Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) initiates the cytokine/chemokine storm-mediated lung injury. The SARS-CoV unique domain (SUD) with three macrodomains (N, M, and ...C), showing the G-quadruplex binding activity, was examined the possible role in SARS pathogenesis in this study. The chemokine profile analysis indicated that SARS-CoV SUD significantly up-regulated the expression of CXCL10, CCL5 and interleukin (IL)-1β in human lung epithelial cells and in the lung tissues of the mice intratracheally instilled with the recombinant plasmids. Among the SUD subdomains, SUD-MC substantially activated AP-1-mediated CXCL10 expression in vitro. In the wild type mice, SARS-CoV SUD-MC triggered the pulmonary infiltration of macrophages and monocytes, inducing CXCL10-mediated inflammatory responses and severe diffuse alveolar damage symptoms. Moreover, SUD-MC actuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-dependent pulmonary inflammation, as confirmed by the NLRP3 inflammasome inhibitor and the NLRP3
mouse model. This study demonstrated that SARS-CoV SUD modulated NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, providing the potential therapeutic targets for developing the antiviral agents.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The large amounts of engineered titanium dioxide nanoparticles (TiO2NPs) that have been manufactured have inevitably been released into the ecosystem. Reports have suggested that TiO2 is a relatively ...inert material that has low toxicity to animals. However, as various types of NPs increasingly accumulate in the ocean, their effects on aquatic life-forms remain unclear. In this study, a zebrafish model was used to investigate TiO2NP-induced injury and mortality. We found that the treatment dosages of TiO2NP are positively associated with increased motility of zebrafish and the bacterial counts in the water. Notably, gill but not dorsal fin and caudal fin of the zebrafish displayed considerably increased bacterial load. Metagenomic analysis further revealed that gut microflora, such as phyla Proteobacteria, Bacteroidetes, and Actinobacteria, involving more than 95% of total bacteria counts in the NP-injured zebrafish gill samples. These results collectively suggest that opportunistic bacterial infections are associated with TiO2NP-induced mortality in zebrafish. Infections secondary to TiO2NP-induced injury could be a neglected factor determining the detrimental effects of TiO2NPs on wild fish.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This review focuses on the antibacterial activities of visible light-responsive titanium dioxide (TiO
2
) photocatalysts. These photocatalysts have a range of applications including disinfection, air ...and water cleaning, deodorization, and pollution and environmental control. Titanium dioxide is a chemically stable and inert material, and can continuously exert antimicrobial effects when illuminated. The energy source could be solar light; therefore, TiO
2
photocatalysts are also useful in remote areas where electricity is insufficient. However, because of its large band gap for excitation, only biohazardous ultraviolet (UV) light irradiation can excite TiO
2
, which limits its application in the living environment. To extend its application, impurity doping, through metal coating and controlled calcination, has successfully modified the substrates of TiO
2
to expand its absorption wavelengths to the visible light region. Previous studies have investigated the antibacterial abilities of visible light-responsive photocatalysts using the model bacteria
Escherichia coli
and human pathogens. The modified TiO
2
photocatalysts significantly reduced the numbers of surviving bacterial cells in response to visible light illumination. They also significantly reduced the activity of bacterial endospores; reducing their toxicity while retaining their germinating abilities. It is suggested that the photocatalytic killing mechanism initially damages the surfaces weak points of the bacterial cells, before totally breakage of the cell membranes. The internal bacterial components then leak from the cells through the damaged sites. Finally, the photocatalytic reaction oxidizes the cell debris. In summary, visible light-responsive TiO
2
photocatalysts are more convenient than the traditional UV light-responsive TiO
2
photocatalysts because they do not require harmful UV light irradiation to function. These photocatalysts, thus, provide a promising and feasible approach for disinfection of pathogenic bacteria; facilitating the prevention of infectious diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Dengue hemorrhagic fever (DHF) is a severe form of dengue virus (DENV) infection that can lead to abnormal immune responses, endothelial vascular dysfunction, and hemorrhage pathogenesis. The ...virion-associated envelope protein domain III (EIII) is thought to play a role in the virulence of DENV by damaging endothelial cells. However, it is unclear whether EIII-coated nanoparticles simulating DENV virus particles could cause a more severe pathogenesis than soluble EIII alone. This study aimed to investigate whether EIII-coated silica nanoparticles (EIII-SNPs) could elicit greater cytotoxicity in endothelial cells and hemorrhage pathogenesis in mice compared to EIII or silica nanoparticles alone. The main methods included in vitro assays to assess cytotoxicity and in vivo experiments to examine hemorrhage pathogenesis in mice. EIII-SNPs induced greater endothelial cytotoxicity in vitro than EIII or silica nanoparticles alone. Two-hit combined treatment with EIII-SNPs and antiplatelet antibodies to simulate DHF hemorrhage pathogenesis during secondary DENV infections resulted in higher endothelial cytotoxicity than either treatment alone. In mouse experiments, two-hit combined treatment with EIII-SNPs and antiplatelet antibodies resulted in more severe hemorrhage pathogenesis compared to single treatments of EIII, EIII-SNPs, or antiplatelet antibodies alone. These findings suggest that EIII-coated nanoparticles are more cytotoxic than soluble EIII and could be used to develop a tentative dengue two-hit hemorrhage pathogenesis model in mice. Additionally, our results indicated that EIII-containing DENV particles could potentially exacerbate hemorrhage pathogenesis in DHF patients who have antiplatelet antibodies, highlighting the need for further research on the potential role of EIII in DHF pathogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Psychological stress is associated with increased risk of gastrointestinal (GI) tract diseases. Evidence indicated that platelets facilitate GI tissue repair in intestinal anastomosis models. ...However, whether platelets are involved in native mechanism of the rescue of stress-induced GI injury for maintaining the GI homeostasis remains elusive. Because P-selectin-deficient (Selp−/−) mice displayed higher stress-induced GI injury compared to the wild-type (Selp+/+) mice, and P-selectin is specifically expressed in platelets, we hypothesize that P-selectin-expressing platelets play a protective role in the rescue of stress-induced GI injury. Our goal is to clarify the putative protective role of platelets in a GI system, thereby develop a feasible intervention strategy, such as platelet transfer, to overcome stress-induced GI injury. Through monitoring the plasma levels of GI-nonabsorbable Evans blue dye to reveal the progression course of GI injury in live mice, we found that intravenous treatments of purified platelets ameliorated stress-induced GI leakage. The transfer of platelets from wild-type mice was more potent than from Selp−/− mice in the rescue of stress-induced-GI leakage in the recipients. As such, platelet transfer-mediated rescue was conducted in a P-selectin dependent manner. Additionally, platelet-mediated protection is associated with corrections of stress-induced aberrant GI mRNA expressions, including tight junctions claudin 3 and occludin, as well as stress-induced genes activating transcription factor 3 and AMP-activated protein kinase, after the transfer of wild-type platelets into wild-type and Selp−/− mice. Furthermore, the stress-induced apoptosis of CD326+ GI epithelial cells was rescued by the transfer of wild type, but not P-selectin-deficient platelets. These results suggest that platelet plays a protective role for maintaining the GI homeostasis during stress in vivo, and that P-selectin is a molecular target for managing stress-induced GI tract injury.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ultraviolet (UV) radiation from sunlight has various adverse effects; thus, UV blockage is recommended for preventing sunburn. Common sunscreen ingredients, such as nanosized titanium dioxide and ...zinc oxide, offer effective protection and enhance cosmetic appearance; however, health concerns have been raised regarding their photocatalytic activity, which generates reactive oxygen species under UV illumination. Silver nanoparticles (AgNPs) are known as safe materials for use in a wide spectrum of biomedical applications. In vitro studies have revealed that AgNPs may have a protective effect against UV irradiation, but the effects in animal studies remain unclear. The present study demonstrated that AgNPs effectively protect against UVB-induced skin damage both in cell cultures and mouse models. These results suggested that AgNPs are feasible and safe as sunscreen ingredients for protection against UVB-induced skin damage.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Metformin is one of the most commonly used drugs for type 2 diabetes mellitus. In addition to its anti-diabetic property, evidence suggests more potential applications for metformin, such as ...antiaging, cellular protection, and anti-inflammation. Studies have reported that metformin activates pathways with anti-inflammatory effects, enhances the integrity of gut epithelial tight junctions, and promotes a healthy gut microbiome. These actions contribute to the protective effect of metformin against gastrointestinal (GI) tract injury. However, whether metformin plays a protective role in psychological-stress-associated GI tract injury remains elusive. We aim to elucidate the potential protective effect of metformin on the GI system and develop an effective intervention strategy to counteract GI injury induced by acute psychological stress. By monitoring the levels of GI-nonabsorbable Evans blue dye in the bloodstream, we assessed the progression of GI injury in live mice. Our findings demonstrate that the administration of metformin effectively mitigated GI leakage caused by psychological stress. The GI protective effect of metformin is more potent when used on wild-type mice than on activating-transcription-factor 3 (ATF3)-deficient (
) mice. As such, metformin-mediated rescue was conducted in an ATF3-dependent manner. In addition, metformin-mediated protection is associated with the induction of stress-induced GI mRNA expressions of the stress-induced genes ATF3 and AMP-activated protein kinase. Furthermore, metformin treatment-mediated protection of CD326
GI epithelial cells against stress-induced apoptotic cell death was observed in wild-type but not in
mice. These results suggest that metformin plays a protective role in stress-induced GI injury and that ATF3 is an essential regulator for metformin-mediated rescue of stress-induced GI tract injury.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Lethal toxin (LT) is the critical virulence factor of
, the causative agent of anthrax. One common symptom observed in patients with anthrax is thrombocytopenia, which has also been observed in mice ...injected with LT. Our previous study demonstrated that LT induces thrombocytopenia by suppressing megakaryopoiesis, but the precise molecular mechanisms behind this phenomenon remain unknown. In this study, we utilized 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocytic differentiation in human erythroleukemia (HEL) cells to identify genes involved in LT-induced megakaryocytic suppression. Through cDNA microarray analysis, we identified Dachshund homolog 1 (
) as a gene that was upregulated upon TPA treatment but downregulated in the presence of TPA and LT, purified from the culture supernatants of
. To investigate the function of DACH1 in megakaryocytic differentiation, we employed short hairpin RNA technology to knock down DACH1 expression in HEL cells and assessed its effect on differentiation. Our data revealed that the knockdown of DACH1 expression suppressed megakaryocytic differentiation, particularly in polyploidization. We demonstrated that one mechanism by which
LT induces suppression of polyploidization in HEL cells is through the cleavage of MEK1/2. This cleavage results in the downregulation of the ERK signaling pathway, thereby suppressing
gene expression and inhibiting polyploidization. Additionally, we found that known megakaryopoiesis-related genes, such as
,
,
,
,
, and
genes may be positively regulated by
. Furthermore, we observed an upregulation of DACH1 during in vitro differentiation of CD34-megakaryocytes and downregulation of DACH1 in patients with thrombocytopenia. In summary, our findings shed light on one of the molecular mechanisms behind LT-induced thrombocytopenia and unveil a previously unknown role for DACH1 in megakaryopoiesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Typically occurring during secondary dengue virus (DENV) infections, dengue hemorrhagic fever (DHF) causes abnormal immune responses, as well as endothelial vascular dysfunction, for which the ...responsible viral factor remains unclear. During peak viremia, the plasma levels of virion-associated envelope protein domain III (EIII) increases to a point at which cell death is sufficiently induced in megakaryocytes
. Thus, EIII may constitute a virulence factor for endothelial damage. In this study, we examined endothelial cell death induced by treatment with DENV and EIII
. Notably, pyroptosis, the major type of endothelial cell death observed, was attenuated through treatment with Nlrp3 inflammasome inhibitors. EIII injection effectively induced endothelial abnormalities, and sequential injection of EIII and DENV-NS1 autoantibodies induced further vascular damage, liver dysfunction, thrombocytopenia, and hemorrhage, which are typical manifestations in DHF. Under the same treatments, pathophysiological changes in the Nlrp3 inflammasome-deficient mice were notably reduced compared with those in the wild-type mice. These results suggest that the Nlrp3 inflammasome constitutes a potential therapeutic target for treating DENV-induced hemorrhage in DHF.
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