Antibiotics have made it possible to treat bacterial infections such as meningitis and bacteraemia that, prior to their introduction, were untreatable and consequently fatal. Unfortunately, in recent ...decades overuse and misuse of antibiotics as well as social and economic factors have accelerated the spread of antibiotic-resistant bacteria, making drug treatment ineffective. Currently, at least 700,000 people worldwide die each year due to antimicrobial resistance (AMR). Without new and better treatments, the World Health Organization (WHO) predicts that this number could rise to 10 million by 2050, highlighting a health concern not of secondary importance. In February 2017, in light of increasing antibiotic resistance, the WHO published a list of pathogens that includes the pathogens designated by the acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) to which were given the highest “priority status” since they represent the great threat to humans. Understanding the resistance mechanisms of these bacteria is a key step in the development of new antimicrobial drugs to tackle drug-resistant bacteria. In this review, both the mode of action and the mechanisms of resistance of commonly used antimicrobials will be examined. It also discusses the current state of AMR in the most critical resistant bacteria as determined by the WHO’s global priority pathogens list.
Little is known of how and where bacterial recognition triggers the induction of type I interferon. Whether the type of recognition receptor used in these responses is determined by the subcellular ...location of bacteria is not understood. Here we show that phagosomal bacteria such as group B streptococcus, but not cytosolic bacteria, potently induced interferon in conventional dendritic cells by a mechanism that required Toll-like receptor 7, the adaptor MyD88 and the transcription factor IRF1, all of which localized together with bacterial products in degradative vacuoles bearing lysosomal markers. Thus, this cell type-specific recognition pathway links lysosomal recognition of bacterial RNA with a robust, host-protective interferon response.
Mitochondrial fusion depends on the dynamin-like guanosine triphosphatase OPA1, whose activity is controlled by proteolytic cleavage. Dysfunction of mitochondria induces OPA1 processing and results ...in mitochondrial fragmentation, allowing the selective removal of damaged mitochondria. In this study, we demonstrate that two classes of metallopeptidases regulate OPA1 cleavage in the mitochondrial inner membrane: isoenzymes of the adenosine triphosphate (ATP)-dependent matrix AAA (ATPase associated with diverse cellular activities m-AAA) protease, variable assemblies of the conserved subunits paraplegin, AFG3L1 and -2, and the ATP-independent peptidase OMA1. Functionally redundant isoenzymes of the m-AAA protease ensure the balanced accumulation of long and short isoforms of OPA1 required for mitochondrial fusion. The loss of AFG3L2 in mouse tissues, down-regulation of AFG3L1 and -2 in mouse embryonic fibroblasts, or the expression of a dominant-negative AFG3L2 variant in human cells decreases the stability of long OPA1 isoforms and induces OPA1 processing by OMA1. Moreover, cleavage by OMA1 causes the accumulation of short OPA1 variants if mitochondrial DNA is depleted or mitochondrial activities are impaired. Our findings link distinct peptidases to constitutive and induced OPA1 processing and shed new light on the pathogenesis of neurodegenerative disorders associated with mutations in m-AAA protease subunits.
Urinary tract infections (UTIs) are among the most common bacterial infections worldwide, occurring in both community and healthcare settings. Although the clinical symptoms of UTIs are heterogeneous ...and range from uncomplicated (uUTIs) to complicated (cUTIs), most UTIs are usually treated empirically. Bacteria are the main causative agents of these infections, although more rarely, other microorganisms, such as fungi and some viruses, have been reported to be responsible for UTIs. Uropathogenic
(UPEC) is the most common causative agent for both uUTIs and cUTIs, followed by other pathogenic microorganisms, such as
,
,
and
spp. In addition, the incidence of UTIs caused by multidrug resistance (MDR) is increasing, resulting in a significant increase in the spread of antibiotic resistance and the economic burden of these infections. Here, we discuss the various factors associated with UTIs, including the mechanisms of pathogenicity related to the bacteria that cause UTIs and the emergence of increasing resistance in UTI pathogens.
The implementation of nature-based solutions (NBSs) can be a suitable and sustainable approach to coping with environmental issues related to diffuse water pollution from agriculture. NBSs exploit ...natural mitigation processes that can promote the removal of different contaminants from agricultural wastewater, and they can also enable the recovery of otherwise lost resources (i.e., nutrients). Among these, nitrogen impacts different ecosystems, resulting in serious environmental and human health issues. Recent research activities have investigated the capability of NBS to remove nitrogen from polluted water. However, the regulating mechanisms for nitrogen removal can be complex, since a wide range of decontamination pathways, such as plant uptake, microbial degradation, substrate adsorption and filtration, precipitation, sedimentation, and volatilization, can be involved. Investigating these processes is beneficial for the enhancement of the performance of NBSs. The present study provides a comprehensive review of factors that can influence nitrogen removal in different types of NBSs, and the possible strategies for nitrogen recovery that have been reported in the literature.
Ruta graveolens (rue) is a spontaneous plant in the Mediterranean area with a strong aroma and a very intense bitter taste, used in gastronomy and in folk medicine. From the leaves, stems and fruits ...of rue, we isolated rutin, rutamarin, three furanocoumarins, two quinolinic alkaloids, a dicoumarin and two long chain ketones. Bitter taste and chemesthetic properties have been evaluated by in vitro assays with twenty receptors of the TAS2R family and four TRP ion channels involved in gustation and nociception. Among the alkaloids, skimmianine was active as a specific agonist of T2R14, whereas kokusaginin did not activate any of the tested receptors. The furanocoumarins activates TAS2R10, 14, and 49 with different degrees of selectivity, as well as the TRPA1 somatosensory ion channel. Rutamarin is an agonist of TRPM5 and TRPV1 and a strong antagonist of TRPM8 ion channels.
Group B Streptococcus (GBS) is a frequent agent of life-threatening sepsis and meningitis in neonates and adults with predisposing conditions. We tested the hypothesis that activation of the ...inflammasome, an inflammatory signaling complex, is involved in host defenses against this pathogen. We show in this study that murine bone marrow-derived conventional dendritic cells responded to GBS by secreting IL-1β and IL-18. IL-1β release required both pro-IL-1β transcription and caspase-1-dependent proteolytic cleavage of intracellular pro-IL-1β. Dendritic cells lacking the TLR adaptor MyD88, but not those lacking TLR2, were unable to produce pro-IL-1β mRNA in response to GBS. Pro-IL-1β cleavage and secretion of the mature IL-1β form depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) sensor and the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain adaptor. Moreover, activation of the NLRP3 inflammasome required GBS expression of β-hemolysin, an important virulence factor. We further found that mice lacking NLRP3, apoptosis-associated speck-like protein, or caspase-1 were considerably more susceptible to infection than wild-type mice. Our data link the production of a major virulence factor by GBS with the activation of a highly effective anti-GBS response triggered by the NLRP3 inflammasome.
The purpose of our study was to compare diagnostic performance of old and new Lake Louise Criteria (oLLC and nLLC) among different clinical presentations: infarct-like (IL), cardiomyopathic (CM) and ...arrhythmic (AR). 102 patients with clinical suspicion of acute myocarditis underwent cardiac magnetic resonance (CMR) on a 1.5 T scanner. Protocol included cine-SSFP, T2-weighted STIR, T2 mapping, early and late gadolinium enhancement and T1 mapping acquired before and after gadolinium administration. The degree of agreement has been calculated with Cohen’s K test. 42 patients also underwent endomyocardial biopsy (EMB). IL onset was present in 54/102 patients, CM in 28/102 and AR in 20/102. nLLC were positive in 58.3% of the patients, while oLLC in 37.9%, k = 0.57 (IC: 0.428–0.713). The degree of agreement between nLLC and oLLC was 0.49 (IC: 0.111–0.876) for AR onset (nLLC positive in 35% vs oLLC in 15%), 0.25 (IC: 0.035–0.459) for CM pattern (nLLC positive in 60.7% vs oLLC 17.9%) and 0.73 (IC: 0.543–0.912) for IL presentation (nLLC positive in 66.7% vs oLLC in 57.4%). Diagnostic accuracy was 75% for both nLLC and oLLC among IL onset, and 41.6% for oLLC vs 66.7% for nLLC, as regards CM clinical presentation. nLLC have improved diagnostic performance of CMR for the diagnosis of acute myocarditis, in particular for atypical clinical presentation.
TLR7/8 in the Pathogenesis of Parkinson's Disease Campolo, Michela; Filippone, Alessia; Biondo, Carmelo ...
International journal of molecular sciences,
12/2020, Letnik:
21, Številka:
24
Journal Article
Recenzirano
Odprti dostop
Neuroinflammation and autoimmune mechanisms have a key part in the pathogenesis of Parkinson's disease (PD). Therefore, we evaluated the role of Toll-like receptors (TLRs) as a link between ...inflammation and autoimmunity in PD. An in vivo model of PD was performed by administration of 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) at the dose of 20 mg/kg every 2 h for a total administration of 80/kg, both in single Knock Out (KO) mice for TLR7, TLR 8, and TLR9 and in double KO mice for TLR 7/8
. All animals were compared with WT animals used as a control group. All animals were sacrificed after 7 days form the first administration of MPTP. The genetic absence of TLR 7 and 8 modified the PD pathway, increasing the immunoreactivity for TH and DAT compared to PD groups and decreasing microglia and astrocytes activation. Moreover, the deletion of TLR7 and TLR8 significantly reduced T-cell infiltration in the substantia nigra and lymph nodes, suggesting a reduction of T-cell activation. Therefore, our result highlights a possibility that an immunotherapy approach, by using a dual antagonist of TLR 7 and 8, could be considered as a possible target to develop new therapies for Parkinson diseases.
Coronavirus disease 2019 (COVID-19) is a potentially serious acute respiratory infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the World Health Organization ...(WHO) declared COVID-19 a global pandemic, the virus has spread to more than 200 countries with more than 500 million cases and more than 6 million deaths reported globally. It has long been known that viral respiratory tract infections predispose patients to bacterial infections and that these co-infections often have an unfavourable clinical outcome. Moreover, nosocomial infections, also known as healthcare-associated infections (HAIs), are those infections that are absent at the time of admission and acquired after hospitalization. However, the impact of coinfections or secondary infections on the progression of COVID-19 disease and its lethal outcome is still debated. The aim of this review was to assess the literature on the incidence of bacterial co-infections and superinfections in patients with COVID-19. The review also highlights the importance of the rational use of antibiotics in patients with COVID-19 and the need to implement antimicrobial stewardship principles to prevent the transmission of drug-resistant organisms in healthcare settings. Finally, alternative antimicrobial agents to counter the emergence of multidrug-resistant bacteria causing healthcare-associated infections in COVID-19 patients will also be discussed.
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