Combined effect of celecoxib and glucosamine sulfate on inflammatory factors and oxidative stress indicators in patients with knee osteoarthritis

Purpose: To investigate the combined effect of celecoxib and glucosamine sulfate on inflammatory factors and oxidative stress indicators in patients with knee osteoarthritis (KOA).Methods: Patients were randomly assigned to two groups of 60 patients each: control group and study group. The control group received celecoxib at a dose of 200 mg/kg/day, while the study group received glucosamine sulfate (500 mg/kg) in addition to celecoxib, thrice a day. Treatment in both groups lasted 8 weeks. The serum levels of tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), prostaglandin-2 (PGE2), malondialdehyde (MDA), and activity of superoxide dismutase (SOD) were assayed before and after treatment. Visual analogue scale (VAS), osteoarthritis index, Lysholm knee score scale (LKSS), and adverse reactions were also evaluated.Results: After treatment, total effectiveness was significantly higher in the study group (91.33 %) than in control group (71.67 %, p < 0.05). Serum TNF-α, IL-1 and PGE2 were significantly lesser in the glucosamine sulfate-treated patients than in control group (p < 0.05). The activity of SOD was significantly higher in glucosamine sulfate-exposed patients than control patients (p < 0.05). On the other hand, VAS and WOMAC scores were markedly lower in patients given glucosamine sulfate than in control patients (p < 0.05).Conclusion: The combination of celecoxib with glucosamine sulfate effectively reduces immune inflammatory response, oxidative stress damage, and joint pain associated with KOA.Keywords: Celecoxib, Glucosamine sulfate, Osteoarthritis, Inflammatory factors, Oxidative stres

Nisin and ε-polylysine combined treatment enhances quality of fresh-cut jackfruit at refrigerated storage

This study investigated the effects of nisin combined with ε-polylysine on microorganisms and the refrigerated quality of fresh-cut jackfruit. After being treated with distilled water (control), nisin (0.5 g/L), ε-polylysine (0.5 g/L), and the combination of nisin (0.1 g/L) and ε-polylysine (0.4 g/L), microporous modified atmosphere packaging (MMAP) was carried out and stored at 10 ± 1°C for 8 days. The microorganisms and physicochemical indexes were measured every 2 days during storage. The results indicated that combined treatment (0.1 g/L nisin, 0.4 g/L ε-polylysine) had the best preservation on fresh-cut jackfruit. Compared with the control, combined treatment inhibited microbial growth (total bacterial count, mold and yeast), reduced the weight loss rate, respiratory intensity, polyphenol oxidase and peroxidase activities, and maintained higher sugar acid content, firmness, and color. Furthermore, it preserved higher levels of antioxidant compounds, reduced the accumulation of malondialdehyde and hydrogen peroxide, thereby reducing oxidative damage and maintaining high nutritional and sensory qualities. As a safe application of natural preservatives, nisin combined with ε-polylysine treatment has great application potential in the fresh-cut jackfruit industry

Immune-checkpoint protein VISTA in allergic, autoimmune disease and transplant rejection

Negative checkpoint regulators (NCRs) reduce the T cell immune response against self-antigens and limit autoimmune disease development. V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint in the B7 family, has recently been identified as one of the NCRs. VISTA maintains T cell quiescence and peripheral tolerance. VISTA targeting has shown promising results in treating immune-related diseases, including cancer and autoimmune disease. In this review, we summarize and discuss the immunomodulatory role of VISTA, its therapeutic potential in allergic, autoimmune disease, and transplant rejection, as well as the current therapeutic antibodies, to present a new method for regulating immune responses and achieving durable tolerance for the treatment of autoimmune disease and transplantation

Tumor-associated microglia and macrophages in glioblastoma: From basic insights to therapeutic opportunities

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Currently, the standard treatment of glioblastoma includes surgery, radiotherapy, and chemotherapy. Despite aggressive treatment, the median survival is only 15 months. GBM progression and therapeutic resistance are the results of the complex interactions between tumor cells and tumor microenvironment (TME). TME consists of several different cell types, such as stromal cells, endothelial cells and immune cells. Although GBM has the immunologically “cold” characteristic with very little lymphocyte infiltration, the TME of GBM can contain more than 30% of tumor-associated microglia and macrophages (TAMs). TAMs can release cytokines and growth factors to promote tumor proliferation, survival and metastasis progression as well as inhibit the function of immune cells. Thus, TAMs are logical therapeutic targets for GBM. In this review, we discussed the characteristics and functions of the TAMs and evaluated the state of the art of TAMs-targeting strategies in GBM. This review helps to understand how TAMs promote GBM progression and summarizes the present therapeutic interventions to target TAMs. It will possibly pave the way for new immune therapeutic avenues for GBM patients

Quantitative proteomics identification of phosphoglycerate mutase 1 as a novel therapeutic target in hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. There is an urgent need to develop novel biomarkers for early diagnosis, as well as to identify new drug targets for therapeutic interventions. PATIENTS AND METHODS: 54 paired HCC samples and 21 normal liver tissues were obtained from West China Hospital of Sichuan University. Informed consent was obtained from all the patients or their relatives prior to analysis, and the project was approved by the Institutional Ethics Committee of Sichuan University. Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC)-based proteomics was employed to profile the differentially expressed proteins between a HepG2 human hepatoma cell line and an immortal hepatic cell line L02. Validation of PGAM1 expression was performed by semi-quantitative RT-PCR, immunoblot and immunohistochemistry using clinical samples. shRNA expressing plasmids specifically targeting PGAM1 were designed and constructed by GenePharma Corporation (Shanghai, China), and were utilized to silence expression of PGAM1 in vitro and in vivo. Cell proliferation was measured by a combination of colony formation assay and Ki67 staining. Apoptosis was examined by flow cytometry and TUNEL assay. RESULTS: A total of 63 dysregulated proteins were identified, including 51 up-regulated proteins, and 12 down-regulated proteins (over 2-fold, p < 0.01). Phosphoglycerate mutase 1 (PGAM1) was found markedly upregulated. Clinico-pathological analysis indicated that overexpression of PGAM1 was associated with 66.7% HCC, and strongly correlated with poor differentiation and decreased survival rates (p < 0.01). shRNAs-mediated repression of PGAM1 expression resulted in significant inhibition in liver cancer cell growth both in vitro and in vivo. CONCLUSION: Our studies suggested that PGAM1 plays an important role in hepatocarcinogenesis, and should be a potential diagnostic biomarker, as well as an attractive therapeutic target for hepatocellular carcinoma

An Allosteric Inhibitor of Protein Arginine Methyltransferase 3

PRMT3, a protein arginine methyltransferase, has been shown to influence ribosomal biosynthesis by catalyzing the dimethylation of the 40S ribosomal protein S2. Although PRMT3 has been reported to be a cytosolic protein, it has been shown to methylate histone H4 peptide (H4 1-24) in vitro. Here, we report the identification of a PRMT3 inhibitor (1-(benzo[d][1,2,3]thiadiazol-6-yl)-3-(2-cyclohexenylethyl)urea; compound 1) with IC50 value of 2.5 μM by screening a library of 16,000 compounds using H4 (1-24) peptide as a substrate. The crystal structure of PRMT3 in complex with compound 1 as well as kinetic analysis reveals an allosteric mechanism of inhibition. Mutating PRMT3 residues within the allosteric site or using compound 1 analogs that disrupt interactions with allosteric site residues both abrogated binding and inhibitory activity. These data demonstrate an allosteric mechanism for inhibition of protein arginine methyltransferases, an emerging class of therapeutic targets

Hydrogen Sulfide Protects against Chemical Hypoxia-Induced Cytotoxicity and Inflammation in HaCaT Cells through Inhibition of ROS/NF-κB/COX-2 Pathway

Hydrogen sulfide (H2S) has been shown to protect against oxidative stress injury and inflammation in various hypoxia-induced insult models. However, it remains unknown whether H2S protects human skin keratinocytes (HaCaT cells) against chemical hypoxia-induced damage. In the current study, HaCaT cells were treated with cobalt chloride (CoCl2), a well known hypoxia mimetic agent, to establish a chemical hypoxia-induced cell injury model. Our findings showed that pretreatment of HaCaT cells with NaHS (a donor of H2S) for 30 min before exposure to CoCl2 for 24 h significantly attenuated CoCl2-induced injuries and inflammatory responses, evidenced by increases in cell viability and GSH level and decreases in ROS generation and secretions of IL-1β, IL-6 and IL-8. In addition, pretreatment with NaHS markedly reduced CoCl2-induced COX-2 overexpression and PGE2 secretion as well as intranuclear NF-κB p65 subunit accumulation (the central step of NF-κB activation). Similar to the protective effect of H2S, both NS-398 (a selective COX-2 inhibitor) and PDTC (a selective NF-κB inhibitor) depressed not only CoCl2-induced cytotoxicity, but also the secretions of IL-1β, IL-6 and IL-8. Importantly, PDTC obviously attenuated overexpression of COX-2 induced by CoCl2. Notably, NAC, a ROS scavenger, conferred a similar protective effect of H2S against CoCl2-induced insults and inflammatory responses. Taken together, the findings of the present study have demonstrated for the first time that H2S protects HaCaT cells against CoCl2-induced injuries and inflammatory responses through inhibition of ROS-activated NF-κB/COX-2 pathway