Dysfunctional endothelial cell (EC) barrier and increased lung vascular permeability is a cardinal feature of acute lung injury and sepsis that may result in a pathophysiological condition ...characterized by alveolar flooding, pulmonary edema, and subsequent hypoxemia. In lung ECs, activation of Rho-associated kinase-1 (ROCK1) phosphorylates myosin light chain (MLC)-associated phosphatase at its inhibitory site, which favors phosphorylation of MLC, stress fiber formation, and hyperpermeability during acute lung injury. The role of microRNA-144 (miR-144) has been well investigated in many human diseases, including cardiac ischemia/reperfusion-induced injury, lung cancer, and lung viral infection; however, its role in pulmonary EC barrier regulation remains obscure. Here, we investigated the miR-144-mediated mechanism in the protection of endothelial barrier function in an LPS-induced lung injury model. By using transendothelial electrical resistance and transwell permeability assay to examine
permeability and immunofluorescence microscopy to determine barrier integrity, we showed that ectopic expression of miR-144 effectively blocked lung EC barrier disruption and hyperpermeability in response to proinflammatory agents. Furthermore, using a gain-and-loss-of-function strategy, overexpression of miR-144 significantly decreased ROCK1 expression. Concomitantly, miR-144 inhibits ROCK1-mediated phosphorylation of MLC phosphatase
and thus phosphorylation of MLC
to counteract stress fiber formation in LPS-activated EC. Finally, in LPS-challenged mice, intranasal delivery of miR-144 mimic via liposomes attenuated endotoxemia-induced increases in lung wet/dry ratio, vascular permeability, and inflammation. In conclusion, these data suggest that miR-144-attenuated activation of inflammatory ROCK1/MLC pathway in vascular ECs is a promising therapeutic strategy to counter inflammatory lung injury.
Autoimmune Haemolytic Anaemia (AIHA) is a rare haematological disorder characterised by autoantibodies directed against autologous red blood cells. It can be idiopathic or secondary and classified as ...Warm type AIHA (WAIHA), cold, or mixed. The primary treatment for WAIHA is a long course of steroid administration, which has an early response rate of 80-90%. However, up to 20-30% of patients require second-line therapy. In the last decade, rituximab has replaced splenectomy as the first-choice therapy for refractory WAIHA patients due to its efficacy and safety. There is a paucity of reported cases of WAIHA refractory to both steroids and rituximab that have responded to splenectomy. This is a case of a 35-year-old female with a history of jaundice and anaemia for the past two years. The patient was diagnosed with WAIHA with a Direct Antibody Test (DAT) positive, IgG positive, and C3d negative results, and massive splenomegaly that was initially refractory to steroids and rituximab but responded to splenectomy. Significant splenomegaly may be an indication for choosing splenectomy over rituximab as a second-line treatment in steroid-refractory WAIHA.
Sepsis remains one of the leading causes of death in burn patients who survive the initial insult of injury. Disruption of the intestinal epithelial barrier has been shown after burn injury; this can ...lead to the translocation of bacteria or their products (e.g., endotoxin) from the intestinal lumen to the circulation, thereby increasing the risk for sepsis in immunocompromised individuals. Since the maintenance of the epithelial barrier is largely dependent on the intestinal microbiota, we examined the diversity of the intestinal microbiome of severely burned patients and a controlled mouse model of burn injury. We show that burn injury induces a dramatic dysbiosis of the intestinal microbiome of both humans and mice and allows for similar overgrowths of Gram-negative aerobic bacteria. Furthermore, we show that the bacteria increasing in abundance have the potential to translocate to extra-intestinal sites. This study provides an insight into how the diversity of the intestinal microbiome changes after burn injury and some of the consequences these gut bacteria can have in the host.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vitiligo is impacted by environmental triggers. We studied the contribution of the microbiome in FH mice, in which depigmentation is mediated by tyrosinase-reactive T cells. The mice received oral ...antibiotics and were monitored for depigmentation. The microbiome was studied in fecal and skin samples using 16S rRNA analysis. The resulting T-cell distributions were evaluated. In untreated mice, pigment loss did not expand to the pelage, whereas mice in the ampicillin group were approximately 1/3 depigmented at 30 weeks. In contrast to models of autoimmunity that are less dependent on IFN-γ, ampicillin but not neomycin treatment correlated with accelerated disease and reduced bacteria in the fecal pellets. Modified cytokine patterns in the tissue and serum suggest a response that transcends the gut. Ampicillin-induced depigmentation was accompanied by gut but not skin dysbiosis, and reduced T cell numbers in both sites. Neomycin induced a redistribution of gut T cells and an accumulation of skin regulatory T cells. This treatment spurred a Bacteroides-dominated population of fecal bacteria. Reduced diversity is prominent particularly after ampicillin treatment, when the gut is dominated by Pseudomonas species. In line with current concepts relating the microbiome and the immune system, we predict that dietary measures might promote skin health and delay vitiligo onset.
Shigella sonnei is a gram-negative bacterium and is the primary cause of shigellosis in advanced countries. An exceptional rise in the prevalence of the disease has been reported in Asia, the Middle ...East, and Latin America. To date, no preventive vaccine is available against S. sonnei infections. This pathogen has shown resistances towards both first- and second-line antibiotics. Therefore, an effective broad spectrum vaccine development against shigellosis is indispensable. In the present study, vaccinomics-aided immunoinformatics strategies were pursued to identify potential vaccine candidates from the S. sonnei whole proteome data. Pathogen essential proteins that are non-homologous to human and human gut microbiome proteome set, are feasible candidates for this purpose. Three antigenic outer membrane proteins were prioritized to predict lead epitopes based on reverse vaccinology approach. Multi-epitope-based chimeric vaccines was designed using lead B- and T-cell epitopes combined with suitable linker and adjuvant peptide sequences to enhance immune responses against the designed vaccine. The SS-MEVC construct was prioritized based on multiple physicochemical, immunological properties, and immune-receptors docking scores. Immune simulation analysis predicted strong immunogenic response capability of the designed vaccine construct. The Molecular dynamic simulations analysis ensured stable molecular interactions of lead vaccine construct with the host receptors. In silico restriction and cloning analysis predicted feasible cloning capability of the SS-MEVC construct within the E. coli expression system. The proposed vaccine construct is predicted to be more safe, effective and capable of inducing robust immune responses against S. sonnei infections and may be worthy of examination via in vitro/in vivo assays.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: In poor nations like India, enteric fever is a severe health issue. For the purpose of diagnosing enteric fever, the Widal test is frequently utilized. In the Western Region of India, ...this study attempted to measure the baseline antibody titres for Salmonella typhi and paratyphi A, B in healthy persons. Methods: A total of 150 blood samples from healthy persons were taken, and the pattern of antibody titre was determined using the conventional quantitative tube method. Results: Among 150 blood samples, 103 had shown significant antibody titres (≥ 1:20). The significant proportion (10.7%) of the individuals had anti-O titre ≥ 1:80. Similarly, 86 had anti-H titres of ≥ 1:20 to S. enteric serotype typhi, 23 had a titre of ≥1:80 and 4 had a titre of ≥1:160 respectively. We found 10% and 1.3% for paratyphi A and B, anti-H titres of ≥ 1:20respectively. Conclusion: The study's findings suggest that the Western Development Region of India should modify the threshold values for antibody titres against S. typhi to > 1:80 for both anti-O and anti-H titres.
Consumption of green tea polyphenols (GTPs) in drinking water prevents photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. Using ...IL-12p40 knockout (KO) mice and their wild-type counterparts and an established photocarcinogenesis protocol, we found that although administration of GTPs (0.2%, w/v) in drinking water significantly reduced UVB-induced tumor development in wild-type mice, this treatment had a nonsignificant effect in IL-12-KO mice. GTPs resulted in reduction in the levels of markers of inflammation (cyclooxygenase-2, prostaglandin E2, proliferating cell nuclear antigen, and cyclin D1) and proinflammatory cytokines (tumor necrosis factor-α, IL-6, and IL-1β) in chronically UVB-exposed skin and skin tumors of wild-type mice but less effective in IL-12p40-KO mice. UVB-induced DNA damage (cyclobutane pyrimidine dimers) was resolved rapidly in GTPs-treated wild-type mice than untreated wild-type mice and this resolution followed the same time course as the GTPs-induced reduction in the levels of inflammatory responses. This effect of GTPs was less pronounced in IL-12-KO mice. The above results were confirmed by treatment of IL-12-KO mice with murine recombinant IL-12 and treatment of wild-type mice with neutralizing anti-IL-12 antibody. To our knowledge, it is previously unreported that prevention of photocarcinogenesis by GTPs is mediated through IL-12-dependent DNA repair and a subsequent reduction in skin inflammation.
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The over-expressed colonic brain-derived neurotrophic factor (BDNF) has been reported to be associated with abdominal pain in patients with irritable bowel syndrome (IBS). However, the ...neuropathological mechanism is unclear. We here investigated the involvement of enteroglial cells (EGCs) and enteric nerves in IBS-like visceral hypersensitivity. We showed that glial fibrillary acidic protein (GFAP), tyrosine receptor kinase B (TrkB) and substance P (SP) were significantly increased in the colonic mucosa of IBS patients. The upregulation of those proteins was also observed in the colon of mice with visceral hypersensitivity, but not in the colon of BDNF(+/-) mice. Functionally, TrkB or EGC inhibitors, or BDNF knockdown significantly suppressed visceral hypersensitivity in mice. Using the EGC cell line, we found that recombinant human BDNF (r-HuBDNF) could directly activate EGCs via the TrkB-phospholipase Cγ1 pathway, thereby inducing a significant upregulation of SP. Moreover, supernatants from r-HuBDNF-activated EGC culture medium, rather than r-HuBDNF alone, triggered markedly augmented discharges in isolated intestinal mesenteric afferent nerves. r-HuBDNF alone could cause mesenteric afferent mechanical hypersensitivity independently, and this effect was synergistically enhanced by activated EGCs. We conclude that EGC-enteric nerve unit may be involved in IBS-like visceral hypersensitivity, and this process is likely initiated by BDNF-TrkB pathway activation.
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