Pseudomonas aeruginosa is an opportunistic pathogen that is a leading cause of morbidity and mortality in cystic fibrosis patients and immunocompromised individuals. Eradication of P. aeruginosa has ...become increasingly difficult due to its remarkable capacity to resist antibiotics. Strains of Pseudomonas aeruginosa are known to utilize their high levels of intrinsic and acquired resistance mechanisms to counter most antibiotics. In addition, adaptive antibiotic resistance of P. aeruginosa is a recently characterized mechanism, which includes biofilm-mediated resistance and formation of multidrug-tolerant persister cells, and is responsible for recalcitrance and relapse of infections. The discovery and development of alternative therapeutic strategies that present novel avenues against P. aeruginosa infections are increasingly demanded and gaining more and more attention. Although mostly at the preclinical stages, many recent studies have reported several innovative therapeutic technologies that have demonstrated pronounced effectiveness in fighting against drug-resistant P. aeruginosa strains. This review highlights the mechanisms of antibiotic resistance in P. aeruginosa and discusses the current state of some novel therapeutic approaches for treatment of P. aeruginosa infections that can be further explored in clinical practice.
COVID‐19 and cutaneous manifestations: a systematic review Zhao, Qing; Fang, Xiaokai; Pang, Zheng ...
JEADV. Journal of the European Academy of Dermatology and Venereology/Journal of the European Academy of Dermatology and Venereology,
November 2020, Letnik:
34, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The cutaneous manifestations of COVID‐19 patients have been increasingly reported, but not summarized, and the potential mechanisms remain to be investigated. Herein, we performed a comprehensive ...review of literatures (from inception to 30 May 2020) using PubMed, CNKI, medRxiv and bioRxiv with the terms “((novel coronavirus) OR (2019 novel coronavirus) OR (2019‐nCoV) OR (Coronavirus disease 2019) OR (COVID‐19) OR (SARS‐CoV‐2)) AND ((Dermatology) OR (skin) OR (rash) OR (cutaneous))” and “((ACE2) OR (Angiotensin‐converting enzyme)) AND ((skin) OR (epidermis) OR (dermis)).” Totally, 44 articles met the inclusion criteria. A total of 507 patients with cutaneous manifestations were summarized, and 96.25% patients were from Europe. The average age of the patients was 49.03 (range: 5–91) with a female ratio of 60.44%. The skin lesions were polymorphic, and erythema, chilblain‐like and urticarial lesions were most common, occurring on an average of 9.92 days (range: 1–30) after the onset of systemic symptoms. The receptor of SARS‐CoV‐2, ACE2, was found to be expressed on skin, mainly on keratinocytes. Our review systematically presented the clinical characteristics of 507 patients and showed that skin might be the potential target of the infection according to ACE2 expression. More work should be done to better understand the underlying pathogenesis.
Activation of the sympatho‐β‐adrenergic receptors (β‐ARs) system is a hallmark of heart failure, leading to fibrosis and arrhythmias. Connexin 43 (Cx43) is the most abundant gap junctional protein in ...the myocardium. Current knowledge is limited regarding Cx43 remodelling in diverse cell types in the diseased myocardium and the underlying mechanism. We studied cell type‐dependent changes in Cx43 remodelling due to β‐AR overactivation and molecular mechanisms involved. Mouse models of isoproterenol stimulation or transgenic cardiomyocyte overexpression of β2‐AR were used, which exhibited cardiac fibrosis and up‐regulated total Cx43 abundance. In both models, whereas Cx43 expression in cardiomyocytes was reduced and more laterally distributed, fibroblasts exhibited elevated Cx43 expression and enhanced gap junction communication. Mechanistically, activation of β2‐AR in fibroblasts in vitro elevated Cx43 expression, which was abolished by the β2‐antagonist ICI‐118551 or protein kinase A inhibitor H‐89, but simulated by the adenylyl cyclase activator forskolin. Our in vitro and in vivo data showed that β‐AR activation‐induced production of IL‐18 sequentially stimulated Cx43 expression in fibroblasts in a paracrine fashion. In summary, our findings demonstrate a pivotal role of β‐AR in mediating distinct and cell type‐dependent changes in the expression and distribution of Cx43, leading to pathological gap junction remodelling in the myocardium.
Pseudomonas aeruginosa
is an opportunistic pathogen causing life-threatening infections in cystic fibrosis patients and immunocompromised individuals, and it is a leading cause of nosocomial ...infections associated with significant morbidity and mortality. Treatment of
P. aeruginosa
infections is challenging due to the antibiotic resistance to most of the conventional antibiotics. Development of alternative therapeutic options is urgently demanded for the patients who have antibiotic-resistant infections. Traditional Chinese medicine (TCM) has a clinical history of thousands of years for prevention and treatment of infectious diseases in China, taking advantages of improving clinical outcomes, producing less side effects, inhibiting pathogen, and modulating host immunity. Recent research has revealed a variety of natural products derived from TCM showing significant antimicrobial effects on antibiotic-resistant strains of
P. aeruginosa
alone or combined with antibiotics
in vitro
or in animal models, suggesting that TCM is a promising complementary and alternative therapeutic approach for treatment of chronic
P. aeruginosa
infections. This review summarizes the recent findings attempting to dissect the mechanisms of TCM combating
P. aeruginosa
infections and highlights the molecular targets of TCM on
P. aeruginosa
and host.
The friction spot welding (FSpW) method was used to weld 2198-T8 Al-Li alloy at rotational speeds of 500 rpm, 1000 rpm, and 1800 rpm. It was shown that the grains in the FSpW joints were transformed ...from "pancake" grains to fine equiaxed grains by the heat input of welding, and the reinforcing phases of S' and θ were all redissolved into the Al matrix. This leads to a decrease in the tensile strength of the FsPW joint compared to the base material and a change in the fracture mechanism from mixed ductile-brittle fracture to ductile fracture. Finally, the tensile properties of the welded joint depend on the size and morphology of the grains and their dislocation density. At the rotational speed setting of 1000 rpm in this paper, the mechanical properties of welded joints consisting of fine and uniformly distributed equiaxed grains are best. Therefore, a reasonable set of the rotational speed of FSpW can improve the mechanical properties of the welded joints of 2198-T8 Al-Li alloy.
is an opportunistic pathogen that causes life-threatening infections in cystic fibrosis patients and immunocompromised individuals. A tightly regulated immune response possessed by healthy ...individuals can effectively control
infections, whereas the patients with dysregulated immune response are susceptible to this bacterial pathogen. Early growth response 1 (Egr-1) is a zinc-finger transcription factor involved in regulation of various cellular functions, including immune responses. We previously identified that Egr-1 was deleterious to host in a mouse model of acute
pneumonia by promoting systemic inflammation and impairing bacterial clearance in lung, which associated with reduced phagocytosis and bactericidal ability of leucocytes, including macrophages and neutrophils. However, the molecular mechanisms underlying the Egr-1-suppressed phagocytosis of
are incompletely understood. Herein, we investigated whether the Egr-1-regulated autophagy play a role in macrophage phagocytosis during
infection by overexpression or knockdown of Egr-1. We found that overexpression of Egr-1 inhibited the phagocytic activity of macrophages, and the autophagy activator rapamycin and inhibitor chloroquine could reverse the effects of Egr-1 knockdown and Egr-1 overexpression on phagocytosis of
, respectively. Furthermore, the Egr-1-overexpressing macrophages displayed upregulated expression of autophagy-related proteins LC3A, LC3B and Atg5, and decreased levels of p62 in macrophages. Further studies revealed that the macrophages with Egr-1 knockdown displayed enhanced activation of transcription factor NRF2 and expression of scavenger receptors MACRO and MSR1. Altogether, these findings suggest that Egr-1 suppresses the phagocytosis of
by macrophages through upregulation of autophagy and inhibition of NRF2 signaling.
Neuregulin-4 (Nrg4) is a newly discovered adipokine that is synthesized in many tissues and plays an important role in modulating systemic energy metabolism and in the development of metabolic ...disorders. However, little is known about the relationship between Nrg4 and coronary artery disease (CAD). In this study, we investigated the association between Nrg4 and the presence and severity of CAD.We enrolled 73 patients diagnosed by coronary angiography (CAG) as having CAD and 32 controls. The CAD group was divided into two subgroups according to their SYNTAX score. Plasma levels of Nrg4 were measured in all participants and compared among different groups. The relationship between Nrg4 and CAD was analyzed. Receiver operating characteristic (ROC) analysis was conducted to evaluate the usefulness Nrg4 in assessing the presence and severity of CAD.Nrg4 levels were negatively associated with the SYNTAX score (r = −0.401, P = 0.000). The patients with a higher SYNTAX score had significantly lower Nrg4 levels as compared with the low SYNTAX score subgroup and the controls (P < 0.05). The Nrg4 levels of the low SYNTAX score subgroup were much lower than controls (P < 0.05). Furthermore, an association between Nrg4 and CAD (odds ratio, 0.279; 95% confidence interval, 0.088-0.882) was observed. Nrg4 had 43.8% sensitivity and 96.9% specificity for identifying CAD, and 73.1% sensitivity and 87.3% specificity for identifying patients who had severe coronary artery lesions.Nrg4 levels were found to be inversely associated with the presence and severity of CAD.
Drug resistance, undesirable toxicity and lack of selectivity are the major challenges of conventional cancer therapies, which cause poor clinical outcomes and high mortality in many cancer patients. ...Development of alternative cancer therapeutics are highly required for the patients who are resistant to the conventional cancer therapies, including radiotherapy and chemotherapy. The success of a new cancer therapy depends on its high specificity to cancer cells and low toxicity to normal cells. Utilization of bacteria has emerged as a promising strategy for cancer treatment. Attenuated or genetically modified bacteria were used to inhibit tumor growth, modulate host immunity, or deliver anti-tumor agents. The bacteria-derived immunotoxins were capable of destructing tumors with high specificity. These bacteria-based strategies for cancer treatment have shown potent anti-tumor effects both
and
, and some of them have proceeded to clinical trials.
, a Gram-negative bacterial pathogen, is one of the common bacteria used in development of bacteria-based cancer therapy, particularly known for the
exotoxin A-based immunotoxins, which have shown remarkable anti-tumor efficacy and specificity. This review concisely summarizes the current knowledge regarding the utilization of
in cancer treatment, and discusses the challenges and future perspectives of the
-based therapeutic strategies.
Mitochondrial dysfunction facilitates heart failure development forming a therapeutic target, but the mechanism involved remains unclear. We studied whether the Hippo signaling pathway mediates ...mitochondrial abnormalities that results in onset of dilated cardiomyopathy (DCM).
Mice with DCM due to overexpression of Hippo pathway kinase Mst1 were studied. DCM phenotype was evident in adult animals but contractile dysfunction was identified as an early sign of DCM at 3 weeks postnatal. Electron microscopy, multi-omics and biochemical assays were employed.
In 3-week and adult DCM mouse hearts, cardiomyocyte mitochondria exhibited overt structural abnormalities, smaller size and greater number. RNA sequencing revealed comprehensive suppression of nuclear-DNA (nDNA) encoded gene-sets involved in mitochondria turnover and all aspects of metabolism. Changes in cardiotranscriptome were confirmed by lower protein levels of multiple mitochondrial proteins in DCM heart of both ages. Mitochondrial DNA-encoded genes were also downregulated; due apparently to repression of nDNA-encoded transcriptional factors. Lipidomics identified remodeling in cardiolipin acyl-chains, increased acylcarnitine content but lower coenzyme Q10 level. Mitochondrial dysfunction was featured by lower ATP content and elevated levels of lactate, branched-chain amino acids and reactive oxidative species. Mechanistically, inhibitory YAP-phosphorylation was enhanced, which was associated with attenuated binding of transcription factor TEAD1. Numerous suppressed mitochondrial genes were identified as YAP-targets.
Hippo signaling activation mediates mitochondrial damage by repressing mitochondrial genes, which causally promotes the development of DCM. The Hippo pathway therefore represents a therapeutic target against mitochondrial dysfunction in cardiomyopathy.
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