Tepidibacillus marianensis sp. nov., a novel heterotrophic iron-reducing bacterium isolated from Mariana Trench sediment.

A novel chemoheterotrophic iron-reducing micro-organism, designated as strain LSZ-M11000T, was isolated from sediment of the Marianas Trench. Phylogenetic analysis based on the 16S rRNA gene revealed that strain LSZ-M11000T belonged to genus Tepidibacillus, with 97 % identity to that of Tepidibacillus fermentans STGHT, a mesophilic bacterium isolated from the Severo-Stavropolskoye underground gas storage facility in Russia. The polar lipid profile of strain LSZ-M11000T consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, as well as other unidentified phospholipids and lipids. The major fatty acids were C16 : 0 (28.4 %), C18 : 0 (15.8 %), iso-C15 : 0 (12.9 %), and anteiso-C15 : 0 (12.0 %). Strain LSZ-M11000T had no menaquinone. Genome sequencing revealed that the genome size of strain LSZ-M11000T was 2.97 Mb and the DNA G+C content was 37.9 mol%. The average nucleotide identity values between strain LSZ-M11000T and its close phylogenetic relatives, Tepidibacillus fermentans STGHT and Tepidibacillus decaturensis Z9T, were 76.4 and 72.6 %, respectively. The corresponding DNA-DNA hybridization estimates were 20.9 and 23.4 %, respectively. Cells of strain LSZ-M11000T were rod-shaped (1.0-1.5×0.3-0.5 µm). Using pyruvate as an electron donor, it was capable of reducing KMnO4, MnO2, As(V), NaNO3, NaNO2, Na2SO4, Na2S2O3, and K2Cr2O7. Based on phenotypic, genotypic, and phylogenetic evidence, strain LSZ-M11000T is proposed to be a novel strain of the genus Tepidibacillus, for which the name Tepdibacillus marianensis is proposed. The type strain is LSZ-M11000T (=CCAM 1008T=JCM 39431T).

Baricitinib Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice by Inhibiting TGF-ß1 Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with unknown etiology, high mortality and limited treatment options. It is characterized by myofibroblast proliferation and extensive deposition of extracellular matrix (ECM), which will lead to fibrous proliferation and the destruction of lung structure. Transforming growth factor-ß1 (TGF-ß1) is widely recognized as a central pathway of pulmonary fibrosis, and the suppression of TGF-ß1 or the TGF-ß1-regulated signaling pathway may thus offer potential antifibrotic therapies. JAK-STAT is a downstream signaling pathway regulated by TGF-ß1. JAK1/2 inhibitor baricitinib is a marketed drug for the treatment of rheumatoid arthritis, but its role in pulmonary fibrosis has not been reported. This study explored the potential effect and mechanism of baricitinib on pulmonary fibrosis in vivo and in vitro. The in vivo studies have shown that baricitinib can effectively attenuate bleomycin (BLM)-induced pulmonary fibrosis, and in vitro studies showed that baricitinib attenuates TGF-ß1-induced fibroblast activation and epithelial cell injury by inhibiting TGF-ß1/non-Smad and TGF-ß1/JAK/STAT signaling pathways, respectively. In conclusion, baricitinib, a JAK1/2 inhibitor, impedes myofibroblast activation and epithelial injury via targeting the TGF-ß1 signaling pathway and reduces BLM-induced pulmonary fibrosis in mice.

Zanubrutinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease with high mortality and limited treatment. Only two drugs are currently approved for the treatment of IPF, but both have limitations and neither drug could prolong survival time of patients. The etiology of IPF is unclear, but there is growing evidence that B cells and B cell receptor signaling play important roles in the pathogenesis of IPF. Zanubrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK), which is a key enzyme downstream of B cell receptor signaling pathway, has approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). While its role in pulmonary fibrosis remains unknown. In this study, we explored the potential effect and mechanisms of zanubrutinib on pulmonary fibrosis in vivo and in vitro. METHODS: In the in vivo experiments, different doses of zanubrutinib were administered in a mouse model of bleomycin-induced pulmonary fibrosis, and pathological manifestations and lung function indices were evaluated. In vitro experiments were performed using TGF-ß1-stimulated fibroblasts to evaluate the effect of zanubrutinib on the activation and autophagy phenotype of fibroblasts and to explore the underlying signaling pathway mechanism. RESULTS: In vivo experiments demonstrated that zanubrutinib effectively attenuated bleomycin (BLM)-induced pulmonary fibrosis in mice. An in vitro mechanistic study indicated that zanubrutinib suppresses collagen deposition and myofibroblast activation by inhibiting the TGF-ß1/Smad pathway and induces autophagy through the TGF-ß1/mTOR pathway. CONCLUSIONS: Zanubrutinib alleviated bleomycin-induced lung fibrosis in mice by inhibiting the TGF-ß1 signaling pathway.

Pseudomonas marianensis sp. nov., a marine bacterium isolated from deep-sea sediments of the Mariana Trench.

A novel marine Gram-stain-negative, aerobic, rod-shaped bacterium, designated as strain PS1T, was isolated from the deep-sea sediments of the Mariana Trench and characterized phylogenetically and phenotypically. Bacterial optimal growth occurred at 35 °C (ranging 10-45 °C), pH 6 (ranging pH 5-10) and with 11% (w/v) NaCl (ranging 0-17%). The 16S rRNA gene sequence similarity results revealed that strain PS1T was most closely related to Pseudomonas stutzeri ATCC 17588T, Pseudomonas nitrititolerans GL14T, Pseudomonas zhaodongensis NEAU-ST5-21T, Pseudomonas xanthomarina DSM 18231T and Pseudomonas kunmingensis HL22-2T with 98.3-98.7%. The digital DNA-DNA hybridization values and the average nucleotide identity between strain PS1T and the reference strains were 20.4-40.1% and 78.7-79.4%, respectively. The major respiratory quinone is ubiquinone Q-9. The major polar lipids were phosphatidylethanolamine, diphosphatidyglycerol, phosphatidylglycerol, phosphatidylcholine, aminoglycolipid, two unidentified glycolipids and one unidentified lipid. The predominant cellular fatty acids of strain PS1T were summed feature 8 (C18:1ω7c and/or C18:1ω6c), summed feature 3 (C16:1ω7c and/or C16:1ω6c), C16:0 and cyclo-C19:0 ω8c. The G + C content of the genomic DNA was 63.0%. The combined genotypic and phenotypic data indicated that strain PS1T represents a novel species of the genus Pseudomonas, for which the name Pseudomonas marianensis sp. nov. is proposed, with the type strain PS1T (= DSM 112238T = MCCC 1K05112T).

Zanubrutinib ameliorates lipopolysaccharide-induced acute lung injury via regulating macrophage polarization.

Acute lung injury (ALI) is a disease characterized by pulmonary diffusion dysfunction and its exacerbation stage is acute respiratory distress syndrome (ARDS), which may develop to multiple organ failure and seriously threatens human health. ALI has high mortality rates and few effective treatments, thus effective protection measures for ALI are becoming increasingly important. Macrophages play a key regulatory role in the pathogenesis of ALI, and the degree of macrophage polarization is closely related to the severity and prognosis of ALI. In this study, we evaluated the effects of Zanubrutinib (ZB), a BTK small molecule inhibitor approved by the FDA for the treatment of cell lymphoma, on macrophage polarization and acute lung injury. In the in vivo study, we constructed a mouse model of Lipopolysaccharide (LPS)-induced acute lung injury and found that ZB could improve the acute injury of mouse lungs by inhibiting the secretion of proinflammatory factors and promoting the secretion of anti-inflammatory factors, reduce the number of inflammatory cells in alveolar lavage fluid, and then alleviate the inflammatory response. In vivo and in vitro studies have shown that ZB could inhibit the M1 macrophage polarization and promote the M2 macrophage polarization. Subsequent mechanistic studies revealed that ZB could inhibit the macrophage M1 polarization via targeting BTK activation and inhibiting JAK2/STAT1 and TLR4/MyD88/NF-κB signaling pathways, and promote the macrophage M2 polarization by promoting the activation of STAT6 and PI3K / Akt signaling pathways. In summary, ZB has shown therapeutic effect in LPS-induced acute lung injury in mice, which provides a potential candidate drug to treat acute lung injury.

Isorhamnetin alleviates lipopolysaccharide-induced acute lung injury by inhibiting mTOR signaling pathway.

Aim: Acute Lung Injury (ALI) is an acute hypoxic respiratory insufficiency caused by various traumatic factors, manifested as progressive hypoxemia and respiratory distress, and lung imaging shows a heterogeneous osmotic outbreak. Isorhamnetin (ISO) is a flavonoid compound isolated and purified from medicinal plants, such as Hippophae rhamnoides L. and Ginkgo, and has multiple pharmacological functions, such as anti-tumor, anti-myocardial hypoxia, and cardiovascular protection. Our previous study has shown that ISO could attenuate lipopolysaccharide (LPS)-induced acute lung injury in mice, but its mechanism is not clear.Methods: In this study, we used LPS-induced mouse and cell models to research the mechanism of ISO alleviating acute lung injury.Results: The results showed that ISO could attenuate the injury of type II alveolar epithelial cells by inhibiting the TLR4/NF-κB pathway. Further studies showed that ISO could inhibit the activation of mTOR signal in vivo and in vitro and promote autophagy in alveolar epithelial cells to reduce lung injury caused by LPS. In addition, ISO could inhibit LPS-induced epithelial cell apoptosis.Conclusion: Overall, ISO could suppress injury and apoptosis of epithelial cells and activate autophagy to protect epithelial cells via inhibiting mTOR signal and attenuating LPS-induced acute lung injury in mice.

Cabozantinib ameliorates lipopolysaccharide-induced lung inflammation and bleomycin--induced early pulmonary fibrosis in mice.

The lung, as the primary organ for gas exchange in mammals, is the main target organ for many pathogens and allergens, which may cause acute lung injury. A certain proportion of acute lung injury may progress into irreversible pulmonary fibrosis. Both acute lung injury and pulmonary fibrosis have high mortality rates and few effective treatments. Cabozantinib is a multi-target small molecule tyrosine kinase inhibitor and has been approved for the treatment of multiple malignant solid tumors. In this study, we explored the role of cabozantinib in acute lung injury and pulmonary fibrosis in vivo and in vitro. In the lipopolysaccharide and bleomycin induced mouse lung injury models, cabozantinib significantly improved the pathological state and reduced the infiltration of inflammatory cells in the lung tissues. In the bleomycin induced pulmonary fibrosis model, cabozantinib significantly reduced the area of pulmonary fibrosis and improved lung function in mice. The results of in vitro studies showed that cabozantinib could inhibit the inflammatory response and apoptosis of alveolar epithelial cells by inhibiting the activation of TLR4/NF-κB and NLRP3 inflammasome pathways. At the same time, cabozantinib could inhibit the activation of lung fibroblasts through suppressing the TGF-ß1/Smad pathway, and promote the apoptosis of fibroblasts. In summary, cabozantinib could alleviate lung injury through regulating the TLR4 /NF-κB/NLRP3 inflammasome pathway, and alleviate pulmonary fibrosis by inhibiting the TGF-ß1/Smad3 signaling pathway.

Bergenin attenuates bleomycin-induced pulmonary fibrosis in mice via inhibiting TGF-ß1 signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by epithelial cell damage, fibroblast activation, and collagen deposition. IPF has high mortality and limited therapies, which urgently needs to develop safe and effective therapeutic drugs. Bergenin, a compound derived from a variety of medicinal plants, has demonstrated multiple pharmacological activities including anti-inflammatory and anti-tumor, also acts as a traditional Chinese medicine to treat chronic bronchitis, but its effect on the pulmonary fibrosis is unknown. In this study, we demonstrated that bergenin could attenuate bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro studies indicated that bergenin inhibited the transforming growth factor-ß1 (TGF-ß1)-induced fibroblast activation and the extracellular matrix accumulation by inhibiting the TGF-ß1/Smad signaling pathway. Further studies showed that bergenin could induce the autophagy formation of myofibroblasts by suppressing the mammalian target of rapamycin signaling and that bergenin could promote the myofibroblast apoptosis. In vivo experiments revealed that bergenin substantially inhibited the myofibroblast activation and the collagen deposition and promoted the autophagy formation. Overall, our results showed that bergenin attenuated the BLM-induced pulmonary fibrosis in mice by suppressing the myofibroblast activation and promoting the autophagy and the apoptosis of myofibroblasts.

Ellagic Acid Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting Wnt Signaling Pathway.

Idiopathic pulmonary fibrosis is a progressive lung disease with high mortality and limited therapy that is characterized by epithelial cell damage and fibroblast activation. Ellagic acid is a natural polyphenol compound widely found in fruits and nuts that has multiple pharmacological activities. In this study, we explored the potential effects and mechanisms of Ellagic acid on pulmonary fibrosis in vivo and in vitro. In vivo studies showed that Ellagic acid significantly alleviated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro experiments indicated that Ellagic acid could suppress Wnt signaling and attenuate Wnt3a-induced myofibroblast activation and the phosphorylation of Erk2 and Akt. Further studies showed that Ellagic acid could induce autophagy formation in myofibroblasts mainly by suppressing mTOR signaling and promoting apoptosis of myofibroblasts. In vivo experiments revealed that Ellagic acid significantly inhibited myofibroblast activation and promoted autophagy formation. Taken together, our results show that Ellagic acid effectively attenuates BLM-induced pulmonary fibrosis in mice by suppressing myofibroblast activation and promoting autophagy and apoptosis of myofibroblasts by inhibiting the Wnt signaling pathway.

Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-ß1 Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-ß1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-ß1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-ß1 signaling pathway.

Physiological and genomic features of Paraoceanicella profunda gen. nov., sp. nov., a novel piezophile isolated from deep seawater of the Mariana Trench.

A novel piezophilic alphaproteobacterium, strain D4M1T , was isolated from deep seawater of the Mariana Trench. 16S rRNA gene analysis showed that strain D4M1T was most closely related to Oceanicella actignis PRQ-67T (94.2%), Oceanibium sediminis O448T (94.2%), and Thioclava electrotropha ElOx9T (94.1%). Phylogenetic analyses based on both 16S rRNA gene and genome sequences showed that strain D4M1T formed an independent monophyletic branch paralleled with the genus Oceanicella in the family Rhodobacteraceae. Cells were Gram-stain-negative, aerobic short rods, and grew optimally at 37°C, pH 6.5, and 3.0% (w/v) NaCl. Strain D4M1T was piezophilic with the optimum pressure of 10 MPa. The principal fatty acids were C18:1 ω7c/C18:1 ω6c and C16:0 , major respiratory quinone was ubiquinone-10, and predominant polar lipids were phosphatidylglycerol, phosphatidylethanolamine, and an unidentified aminophospholipid. The complete genome contained 5,468,583-bp with a G + C content of 70.2 mol% and contained 4,855 protein-coding genes and 78 RNA genes. Genomic analysis revealed abundant clues on bacterial high-pressure adaptation and piezophilic lifestyle. The combined evidence shows that strain D4M1T represents a novel species of a novel genus in the family Rhodobacteraceae, for which the name Paraoceanicella profunda gen. nov., sp. nov. is proposed (type strain D4M1T  = MCCC 1K03820T  = KCTC 72285T ).

Algoriphagus litoralis sp. nov., isolated from the junction between the ocean and a freshwater lake.

A Gram-stain negative, non-motile and short rod shaped bacterium, designated strain DSL-12T, was isolated from seawater of the East China Sea and characterised phylogenetically and phenotypically. Optimal growth was found to occur at 28 °C (range 4-40 °C), pH 7 (range 6-12) and with 3% (w/v) NaCl (range 0-8%). Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain DSL-12T is related to members of the genus Algoriphagus and shares high sequence similarities with Algoriphagus boritolerans DSM 17298T (97.6%) and Algoriphagus alkaliphilus DSM 22703T (97.6%). The 16S rRNA gene sequence identities between strain DSL-12T and other current members of the genus Algoriphagus were below 96.4%. The digital DNA-DNA hybridization values between strain DSL-12T and the type strains A. boritolerans DSM 17298T and A. alkaliphilus DSM 22703T were found to be 21.2 ± 2.4% and 20.2 ± 2.4%, respectively. The average nucleotide identity (ANI) values between strain DSL-12T and A. boritolerans DSM 17298T and A. alkaliphilus DSM 22703T were found to be 83.2% and 82.8%, respectively. The sole respiratory quinone was identified as MK-7. The major polar lipids were identified as phosphatidylethanolamine, diphosphatidylglycerol, one unidentified phospholipid and two unidentified lipids. The major fatty acids identified as were iso-C15:0, summed feature 8 (C18:1ω7c and/or C18:1ω6c), C16:0, summed feature 3 (C16:1ω7c and/or C16:1ω6c) and iso-C17:0. The G+C content of the genomic DNA was determined to be 43.3 mol%. The combined genotypic and phenotypic data indicate that strain DSL-12T represents a novel species of the genus Algoriphagus, for which the name Algoriphagus litoralis sp. nov. is proposed, with the type strain DSL-12T (= KCTC 62647T = MCCC 1K03536T).

Marinobacter profundi sp. nov., a slightly halophilic bacterium isolated from a deep-sea sediment sample of the New Britain Trench.

A piezotolerant, cold-adapted, slightly halophilic bacterium, designated strain PWS21T, was isolated from a deep-sea sediment sample collected from the New Britain Trench. Cells were observed to be Gram-stain negative, rod-shaped, oxidase- and catalase-positive. Growth of the strain was observed at 4-45 °C (optimum 37 °C), at pH 5.0-9.0 (optimum 7.0) and in 0.5-20% (w/v) NaCl (optimum 3-4%). The optimum pressure for growth was 0.1 MPa (megapascal) with tolerance up to 70 MPa. 16S rRNA gene sequence analysis showed that strain PWS21T is closely related to Marinobacter guineae M3BT (98.4%) and Marinobacter lipolyticus SM19T (98.2%). Multilocus sequence analysis (MLSA) based on sequences of housekeeping genes gyrB, recA, atpD, rpoB and rpoD indicates that strain PWS21T represents a distinct evolutionary lineage within the genus Marinobacter. Furthermore, strain PWS21T showed low ANI and diDDH values to the closely related species. The principal fatty acids were identified as C12:0, C12:0 3-OH, C16:1ω9c, C16:0 and C18:1ω9c. Ubiquinone-9 was identified as the major respiratory quinone. The polar lipids were identified as phosphatidylethanolamine (PE), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), aminophospholipid (APL), two unidentified lipids and an unidentified phospholipid (PL). The G + C content of the genomic DNA was determined to be 60.3 mol%. On the basis of phenotypic, chemotaxonomic and molecular data, we conclude that strain PWS21T represents a novel species of the genus Marinobacter, for which the name Marinobacter profundi sp. nov. is proposed (type strain PWS21T = KCTC 52990T = MCCC 1K03345T).

Applying emerging technologies to improve diabetes treatment.

Insulin, as the most important drug for the treatment of diabetes, can effectively control the blood glucose concentration in humans. Due to its instability, short half-life, easy denaturation and side effects, the administration way of insulin are limited to subcutaneous injection accompany with poor glucose control and low patient compliance. In recent years, emerging insulin delivery systems have been developed in diabetes research. In this review, a variety of stimuli-responsive insulin delivery systems with their response mechanism and regulation principle are described. Further, the introduction of stem cell transplantation and mobile application based delivery technologies are prudent for the diabetes treatment. This article also discusses the advantages and limitations of current strategies, along with the opportunities and challenges for future insulin therapy.