High-mobility group box 1 (HMGB1) is a DNA-binding protein abundantly expressed in the nucleus that has gained much attention for its regulation of immunity and inflammation. Despite this, whether and how HMGB1 contributes to protective and/or pathological responses in vivo is unclear. In this study, we constructed Hmgb1-floxed (Hmgb1 f/f ) mice to achieve the conditional inactivation of the gene in a cell-and tissue-specific manner by crossing these mice with an appropriate Cre recombinase transgenic strain. Interestingly, although mice with HMGB1 ablation in myeloid cells apparently develop normally, they are more sensitive to endotoxin shock compared with control mice, which is accompanied by massive macrophage cell death. Furthermore, these mice also show an increased sensitivity to Listeria monocytogenes infection. We also provide evidence that the loss of HMGB1 in macrophages results in the suppression of autophagy, which is commonly induced by lipopolysaccharide stimulation or L. monocytogenes infection. Thus, intracellular HMGB1 contributes to the protection of mice from endotoxemia and bacterial infection by mediating autophagy in macrophages. These newly generated HMGB1 conditional knockout mice will serve a useful tool with which to study further the in vivo role of this protein in various pathological conditions. LPS | IL-1β | IL-18
Macrophages have critical roles in the pathogenesis of atherosclerosis by activating the innate immune system and producing inflammatory cytokines. Accumulating evidence indicates that angiotensin type 1 receptor (AT1R) blockers exert antiinflammatory effects in inflammatory diseases including atherosclerosis. In this study, we investigated the effect of losartan, an AT1R blocker, on the proinflammatory gene expression induced by bacterial lipopolysaccharide (LPS) in a well-defined in vitro human THP-1 macrophage system. We found that losartan significantly attenuated the LPS-induced expression of proinflammatory genes TNF-a, IL-8 and COX-2. However, exogenous angiotensin II (AngII) had no effect on LPS-induced inflammatory signaling despite the expression of AT1R. In addition, losartan did not block LPS-induced IjB phosphorylation, which is downstream of Toll-like receptor activation. Peroxisome proliferator-activated receptor-gamma (PPARc) antagonists, GW9662 and T0070907, reversed the inhibitory effects of losartan on LPS-induced TNF-a and IL-8 expression in THP-1 macrophages. These observations suggest that losartan inhibits LPS-induced proinflammatory gene expression in macrophages by activating the PPARc pathway rather than by the competitive inhibition of AT1R binding to AngII.
Growth retardation of calves is defined as a symptom of impaired growth and development, probably due to growth hormone disorder as well as natural and environmental factors in livestock. The growth-promoting effects of probiotics were determined in 50 growth-retarded growth calves. They were supplied with Bacillus amyloliquefaciens C-1 (Ba, 4 × 1010CFU/d, n = 16), B. subtilis (Bs, 4 × 1010CFU/d, n = 18), and negative control (NC, n = 16) for 30 days. Pre- and post-intervention, the growth performance (weight gain rate, feed intake and feed conversion rate) was analyzed, the serum GH, IGH-1 and immunoglobulin levels were assayed, and the fecal microbiota was detected. Calves in Ba and Bs groups demonstrated increased body weight gain, feed intake and GH/IGF-1 levels, as well as a more efficient feed conversion rate, compared with NC group (P < 0.05). Additionally, the abundances of bacteria contributing to the production of energy and SCFAs (short chain fatty acids), including Proteobacteria, Rhodospirillaceae, Campylobacterales, and Butyricimonas were increased compared with NC group (P < 0.05, FDR < 0.1); and the suspected pathogens, which included Anaeroplasma and Acholeplasma were decreased (P < 0.05, FDR < 0.1) in both the Bs and Ba groups. Akkermansia, which is involved in the intestinal mucosal immune response, was increased in Bs group after intervention (P < 0.05, FDR < 0.1), but exhibited no obvious difference in Ba group. The increased bacterial genera in Ba group were Sphaerochaeta and Treponema (P < 0.05, FDR < 0.1). These results indicate that the probiotics B. amyloliquefaciens and B. subtilis exhibited similar therapeutic potential in terms of growth performance by regulating hormones, and improving the intestinal and rumen development in growth-retarded animals.
Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II, thereby improving the pathologies of cardiovascular disease or acute lung injury. Here we show that B38-CAP, an ACE2-like enzyme, is protective against SARS-CoV-2-induced lung injury. Endogenous ACE2 expression is downregulated in the lungs of SARS-CoV-2-infected hamsters, leading to elevation of angiotensin II levels. Recombinant Spike also downregulates ACE2 expression and worsens the symptoms of acid-induced lung injury. B38-CAP does not neutralize cell entry of SARS-CoV-2. However, B38-CAP treatment improves the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, B38-CAP significantly improves lung edema and pathologies of lung injury. These results provide the first in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19 patients.
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