scholarly journals A Novel Anti-Infective Peptide BCCY-1 With Immunomodulatory Activities

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinyang Cai ◽  
Xianwei Cui ◽  
Xing Wang ◽  
Lianghui You ◽  
Chenbo Ji ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Innate Immune Responses ◽  
Chemokine Production ◽  
Promising Alternative ◽  
Effector Cells ◽  
Valuable Complement ◽  
Global Threat ◽  
High Level ◽  
Pathogen Clearance

Antibiotic resistance has been considered to be a global threat which underscores the need to develop novel anti-infective therapeutics. Modulation of innate immunity by synthetic peptides is an attractive strategy to overcome this circumstance. We recently reported that BCCY-1, a human β-casein-derived peptide displays regulatory activities on monocytes, thereby enhancing their actions in innate immune responses. However, the function of peptide BCCY-1 in host defense against infection remains unknown. In this study, we investigated the in vivo characteristics and effects of peptide BCCY-1 in mouse models of bacterial infection. Following intraperitoneal injection, the peptide BCCY-1 exhibited high level of cellular uptake by monocytes without obvious toxicities. Results revealed that peptide BCCY-1, but not the scrambled version, stimulated the chemokine production and monocyte recruitment in vivo. Treatment with BCCY-1 enhanced the pathogen clearance and protected mice against lethal infections. Because the anti-infective effects of BCCY-1 was abolished by in vivo depletion of monocytes/macrophages rather than lymphocytes and granulocytes, we conclude that monocytes/macrophages are key effector cells in BCCY-1-mediated anti-infective protection. Additionally, BCCY-1 lacks direct antimicrobial activity. To our knowledge, a human β-casein-derived peptide that counters infection by selective regulation of innate immunity has not been reported previously. These results suggest peptide BCCY-1 as a promising alternative approach and a valuable complement to current anti-infective strategy.

scholarly journals High-Level Production of Porphyrins in Metabolically Engineered Escherichia coli: Systematic Extension of a Pathway Assembled from Overexpressed Genes Involved in Heme Biosynthesis

2003 ◽  
Vol 69 (8) ◽  
pp. 4875-4883 ◽  
Author(s):  
Seok Joon Kwon ◽  
Arjo L. de Boer ◽  
Ralf Petri ◽  
Claudia Schmidt-Dannert
Keyword(s):  
Escherichia Coli ◽  
High Performance ◽  
Protoporphyrin Ix ◽  
Spectroscopic Properties ◽  
Heme Biosynthesis ◽  
Promising Alternative ◽  
High Yields ◽  
High Level

ABSTRACT Due to their spectroscopic properties porphyrins are of special interest for a variety of applications, ranging from drug development or targeting to material sciences and chemical and biological sensors. Since chemical syntheses are limited in terms of regio- and stereoselective functionalization of porphyrins, a biosynthetic approach with tailored enzyme catalysts offers a promising alternative. In this paper, we describe assembly of the entire heme biosynthetic pathway in a three-plasmid system and overexpression of the corresponding genes with Escherichia coli as a host. Without further optimization, this approach yielded remarkable porphyrin production levels, up to 90 μmol/liter, which is close to industrial vitamin B12 production levels. Different combinations of the genes were used to produce all major porphyrins that occur as intermediates in heme biosynthesis. All these porphyrin intermediates were obtained in high yields. The product spectrum was analyzed and quantified by using high-performance liquid chromatography. Intriguingly, although protoporphyrin IX could be produced at high levels, overexpressed Bacillus subtilis ferrochelatase could not convert this substrate appreciably into heme. However, further investigation clearly revealed a high level of expression of the ferrochelatase and a high level of activity in vitro. These results may indicate that heme has a regulatory impact on the iron uptake of E. coli or that the ferrochelatase is inactive in vivo due to an incompatible enzyme interaction.

scholarly journals Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in β-thalassemic mice

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4175-4178 ◽  
Author(s):  
Leszek Lisowski ◽  
Michel Sadelain
Keyword(s):  
Gene Transfer ◽  
Control Region ◽  
Therapeutic Option ◽  
Globin Gene ◽  
Locus Control Region ◽  
Thalassemia Major ◽  
Hematopoietic Stem ◽  
Promising Alternative ◽  
High Level

Globin gene transfer in autologous hematopoietic stem cells is a promising therapeutic option for subjects with β-thalassemia major. In this approach, high level, erythroid-specific globin transgene expression should correct ineffective erythropoiesis and hemolytic anemia following the delivery of only 1 to 2 vector copies per cell. The generation of vectors that provide high-level globin expression and require low vector copy (VC) integration is therefore essential for both safety and efficacy. We show here the major roles played by 2 lesser-known locus control region elements, termed HS1 and HS4. Partial deletions within HS4 markedly reduce in vivo globin expression requiring multiple VC per cell to correct the anemia. Most strikingly, addition of HS1 to HS2-3-4 increases globin expression by 52%, yielding 9 g Hb/VC in β-thalassemic mice. Thus, while vectors encoding HS2-3-4 provide curative levels of hemoglobin at 1 to 2 copies per cell, adding HS1 is a promising alternative strategy if upcoming clinical trials prove higher levels of expression to be necessary.

scholarly journals Leptin signaling impairs macrophage defenses against Salmonella Typhimurium

2019 ◽  
Vol 116 (33) ◽  
pp. 16551-16560 ◽  
Author(s):  
Julia Fischer ◽  
Saray Gutièrrez ◽  
Raja Ganesan ◽  
Chiara Calabrese ◽  
Rajeev Ranjan ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Bacterial Infections ◽  
Leptin Receptor ◽  
Gram Negative ◽  
Leptin Signaling ◽  
Therapeutic Implications ◽  
Phosphorylated Akt ◽  
Pathogen Clearance

The dynamic interplay between metabolism and immune responses in health and disease, by which different immune cells impact on metabolic processes, are being increasingly appreciated. However, the potential of master regulators of metabolism to control innate immunity are less understood. Here, we studied the cross-talk between leptin signaling and macrophage function in the context of bacterial infections. We found that upon infection with Gram-negative pathogens, such as Salmonella Typhimurium, leptin receptor (Lepr) expression increased in both mouse and human macrophages. Unexpectedly, both genetic Lepr ablation in macrophages and global pharmacologic leptin antagonization augmented lysosomal functions, reduced S. Typhimurium burden, and diminished inflammation in vitro and in vivo. Mechanistically, we show that leptin induction activates the mTORC2/Akt pathway and subsequently down-regulates Phlpp1 phosphatase, allowing for phosphorylated Akt to impair lysosomal-mediated pathogen clearance. These data highlight a link between leptin signaling, the mTORC2/Phlpp1/Akt axis, and lysosomal activity in macrophages and have important therapeutic implications for modulating innate immunity to combat Gram-negative bacterial infections.

scholarly journals An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2302
Author(s):  
Mohammad Enamul Hoque Kayesh ◽  
Michinori Kohara ◽  
Kyoko Tsukiyama-Kohara
Keyword(s):  
Innate Immunity ◽  
Innate Immune ◽  
Vaccine Adjuvants ◽  
Innate Immune Responses ◽  
Chemokine Production ◽  
Proper Understanding ◽  
Tlr Agonists ◽  
Downstream Signaling ◽  
Immune Mediated ◽  
Molecular Patterns

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to coronavirus disease (COVID-19), a global health pandemic causing millions of deaths worldwide. However, the immunopathogenesis of COVID-19, particularly the interaction between SARS-CoV-2 and host innate immunity, remains unclear. The innate immune system acts as the first line of host defense, which is critical for the initial detection of invading pathogens and the activation and shaping of adaptive immunity. Toll-like receptors (TLRs) are key sensors of innate immunity that recognize pathogen-associated molecular patterns and activate downstream signaling for pro-inflammatory cytokine and chemokine production. However, TLRs may also act as a double-edged sword, and dysregulated TLR responses may enhance immune-mediated pathology, instead of providing protection. Therefore, a proper understanding of the interaction between TLRs and SARS-CoV-2 is of great importance for devising therapeutic and preventive strategies. The use of TLR agonists as vaccine adjuvants for human disease is a promising approach that could be applied in the investigation of COVID-19 vaccines. In this review, we discuss the recent progress in our understanding of host innate immune responses in SARS-CoV-2 infection, with particular focus on TLR response. In addition, we discuss the use of TLR agonists as vaccine adjuvants in enhancing the efficacy of COVID-19 vaccine.

Deficiency In Stress Response Gadd45a and Gadd45b Alters MAPK Kinase Signaling Leading to Functional Defects In Innate Immune Responses of Neutrophils and Macrophages In Vitro and In Vivo

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 927-927
Author(s):  
Dominic M. Salerno ◽  
Jennifer Tront ◽  
Barbara Hoffman ◽  
Dan Liebermann
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Family Members ◽  
Mapk Signaling ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Specific Chemical ◽  
Functional Defects

Abstract Abstract 927 Stress sensor GADD45 proteins modulate p38-NF-Kb and JNK signaling; which play major roles in leukocyte activation and innate immunity. We have previously documented that GADD45a-deficient and GADD45b-deficient mice exhibit impaired responses to hematological stress, including acute stimulation with inflammatory cytokines (Gupta et. al, Oncogene. 25:5537, 2006). Whether GADD45 genes modulate myeloid compartment function, notably the response of macrophages & granulocytes to inflammatory stress, remains largely unexplored. Data obtained thus far indicate that bone marrow (BM) derived neutrophils and macrophages lacking GADD45 family members exhibit defects in chemotaxis towards inflammatory stimuli. BM derived neutrophils and macrophages lacking GADD45 family members were also observed to exhibit defects in the production of reactive oxygen species (ROS) upon treatment with LPS (500ng/mL) in vitro. Furthermore, BM derived macrophages from mice lacking GADD45a and GADD45b were found to be defective in phagocytosis and cellular adhesion upon stimulation with LPS (500ng/mL) in vitro. Additionally, it was observed that BM derived neutrophils and macrophages lacking GADD45 family members exhibit defects in inflammatory cytokine secretion in response to activation with LPS. Notably, GADD45a, GADD45b & GADD45g null mice injected intraperitoneally with sublethal doses of LPS were significantly more susceptible to septic shock compared to wt mice, showing significantly increased morbidity. Moreover at 18 hrs. post-injection, the spleens of KO mice harbored apoptotic foci in the white pulp, identified as tingible body macrophages ingesting dying cells. To dissect the signaling pathways involved, MAPK specific chemical inhibitors were used to correlate MAPK signaling alteration to defects in innate immune responses of neutrophils and macrophages lacking GADD45a or GADD45b. LPS stimulated wt neutrophils treated with MAPK inhibitors exhibited defects in signaling and innate immune responses mimicking neutrophils and macrophages lacking GADD45a or GADD45b. Collectively, these novel data provide evidence to show that deficiency in GADD45a and GADD45b leads to functional defects in the myeloid innate immune responses of neutrophils and macrophages in vitro and in vivo. These findings increase our understanding of innate immunity and have the potential to contribute towards development of novel approaches to clinical treatment of sepsis. Disclosures: No relevant conflicts of interest to declare.

Does Brand Awareness Impact Purchase Decision: A Case of Organic Grocery

2018 ◽  
Vol 6 (7) ◽  
pp. 45
Author(s):  
Gunjan Gumber ◽  
Jyoti Rana
Keyword(s):  
Organic Food ◽  
Brand Awareness ◽  
National Capital Region ◽  
Promising Alternative ◽  
Brand Recall ◽  
Brand Building ◽  
Brand Recognition ◽  
National Capital ◽  
High Level ◽  
Structured Questionnaire

In India, the concept of organic food is gaining widespread acceptability. Consumers are becoming more conscious about their health and are looking for food that serves as a promising alternative. Corporates, NGOs, Spiritual leaders and Government are also promoting this food, as it is free from irradiation, chemicals and artificial additives. A number of organic food brands are available in the market. The main objective of this study is to find out the level of brand awareness and its influence on purchase of organic grocery. The data was collected from 150 organic consumers in National Capital Region (Delhi, Gurgaon, Faridabad and Noida) through a structured questionnaire. Questions related to brand recall, brand recognition and purchase of organic grocery were asked. It was found that in general, there is a low level of brand awareness among consumers, and those who have high level of awareness; they consume organic grocery more often. The study will help corporates to make effective communication and brand-building strategies.

scholarly journals Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 348
Author(s):  
Francesco Menzella ◽  
Giulia Ghidoni ◽  
Carla Galeone ◽  
Silvia Capobelli ◽  
Chiara Scelfo ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Severe Asthma ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Antiviral Effect ◽  
Point Of View ◽  
Type I ◽  
Effector Cells ◽  
Viral Spread ◽  
Increased Risk

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although extremely limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which can stabilize the effector cells, and is becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allow a great improvement in the management of asthma.

scholarly journals Aberrantly high activation of a FoxM1–STMN1 axis contributes to progression and tumorigenesis in FoxM1-driven cancers

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jun Liu ◽  
Jipeng Li ◽  
Ke Wang ◽  
Haiming Liu ◽  
Jianyong Sun ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Poor Prognosis ◽  
Soft Agar ◽  
Transcriptional Level ◽  
Regulation Mechanism ◽  
Strong Positive Correlation ◽  
Cell Viability Assay ◽  
High Level

AbstractFork-head box protein M1 (FoxM1) is a transcriptional factor which plays critical roles in cancer development and progression. However, the general regulatory mechanism of FoxM1 is still limited. STMN1 is a microtubule-binding protein which can inhibit the assembly of microtubule dimer or promote depolymerization of microtubules. It was reported as a major responsive factor of paclitaxel resistance for clinical chemotherapy of tumor patients. But the function of abnormally high level of STMN1 and its regulation mechanism in cancer cells remain unclear. In this study, we used public database and tissue microarrays to analyze the expression pattern of FoxM1 and STMN1 and found a strong positive correlation between FoxM1 and STMN1 in multiple types of cancer. Lentivirus-mediated FoxM1/STMN1-knockdown cell lines were established to study the function of FoxM1/STMN1 by performing cell viability assay, plate clone formation assay, soft agar assay in vitro and xenograft mouse model in vivo. Our results showed that FoxM1 promotes cell proliferation by upregulating STMN1. Further ChIP assay showed that FoxM1 upregulates STMN1 in a transcriptional level. Prognostic analysis showed that a high level of FoxM1 and STMN1 is related to poor prognosis in solid tumors. Moreover, a high co-expression of FoxM1 and STMN1 has a more significant correlation with poor prognosis. Our findings suggest that a general FoxM1-STMN1 axis contributes to cell proliferation and tumorigenesis in hepatocellular carcinoma, gastric cancer and colorectal cancer. The combination of FoxM1 and STMN1 can be a more precise biomarker for prognostic prediction.

scholarly journals Baicalin Represses Type Three Secretion System of Pseudomonas aeruginosa through PQS System

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1497
Author(s):  
Pansong Zhang ◽  
Qiao Guo ◽  
Zhihua Wei ◽  
Qin Yang ◽  
Zisheng Guo ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Mammalian Cells ◽  
Secretion System ◽  
Chinese Herbs ◽  
Infection Model ◽  
Lung Pathology ◽  
Promising Alternative ◽  
The Impact

Therapeutics that target the virulence of pathogens rather than their viability offer a promising alternative for treating infectious diseases and circumventing antibiotic resistance. In this study, we searched for anti-virulence compounds against Pseudomonas aeruginosa from Chinese herbs and investigated baicalin from Scutellariae radix as such an active anti-virulence compound. The effect of baicalin on a range of important virulence factors in P. aeruginosa was assessed using luxCDABE-based reporters and by phenotypical assays. The molecular mechanism of the virulence inhibition by baicalin was investigated using genetic approaches. The impact of baicalin on P. aeruginosa pathogenicity was evaluated by both in vitro assays and in vivo animal models. The results show that baicalin diminished a plenty of important virulence factors in P. aeruginosa, including the Type III secretion system (T3SS). Baicalin treatment reduced the cellular toxicity of P. aeruginosa on the mammalian cells and attenuated in vivo pathogenicity in a Drosophila melanogaster infection model. In a rat pulmonary infection model, baicalin significantly reduced the severity of lung pathology and accelerated lung bacterial clearance. The PqsR of the Pseudomonas quinolone signal (PQS) system was found to be required for baicalin’s impact on T3SS. These findings indicate that baicalin is a promising therapeutic candidate for treating P. aeruginosa infections.

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