Regulatory role of PI16 in autoimmune arthritis and intestinal inflammation: implications for Treg cell differentiation and function.

BACKGROUND: Regulatory T cells (Tregs) are crucial in maintaining immune homeostasis and preventing autoimmunity and inflammation. A proportion of Treg cells can lose Foxp3 expression and become unstable under inflammation conditions. The precise mechanisms underlying this phenomenon remain unclear. METHODS: The PI16 gene knockout mice (PI16fl/flFoxp3Cre) in Treg were constructed, and the genotypes were identified. The proportion and phenotypic differences of immune cells in 8-week-old mice were detected by cell counter and flow cytometry. Two groups of mouse Naïve CD4+T cells were induced to differentiate into iTreg cells to observe the effect of PI16 on the differentiation and proliferation of iTreg cells, CD4+CD25+Treg and CD4+CD25- effector T cells (Teff) were selected and co-cultured with antigen presenting cells (APC) to observe the effect of PI16 on the inhibitory ability of Treg cells in vitro. The effects of directed knockout of PI16 in Treg cells on inflammatory symptoms, histopathological changes and immune cell expression in mice with enteritis and autoimmune arthritis were observed by constructing the model of antigen-induced arthritis (AIA) and colitis induced by dextran sulfate sodium salt (DSS). RESULTS: We identified peptidase inhibitor 16 (PI16) as a negative regulator of Treg cells. Our findings demonstrate that conditional knock-out of PI16 in Tregs significantly enhances their differentiation and suppressive functions. The conditional knockout of the PI16 gene resulted in a significantly higher abundance of Foxp3 expression (35.12 ± 5.71% vs. 20.00 ± 1.61%, p = 0.034) in iTreg cells induced in vitro compared to wild-type mice. Mice with Treg cell-specific PI16 ablation are protected from autoimmune arthritis (AIA) and dextran sulfate sodium (DSS)-induced colitis development. The AIA model of PI16CKO is characterized by the reduction of joint structure and the attenuation of synovial inflammation and in DSS-induced colitis model, conditional knockout of the PI16 reduce intestinal structural damage. Additionally, we found that the deletion of the PI16 gene in Treg can increase the proportion of Treg (1.46 ± 0.14% vs. 0.64 ± 0.07%, p < 0.0001) and decrease the proportion of Th17 (1.00 ± 0.12% vs. 3.84 ± 0.64%, p = 0.001). This change will enhance the shift of Th17/Treg toward Treg cells in AIA arthritis model (0.71 ± 0.06% vs. 8.07 ± 1.98%, p = 0.003). In DSS-induced colitis model of PI16CKO, the proportion of Treg in spleen was significantly increased (1.40 ± 0.15% vs. 0.50 ± 0.11%, p = 0.003), Th17 (2.18 ± 0.55% vs. 6.42 ± 1.47%, p = 0.017), Th1 (3.42 ± 0.19% vs. 6.59 ± 1.28%, p = 0.028) and Th2 (1.52 ± 0.27% vs. 2.76 ± 0.38%, p = 0.018) in spleen was significantly decreased and the Th17/Treg balance swift toward Treg cells (1.44 ± 0.50% vs. 24.09 ± 7.18%, p = 0.012). CONCLUSION: PI16 plays an essential role in inhibiting Treg cell differentiation and function. Conditional knock out PI16 gene in Treg can promote the Treg/Th17 balance towards Treg dominance, thereby alleviating the condition. Targeting PI16 may facilitate Treg cell-based therapies for preventing autoimmune diseases and inflammatory diseases. The research provides us with novel insights and future research avenues for the treatment of autoimmune diseases, particularly arthritis and colitis.

Stem cell-based ischemic stroke therapy: Novel modifications and clinical challenges.

Ischemic stroke (IS) causes severe disability and high mortality worldwide. Stem cell (SC) therapy exhibits unique therapeutic potential for IS that differs from current treatments. SC's cell homing, differentiation and paracrine abilities give hope for neuroprotection. Recent studies on SC modification have enhanced therapeutic effects for IS, including gene transfection, nanoparticle modification, biomaterial modification and pretreatment. These methods improve survival rate, homing, neural differentiation, and paracrine abilities in ischemic areas. However, many problems must be resolved before SC therapy can be clinically applied. These issues include production quality and quantity, stability during transportation and storage, as well as usage regulations. Herein, we reviewed the brief pathogenesis of IS, the "multi-mechanism" advantages of SCs for treating IS, various SC modification methods, and SC therapy challenges. We aim to uncover the potential and overcome the challenges of using SCs for treating IS and convey innovative ideas for modifying SCs.

Peptidase inhibitor 16 promotes inflammatory arthritis by suppressing Foxp3 expression via regulating K48-linked ubiquitin degradation Bmi-1 in regulatory T cells.

Abnormalities of regulatory T cells (Tregs) has been suggested in rheumatoid arthritis (RA), and Forkhead box P3 (Foxp3) is the key transcriptional factor of Tregs expression. However, the underlying molecular mechanism remains unclear. Here, we demonstrated peptidase inhibitor 16 (PI16) was significantly increased in the peripheral blood, synovial fluid, and synovial tissue from RA patients. PI16 transgenic mice (PI16Tg) aggravated arthritis severity partly through suppressing Foxp3 expression. Mechanistically, PI16 could interact with and stabilize Bmi-1 in Tregs via inhibiting K48-linked polyubiquitin of Bmi-1, which promotes the enrichment of repressive histone mark in Foxp3 promoter. Furthermore, Bmi-1 specific inhibitor PTC209 could restore Foxp3 expression and alleviate arthritis progression in PI16Tg mice, accompanied by increased recruitment of active histone mark in the promoter of Tregs. Our results suggest that PI16-Bmi-1 axis plays an important role in RA and other autoimmune diseases by suppressing Foxp3 expression in Tregs via Bmi-1-mediated histone modification.

Interleukin 22 and its association with neurodegenerative disease activity.

It is worth noting that neuroinflammation is well recognized as a symptom of neurodegenerative diseases (NDs). The regulation of neuroinflammation becomes an attractive focus for innovative ND treatment technologies. There is evidence that IL-22 is associated with the development and progression of a wide assortment of NDs. For example, IL-22 can activate glial cells, causing them to generate pro-inflammatory cytokines and encourage lymphocyte infiltration in the brain. IL-22 mRNA is highly expressed in Alzheimer's disease (AD) patients, and a high expression of IL-22 has also been detected in the brains of patients with other NDs. We examine the role of IL-22 in the development and treatment of NDs in this review, and we believe that IL-22 has therapeutic potential in these diseases.

Progress in the treatment of drug-induced liver injury with natural products.

There are numerous prescription drugs and non-prescription drugs that cause drug-induced liver injury (DILI), which is the main cause of liver disease in humans around the globe. Its mechanism becomes clearer as the disease is studied further. For an instance, when acetaminophen (APAP) is taken in excess, it produces N-acetyl-p-benzoquinone imine (NAPQI) that binds to biomacromolecules in the liver causing liver injury. Treatment of DILI with traditional Chinese medicine (TCM) has shown to be effective. For example, activation of the Nrf2 signaling pathway as well as regulation of glutathione (GSH) synthesis, coupling, and excretion are the mechanisms by which ginsenoside Rg1 (Rg1) treats APAP-induced acute liver injury. Nevertheless, reducing the toxicity of TCM in treating DILI is still a problem to be overcome at present and in the future. Accumulated evidences show that hydrogel-based nanocomposite may be an excellent carrier for TCM. Therefore, we reviewed TCM with potential anti-DILI, focusing on the signaling pathway of these drugs' anti-DILI effect, as well as the possibility and prospect of treating DILI by TCM based on hydrogel materials in the future. In conclusion, this review provides new insights to further explore TCM in the treatment of DILI.

Serum Krebs von den Lungen-6 concentrations reflect severity of anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis associated interstitial lung disease.

OBJECTIVES: Rapidly progressive interstitial lung disease (RP-ILD) is a major complication of anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis (anti-MDA5+DM) with a high mortality rate. The aim of the study is to determine whether serum Krebs von den Lungen-6 (KL-6) could be a prognostic biomarker to predict RP-ILD and prognosis in anti-MDA5+DM patients. METHODS: A total of 21 anti-MDA5+DM patients with RP-ILD and 20 anti-MDA5+DM patients without RP-ILD were retrospectively included in this study. Serum KL-6 concentration (pg/mL) was measured using the latex agglutination test. RESULTS: Serum KL-6 level was higher in RP-ILD patients than those in non-RR-ILD patients (1195.61±872.93 vs. 452.6±465.51 pg/mL, p=0.002). The best cut-off value of KL-6 serum level was 500.9 pg/mL using ROC curve (AUC area = 0.7976, p=0.0011). KL-6 >500.9 pg/mL was an independent risk factor for RP-ILD using multivariate analysis (OR=56.38, 95% CI 5.51-577.504, p=0.001). Serum KL-6 concentrations were significantly higher in dead patients than those in the survivor group (1209.34±840.55 vs. 592.41±667.76, p=0.0033), and higher KL-6 concentration was also an independent risk factor for all-cause death after adjusting confounders (OR = 21.94, 95% CI 3.3-145.73, p=0.001). Anti-MDA5+DM patients with higher KL-6 level displayed a significantly decreased one-year survival rate, as compared with lower KL-6 level (36.36% vs. 89.47%, p=0.0008). CONCLUSIONS: The serum KL-6 levels reflect severity of lung injury and serve as a clinically useful biomarker in detection and monitoring RP-ILD progression in anti-MDA5+DM patients.

Combination of the endophytic manganese-oxidizing bacterium Pantoea eucrina SS01 and biogenic Mn oxides: An efficient and sustainable complex in degradation and detoxification of malachite green.

Recently, Mn oxides (MnOxs) have been attracting considerable interest in the oxidation of organic pollutants. However, the reduction of MnOx in these reactions leads to the deactivation of the catalyst, which must be frequently regenerated. We evaluated the application of a manganese-oxidizing bacterium (MOB) and MnOx in removing toxic dyes. We studied the co-function of a plant-endophytic MOB, Pantoea eucrina SS01, with its bio-generated MnOx and evaluated the detoxification activity and chemical transformation mechanisms of the complex in malachite green (MG) degradation. We found a synergistic effect between MnOx and the strain. Particularly, strain SS01 could adsorb MG but could not degrade it, whereas the addition of Mn(II) promoted MG degradation by the formation of a complex containing the bacterium and MnOx aggregates (SS01-bio-MnOx), with distinct morphology characteristics. The complex showed a marked sustainability in the degradation of MG into less toxic or non-toxic metabolites. In this process, strain SS01 might have enhanced the regeneration of MnOx, accelerating MG degradation. Our data not only contribute to understanding the mechanism of MG removal by the SS01-bio-MnOx complex, but also provide a scientific basis for the future application of MOB and MnOx.

Three-Dimensional Bi2Fe4O9 Nanocubes Loaded on Reduced Graphene Oxide for Enhanced Electromagnetic Absorbing Properties.

Bi2Fe4O9(BFO) nanocubes were prepared in proportion using a simple and easy hydrothermal method, and were then assembled on reduced graphene oxide (rGO) multilayered sheets. The excellent microwave absorption properties of Bi2Fe4O9/rGO nanohybrids were achieved by properly adjusting the impedance matching and getting a high attenuation capability contributed from different ratios of the BFO and rGO. A minimum reflection loss value of -61.5 dB at 12.8 GHz was obtained with a Bi2Fe4O9/rGO ratio of 2:1, and the broadest bandwidth below -10 dB was up to 5.0 GHz (from 10.8 to 15.8 GHz) with a thickness of 2.4 mm. Additionally, the elementary mechanism of wave absorption performance is also investigated.

Characterization and bioremediation potential of nickel-resistant endophytic bacteria isolated from the wetland plant Tamarix chinensis.

Wetlands have been proposed as a sink for pollutants such as heavy metals. Wetland plants play a significant role in the phytoremediation of heavy metals. Here, we isolated and characterized three novel nickel (Ni)-resistant endophytic bacteria (NiEB) from the wetland plant Tamarix chinensis. The NiEB were identified as Stenotrophomonas sp. S20, Pseudomonas sp. P21 and Sphingobium sp. S42. All isolates tolerated 50 mg L-1 Ni, with isolates S20 and P21 being more tolerant to Ni at up to 400 mg L-1. Moreover, isolate S42 removed 33.7% of nickel sulfate from the water by forming white precipitates. The three isolates exhibited different plant growth-promoting (PGP) traits related to the production of indole acetic acid (IAA), siderophores and 1-aminocyclopropane-1-carboxylate (ACC) deaminase. Phytotoxicity studies revealed that the growth of the wetland plants in a high Ni concentration (200 mg L-1) recovered after co-incubation with isolate S42. Overall, this study presents the first report of NiEB isolation from wetland plants and provides novel insights into the diverse functions of endophytic bacteria in a plant host with the potential to improve Ni phytoremediation.

Bioremediation of malachite green by cyanobacterium Synechococcus elongatus PCC 7942 engineered with a triphenylmethane reductase gene.

Malachite green is a carcinogenic dye that has been detected in fish tissues and freshwater. Here we evaluated the malachite green decoloring ability of a photoautotrophic cyanobacterium, Synechococcus elongatus PCC 7942 (Synechococcus), that lives in freshwater. Results show that 99.5% of the dye was removed by Synechococcus through bioabsorption and bioaccumulation; however, the dye was not degraded or chemically modified. Next, we established an engineered Synechococcus strain to degrade the dye after uptake. The triphenylmethane reductase gene katmr was heterologously expressed, resulting in high production of a soluble recombinant protein. The engineered strain showed advanced decoloring abilities at a low cell density and in stressful environments. It degraded malachite green into the smaller molecules 4-methylaminobenzoic acid and 4-hydroxyl-aniline. After treatment with the engineered cyanobacterium, the growth of wheat seeds was fully recovered in the presence of malachite green. These results demonstrate the potential application of the engineered Synechococcus as a photosynthetic cell factory for the removal of malachite green from wastewater.