Forkhead Box i2 Transcription Factor Regulates Systemic Energy Metabolism Via Neuropeptide AgRP.

The neuropeptide AgRP is essential for maintaining systemic energy homeostasis. In the current study, we show that hypothalamic Foxi2, as a novel regulator of nutrient sensing, controls systemic energy metabolism by specifically stimulating AgRP expression. Foxi2 was highly expressed in the hypothalamus, and its expression was induced by fasting. Immunofluorescence assays demonstrated that Foxi2 was localized in AgRP neurons. We stereotactically injected adeno-associated virus to selectively overexpress Foxi2 in AgRP-IRES-Cre mice and found that Foxi2 overexpression in AgRP neurons specifically increased AgRP expression, thereby increasing food intake and reducing energy expenditure, subsequently leading to obesity and insulin resistance. Mechanistically, Foxi2 stimulated AgRP expression by directly binding to it and activating its transcription. Furthermore, Foxi2 overexpression activated AgRP neuron activity, as revealed by whole-cell patch-clamp experiments. Conversely, global Foxi2-mutant mice became leaner with age and were resistant to high-fat diet-induced obesity and metabolic disturbances. Collectively, our data suggest that Foxi2 plays an important role in controlling energy metabolism by regulating AgRP expression.

Signature Based on Six Autophagy-related Genes to Predict Prognosis of Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: The present study aimed to develop an autophagy-related gene prognostic prediction model to provide survival risk prediction for head and neck squamous cell carcinoma (HNSCC) patients. METHODS: The K-mean cluster analysis was performed on HNSCC samples based on the expression values of 210 autophagy-related genes for candidate signature gene selection. LASSO Cox regression analysis was generated using the potential genes and the risk score was calculated from the prognosis model. The risk score was processed as an independent prognostic indicator to construct the nomogram model. The immune status including immune cell infiltration ratio and checkpoints of patients with HNSCC in high- and low-risk groups was also explored. RESULTS: LASSO Cox regression analysis was performed on the selected autophagy-related genes. According to the lambda value corresponding to the number of different genes in the LASSO Cox analysis, six genes (GABARAPL2, SAR1A, ST13, GAPDH, FADD and LAMP1) were finally chosen. The risk score based on the genes was generated, which was an independent prognostic marker for HNSCC. The prognostic prediction model (nomogram) was further optimized by the independent prognostic factors (risk score), which can better predict the prognosis and survival of patients. With the risk score and prognosis model, eight types of immune cells and six key immune checkpoints (CTLA4, PD1, IDO1, TDO2, LAG3, TIGIT) displayed expression specificity. CONCLUSION: This study identified several potential prognostic biomarkers and established an autophagy-related prognostic prediction model for HNSCC, which provides a valuable reference for future clinical research.

Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression.

Bile acid (BA) homeostasis is regulated by the extensive cross-talk between liver and intestine. Many bile-acid-activated signaling pathways have become attractive therapeutic targets for the treatment of metabolic disorders. In this study we investigated the regulatory mechanisms of BA in the intestine. We showed that the BA levels in the gallbladder and faeces were significantly increased, whereas serum BA levels decreased in systemic Krüppel-like factor 9 (Klf9) deficiency (Klf9-/-) mice. These phenotypes were also observed in the intestine-specific Klf9-deleted (Klf9vil-/-) mice. In contrast, BA levels in the gallbladder and faeces were reduced, whereas BA levels in the serum were increased in intestinal Klf9 transgenic (Klf9Rosa26+/+) mice. By using a combination of biochemical, molecular and functional assays, we revealed that Klf9 promoted the expression of apical sodium-dependent bile acid transporter (Asbt) in the terminal ileum to enhance BA absorption in the intestine. Reabsorbed BA affected liver BA synthetic enzymes by regulating Fgf15 expression. This study has identified a previously neglected transcriptional pathway that regulates BA homeostasis.

Progress in drug delivery system for fibrosis therapy.

Fibrosis is a necessary process in the progression of chronic disease to cirrhosis or even cancer, which is a serious disease threatening human health. Recent studies have shown that the early treatment of fibrosis is turning point and particularly important. Therefore, how to reverse fibrosis has become the focus and research hotspot in recent years. So far, the considerable progress has been made in the development of effective anti-fibrosis drugs and targeted drug delivery. Moreover, the existing research results will lay the foundation for more breakthrough delivery systems to achieve better anti-fibrosis effects. Herein, this review summaries anti-fibrosis delivery systems focused on three major organ fibrotic diseases such as liver, pulmonary, and renal fibrosis accompanied by the elaboration of relevant pathological mechanisms, which will provide inspiration and guidance for the design of fibrosis drugs and therapeutic systems in the future.

pH-sensitive and specific ligand-conjugated chitosan nanogels for efficient drug delivery.

Nanogels have been recently attracted attentions because they exhibit significantly different behaviors compared with nanoparticles. Among them, chitosan (CS) nanogels have gained considerable attentions from researchers for in vivo applications due to bioactivity, biodegradability, mucoadhesiveness, and biocompatibility of CS. In this review, we have summarized the applications of CS nanogels for efficient drug delivery. Specifically, CS nanogels can be modified by pH-sensitive groups or specific ligands to obtain the corresponding functions. These functional CS nanogels have been used to deliver therapeutic agents, such as anti-cancer drugs, genes, and vaccines. By reviewing the recent research progress on CS nanogels in pharmaceutical applications, it will provide biomaterial researchers potential help for the development of CS nanogel delivery system to meet clinical needs.

Inhibition of breast cancer proliferation and metastasis by strengthening host immunity with a prolonged oxygen-generating phototherapy hydrogel.

Hypoxia is a potent tumor microenvironmental (TME) factor promoting immunosuppression and metastatic progression. For current anticancer therapeutic strategies, the combination of hypoxia alleviation and photodynamic therapy (PDT) might be a useful approach to further improve anticancer efficacy. In this study, we alleviated tumor hypoxia using a prolonged oxygen-generating phototherapy hydrogel (POP-Gel), which effectively elevated the oxygen level and shrank the hypoxic regions of tumors for up to 5 days evaluated by photoacoustic (PA) imaging and immunofluorescence staining, meeting the requirement of the "once injection, sustained treatment" strategy and significantly increasing PDT efficacy. The long-period improvement of the tumor hostile environment downregulated the expression of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF), further preventing tumor growth and metastasis. More importantly, the enhanced PDT triggered a more intense immune response, improving the inhibition of triple negative breast cancer growth even tumor elimination. The POP-Gel may contribute useful insights into the combination of hypoxia alleviation and PDT.

Light triggered oxygen-affording engines for repeated hypoxia-resistant photodynamic therapy.

Hypoxia is the trickiest barrier for oncotherapy, which can cause the resistance of various tumor treatments, even promote cancer progression and metastasis, especially in the treatment of photodynamic therapy (PDT). Therefore, alleviating tumor hypoxia would be a favorable modality to improve PDT treatment. In this study, we designed an innovative biological oxygen-evolving material, autotrophic light-triggered green affording­oxygen engine (ALGAE), which could perform an on-off switchable and inexhaustible oxygen generation triggered by the same irradiation of PDT with good biocompatibility and degradability. And the hypoxia-resistant PDT induced by ALGAE could successfully eradicate tumors and avoid tumor metastasis. The ALGAE system could be standby in a long period for efficient oxygen-affording around tumors, which not only dramatically alleviated tumor hypoxia but also achieved a high-efficiency and repetitive PDT treatments. Furthermore, the innovative biological oxygen-affording engine described in the study presents a new class of oxygen-generating material for hypoxia-resistant cancer therapy.

Chemical Modification of Chitosan for Efficient Vaccine Delivery.

Chitosan, which exhibits good biocompatibility, safety, microbial degradation and other excellent performances, has found application in all walks of life. In the field of medicine, usage of chitosan for the delivery of vaccine is favored by a wide range of researchers. However, due to its own natural limitations, its application has been constrained to the beginning of study. In order to improve the applicability for vaccine delivery, researchers have carried out various chemical modifications of chitosan. This review summarizes a variety of modification methods and applications of chitosan and its derivatives in the field of vaccine delivery.

Anti-CD24 neutralizing antibody exacerbates Concanavalin A-induced acute liver injury in mice via liver M1 macrophages.

Liver largely relies on its innate immunity to initiate quick and effective defense against potentially toxic agents, and innate immune cells are major players in this process. However, excessive inflammation due to out-of-control immune response may eventually cause liver injury. Thus, it is important to fully understand the regulatory mechanisms associated with liver inflammation. Here we showed that anti-CD24 neutralizing antibody exacerbated hepatic inflammation in a Con A-induced acute liver injury murine model. Our results supported that hepatic macrophages were required for anti-CD24 neutralizing antibody-aggravated liver inflammation, as depletion of macrophages significantly alleviated Con A-induced inflammation. M1 macrophages, but not M2 macrophages, were specifically induced by Con A, and more greatly by Con A in combination with anti-CD24 neutralizing antibody. The combined treatment further promoted M1 hepatic macrophages to express TNF-α, which increased hepatocytes apoptosis. Taken together, these data suggest that anti-CD24 neutralizing antibody plays an important role in aggravating inflammation in the process of Con A-induced acute liver injury in mice. The possible mechanism might involve the enhanced secretion of TNF-α by hepatic M1 macrophages. This study also implicates a role for CD24 in negative regulation of Con A-induced liver inflammation.