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.

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.

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.

Cancer has become a global public health problem and its harmful effects have received widespread attention. Conventional treatments such as surgical resection, radiotherapy and other techniques are applicable to clinical practice, but new drugs are constantly being developed and other therapeutic approaches such as immunotherapy are being applied. In addition to studying the effects on individual tumor cells, it is important to explore the role of tumor microenvironment (TME) on tumor cell development since tumor cells do not exist alone but in the tumor microenvironment. In the TME, tumor cells are interconnected with other stromal cells and influence each other, among which tumor-associated macrophages (TAMs) are the most numerous immune cells. At the same time, it was found that cancer cells have different levels of autophagy from normal cells. In cancer therapy, the occurrence of autophagy plays an important role in promoting tumor cell death or inhibiting tumor cell death, and is closely related to the environment. Therefore, elucidating the regulatory role of autophagy between TAMs and tumor cells is an important breakthrough, providing new perspectives for further research on anti-tumor immune mechanisms and understanding the efficacy of cancer immunotherapy.

Colorectal cancer (CRC) is a common and highly metastatic cancer affecting people worldwide. Drug resistance and unwanted side effects are some of the limitations of current treatments for CRC. Naringenin (NAR) is a naturally occurring compound found in abundance in various citrus fruits such as oranges, grapefruits, and tomatoes. It possesses a diverse range of pharmacological and biological properties that are beneficial for human health. Numerous studies have highlighted its antioxidant, anti-cancer, and anti-inflammatory activities, making it a subject of interest in scientific research. This review provides a comprehensive overview of the effects of NAR on CRC. The study’s findings indicated that NAR: 1) interacts with estrogen receptors, 2) regulates the expression of genes related to the p53 signaling pathway, 3) promotes apoptosis by increasing the expression of proapoptotic genes (Bax, caspase9, and p53) and downregulation of the antiapoptotic gene Bcl2, 4) inhibits the activity of enzymes involved in cell survival and proliferation, 5) decreases cyclin D1 levels, 6) reduces the expression of cyclin-dependent kinases (Cdk4, Cdk6, Cdk7) and anti-apoptotic genes (Bcl2, x-IAP, c-IAP-2) in CRC cells. In vitro CDK2 binding assay was also performed, showing that the NAR derivatives had better inhibitory activities on CDK2 than NAR. Based on the findings of this study, NAR is a potential therapeutic agent for CRC. Additional pharmacology and pharmacokinetics studies are required to fully elucidate the mechanisms of action of NAR and establish the most suitable dose for subsequent clinical investigations.

Abstract. Ferroptosis is a novel non-apoptotic form of cell death characterized by iron-dependent reactive oxygen species (ROS)-mediated lipid peroxidation. In several different cell systems, the tumor suppressor p53 can enhance sensitivity to ferroptotic inducers. At least half of all human cancers show loss of function of p53. Furthermore, many of those tumors express mutant forms of p53 that has lost its wild-type function. Several groups have designed small molecules that can reactivate the wild-type function of these missense p53 mutants. We reasoned that p53 reactivators may also enhances sensitivity of certain cancer cells to ferroptosis stimuli. To test this idea we combined a number of different p53 reactivators with small molecule inducers of ferroptosis. In contrast, we observed that several p53 reactivators protected cells from cell death induced by ferroptotic inducers. Suprisingly, this protection still occurred in p53-null cell lines. We observed that these reactivators were neither free radical scavengers nor ion chelators. One of these p53 reactivator molecules, NSC 59984, reduced expression of GPX4, which is unlikely to explain the ability to reduced sensitivity to ferroptosis. We suggested that these p53 reactivators function via an unknown, p53-independent manner to suppress ferroptosis.

Fluoride (F) has been employed worldwide to control dental caries. More recently, it has been suggested that the consumption of low doses of F in the drinking water may reduce blood glucose levels, introducing a new perspective for the use of F for the management of blood glucose. However, the exact mechanism by which F affects blood glucose levels remains largely unexplored. Given that the small gut plays a pivotal role in glucose homeostasis, the aim of this present study was to investigate the proteomic changes induced by low doses of F in the ileum of female non-obese-diabetic (NOD) mice. Forty-two female NOD mice were divided into two groups based on the F concentration in their for 14 weeks: 0 (control) or 10 mg/L. At the end of the experimental period, the ileum was collected for proteomic and Western Blotting analyses. Proteomic analysis indicated an increase in isoforms of actin, gastrotropin (confirmed by Western Blotting), several H2B histones and enzymes involved in antioxidant processes, as well as a decrease in enzymes essential for energy metabolism. In summary, our data indicates an adaptive response of the organism to preserve protein synthesis in the ileum, despite significant alterations in energy metabolism typically induced by F, therefore highlighting the safety of controlled fluoridation in water supplies.

The study focused on the impact and action mechanism of different organic selenium products on the bioactivity of two strains of Lactobacillus paracasei. The growth, antioxidant activity, extracellular polysaccharide secretion, quorum sensing and biofilm formation of the strains before and after the addition of organic selenium crude products and three organic selenium standard were evaluated. The results showed that the addition of crude organic selenium had a promoting effect on the growth, antioxidant activity, extracellular polysaccharide, biofilm formation, and AI-2 activity of the strain. The organic selenium standards had a regulatory effect (positive and negative) on biofilm formation and the activity of the QS signal molecule AI-2 in the strain. L-selenocysteine had the strongest regulatory effect, with maximum GIM1.80 biofilm formation when it reached a critical concentration of 0.4 μg/ml; L-selenomethionine resulted in the highest activity of the signal molecule AI-2 of GDMCC1.155, when it reached a critical concentration of 0.4 μg/ml. The results of scanning electron microscopy demonstrated that organic selenium effectively improved the morphology and structure of the bacterial cells of the two strains. Molecular docking revealed that the mechanism by which organic selenium regulates quorum sensing in Lactobacillus was achieved by binding two crucial receptor proteins (histidine protein kinase HKP and periplasmic binding protein LuxP) from specific sites. It provides a new alternative (organic selenium) for regulating the viability and beneficial activity of Lactobacillus paracasei. Significance statement: The study found that organic selenium can both positively and negatively regulate quorum sensing and biofilm formation of Lactobacillus, and the critical concentrations have also been obtained. Meanwhile, it was found that organic selenium can promote the growth, antioxidant activity, and biofilm formation of Lactobacillus by activating quorum sensing, so as to better exert its probiotic properties. Furthermore, the regulating mechanism of organic selenium on the activity of Lactobacillus was revealed. This study provides a new alternative for regulating and stimulating the beneficial activity of probiotics.

Tubulointerstitial fibrosis is an inevitable consequence of all progressive chronic kidney disease (CKD) and contributes to a substantial health burden worldwide. Icariin, an active flavonoid glycoside obtained from Epimedium species, exerts potential antifibrotic effect. The study aimed to explore the protective effects of icariin against tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO)-induced CKD mice and TGF-β1-treated HK-2 cells, and furthermore, to elucidate the underlying mechanisms. The results demonstrated that icariin significantly improved renal function, alleviated tubular injuries, and reduced fibrotic lesions in UUO mice. Furthermore, icariin suppressed renal inflammation, reduced oxidative stress as evidenced by elevated SOD activity and decreased MDA level. Additionally, TOMM20 immunofluorescence staining and transmission electron microscope revealed that mitochondrial mass and morphology of tubular epithelial cells in UUO mice was improved by icariin. In HK-2 cells treated with TGF-β1, icariin markedly decreased profibrotic proteins expression, inhibited inflammatory factors, and protected mitochondria along with improving mitochondrial morphology, reducing reactive oxygen species (ROS) and mitochondrial ROS (mtROS) overproduction, and preserving membrane potential. Further investigations demonstrated that icariin could activate Nrf2/HO-1 pathway both in vivo and in vitro, whereas inhibition of Nrf2 by ML385 counteracted the protective effects of icariin on TGF-β1-induced HK-2 cells. In conclusion, icariin protects against renal inflammation and tubulointerstitial fibrosis at least partly through Nrf2-mediated attenuation of mitochondrial dysfunction, which suggests that icariin could be developed as a promising therapeutic candidate for the treatment of CKD.

Bovine colostrum is a rich source of bioactive compounds, including growth factors, that may promote tissue regeneration. Studies suggest it has potential therapeutic benefits in humans, but further research is needed to fully understand its mechanisms of action. This study aims to review scientific articles on the use of bovine colostrum as a bioactive agent for tissue regeneration in humans and twelve articles were selected. In vitro studies show that bovine colostrum can benefit cells by reducing cell proliferation and inducing differentiation. The concentration of colostrum used has a direct impact on the results, with no positive results observed at some high concentrations (20%). Extracted portions of colostrum (EVs and IMF) showed better results than the complete colostrum. In vivo studies show that bovine colostrum is a promising natural source for wound healing, as its bioactive factors help in the orderly progression of the healing process. However, some studies did not find any benefit related to tissue regeneration, and more research is needed to explore the full potential of colostrum in regenerative medicine and to develop more effective therapies for wound healing.