A novel and safe small molecule enhances hair follicle regeneration by facilitating metabolic reprogramming.

Targeting hair follicle regeneration has been investigated for the treatment of hair loss, and fundamental studies investigating stem cells and their niche have been described. However, knowledge of stem cell metabolism and the specific regulation of bioenergetics during the hair regeneration process is currently insufficient. Here, we report the hair regrowth-promoting effect of a newly synthesized novel small molecule, IM176OUT05 (IM), which activates stem cell metabolism. IM facilitated stemness induction and maintenance during an induced pluripotent stem cell generation process. IM treatment mildly inhibited mitochondrial oxidative phosphorylation and concurrently increased glycolysis, which accelerated stemness induction during the early phase of reprogramming. More importantly, the topical application of IM accelerated hair follicle regeneration by stimulating the progression of the hair follicle cycle to the anagen phase and increased the hair follicle number in mice. Furthermore, the stem cell population with a glycolytic metabotype appeared slightly earlier in the IM-treated mice. Stem cell and niche signaling involved in the hair regeneration process was also activated by the IM treatment during the early phase of hair follicle regeneration. Overall, these results show that the novel small molecule IM promotes tissue regeneration, specifically in hair regrowth, by restructuring the metabolic configuration of stem cells.

The Improving Effect of HL271, a Chemical Derivative of Metformin, a Popular Drug for Type II Diabetes Mellitus, on Aging-induced Cognitive Decline.

In recent years, as the aging population grows, aging-induced cognitive impairments including dementia and Alzheimer's disease (AD) have become the biggest challenges for global public health and social care. Therefore, the development of potential therapeutic drugs for aging-associated cognitive impairment is essential. Metabolic dysregulation has been considered to be a key factor that affects aging and dementia. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a primary sensor of cellular energy states and regulates cellular energy metabolism. Metformin (1,1-dimethylbiguanide hydrochloride) is a well-known AMPK activator and has been widely prescribed for type 2 diabetes mellitus (T2DM). Since the incidence of T2DM and dementia increases with aging, metformin has been considered to be one of the most promising drugs to target dementia and its related disorders. To that end, here, we tested the efficacy of metformin and HL271, a novel metformin derivative, in aging-induced cognitive decline. Water (control), metformin (100 mg/kg) or HL271 (50 mg/kg) were orally administered to aged mice for two months; then, the mice were subjected to behavioral tests to measure their cognitive function, particularly their contextual, spatial and working memory. AMPK phosphorylation was also measured in the drug-treated mouse brains. Our results show that oral treatment with HL271 (50 mg/kg) but not metformin (100 mg/kg) improved cognitive decline in aged mice. AMPK activation was correlated with behavior recovery after aging-induced cognitive decline. Taken together, these results suggest that the newly synthesized AMPK activator, HL271, could be a potential therapeutic agent to treat age-related cognitive decline.

AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages.

Cirrhosis, the end-stage of hepatic fibrosis, is not only life-threatening by itself, but also a causative factor of liver cancer. Despite efforts to develop treatment for liver fibrosis, there are no approved agents as anti-fibrotic drugs to date. In the present study, we aimed to investigate the anti-fibrotic effect of the AMP-activated protein kinase (AMPK) activator, HL156A. A mouse model of thioacetamide (TAA)-induced liver fibrosis was used to examine the effect of HL156A in vivo. Mice received either TAA alone or a combination of TAA and HL156A intraperitoneally for a total duration of 6 weeks. Including HL156A during exposure to TAA significantly reduced extracellular matrix (ECM) deposition and production of the hepatic transforming growth factor-ß1 (TGF-ß1). Immunohistochemical analysis revealed that the activation of hepatic stellate cells and the capillarization of liver sinusoids were also diminished significantly by HL156A co-treatment. The anti-fibrotic effect of HL156A was further studied in vitro by using a rat hepatic stellate cell line, HSC-T6 cells. The induction of α-smooth muscle actin (α-SMA) by TGF-ß1 treatment was reversed by HL156A, which was likely via the activation of AMPK. Moreover, HL156A showed anti-inflammatory effects on macrophages. Treatment with HL156A diminished LPS-induced activation of both Raw264.7 macrophage cells and primary cultured mouse macrophages. Taken together, these results imply that the AMPK activator HL156A inhibits hepatic fibrosis via multiple mechanisms and could be a potentially effective agent for fibrosis treatment.

HL271, a novel chemical compound derived from metformin, differs from metformin in its effects on the circadian clock and metabolism.

Metformin is a treatment of choice for patients with type 2 diabetes. Its action involves the phosphorylation of 5'-adenosine monophosphate activated protein kinase (AMPK), leading to inhibition of liver gluconeogenesis. The effects of a novel chemical compound derived from metformin, HL271, on molecular and physiological actions involving AMPK and rhythmically-expressed circadian clock genes were investigated. HL271 potently activated AMPK in a dose-dependent manner, and produced shortening of the circadian period and enhanced degradation of the clock genes PER2 and CRY1. Although the molecular effects of HL271 resembled those of metformin, it produced different physiological effects in mice with diet-induced obesity. HL271 did not elicit glucose-lowering or insulin-sensitizing effects, possibly because of altered regulation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1. This indicated that, although HL271 acted on circadian clock machinery through a similar molecular mechanism to metformin, it differed in its systemic effect on glucose and lipid metabolite regulations.

The effect of metformin on alveolar bone in ligature-induced periodontitis in rats: a pilot study.

BACKGROUND: The use of metformin, an antidiabetic agent, is associated with a reduced risk of fractures in patients with diabetes, suggesting that metformin exerts a beneficial effect on bone tissues. The objective of this study was to assess the effect of metformin on alveolar bone loss in ligature-induced periodontitis and osteoblast, osteoclast, and adipocyte differentiation. METHODS: Periodontitis was induced by a ligature around the mandibular first molar of each rat. The rats were divided into two groups: 1) rats with ligature receiving a vehicle (n = 5), and 2) rats with ligature receiving metformin (n = 5). On day 10, after the induction of periodontitis, the alveolar bone volume between the first and second molar was determined via microcomputed tomography. The effect of metformin on osteoblast, osteoclast, and adipocyte differentiation was assessed using MC3T3-E1, cocultures of mouse bone marrow cells and calvaria-derived osteoblasts, and 3T3-L1/C3H10T1/2 cells, respectively. Osteoblast, osteoclast, and adipocyte differentiation was estimated by the degree of mineralization, the formation of tartrate-resistant acid phosphatase-positive multinucleated cells, and the accumulation of triglycerides, respectively. RESULTS: In ligature-induced periodontitis, the metformin treatment of rats induced a significant reduction in alveolar bone loss compared to vehicle-treated rats. With regard to osteoblast differentiation, metformin augmented the mineralization of MC3T3-E1 cells approximately two-fold over the non-treated cells. However, metformin was shown to exert no effects on osteoclast formation induced by 1,25-dihydroxyvitamin D(3), lipopolysaccharide, and prostaglandin E(2). Moreover, metformin exerted no effect on adipocyte differentiation. CONCLUSION: Our findings suggest that metformin may exert a beneficial effect on alveolar bone in periodontitis by increasing osteoblast differentiation.