Similar to other organs, the skin undergoes a natural aging process. Moreover, constant direct exposure to environmental stresses, including ultraviolet irradiation, causes the signs of skin aging to appear rather early. Reactive oxygen species (ROS) and inflammatory responses accelerate skin damage in extrinsic aging. In this study, we aimed to investigate the skin protective effects of polymethoxyflavones found in Kaempferia parviflora against oxidative stress and inflammation-induced damage in human dermal fibroblasts (HDFs) stimulated by tumor necrosis factor-α (TNF-α). The experimental data identified 5,7,4′ trimethoxyflavone (TMF) as the most potent constituent in preventing TNF-α-induced HDF damage among the tested compounds and it was not only effective in inhibiting matrix metalloproteinase-1 (MMP-1) production but also in stimulating collagen, type I, and alpha 1 (COLIA1) expression. TMF suppressed TNF-α-stimulated generation of ROS and pro-inflammatory mediators, such as cyclooxygenase-2 (COX-2), interleukin (IL)-1β, and IL-6 in HDFs. TMF also inhibited the pathways regulating fibroblast damage, including mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and nuclear factor-kappa B (NF-κB). In conclusion, TMF may be a potential agent for preventing skin aging and other dermatological disorders associated with oxidative stress and inflammation.

It is known that receptor for advanced glycation end products (RAGE) and its ligands accumulate in the fat tissues of obese individuals, and RAGE ligands induce M1 macrophage polarization, which in turn induces inflammation. We evaluated the effect of pyridoxamine on RAGE ligand accumulation and M1 polarization in the visceral, subcutaneous, and perivascular fat tissues of Sprague-Dawley rats fed a high fat diet (HFD). Pyridoxamine reduced HFD-induced weight gain, attenuated adipocyte size increases, RAGE ligand accumulations, RAGE-RAGE ligands binding, decreased macrophage M1 polarization and increased M2 polarization in visceral fat tissues, but not in subcutaneous tissues. Pyridoxamine induced glyoxalase 1 (Glo-1) expression in visceral fat in the HFD group, whereas pyridoxamine induced Glo-1 expression in perivascular fat tissues was no higher than that observed in the normal fat diet (NFD) controls. In vitro, pyridoxamine suppressed the release of RAGE ligands from AGE treated macrophages, but non-significantly attenuated RAGE ligands release in AGE treated adipocytes. Pyridoxamine was found to suppress weight increases and M1 polarization, and to increase Glo-1 expression through the RAGE pathway in perivascular and visceral fat tissues of HFD-induced obese rats. These findings suggest pyridoxamine is a candidate for the treatment of obesity or complications related to obesity-induced inflammation.

Post-ischemic reperfusion injury (PIRI) triggers an intense inflammatory response which is essential for repair but is also implicated in pathogenesis of post-ischemic remodeling in several organs in human. Stem cell therapy has recently emerged as a promising method for treatment of PIRI in human. However, satisfactory results have not been reported due to severe loss of injected stem cells in PIRI including critical limb ischemia (CLI). For investigating the advanced glycation end-product-albumin (AGE-albumin) from activated macrophages is critical in both muscle cell and stem cell death, we evaluated the recovery of PIRI-CLI by injection of human bone marrow derived mesenchymal stem cells (hBD-MSCs) with or without soluble receptor for AGEs (sRAGE). Our results showed that activated M1 macrophages synthesize and secrete AGE-albumin, which induced the skeletal muscle cell death and injected hBD-MSCs in PIRI-CLI through RAGE increase. Combined injection of sRAGE and hBD-MSCs resulted in enhanced survival of hBD-MSCs and angiogenesis in PIRI-CLI mice. Taken together, AGE-albumin from activated macrophages is critical for both skeletal muscle cell and hBD-MSCs death in PIRI-CLI. Therefore, the inhibition of AGE-albumin from activated macrophages could be a successful therapeutic strategy for treatment of PIRI including CLI with or without stem cell therapy.