Modulating the polarization phenotype of microglia - A valuable strategy for central nervous system diseases.

Central nervous system (CNS) diseases have become one of the leading causes of death in the global population. The pathogenesis of CNS diseases is complicated, so it is important to find the patterns of the disease to improve the treatment strategy. Microglia are considered to be a double-edged sword, playing both harmful and beneficial roles in CNS diseases. Therefore, it is crucial to understand the progression of the disease and the changes in the polar phenotype of microglia to provide guidance in the treatment of CNS diseases. Microglia activation may evolve into different phenotypes: M1 and M2 types. We focused on the roles that M1 and M2 microglia play in regulating intercellular dialogues, pathological reactions and specific diseases in CNS diseases. Importantly, we summarized the strategies used to modulate the polarization phenotype of microglia, including traditional pharmacological modulation, biological therapies, and physical strategies. This review will contribute to the development of potential strategies to modulate microglia polarization phenotypes and provide new alternative therapies for CNS diseases.

Lipid dysregulation associated with progression of silica-induced pulmonary fibrosis.

Silicosis is an irreversible, progressive, fibrotic lung disease caused by long-term exposure to dust-containing silica particles at the workplace. Despite the precautions enforced, the rising incidence of silicosis continues to occur globally, particularly in developing countries. A better understanding of the disease progression and potential metabolic reprogramming of silicosis is warranted. The low- or high-dose silica-induced pulmonary fibrosis in mice was constructed to mimic chronic or accelerated silicosis. Silica-induced mice lung fibrosis was analyzed by histology, lung function, and computed tomography scans. Non-targeted metabolomics of the lung tissues was conducted by ultra-high-performance liquid chromatography-mass spectrometry to show the temporal metabolic trajectory. The low-dose silica-induced silicosis characterized inflammation for up to 42 days, with the onset of cellular silicon nodules. Conversely, the high-dose silica-induced silicosis characterized inflammation for up to 14 days, after which the disease developed rapidly, with a large volume of collagen deposition, presenting progressive massive fibrosis. Both low- and high silica-induced fibrosis had aberrant lipid metabolism. Combined with the RNA-Seq data, this multiomics study demonstrated alterations in the enzymes involved in sphingolipid metabolism. Time-dependent metabolic reprogramming revealing abnormal glycerophospholipid metabolism was intimately associated with the process of inflammation, whereas sphingolipid metabolism was crucial during lung fibrosis. These findings suggest that lipid dysregulation, especially sphingolipid metabolism, was involved in the process of silicosis.

Dietary Antimicrobial Peptides Improve Intestinal Function, Microbial Composition and Oxidative Stress Induced by Aeromonas hydrophila in Pengze Crucian Carp (Carassius auratus var. Pengze).

There is increasing evidence for the potential use of antimicrobial peptides as dietary supplements and antibiotic substitutes. In this study, we analyzed the differential effects of varying levels of antimicrobial peptides on the intestinal function and intestinal microbial and disease resistance of Pengze crucian carp. Approximately 630 experimental fishes were randomized in the control group (G0: 0 mg/kg) and in five groups supplemented with different doses of AMPs (G1: 100 mg/kg, G2: 200 mg/kg, G3: 400 mg/kg, G4: 800 mg/kg, and G5: 1600 mg/kg) and were fed for ten weeks. Three replicates per group of 35 fish were performed. The results showed that AMPs promoted intestinal villus development and increased intestinal muscular thickness (p < 0.05) and goblet cell abundance. The enzymatic activities of all groups supplemented with AMPs were effectively improved. AMP supplementation significantly enhanced the activities of antioxidant enzymes and digestive enzymes in the intestines of G3 animals (p < 0.05). Compared with G0 animals, AMP-supplemented animals regulated the expression of intestinal immune-related genes and exhibited significant differences in the G3 animal group (p < 0.05). The abundance of intestinal Firmicutes and Bacteroidetes increased in the AMP-supplemented groups, but the Firmicutes/Bacteroidetes ratio was lower than that in the G0 group. AMP supplementation also decreased the abundance of Fusobacterium while increasing the proportion of Actinobacteria (p < 0.05). After Aeromonas hydrophila infection, the expression levels of anti-inflammatory factors in the intestinal tract of G3 animals were significantly upregulated, and the level of the proinflammatory factor was decreased (p < 0.05). The intestinal Cetobacterium levels of G3 animals were significantly increased (p < 0.01), while the Proteobacteria levels were decreased, and the intestinal goblet cell proliferation was significantly lower than that of G0 animals (p < 0.05). This indicates that groups supplemented with AMPs have better disease resistance than the G0 group and can rapidly reduce the adverse effects caused by inflammatory response. Taken together, the present results suggest that AMP supplementation can improve intestinal function and intestinal microbial and pathogen resistance in Pengze crucian carp.

Rare cases of severe life-threatening lead poisoning due to accident or chronic occupational exposure to lead and manganese: Diagnosis, treatment, and prognosis.

BACKGROUND: Chronic long-term, low-dose environmental and occupational exposure to lead (Pb) has been extensively studied in large cohorts worldwide among general populations, miners, smelters, or battery workers. However, studies on severe life-threatening Pb poisoning due to accidental or chronic occupational exposure to Pb and manganese (Mn) were rarely reported. METHODS: We present one case of acute severe Pb poisoning and compare it with another severe chronic occupational exposure case involving Pb and Mn. A 27-year-old woman mistakenly took a large quantity of pure Pb powder as an herbal remedy; she developed abdominal colic, severe nausea, vomiting, fatigue, and cutaneous and sclera icterus. Laboratory tests showed her blood lead level (BLL) of 173.5 µg dL-1 and urinary lead level (ULL) of 1240 µg dL-1. The patient was diagnosed with acute Pb poisoning and acute liver failure. In another chronic exposure case, a 56-year-old man worked in a Pb and Mn smelting factory for 15 years. He was brought to the emergency room with severe nausea, vomiting, and paroxysmal abdominal colic, which was intolerable during the onset of pain. His BLL was 64.8 µg dL-1 and ULL was 38 µg dL-1, but his blood and urinary Mn levels were normal. The patient was diagnosed with chronic Pb poisoning. Both patients received chelation therapy with calcium disodium ethylene-diamine-tetraacetate (CaNa2EDTA). The woman with acute severe Pb intoxication recovered well and was discharged from the hospital after treatment, and the man who survived severe Pb poisoning was diagnosed with lung cancer. CONCLUSION: Clinical manifestations of acute and chronic severe Pb poisoning are different. Chelation therapy with CaNa2EDTA is proven to be an effective life-saving therapy in both cases by reducing BLL. Occupational exposure to both Pb and Mn does not appear to increase Mn neurotoxicity; however, the probability that co-exposure to Mn may increase Pb toxicity in the same patient cannot be excluded.

Effects of dietary Gelsemium elegans alkaloids on intestinal morphology, antioxidant status, immune responses and microbiota of Megalobrama amblycephala.

Numerous plant extracts used as feed additives in aquaculture have been shown to stimulate appetite, promote growth and enhance immunostimulatory and disease resistance in cultured fish. However, there are few studies on the famous Chinese herbal medicine Gelsemium elegans, which attracts our attention. In this study, we used the Megalobrama amblycephala to investigate the effects of G. elegans alkaloids on fish intestinal health after diet supplementation with 0, 5, 10, 20 and 40 mg/kg G. elegans alkaloids for 12 weeks. We found that dietary G. elegans alkaloids at 40 mg/kg improved intestinal morphology by increasing villus length, muscle thickness and villus number in the foregut and midgut and muscle thickness in the hindgut (P < 0.05). These alkaloids also significantly improved intestinal antioxidant capabilities by increasing superoxide dismutase, catalase, total antioxidant capacity and malondialdehyde levels and up-regulated intestinal Cu/Zn-SOD and Mn-SOD (P < 0.05) at 20 and 40 mg/kg. Dietary G. elegans alkaloids improved intestinal immunity via up-regulating the pro-inflammatory cytokines IL-1ß, IL-8, TNF-α and IFN-α and down-regulating expression of the anti-inflammatory cytokines IL-10 and TGF-ß (P < 0.05) at 20 and 40 mg/kg. The expression of Toll-like receptors TRL1, 3, 4 and 7 were also up-regulated in intestine of M. amblycephala (P < 0.05). In intestinal microbiota, the abundance of Proteobacteria was increased while the Firmicutes abundance was decreased at phylum level after feeding the alkaloids (P < 0.05). The alkaloids also increased the abundance of the probiotic Rhodobacter and decreased the abundance of the pathogenic Staphylococcus at genus level (P < 0.05). In conclusion, dietary G. elegans alkaloid supplementation promoted intestine health by improving intestine morphology, immunity, antioxidant abilities and intestinal microbiota in M. amblycephala.

Effects of dietary Gelsemium elegans alkaloids on growth performance, immune responses and disease resistance of Megalobrama amblycephala.

The present study aim to investigate the effects of dietary Gelsemium elegans alkaloids supplementation in Megalobrama amblycephala. A basal diet supplemented with 0, 5, 10, 20 and 40 mg/kg G. elegans alkaloids were fed to M. amblycephala for 12 weeks. The study indicated that dietary 20 mg/kg and 40 mg/kg G. elegans alkaloids supplementation could significantly improve final body weight (FBW), weight gain rate (WGR), specific growth rate (SGR), feed conversion ratio (FCR) and protein efficiency ratio (PER) (P < 0.05). The 20 mg/kg and 40 mg/kg G. elegans alkaloids groups showed significantly higher whole body and muscle crude protein and crude lipid contents compared to the control group (P < 0.05). The amino acid contents in muscle were also significantly increased in 20 mg/kg and 40 mg/kg groups (P < 0.05). Dietary 40 mg/kg G. elegans alkaloids had a significant effect on the contents of LDH, AST, ALT, ALP, TG, TC, LDL-C, HDL-C, ALB and TP in M. amblycephala (P < 0.05). Fish fed 20 mg/kg and 40 mg/kg dietary G. elegans alkaloids showed significant increase in complement 3, complement 4 and immunoglobulin M contents. The liver antioxidant enzymes (SOD, CAT and T-AOC) and MDA content significantly increased at 20 mg/kg and 40 mg/kg G. elegans alkaloids supplement (P < 0.05). The mRNA levels of immune-related genes IL-1ß, IL8, TNF-α and IFN-α were significantly up-regulated, whereas TGF-ß and IL10 genes were significantly down-regulated in the liver, spleen and head kidney of fish fed dietary supplementation with 20 mg/kg and 40 mg/kg G. elegans alkaloids. After challenge with Aeromonas hydrophila, significant higher survival rate was observed at 20 mg/kg and 40 mg/kg G. elegans alkaloids supplement (P < 0.05). Therefore, these results indicated that M. amblycephala fed a diet supplemented with 20 mg/kg and 40 mg/kg G. elegans alkaloids could significantly promote its growth performance, lipids and amino acids deposition, immune ability and resistance to Aeromonas hydrophila.

Induction of oxidative stress, apoptosis and DNA damage by koumine in Tetrahymena thermophila.

Koumine is a component of the Chinese medicinal herb Gelsemium elegans and is toxic to vertebrates. We used the ciliate Tetrahymena thermophila as a model to evaluate the toxic effects of this indole alkaloid in eukaryotic microorganisms. Koumine inhibited T. thermophila growth and viability in a dose-dependent manner. Moreover, this drug produced oxidative stress in T. thermophila cells and expressions of antioxidant enzymes were significantly elevated at high koumine levels (p < 0.05). Koumine also caused significant levels of apoptosis (p < 0.05) and induced DNA damage in a dose-dependent manner. Mitophagic vacuoles were present in cells indicating induction of autophagy by this drug. Expression of ATG7, MTT2/4, CYP1 and HSP70 as well as the MAP kinase pathway gene MPK1 and MPK3 were significantly altered after exposed to koumine. This study represents a preliminary toxicological evaluation of koumine in the single celled eukaryote T. thermophila.

Oridonin derivative ameliorates experimental colitis by inhibiting activated T-cells and translocation of nuclear factor-kappa B.

OBJECTIVE: To confirm the potential therapeutic efficacy of HAO472 against inflammatory bowel disease (IBD), we investigated the modulatory functions of HAO472 in a mouse model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. METHODS: Colitis was induced via an intrarectal injection of TNBS in mice. HAO472 (5.0 mg/kg or 7.5 mg/kg) or 1 mg/kg dexamethasone (DX) was injected intraperitoneally into the mice after the TNBS administration. Behavioral and weight changes, macroscopic and histological assessments of colon, the expressions of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17A, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) in the colonic tissues were evaluated. The effect of HAO472 on NF-κB signaling pathway in lymphocytes was also invesigated. RESULTS: HAO472 significantly ameliorated the clinical symptoms, reduced the severity of the inflammation and decreased mortality in the mouse model. HAO472 also reduced TNF-α, IFN-γ, IL-17A, iNOS/COX-2 and lymphocyte proliferation. These changes were associated with a significant decrease in NF-κB p65 expression and activity. CONCLUSION: HAO472 has positive effects on TNBS-induced colitis by modulating the subsets and functions of lymphocytes, suppressing inflammation and inhibiting the nuclear translocation of NF-κB p65 subunits.

Traditional Chinese medicine's intervention in endothelial nitric oxide synthase activation and nitric oxide synthesis in cardiovascular system.

Cardiovascular disease (CVD) is one of the most dangerous diseases which has become a major cause of human death. Many researches evidenced that nitric oxide (NO)/endothelial nitric oxide synthase (eNOS) system plays a significant role in the occurrence and development of CVD. NO, an important signaling molecule, closely associated with the regulation of vasodilatation, blood rheology, blood clotting and other physiological and pathological processes. The synthesis of NO in the endothelial cells primarily depends on the eNOS activity, thus the exploration of the mechanisms and effects of the eNOS activation on NO production is of great significance. Recently, studies on the effects of traditional Chinese medicine (TCM) and its extracts on eNOS activation and NO synthesis have gradually attracted more and more attentions. In this paper, we reviewed the mechanisms of NO synthesis and eNOS activation in the vascular endothelial cells (VECs) and intervention of TCM, so as to provide reference and train of thought to the intensive study of NO/eNOS system and the research and development of new drug for the treatment of CVD.