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Far infrared promotes wound healing through activation of Notch1 signaling. J Mol Med (Berl). 2017 Aug 22.

  • The Notch signaling pathway is critically involved in cell proliferation, differentiation, development, and homeostasis. Far infrared (FIR) has an effect that promotes wound healing. However, the underlying molecular mechanisms are unclear. In the present study, we employed in vivo and HaCaT (a human skin keratinocyte cell line) models to elucidate the role of Notch1 signaling in FIR-promoted wound healing. We found that FIR enhanced keratinocyte migration and proliferation. FIR induced the Notch1 signaling pathway in HaCaT cells and in a microarray dataset from the Gene Expression Omnibus database. We next determined the mRNA levels of NOTCH1 in paired normal and wound skin tissues derived from clinical patients using the microarray dataset and Ingenuity Pathway Analysis software. The result indicated that the Notch1/Twist1 axis plays important roles in wound healing and tissue repair. In addition, inhibiting Notch1 signaling decreased the FIR-enhanced proliferation and migration. In a full-thickness wound model in rats, the wounds healed more rapidly and the scar size was smaller in the FIR group than in the light group. Moreover, FIR could increase Notch1 and Delta1 in skin tissues. The activation of Notch1 signaling may be considered as a possible mechanism for the promoting effect of FIR on wound healing. FIR stimulates keratinocyte migration and proliferation. Notch1 in keratinocytes has an essential role in FIR-induced migration and proliferation. NOTCH1 promotes TWIST1-mediated gene expression to assist wound healing. FIR might promote skin wound healing in a rat model.

Far-infrared promotes burn wound healing by suppressing NLRP3 inflammasome caused by enhanced autophagy. J Mol Med (Berl). 2016 Feb 11.

  • Understanding the underlying molecular mechanisms in burn wound progression is crucial to providing appropriate diagnoses and designing therapeutic regimens for burn patients. When inflammation becomes unregulated, recurrent, or excessive, it interferes with burn wound healing.Autophagy, which is a homeostatic and catabolic degradation process, was found to protect against ischemic injury, inflammatory diseases, and apoptosis in some cases. In the present study, we investigated whether far-infrared (FIR) could ameliorate burn wound progression and promote wound< healing both in vitro and in a rat model of deep second-degree burn. We found that FIR induced autophagy in differentiated THP-1 cells (human monocytic cells differentiated to macrophages). Furthermore, FIR inhibited both the NLRP3 inflammasome and the production of IL-1β in lipopolysaccharide-activated THP-1 macrophages. In addition, FIR induced the ubiquitination of ASC, which is the adaptor protein of the inflammasome, by increasing tumor necrosis factor receptor-associated factor 6 (TRAF6), which is a ubiquitin E3 ligase. Furthermore, the exposure to FIR then promoted the delivery of inflammasome to autophagosomes for degradation. In a rat burn model, FIR ameliorated burn-induced epidermal thickening, inflammatory cell infiltration, and loss of distinct collagen fibers. Moreover, FIR enhanced autophagy and suppressed the activity of theNLRP3 inflammasome in the rat skin tissue of the burn model. Based on these results, we suggest that FIR-regulated autophagy and inflammasomes will be important for the discovery of novel therapeutics to promote the healing of burn wounds.

MicroRNA-134 Contributes to Glucose-Induced Endothelial Cell Dysfunction and This Effect Can Be Reversed by Far-Infrared Irradiation. PLoS One. 2016 Jan 22;11(1):e0147067.

  • Diabetes mellitus (DM) is a metabolic disease that is increasing worldwide. Furthermore, it is associated with the deregulation of vascular-related functions, which can develop into major complications among DM patients. Endothelial colony forming cells (ECFCs) have the potential to bring about medical repairs because of their post-natal angiogenic activities; however, such activities are impaired by high glucose- (HG) and the DM-associated conditions. Far-infrared radiation (FIR) transfers energy as heat that is perceived by the thermoreceptors in human skin. Several studies have revealed that FIR improves vascular endothelial functioning and boost angiogenesis. FIR has been used as anti-inflammatory therapy and as a clinical treatment for peripheral circulation improvement. In addition to vascular repair, there is increasing evidence to show that FIR can be applied to a variety of diseases, including cardiovascular disorders, hypertension and arthritis. Yet mechanism of action of FIR and the biomarkers that indicate FIR effects remain unclear. MicroRNA-134 (miR-134-5p) was identified by small RNA sequencing as being increased in high glucose (HG) treated dfECFCs (HG-dfECFCs). Highly expressed miR-134 was also validated in dmECFCs by RT-qPCR and it is associated with impaired angiogenic activities of ECFCs. The functioning of ECFCs is improved by FIR treatment and this occurs via a reduction in the level of miR-134 and an increase in the NRIP1 transcript, a direct target of miR-134. Using a mouse ischemic hindlimb model, the recovery of impaired blood flow in the presence of HG-dfECFCs was improved by FIR pretreatment and this enhanced functionality was decreased when there was miR-134 overexpression in the FIR pretreated HG-dfECFCs. In conclusion, our results reveal that the deregulation of miR-134 is involved in angiogenic defects found in DM patients. FIR treatment improves the angiogenic activity of HG-dfECFCs and dmECFCs and FIR has potential as a treatment for DM. Detection of miR-134 expression in FIR-treated ECFCs should help us to explore further the effectiveness of FIR therapy.

The Application of Far-Infrared in the Treatment of Wound Healing: A Short Evidence-Based Analysis. J Evid Based Complementary Altern Med. 2015 Dec 23.

  • Far-infrared (FIR) radiation therapy has been used for soothing effect in wound treatment. Studies have shown that FIR could enhance wound healing processes in rat models. Although these research results supported that FIR may play an important for wound healing, it had no consensus in clinical practices. It is suggested that more persuasive systemic clinical researches are needed to explore the effectiveness of FIR therapy for wound healing.

Gender-Related Effect in Oxygenation Dynamics by Using Far-Infrared Intervention with Near-Infrared Spectroscopy Measurement: A Gender Differences Controlled Trial. PLoS One. 2015 Nov 10;10(11):e0135166.

  • Many studies have indicated the microcirculation can directly respond to disease-related symptoms. However, the capacity of microcirculation would vary due to the gender differences. Near-infrared spectroscopy (NIRS) is a noninvasive technique to monitor tissue oxygenation dynamics. In this study, the far-infrared (FIR) source was used for physiological intervention of microcirculation. The experimental results show that the nature difference of oxygenation status exists between male and female during FIR irradiation. Therefore, we suggest the NIRS-based assessment should be calibrated with the gender-related effect for clinical diagnosis of peripheral arterial disease.

Stimulatory Influences of Far Infrared Therapy on the Transcriptome and Genetic Networks of Endothelial Progenitor Cells Receiving High Glucose Treatment. Acta Cardiol Sin. 2015 Sep;31(5):414-28.


    • Endothelial progenitor cells (EPCs) play a fundamental role in vascular repair and angiogenesis- related diseases. It is well-known that the process of angiogenesis is faulty in patients with diabetes. Long-term exposure of peripheral blood EPCs to high glucose (HG-EPCs) has been shown to impair cell proliferation and other functional competencies. Far infrared (FIR) therapy can promote ischemia-induced angiogenesis in diabetic mice and restore high glucose-suppressed endothelial progenitor cell functions both in vitro and in vivo. However, the detail mechanisms and global transcriptome alternations are still unclear.


    • METHODS:
    • In this study, we investigated the influences of FIR upon HG-EPC gene expressions. EPCs were obtained from the peripheral blood and treated with high glucose. These cells were then subjected to FIR irradiation and functional assays.


    • RESULTS:
    • Those genes responsible for fibroblast growth factors, Mitogen-activated protein kinases (MAPK), Janus kinase/signal transducer and activator of transcription and prostaglandin signaling pathways were significantly induced in HG-EPCs after FIR treatment. On the other hand, mouse double minute 2 homolog, genes involved in glycogen metabolic process, and genes involved in cardiac fibrosis were down-regulated. We also observed complex genetic networks functioning in FIR-treated HG-EPCs, in which several genes, such as GATA binding protein 3, hairy and enhancer of split-1, Sprouty Homolog 2, MAPK and Sirtuin 1, acted as hubs to maintain the stability and connectivity of the whole genetic network.


  • Deciphering FIR-affected genes will not only provide us with new knowledge regarding angiogenesis, but also help to develop new biomarkers for evaluating the effects of FIR therapy. Our findings may also be adapted to develop new methods to increase EPC activities for treating diabetes-related ischemia and metabolic syndrome-associated cardiovascular disorders.

Postconditioning with far-infrared irradiation increases hemeoxygenase-1 expression and protects against ischemia/reperfusion injury in rat testis. Life Sci. 2013 Jan 17;92(1):35-41.

    • AIMS:

    • Studies have shown that heme oxygenase-1 (HO-1) has a protective role in the mechanism underlying hypoxic preconditioning. We used a far-infrared radiation (FIR) heater to investigate the postconditioning protective role of HO-1against ischemia/reperfusion (I/R) injury in rat testis.


    • Forty rats were used. Testis ischemia was mimicked by total obstructive clamping of testis vessels for 1,2, or 4 h, and concomitant postconditioning with 30 min FIR or heat light during initially 30 min reperfusion. HO-1 expression and apoptosis of testis tissues were examined by immunohistochemistry and in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, respectively. HO-1 protein level and caspase-3 activity were analyzed by Western blotting.


    • There was less apoptotic activity in rat testis after FIR, as determined by TUNEL assay. Higher HO-1 protein expression was observed by immunohistochemistry and Western blotting (p<0.01) in testis cells after FIRpostconditioning. In contrast, caspase-3 activity was significantly higher in heat light groups, as compared with FIR groups (p<0.01).


  • FIR postconditioning attenuated I/R injury in rat testis by inducing HO-1 expression, which might have a protective role in testis apoptosis after I/R injury.

Far-infrared radiation promotes angiogenesis in human microvascular endothelial cells via extracellular signal-regulated kinase activation. Photochem Photobiol. 2011 Mar-Apr;87(2):441-6.

  • This study was designed to determine the in vitro angiogenic ability of far-infrared (FIR) radiation in the skin-derived cultured human microvascular endothelial cells and to elucidate the role of mitogen-activated protein kinases (MAPKs) in this process. The results revealed that FIR radiation from a WS(TM) TY301 FIR emitter activated p38 and extracellular signal-regulated kinase (ERK), but not Akt or c-Jun N-terminal protein kinases (JNK), and significantly promoted angiogenesis by increasingtube formation in Matrigel and the migration of cells across an eight micron polyester filter. The addition of 50 μM PD98059, a MEK inhibitor, significantly inhibited the activation of ERK and the enhanced angiogenesis; in contrast, the inhibition of p38 phosphorylation did not inhibit the enhanced angiogenesis. After FIR radiation, there was no increase in vascular endothelial growth factor (VEGF) isoforms (VEGF-A, -B, -C and -D) mRNA and VEGF protein, no increase phosphorylation of endothelial nitric oxide synthase (eNOS) detected using Western blotting, and no increase in NO production detected using flow cytometry in cells pre-incubated with the cell-permeable NO-binding dye diluted 4-amino-5-methylamino-2′, 7′-difluorofluorescein diacetate (DAF-FM DA). This study revealed that FIR radiation possesses in vitro angiogenic activity via the activation of the MEK/ERK but not the VEGF/Akt/eNOS-dependent signaling pathways.

Biological effect of far-infrared therapy on increasing skin microcirculation in rats. Photodermatol Photoimmunol Photomed. 2006 Apr;22(2):78-86.

    • Insufficient microcirculation of skin leads to acute and chronic tissue ischemia in cases of trauma, reconstructive surgery, diabetes mellitus and peripheral arterial occlusive disease. The autonomic nervous system and nitric oxide (NO) play important roles in maintaining blood perfusion of the skin. Far-infrared (FIR) therapy provides low energy of light emitted from an artificial radiator and has been used to treat many vascular-related disorders. Nevertheless, the mechanisms through which FIR works remain unclear. The present study aims to test the hypothesis that the effect of FIR is through increasing skin microcirculation by a mechanism other than its thermal effect.


    • METHODS:
    • Sixty rats were used in the present study. A WS TY301 FIR emitter was placed 20 cm above the rats. Skintemperature and blood flow were continuously measured by a K-type thermocouple. Under laboratory control, the abdominal skin temperature steadily increased from 38-39 degrees C, and was kept at constant temperature. Skin microcirculation was measured with a continuous laser Doppler flowmeter.


    • RESULTS:
    • There was no significant change of skin blood flow during FIR treatment. Skin blood flow increased significantly soon after the removal of the FIR emitter. The stimulating effect on skin blood flow was more significant in the rats treated with FIR for 45 min and could be sustained as long as 60 min. These findings suggested a non-thermic biological effect of FIR on skin microcirculation. The promotive effect of FIR on increasing skin blood flow was not influenced by pretreatment of APP (atropine, propranolol and phentolamine), but was suppressed by pretreatment with NG-nitro-L-arginine methyl ester (an endothelial nitric oxide synthase inhibitor).


  • In conclusion, FIR therapy exerts a NO-related biological effect to increase skin microcirculation in rats. This might bring into perspective the clinical application of FIR to treat ischemic disease by augmenting L-arginine/NO pathway.

Promotive effects of far-infrared ray on full-thickness skin wound healing in rats. Exp Biol Med (Maywood). 2003 Jun;228(6):724-9.

  • The biological effects of far-infrared ray (FIR) on whole organisms remain poorly understood. The aim of our study was to investigate not only the hyperthermic effect of the FIR irradiation, but also the biological effects of FIR on wound healing. To evaluate the effect of FIR on a skin wound site, the speed of full-thickness skin wound healing was compared among groups with and without FIR using a rat model. We measured the skin wound area, skin blood flow, and skin temperature before and during FIR irradiation, and we performed histological inspection. Wound healing was significantly more rapid with than without FIR. Skin blood flow and skin temperature did not change significantly before or during FIR irradiation. Histological findings revealed greater collagen regeneration and infiltration of fibroblasts that expressed transforming growth factor-beta1 (TGF-beta1) in wounds in the FIR group than in the group without FIR. Stimulation of the secretion of TGF-beta1 or the activation of fibroblasts may be considered as a possible mechanisms for the promotive effect of FIR on wound healing independent of skin blood flow and skin temperature.