homeostasis via the AIM2 inflammasome
Get PDFAbsent in melanoma 2 (AIM2) is a cytosolic DNA sensor which upon activation assembles a multiprotein complex called the inflammasome. Previous studies have shown that several inflammasome-forming pattern recognition receptors exhibit a protective function against inflammatory bowel disease and colorectal cancer. However, the role of AIM2 in sensing intestinal microbial DNA and regulating inflammatory responses therein was unknown. In a recent study published in Cell Reports, we demonstrated that Aim2-/- mice are highly susceptible to experimental colitis which was associated with a defect in the inflammasome activation as indicated by reduced caspase-1 cleavage and decreased production of IL-1b and IL-18. We also studied the underlying mechanism of AIM2 inflammasome-mediated protection against intestinal injury and inflammation. We found that the inflammasome downstream cytokine IL-18 contributes to intestinal homeostasis via induction of antimicrobial peptides, such as Reg3b, Reg3g, Lcn2, S100A8, and S100A9 in intestinal epithelial cells. As a consequence of the defective production of antimicrobial peptides, Aim2-/- and other inflammasome-deficient mice harbor altered microbiota in the intestine as characterized by significantly higher burden of Escherichia coli. This research highlight will provide an overview of our findings and discuss how sensing of microbial DNA by AIM2 maintains intestinal homeostasis
The ephrin-B2/EphB4 system is required in musculoskeletal development and protects the articulation during osteoarthritis: a research highlight
Get PDFEphrin ligands and their Eph receptors have been implicated in the control of extracellular matrix of some tissues. Although ephrin-B2 and its specific receptor EphB4 were found to be involved in postembryonic control of bone homeostasis, their roles were unclear in musculoskeletal growth and development as well as in osteoarthritis pathology. The role of this ephrin system in musculoskeletal growth and development was delineated in vivo using a cartilage-specific ephrin-B2 knockout mouse model. Its role in osteoarthritis in vivo was explored in mice using a bone-specific overexpression of EphB4 in which osteoarthritis was induced, and in vitro in human osteoarthritic subchondral bone osteoblasts and chondrocytes. In vivo, ephrin-B2 demonstrated to be essential for normal long bone growth and development and its absence in cartilage led to knee and hip osteoarthritis features in aged mice. In vitro data showed that the ephrin-B2-induced EphB4 receptor positively impacted the abnormal metabolism of both osteoarthritic subchondral bone osteoblasts and chondrocytes. The bone?specific EphB4 overexpression in mice validated the in vitro data in that it had beneficial effects not only on the osteoarthritic subchondral bone but also on the cartilage and synovial membrane, and further substantiated the hypothesis that by prophylactically protecting the subchondral bone, the genesis of osteoarthritis could be, at least in part, inhibited. In the context of identifying new candidates targeting osteoarthritis progression, this ephrin system is extremely attractive as a potential novel therapeutic avenue, as therapies having a more global articular approach may prove to be the most successful to arrest or slow the progression of this disease
The role of estrogen receptors in intestinal homeostasis and disease
Get PDFEstrogen has a pivotal role in many biological functions in both reproductive and non-reproductive organs, mediating actions through its receptors, estrogen receptor ? (ER?) and ER?. The expression of ERs is widespread in the body and is implicated in normal physiological processes as well as in disease conditions, including intestinal diseases. Immunohistochemical and functional analyses have revealed that ER? is the predominant ER type in intestinal tract, but not ER?. The ER? mediates to provide protection against duodenal ulcer, inflammatory bowel disease and colon cancer but may also contribute to the progression of constipation. In this review, we summarize the recent findings regarding estrogen and its receptors and their role in intestinal diseases. Based on these findings, it is possible to drive the pathogenesis of intestinal diseases using ER-subtype selective inhibitors or stimulators
“A small leak will sink a great ship”: hypoxia-inducible factor and group III pulmonary hypertension
Get PDFPulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) – a regulatory protein that is vital in adaptation to hypoxic conditions – in the development of secondary pulmonary hypertension. HIF influences development of hypoxia-induced pulmonary hypertension through alteration in voltage-gated potassium channels and homeostatic calcium regulation, resulting in disruption of endothelial cell-cell communication, and eventual vascular remodeling. This article summarizes salient literature related to HIF and secondary pulmonary hypertension, in addition to proposing a final common pathway in known mechanistic pathways that result in endothelial barrier integrity loss – vascular “leak” – primarily through a shared endothelial-epithelial signaling protein family, CCN