Adiponectin is an antidiabetic endogenous adipokine that have protective role in unfavorable metabolic sequalae arising from obesity. Recent evidence suggests a sinister link between hypoadiponectinemia and development of insulin resistance/ type 2 diabetes (T2D). The insulin sensitizing property of adiponectin is through specific adipoq receptors R1 & R2, activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)α pathways. AdipoAI is a novel synthetic analogue of endogenous adiponectin with possibly similar pharmacological effects. Thus, there is a need of orally active small molecules that activate Adipoq subunits, and its downstream signaling could ameliorate obesity related type 2 diabetes. This study was aimed to access the effects of AdipoAI on obesity and T2D. Through in-vitro and in-vivo analyses, we investigated the anti-diabetic potentials of AdipoAI and compared it with AdipoRON, another orally active adiponectin receptors agonist. Our results showed that In-vitro treatment of AdipoAI (0-5µM) increased adiponectin receptor subunits AdipoR1/R2 with increase in AMPK and APPL1 protein expression in C2C12 myotubes. Similarly, in-vivo, oral administration of AdipoAI (25 mg/kg) observed similar effects as that of AdipoRON (50 mg/kg) with improved control of blood glucose and insulin sensitivity in diet-induced obesity (DIO) mice models. Further, AdipoAI significantly reduced epididymal fat content with decrease in inflammatory markers and increase in PPAR-a and AMPK levels and exhibited hepatoprotective effects in liver. Further, AdipoAI and AdipoRON also observed similar results in adipose tissue. Thus, our results suggest that low doses of orally active small molecule agonist of adiponectin AdipoAI can be a promising therapeutic target for obesity and T2D.
PD-1 and CTLA-4 can play an important role in addressing the issue of autoimmune diseases. PD-1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD-1 with its ligands stimulates the production of IL-2, IL-7, IL-10, and IL-12 as well as other cytokines, which can inhibit cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD-1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD-1. In addition, we discuss the importance of PD-1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases.
AIM Cachexia is characterized by losses in lean body mass and its progression results in worsened quality of life and exacerbated outcomes in cancer patients. However, the role and impact of fibrosis during the early stages and development of cachexia in under-investigated. The purpose of this study was to determine if fibrosis occurs during cachexia development, and to evaluate this in both sexes. Methods Female and male C57BL6/J mice were injected with PBS or Lewis Lung Carcinoma (LLC) at 8‐week of age and tumors were allowed to develop for 1, 2, 3, or 4 weeks. 3wk and 4wk female tumor‐bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. In vitro analyses were also performed on co-cultured C2C12 and 3T3 exposed to LLC conditioned media. Immunohistochemistry and quantitative PCR analysis were used to investigate fibrosis and fibrosis related signaling in skeletal muscle. Results Collagen deposition in skeletal muscle was increased in the 1wk, LT and HT groups in female mice. However, collagen deposition was only increased in the 4wk group in male mice. In general female mice displayed earlier alterations in ECM related genes beginning at 1 wk post-LLC injection. Whereas this was not seen in males. Conclusions While overall tumor burden is tightly correlated to cachexia development in both sexes, fibrotic development is not. Male mice did not exhibit early-stage alterations in ECM related genes contrary to what was noted in female mice.