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2021 ◽  
Vol 12 ◽  
Author(s):  
Qun Wang ◽  
Yun Huang ◽  
Min Jia ◽  
Dong Lu ◽  
Hong-Wei Zhang ◽  
...  

Safflower polysaccharide (SPS) is one of the active fractions extracted from safflower petals (Carthamus tinctorius L.) which has been reported to possess antitumor and immune control roles. However, its antitumor mechanisms by regulating the immune pathway remain barely understood. In this study, a mouse model was established by azoxymethane (AOM)/dextran sodium sulfate (DSS) to evaluate the antitumor effect of SPS on colorectal cancer (CRC). The results showed that 50 mg/kg SPS-1, an active fraction isolated from SPS, could significantly inhibit CRC induced by AOM/DSS and changed the polarization of macrophages to the M1 phenotype. Meanwhile, SPS-1 treatment significantly alleviated the characteristic AOM/DSS-induced pathological symptoms, in terms of decreasing the nucleoplasmic ratio, nuclear polarity extinction, and gland hyperplasia. However, the results in vitro showed that SPS-1 did not directly inhibit the growth of CRC cells but could upregulate the NF-κB signal and trigger M1 macrophage transformation. Thus, the condition medium (CM) of Mφ pretreated with SPS-1 was used against CRC cells. As expected, SPS-1–activated Raw 264.7 markedly exhibited antitumor effects by inhibiting cell proliferation and suppressing cell colony formation. In addition, SPS-1–activated Raw 264.7 could also induce CRC cell apoptosis by upregulating the levels of tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Further results suggested that SPS-1–induced transition of the macrophage phenotype could be suppressed by an NF-κB inhibitor, PDTC. Moreover, SPS-1–activated Raw 264.7 inhibiting CRC cell proliferation and inducing apoptosis were also rescued by PDTC. Taken together, all results suggested that SPS-1 could be a therapeutic option for the prevention and treatment of CRC.


2021 ◽  
Vol 580 ◽  
pp. 35-40
Author(s):  
Tomohiko Shirakawa ◽  
Thira Rojasawasthien ◽  
Asako Inoue ◽  
Takuma Matsubara ◽  
Tatsuo Kawamoto ◽  
...  

2021 ◽  
Author(s):  
Pedro Lourenco Katayama ◽  
Isabela de Paula Leirao ◽  
Alexandre Kanashiro ◽  
Joao Paulo Mesquita Luiz ◽  
Fernando Queiroz Cunha ◽  
...  

Recent evidence has suggested that the carotid bodies might act as immunological sensors, detecting pro-inflammatory mediators and signalling to the central nervous system, which, in turn, orchestrates autonomic responses. Here, we demonstrated that the TNF-α receptor type I is expressed in the carotid bodies of rats. The systemic administration of TNF-α increased carotid body afferent discharge and activated glutamatergic neurons in the nucleus tractus solitarius (NTS) that project to the rostral ventrolateral medulla (RVLM), where the majority of pre-sympathetic neurons reside. The activation of these neurons was accompanied by generalized activation of the sympathetic nervous system. Carotid body ablation blunted the TNF-α-induced activation of RVLM-projecting NTS neurons and the increase in splanchnic sympathetic nerve activity. Finally, plasma and spleen levels of cytokines after TNF-α administration were higher in rats subjected to either carotid body ablation or splanchnic sympathetic denervation. Collectively, our findings indicate that the carotid body detects circulating TNF-α to activate a counteracting sympathetic anti-inflammatory mechanism.


2021 ◽  
Vol 8 ◽  
Author(s):  
Wengeng Lu ◽  
Zheng-Mei Xu ◽  
Qing Liu ◽  
Nan-Nan Yu ◽  
Jia-Bin Yu ◽  
...  

Endometritis is a disease that affects reproductive health in dairy cows and causes serious economic damage to the dairy industry world-wide. Although in recent years, the application of mesenchymal stem cell (MSC) therapy for the treatment of inflammatory diseases has attracted much attention, there are few reports of the use of MSCs in dairy cows. In the present study, our objective was to explore the inhibitory effects of bovine adipose-derived mesenchymal stem cells (bAD-MSCs) on lipopolysaccharide (LPS) induced inflammation in bovine endometrial epithelial cells (bEECs) along with the potential underlying molecular mechanisms. We characterized isolated bAD-MSCs using cell surface marker staining and adipogenic/osteogenic differentiation, and analyzed them using immunofluorescence, flow cytometry (surface marker staining), and adipogenic and osteogenic differentiation. Furthermore, to understand the anti-inflammatory effects of bAD-MSCs on LPS induced bEEC inflammation, we used a bAD-MSC/bEEC co-culture system. The results showed that bAD-MSC treatments could significantly decrease LPS induced bEEC apoptosis and pro-inflammatory cytokine expression levels, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Furthermore, our results showed that bAD-MSC treatments could also significantly downregulate LPS induced p38, IkB-a, and JAK1 phosphorylation and Bax protein expression levels, which are closely related to inflammatory progress and cellular apoptosis in bEECs. Our findings demonstrate that bAD-MSCs play an inhibitory role in LPS induced bEEC inflammation and provide new insights for the clinical therapy of endometritis in dairy cows.


2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Xiaoqin Ma ◽  
Chenxia Hao ◽  
Zhaokang Zhang ◽  
Huiting Jiang ◽  
Weixia Zhang ◽  
...  

Osteoarthritis (OA), a highly prevalent chronic joint disease, involves a complex network of inflammatory mediators that not only triggers pain and cartilage degeneration but also accelerates disease progression. Traditional Chinese medicinal shenjinhuoxue mixture (SHM) shows anti-inflammatory and analgesic effects against OA with remarkable clinical efficacy. This study explored the mechanism underlying anti-OA properties of SHM and evaluated its efficacy and safety via in vivo experiments. Through network pharmacology and published literature, we identified the key active phytochemicals in SHM, including β-sitosterol, oleanolic acid, licochalcone A, quercetin, isorhamnetin, kaempferol, morusin, lupeol, and pinocembrin; the pivotal targets of which are TLR-4 and NF-κB, eliciting anti-OA activity. These phytochemicals can enter the active pockets of TLR-4 and NF-κB with docking score ≤ − 3.86   kcal / mol , as shown in molecular docking models. By using surface plasmon resonance assay, licochalcone A and oleanolic acid were found to have good TLR-4-binding affinity. In OA rats, oral SHM at mid and high doses (8.72 g/kg and 26.2 g/kg) over 6 weeks significantly alleviated mechanical and thermal hyperalgesia ( P < 0.0001 ). Accordingly, the expression of inflammatory mediators (TLR-4, interleukin (IL-) 1 receptor-associated kinase 1 (IRAK1), NF-κB-p65, tumor necrosis factor (TNF-) α, IL-6, and IL-1β), receptor activator of the NF-κB ligand (RANKL), and transient receptor potential vanilloid 1 (TRPV1) in the synovial and cartilage tissue of OA rats was significantly decreased ( P < 0.05 ). Moreover, pathological observation illustrated amelioration of cartilage degeneration and joint injury. In chronic toxicity experiment of rats, SHM at 60 mg/kg demonstrated the safety. SHM had an anti-inflammatory effect through a synergistic combination of active phytochemicals to attenuate pain and cartilage degeneration by inhibiting TLR-4 and NF-κB activation. This study provided the experimental foundation for the development of SHM into a more effective dosage form or new drugs for OA treatment.


Toxics ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 276
Author(s):  
Ping-Kun Tsai ◽  
Shih-Pin Chen ◽  
Rosa Huang-Liu ◽  
Chun-Jung Chen ◽  
Wen-Ying Chen ◽  
...  

Air pollution is a major environmental and public health problem worldwide. A nitro-polycyclic aromatic hydrocarbon and the most abundant air pollutant in diesel engine exhaust, 1-nitropyrene (1-NP), is caused by the incomplete combustion of carbonaceous organic substances. Macrophages are effector cells of the innate immune cells that provide resistance in the peripheral tissue. The overactivation of macrophages results in inflammation. The generation of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumour necrosis factor alpha, is induced by 1-NP in a concentration-dependent manner in macrophages. In this study, the production of proinflammatory mediators, such as nitrogen oxide and prostaglandin E2, was induced by 1-NP in a concentration-dependent manner through the expression of iNOS and COX2. The generation of proinflammatory cytokines, iNOS, and COX2 was induced by 1-NP through nuclear factor (NF)-κB p65 phosphorylation and the degradation of its upstream factor, IκB. Finally, Akt phosphorylation was induced by 1-NP in a concentration-dependent manner. These findings suggest that 1-NP exhibits a proinflammatory response through the NF-κB pathway activation due to Akt phosphorylation.


2021 ◽  
Vol 22 (21) ◽  
pp. 11356
Author(s):  
Jiaqiang Deng ◽  
Ping Ouyang ◽  
Weiyao Li ◽  
Lijun Zhong ◽  
Congwei Gu ◽  
...  

Senescence in mesenchymal stem cells (MSCs) not only hinders the application of MSCs in regenerative medicine but is also closely correlated with biological aging and the development of degenerative diseases. In this study, we investigated the anti-aging effects of curcumin (Cur) on canine bone marrow-derived MSCs (cBMSCs), and further elucidated the potential mechanism of action based on the modulation of autophagy. cBMSCs were expanded in vitro with standard procedures to construct a cell model of premature senescence. Our evidence indicates that compared with the third passage of cBMSCs, many typical senescence-associated phenotypes were observed in the sixth passage of cBMSCs. Cur treatment can improve cBMSC survival and retard cBMSC senescence according to observations that Cur (1 μM) treatment can improve the colony-forming unit-fibroblasts (CFU-Fs) efficiency and upregulated the mRNA expression of pluripotent transcription factors (SOX-2 and Nanog), as well as inhibiting the senescence-associated beta-galactosidase (SA-β-gal) activities and mRNA expression of the senescence-related markers (p16 and p21) and pro-inflammatory molecules (tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). Furthermore, Cur (0.1 μM~10 μM) was observed to increase autophagic activity, as identified by upregulation of microtubule-associated protein 1 light chain 3 (LC3), unc51-like autophagy-activating kinase-1 (ULK1), autophagy-related gene (Atg) 7 and Atg12, and the generation of type II of light chain 3 (LC3-II), thereby increasing autophagic vacuoles and acidic vesicular organelles, as well as causing a significant decrease in the p62 protein level. Moreover, the autophagy activator rapamycin (RAP) and Cur were found to partially ameliorate the senescent features of cBMSCs, while the autophagy inhibitor 3-methyladenine (3-MA) was shown to aggravate cBMSCs senescence and Cur treatment was able to restore the suppressed autophagy and counteract 3-MA-induced cBMSC senescence. Hence, our study highlights the important role of Cur-induced autophagy and its effects for ameliorating cBMSC senescence and provides new insight for delaying senescence and improving the therapeutic potential of MSCs.


2021 ◽  
pp. 2678-2685
Author(s):  
Naglaa A. Gomaa ◽  
Samy A. Darwish ◽  
Mahmoud A. Aly

Background and Aim: The transition period is extremely critical for pregnant producing animals. However, there is very limited research on the metabolic and immunological changes in Egyptian water buffalo cows during the transition period. Therefore, this study was conducted to investigate the immunometabolic changes occurring during the transition period in Egyptian water buffalo cows. Materials and Methods: A total of 50 multiparous pregnant Egyptian water buffalo cows were subjected to weekly blood sampling 3 weeks before calving and 3 weeks after calving and on the day of parturition to determine the complete blood count, including red blood cell count, total leukocyte count (TLC), differential leukocyte count, hemoglobin level, and packed cell volume (PCV). Some selected serum biochemical and immunological parameters were analyzed, including serum glucose, beta-hydroxybutyric acid (BHBA), non-esterified fatty acids, triglycerides, high-density lipoprotein, low-density lipoprotein (LDL), very LDL (VLDL), cholesterol, total protein, albumin, globulin, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase, alkaline phosphatase, alanine transaminase, gamma-glutamyl transferase, Haptoglobin, and C-reactive protein and the pro-inflammatory cytokines interleukin β1, interleukin 6 (IL-6), and tumor necrosis factor-alpha. All data were statistically analyzed using the IBM Statistical Package for the Social Sciences statistics software. Results: The neutrophil count showed a statistically significant increase at 2 weeks preparturition. There was also a significant increase in PCV, TLC, neutrophil count, and IL-6 and TNF-α level at the time of parturition and even at 2 weeks post parturition, except PCV that returned to normal levels in the 1st week post parturition. BHBA and BUN levels were increased significantly in the 2nd and 3rd weeks postcalving. Serum creatinine and VLDL levels were decreased significantly at the time of parturition, and VLDL levels showed a significant decrease even till the 3rd week postcalving, whereas creatinine levels gradually returned to the pre-calving levels in the 3rd week postcalving. Other parameters showed no significant changes. Conclusion: The most important immunometabolic changes occur in the first 2 weeks post parturition in Egyptian water buffalo cows, which exhibit a potent, remarkable physiological adaptation achieved by their functional liver, which can help the animal overcome the stressful conditions during the transition period.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Beibei Zhang ◽  
Xiaoying Wu ◽  
Jing Li ◽  
An Ning ◽  
Bo Zhang ◽  
...  

Abstract Background Hepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent or quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remains unknown. Methods In this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in the mice model of S. japonicum infection at different infectious stages. For validating the role of HPCs in hepatic injury, tumor necrosis factor-like-weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs in wild-type and IL-33−/− mice infected with S. japonicum. Results We found that the proliferation of HPCs was accompanied by inflammatory granulomas and fibrosis formation. HPCs expansion promoted liver regeneration and inhibited inflammatory egg granulomas, as well as the deposition of fibrotic collagen. Interestingly, the expression of IL-33 was negatively associated with HPCs’ expansion. There were no obvious differences of liver injury caused by infection between wild-type and IL-33−/− mice with HPCs’ expansion. However, liver injury was more attenuated in IL-33−/− mice than wild-type mice when the proliferation of HPCs was inhibited by anti-TWEAK. Conclusions Our data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33-dependent manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.


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