Selenium maintains intestinal epithelial cells to activate M2 macrophages against deoxynivalenol injury.

Selenium (Se) is indispensable in alleviating various types of intestinal injuries. Here, we thoroughly investigated the protective effect of Se on the regulation of the epithelial cell-M2 macrophages pathway in deoxynivalenol (DON)-induced intestinal damage. In the present study, Se has positive impacts on gut health by improving gut barrier function and reducing the levels of serum DON in vivo. Furthermore, our study revealed that Se supplementation increased the abundances of GPX4, p-PI3K, and AKT, decreased the levels of 4-HNE and inhibited ferroptosis. Moreover, when mice were treated with DON and Fer-1(ferroptosis inhibitor), ferroptosis was suppressed and PI3K/AKT pathway was activated. These results indicated that GPX4-PI3K/AKT-ferroptosis was a predominant pathway in DON-induced intestinal inflammation. Interestingly, we discovered that both the number of M2 anti-inflammatory macrophages and the levels of CSF-1 decreased while the pro-inflammatory cytokine IL-6 increased in the intestine and MODE-K cells supernatant. Therefore, Se supplementation activated the CSF-1-M2 macrophages axis, resulting in a decrease in IL-6 expression and an enhancement of the intestinal anti-inflammatory capacity. This study provides novel insights into how intestinal epithelial cells regulate the CSF-1-M2 macrophage pathway, which is essential in maintaining intestinal homeostasis confer to environmental hazardous stimuli.

Astragaloside IV improves renal function and alleviates renal damage and inflammation in rats with chronic glomerulonephritis.

From Astragalus membranaceus (Fisch.) Bge.var. mongholicus (Bge.) Hsiao, astragaloside IV (AS-IV), a saponin can be purified and is considered traditional Chinese medicine. The purpose of this study was to evaluate the AS-IV-mediated mechanism on chronic glomerulonephritis (CGN). A cationic bovine serum albumin-induced CGN rat model was established and 10, 15, or 20 mg/kg of AS-IV was administered to measure renal function and inflammatory infiltration. Influences of AS-IV on proliferation, cell cycle, and inflammation of LPS-induced rat mesangial cells (RMCs) were determined. The results demonstrated that AS-IV alleviated renal dysfunction, renal lesions, and inflammation in CGN rats. AS-IV prolonged the G0-G1 phase, shortened the S phase, and inhibited cell proliferation and inflammation in RMCs. AS-IV can promote miR-181d-5p expression to inhibit CSF1. miR-181d-5p promotion or CSF1 suppression could further enhance the therapeutic role of AS-IV in CGN rats, while miR-181d-5p silencing or CSF1 overexpression abolished the effect of AS-IV. In conclusion, AS-IV by mediating the miR-181d-5p/CSF1 axis protects against CGN.

Decreased melanoma CSF-1 secretion by Cannabigerol treatment reprograms regulatory myeloid cells and reduces tumor progression.

During solid tumor progression, the tumor microenvironment (TME) evolves into a highly immunosuppressive milieu. Key players in the immunosuppressive environment are regulatory myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which are recruited and activated via tumor-secreted cytokines such as colony-stimulating factor 1 (CSF-1). Therefore, the depletion of tumor-secreted cytokines is a leading anticancer strategy. Here, we found that CSF-1 secretion by melanoma cells is decreased following treatment with Cannabis extracts. Cannabigerol (CBG) was identified as the bioactive cannabinoid responsible for the effects. Conditioned media from cells treated with pure CBG or the high-CBG extract reduced the expansion and macrophage transition of the monocytic-MDSC subpopulation. Treated MO-MDSCs also expressed lower levels of iNOS, leading to restored CD8+ T-cell activation. Tumor-bearing mice treated with CBG presented reduced tumor progression, lower TAM frequencies and reduced TAM/M1 ratio. A combination of CBG and αPD-L1 was more effective in reducing tumor progression, enhancing survival and increasing the infiltration of activated cytotoxic T-cells than each treatment separately. We show a novel mechanism for CBG in modulating the TME and enhancing immune checkpoint blockade therapy, underlining its promising therapeutic potential for the treatment of a variety of tumors with elevated CSF-1 expression.

Carotenoid coloration and coloration-linked gene expression in red tilapia (Oreochromis sp.) tissues.

BACKGROUND: Production, marketability and consumer preference of red tilapia often depends upon the intensity of coloration. Hence, new approaches to develop coloration are now geared to improve market acceptability and profit. This study evaluated the effects of carotenoid-rich diets on the phenotypic coloration, carotenoid level, weight gain and expression of coloration-linked genes in skin, fin and muscle tissues. Carotenoids were extracted from dried Daucus carota peel, Ipomoea aquatica leaves, and Moringa oleifera leaves. Eighty (80) size-14 fish were fed with carotenoid-rich treatments twice a day for 120 days. The phenotypic effect of the carotenoid extracts was measured through a color chart. Skin carotenoid level was measured through UV-vis spectrophotometer. csf1ra, Bcdo2 and StAR expression analysis was done using qRT-PCR. RESULTS: Treatments with carotenoid extracts yielded higher overall scores on phenotypic coloration and tissue carotenoid levels. Differential expression of carotenoid-linked genes such as the elevated expression in csf1ra and lower expression in Bcdo2b following supplementation of the enhanced diet supports the phenotypic redness and increased carotenoid values in red tilapia fed with D. carota peel and I. aquatica leaves. CONCLUSIONS: Overall improvement in the redness of the tilapia was achieved through the supplementation of carotenoid-rich diet derived from readily available plants. Differential expression of coloration-linked genes supports the increase in the intensity of phenotypic coloration and level of carotenoids in the tissues. The study emphasizes the importance of carotenoids in the commercial tilapia industry and highlights the potential of the plant extracts for integration and development of feeds for color enhancement in red tilapia.

Fenugreek steroidal saponins hinder osteoclastogenic bone resorption by targeting CSF-1R which diminishes the RANKL/OPG ratio.

Osteoporosis is skeletal fragility caused by the excessive bone resorption due to osteoclastogenesis. But current drugs are less bioavailable and possess higher toxicity. Our study was conducted to identify safe oral bioavailable drugs from Fenugreek steroidal saponins and to delineate underlying mechanism of them to lower the osteoclastogenic bone resorption. We observed higher molecular docked binding affinities in finally selected eight hit compounds within the range of -11.0 to -10.1 kcal/mol which was greater than currently used drugs. Molecular Dynamics simulation with Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Solvent Accessible Surface Area (SASA) and Gyration trajectory projection reinforced the stability of the protein-ligand complexes. Pharmacokinetics analysis confirmed bioavailability of seven compounds out of eight, and drug likeliness and bioavailability profile evaluation indicated that they all are eligible to be developed as a potent oral inhibitor of CSF-1R. By literature mining knowledge-driven analysis, RNAseq data and Molecular Dynamics Simulation, we proposed that, the hit derivatives block the CSF-1/CSF-1R induced phosphorylation signaling pathway in both osteoclast and osteoblast resulting in hindrance of RANK expression and formation of Reactive oxygen species (ROS) in osteoclast and osteoblast respectively, thus declines the RANKL/OPG ratio, lowering the osteoclast survival, proliferation and differentiation.

Magnetism-mediated targeting hyperthermia-immunotherapy in "cold" tumor with CSF1R inhibitor.

Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called "cold" tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in "cold" colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an "eat-me" signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8+ T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice.

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.

The Yin and Yang of Cytoreductive SBRT in Oligometastases and Beyond.

Background: Oligometastatic disease has emerged as a possibly distinct metastatic phenotype in numerous cancer histologies. With the advancement in treatment modalities including stereotactic body radiation therapy (SBRT), certain patients may derive benefits from local ablative therapy. SBRT alone has already shown to have potential benefits in certain oligometastatic disease types. However, more understanding of the immunologic modulation and microenvironment is needed to guide which patients may benefit from SBRT alone or with combination therapy, if at all. Purpose: The purpose of this review is to offer an update on the emerging data testing SBRT combined with immunotherapy, review the pro-inflammatory and immunosuppressive effects of the tumor microenvironment, discuss novel molecular targets used to augment the immune response, and review potential methods used to decrease toxicity in order to improve the therapeutic ratio.

Rational Drug Design Approach of Receptor Tyrosine Kinase Type III Inhibitors.

Rational drug design is accomplished through the complementary use of structural biology and computational biology of biological macromolecules involved in disease pathology. Most of the known theoretical approaches for drug design are based on knowledge of the biological targets to which the drug binds. This approach can be used to design drug molecules that restore the balance of the signaling pathway by inhibiting or stimulating biological targets by molecular modeling procedures as well as by molecular dynamics simulations. Type III receptor tyrosine kinase affects most of the fundamental cellular processes including cell cycle, cell migration, cell metabolism, and survival, as well as cell proliferation and differentiation. Many inhibitors of successful rational drug design show that some computational techniques can be combined to achieve synergistic effects.

Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment.

BACKGROUND: Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades. METHODS: Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 µL samples using a 'proximity extension assay' (PEA) based immunoassay. Since Transforming growth factor beta (TGF-ß) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA. RESULTS: In CFS/ME patients, the 'normalized protein expression' value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-ß did not differ between patients and controls. CONCLUSIONS: In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014.

The Role of Microglia in Prion Diseases: A Paradigm of Functional Diversity.

Inflammation is a major component of neurodegenerative diseases. Microglia are the innate immune cells in the central nervous system (CNS). In the healthy brain, microglia contribute to tissue homeostasis and regulation of synaptic plasticity. Under disease conditions, they play a key role in the development and maintenance of the neuroinflammatory response, by showing enhanced proliferation and activation. Prion diseases are progressive chronic neurodegenerative disorders associated with the accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC. This review article provides the current knowledge on the role of microglia in the pathogenesis of prion disease. A large body of evidence shows that microglia can trigger neurotoxic pathways contributing to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory, repair and regenerative processes. This dual role of microglia is regulated by multiple pathways and evidences the ability of these cells to polarize into distinct phenotypes with characteristic functions. The awareness that the neuroinflammatory response is inextricably involved in producing tissue damage as well as repair in neurodegenerative disorders, opens new perspectives for the modulation of the immune system. A better understanding of this complex process will be essential for developing effective therapies for neurodegenerative diseases, in order to improve the quality of life of patients and mitigating the personal, economic and social consequences derived from these diseases.

Randomized phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer.

PURPOSE: This randomized, open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent standard-of-care (SOC) chemotherapy in patients with previously treated advanced triple-negative breast cancer (TNBC). METHODS: Patients with advanced TNBC, relapsed after anthracycline- and taxane-based chemotherapy, were randomized to receive either sunitinib (37.5 mg/day) or the investigator's choice of SOC therapy. Progression-free survival was the primary endpoint. RESULTS: Median progression-free survival was 2.0 months with sunitinib and 2.7 months with SOC chemotherapy (one-sided P = 0.888). Median overall survival was not prolonged with sunitinib (9.4 months) compared with SOC chemotherapy (10.5 months; one-sided P = 0.839). The objective response rate was 3% with sunitinib and 7% with SOC chemotherapy (one-sided P = 0.962). CONCLUSIONS: Sunitinib monotherapy did not improve efficacy compared with SOC chemotherapy in patients with previously treated advanced TNBC, for which identification of effective treatments and therapeutic targets remains an urgent need. TRIAL REGISTRATION: NCT00246571.