Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.

Repurposing AS1411 for constructing ANM-PROTACs.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for "undruggable" oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.

Targeted Delivery of Chemotherapeutic Agents for Osteosarcoma Treatment.

Since osteosarcoma (OS) is an aggressive bone cancer with unknown molecular pathways of etiology and pathophysiology, improving patient survival has long been a challenge. The conventional therapy is a complex multidisciplinary management that include radiotherapy, chemotherapy which followed by surgery and then post-operative adjuvant chemotherapy. However, they have severe side effects because the majority of the medicines used have just a minor selectivity for malignant tissue. As a result, treating tumor cells specifically without damaging healthy tissue is currently a primary goal in OS therapy. The coupling of chemotherapeutic drugs with targeting ligands is a unique therapy method for OS that, by active targeting, can overcome the aforementioned hurdles. This review focuses on advances in ligands and chemotherapeutic agents employed in targeted delivery to improve the capacity of active targeting and provide some insight into future therapeutic research for OS.

Toward Overcoming Treatment Failure in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by inflammation and bone erosion. The exact mechanism of RA is still unknown, but various immune cytokines, signaling pathways and effector cells are involved. Disease-modifying antirheumatic drugs (DMARDs) are commonly used in RA treatment and classified into different categories. Nevertheless, RA treatment is based on a "trial-and-error" approach, and a substantial proportion of patients show failed therapy for each DMARD. Over the past decades, great efforts have been made to overcome treatment failure, including identification of biomarkers, exploration of the reasons for loss of efficacy, development of sequential or combinational DMARDs strategies and approval of new DMARDs. Here, we summarize these efforts, which would provide valuable insights for accurate RA clinical medication. While gratifying, researchers realize that these efforts are still far from enough to recommend specific DMARDs for individual patients. Precision medicine is an emerging medical model that proposes a highly individualized and tailored approach for disease management. In this review, we also discuss the potential of precision medicine for overcoming RA treatment failure, with the introduction of various cutting-edge technologies and big data.

Triterpenoids Extracted From Antrodia cinnamomea Mycelia Attenuate Acute Alcohol-Induced Liver Injury in C57BL/6 Mice via Suppression Inflammatory Response.

Excessive alcohol consumption causes liver injury-induced mortality. Here we systematically analyzed the structure of triterpenoids extracted from Antrodia cinnamomea mycelia (ACT) and investigated their protective effects against acute alcohol-induced liver injury in mice. Liquid chromatography-mass spectrometry and liquid chromatography with tandem mass spectrometry were performed to determine the structures of ACT constituents. Alcohol-induced liver injury was generated in C57BL/6 mice by oral gavage of 13 g/kg white spirit (a wine at 56% ABV). Mice were treated with either silibinin or ACT for 2 weeks. Liver injury markers and pathological signaling were then quantified with enzyme-linked immunosorbent assays, antibody array assays, and Western blots, and pathological examinations were performed using hematoxylin-eosin staining and periodic acid-Schiff staining. Triterpenoids extracted from A. cinnamomea mycelia contain 25 types of triterpenoid compounds. A 2-weeks alcohol consumption treatment caused significant weight loss, liver dyslipidemia, and elevation of alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and alkaline phosphatase activities in the serum and/or liver. These effects were markedly reversed after 2-weeks ACT administration. Triterpenoids extracted from A. cinnamomea mycelia alleviated the organ structural changes and inflammatory infiltration of alcohol-damaged tissues. Triterpenoids extracted from A. cinnamomea mycelia inhibited proinflammatory cytokine levels and enhanced anti-inflammatory cytokine levels. Acute alcohol treatment promoted inflammation with significant correlations to hypoxia-inducible factor 1α (HIF-1α), which was reduced by ACT and was partially related to modulation of the protein kinase B (Akt)/70-kDa ribosomal protein S6 kinase phosphorylation (p70S6K) and Wnt/ß-catenin signaling pathways. In conclusion, ACT protected against acute alcohol-induced liver damage in mice mainly through its suppression of the inflammatory response, which may be related to HIF-1α signaling.

Aronia melanocarpa Prevents Alcohol-Induced Chronic Liver Injury via Regulation of Nrf2 Signaling in C57BL/6 Mice.

Aronia melanocarpa (AM), which is rich in anthocyanins and procyanidins, has been reported to exert antioxidative and anti-inflammatory effects. This study aimed to systematically analyze the components of AM and explore its effects on alcohol-induced chronic liver injury in mice. A component analysis of AM revealed 17 types of fatty acids, 17 types of amino acids, 8 types of minerals, and 3 types of nucleotides. Chronic alcohol-induced liver injury was established in mice via gradient alcohol feeding over a period of 6 months, with test groups orally receiving AM in the last 6 weeks. AM administration yielded potential hepatoprotective effects by alleviating weight gain and changes in organ indexes, decreasing the ratio of alanine aminotransferase/aspartate aminotransferase, reducing lipid peroxidation, enhancing antioxidant activities, decreasing oxidation-related factor levels, and regulating inflammatory cytokine levels. Histological analyses suggest that AM treatment markedly prevented organ damage in alcohol-exposed mice. Furthermore, AM activated nuclear factor erythroid 2-like 2 (Nrf2) by downregulating the expression of Kelch-like ECH-associated protein 1, resulting in elevated downstream antioxidative enzyme levels. AM activated Nrf2 via modulation of the phosphatidylinositol-3-hydroxykinase/protein kinase B signaling pathway. Altogether, AM prevented alcohol-induced liver injury, potentially by suppressing oxidative stress via the Nrf2 signaling pathway.

Hepatoprotective Effects of Morchella esculenta against Alcohol-Induced Acute Liver Injury in the C57BL/6 Mouse Related to Nrf-2 and NF-κB Signaling.

This study investigated the hepatoprotective effects of Morchella esculenta fruit body (ME) and the underlying mechanisms in mice with alcohol-induced acute liver injury. Systematic analysis revealed that ME contained 21 types of fatty acid, 17 types of amino acid, and 12 types of mineral. Subsequently, a mouse model of acute alcohol-induced liver injury was established by oral administration of alcohol for 14 days. Fourteen-day administration of ME prevented alcohol-induced increases in alanine aminotransferase and aspartate aminotransferase levels and reduced the activity of acetaldehyde dehydrogenase in blood serum and liver tissue. ME appears to regulate lipid metabolism by suppressing triglycerides, total cholesterol, and high-density lipoprotein in the liver. ME inhibited the production of inflammatory factors including chitinase-3-like protein 1 (YKL 40), interleukin-7 (IL-7), plasminogen activator inhibitor type 1 (PAI-1), and retinol-binding protein 4 (RBP4) in blood serum and/or liver tissue. ME treatment relieved the alcohol-induced imbalance in prooxidative and antioxidative signaling via nuclear factor-erythroid 2-related factor 2 (Nrf-2), as indicated by upregulation of superoxide dismutase-1, superoxide dismutase-2, catalase, heme oxygenase-1, and heme oxygenase-2 expression and downregulation of kelch-like ECH-associated protein 1 (Keap-1) in the liver. Moreover, ME reduced the levels of phosphorylated nuclear factor kappa-B kinase α/ß, inhibitor of nuclear factor kappa-B α and nuclear factor kappa-B p65 (NF-κB p65) in the liver. The hepatoprotective effects of ME against alcohol-induced acute liver injury were thus confirmed. The mechanism of action may be related to modulation of antioxidative and anti-inflammatory signaling pathways, partially via regulation of Nrf-2 and NF-κB signaling.

Sarcodon imbricatus polysaccharides protect against cyclophosphamide-induced immunosuppression via regulating Nrf2-mediated oxidative stress.

Sarcodon imbricatus, a rare medicinal and edible fungus, has various pharmacological bioactivities. The present study systematically investigated the protective effects of S. imbricatus polysaccharides (SIPS) against cyclophosphamide (CTX)-induced immunosuppression in Balb/c mice model. Compared with the CTX-induced immunosuppressive mice, the spleen and thymus indexes in the mice with 28-day SIPS orally administration were significantly increased, bodyweight loss was alleviated, and the natural killer (NK) cytotoxicity and the proliferative activities of lymphocytes were elevated. SIPS regulated the production of immunoglobulins including IgA, IgG and IgM in the serum and spleen. Notably, SIPS promoted the secretion of interleukin-2 (IL-2), IL-6, IL-10, IL-12 and interferon-γ (IFN-γ) of serum and spleen in CTX-induced immunosuppressive mice. Additionally, SIPS inhibited reactive oxygen species (ROS) levels and increased total antioxidant capacity, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities of spleen and thymus, as well as enhanced acid phosphatase (ACP) and lysozyme (LZM) levels of thymus in CTX-induced immunosuppressive mice. Histopathological analysis of spleen revealed the protective effect of SIPS against CTX-induced immunosuppression. More importantly, SIPS promoted the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) and its downstream target genes encoding antioxidant enzymes: SOD1, SOD2, haem oxygenase-1 (HO-1), CAT and quinone oxidoreductase 1 (NQO1). Altogether, SIPS reversed CTX-induced immunosuppression effectively and predominantly through Nrf2-mediated oxidative stress, which provided the useful evidence that SIPS can be served as a novel natural immunomodulator in health foods or medicine.

Ameliorative effects of Antrodia cinnamomea polysaccharides against cyclophosphamide-induced immunosuppression related to Nrf2/HO-1 signaling in BALB/c mice.

The objective of this study was to determine the ameliorative effects of Antrodia cinnamomea polysaccharide (ACPS) against cyclophosphamide (CTX)-induced immunosuppression in BALB/c mice. Four weeks of oral ACPS treatment successfully improved bodyweight and organ indexes and enhanced the function of T cells and the cytotoxicity of natural killer cells. CTX administration has been shown to notably decrease immunoglobulin A, G and M, interleukin 2, 6 and 12, and interferon α and γ levels in serum and in the spleen, and ACPS abolished these effects. Furthermore, ACPS effectively increased the total antioxidant capacity by stimulating superoxidase dismutase, catalase, and glutathione peroxidase activity in serum and in the spleen and by inhibiting the increases in reactive oxygen species and malondialdehyde levels. Notably, ACPS induced the activation of erythroid 2-related factor 2 (Nrf2) related to down-regulating Kelch-like ECH-associated protein 1 expression, which leads to enhanced levels of downstream antioxidative enzymes, including heme oxygenase-1 (HO-1), superoxide dismutase 2, and catalase in the spleen and thymus. Therefore, the protective effects of ACPS on CTX-induced immunosuppression in mice may be the result of a reduction in oxidative stress and involved in the Nrf2/HO-1 pathway. Our study suggests that ACPS has potential for development as an effective anti-immunosuppressive agent.