Exploring the human hair follicle microbiome Lousada, M.B.; Lachnit, T.; Edelkamp, J. ...
British journal of dermatology (1951),
20/May , Letnik:
184, Številka:
5
Journal Article
Recenzirano
Summary
Human hair follicles (HFs) carry complex microbial communities that differ from the skin surface microbiota. This likely reflects that the HF epithelium differs from the epidermal barrier in ...that it provides a moist, less acidic, and relatively ultraviolet light‐protected environment, part of which is immune‐privileged, thus facilitating microbial survival. Here we review the current understanding of the human HF microbiome and its potential physiological and pathological functions, including in folliculitis, acne vulgaris, hidradenitis suppurativa, alopecia areata and cicatricial alopecias. While reviewing the main human HF bacteria (such as Propionibacteria, Corynebacteria, Staphylococci and Streptococci), viruses, fungi and parasites as human HF microbiome constituents, we advocate a broad view of the HF as an integral part of the human holobiont. Specifically, we explore how the human HF may manage its microbiome via the regulated production of antimicrobial peptides (such as cathelicidin, psoriasin, RNAse7 and dermcidin) by HF keratinocytes, how the microbiome may impact on cytokine and chemokine release from the HF, and examine hair growth‐modulatory effects of antibiotics, and ask whether the microbiome affects hair growth in turn. We highlight major open questions and potential novel approaches to the management of hair diseases by targeting the HF microbiome.
Patients with HER2-positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane mucin 1 (MUC1) oncoprotein is aberrantly overexpressed in breast ...cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1 C-terminal subunit (MUC1-C) in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in the downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine-phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (∼20-fold) as compared with that in sensitive cells. In addition, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with the downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance.
Perioperative neurocognitive disorders (PND) result in long-term morbidity and mortality with no effective interventions available. Because interleukin-6 (IL-6), a pro-inflammatory cytokine, is ...consistently up-regulated by trauma, including after surgery, we determined whether IL-6 is a putative therapeutic target for PND in a mouse model.
Following institutional approval, adult (12–14 weeks) male C57/Bl6 mice were pretreated with the IL-6 receptor (IL6R) blocking antibody tocilizumab prior to open tibia fracture with internal fixation under isoflurane anaesthesia. Inflammatory and behavioural responses in a trace fear conditioning (TFC) paradigm were assessed postoperatively. Separately, the effects of IL-6 administration or of depletion of bone marrow-derived monocytes (BM-DMs) with clodrolip on the inflammatory and behavioural responses were assessed. Blood brain barrier disruption, hippocampal microglial activation, and infiltration of BM-DMs were each assessed following IL-6 administration.
The surgery-induced decrement in freezing time in the TFC assay, indicative of cognitive decline, was attenuated by tocilizumab (P<0.01). The surgery-induced increase in pro-inflammatory mediators was significantly reduced by tocilizumab. Exogenously administered IL-6 significantly impaired freezing behaviour (P<0.05) and up-regulated pro-inflammatory cytokines; both responses were prevented by depletion of BM-DMs. IL-6 disrupted the blood brain barrier, and increased hippocampal activation of microglia and infiltration of BM-DMs.
IL-6 is both necessary and sufficient to produce cognitive decline. Following further preclinical testing of its perioperative safety, the IL6R blocker tocilizumab is a candidate for prevention and/or treatment of PND.
The terrestrial carbon (C) cycle has received increasing interest over the past few decades, however, there is still a lack of understanding of the fate of newly assimilated C allocated within plants ...and to the soil, stored within ecosystems and lost to the atmosphere. Stable carbon isotope studies can give novel insights into these issues. In this review we provide an overview of an emerging picture of plant-soil-atmosphere C fluxes, as based on C isotope studies, and identify processes determining related C isotope signatures. The first part of the review focuses on isotopic fractionation processes within plants during and after photosynthesis. The second major part elaborates on plant-internal and plant-rhizosphere C allocation patterns at different time scales (diel, seasonal, interannual), including the speed of C transfer and time lags in the coupling of assimilation and respiration, as well as the magnitude and controls of plant-soil C allocation and respiratory fluxes. Plant responses to changing environmental conditions, the functional relationship between the physiological and phenological status of plants and C transfer, and interactions between C, water and nutrient dynamics are discussed. The role of the C counterflow from the rhizosphere to the aboveground parts of the plants, e.g. via CO2 dissolved in the xylem water or as xylem-transported sugars, is highlighted. The third part is centered around belowground C turnover, focusing especially on above- and belowground litter inputs, soil organic matter formation and turnover, production and loss of dissolved organic C, soil respiration and CO2 fixation by soil microbes. Furthermore, plant controls on microbial communities and activity via exudates and litter production as well as microbial community effects on C mineralization are reviewed. A further part of the paper is dedicated to physical interactions between soil CO2 and the soil matrix, such as CO2 diffusion and dissolution processes within the soil profile. Finally, we highlight state-of-the-art stable isotope methodologies and their latest developments. From the presented evidence we conclude that there exists a tight coupling of physical, chemical and biological processes involved in C cycling and C isotope fluxes in the plant-soil-atmosphere system. Generally, research using information from C isotopes allows an integrated view of the different processes involved. However, complex interactions among the range of processes complicate or currently impede the interpretation of isotopic signals in CO2 or organic compounds at the plant and ecosystem level. This review tries to identify present knowledge gaps in correctly interpreting carbon stable isotope signals in the plant-soil-atmosphere system and how future research approaches could contribute to closing these gaps.
Novel influenza viruses of the H7N9 subtype have infected 33 and killed nine people in China as of 10 April 2013. Their haemagglutinin (HA) and neuraminidase genes probably originated from Eurasian ...avian influenza viruses; the remaining genes are closely related to avian H9N2 influenza viruses. Several characteristic amino acid changes in HA and the PB2 RNA polymerase subunit probably facilitate binding to human-type receptors and efficient replication in mammals, respectively, highlighting the pandemic potential of the novel viruses.
Background
In self-correlation lock-in thermography for thermoelastic stress analysis (TSA), the acquisition position of the reference signal affects the accuracy of the obtained stress amplitude ...distribution. When the reference signal is not large enough compared to the noise, the stress amplitude distribution may be incorrect.
Objective
This study proposes a method that does not require a reference signal and frequency analysis to obtain the stress amplitude distribution with comparable or higher accuracy than that obtained using self-correlation lock-in thermography.
Methods
An observation matrix is generated from the temporal variation across all thermographic pixels to describe the thermal fluctuations due to stress. Thereafter, stress amplitude distribution and the original load signal are extracted from the observation matrix using singular value decomposition (SVD). The proposed method is called SVD thermo-component analysis. To investigate the effectiveness of the proposed method, the reconstructed load signal and stress distribution are obtained from the captured thermal images for the specimen under a sinusoidal load.
Results
The stress amplitude distribution obtained using the proposed method is equivalent to that obtained using conventional lock-in thermography with the original load signal as the reference signal. In addition, the reconstructed load signal obtained using the proposed method successfully represents the original load signal.
Conclusions
SVD thermo-component analysis does not require prior knowlege of the evaluated mechanical structure to select a suitable reference-signal acquisition position as in self-correlation lock-in thermography. Therefore, the proposed TSA method reduce analysis failures compared to the conventional method.
Liver ischemia reperfusion injury (IRI) is an important problem in liver transplantation. Thrombomodulin (TM), an effective drug for disseminated intravascular coagulation, is also known to exhibit ...an anti‐inflammatory effect through binding to the high‐mobility group box 1 protein (HMGB‐1) known as a proinflammatory mediator. We examined the effect of recombinant human TM (rTM) on a partial warm hepatic IRI model in wild‐type (WT) and toll‐like receptor 4 (TLR‐4) KO mice focusing on the HMGB‐1/TLR‐4 axis. As in vitro experiments, peritoneal macrophages were stimulated with recombinant HMGB‐1 protein. The rTM showed a protective effect on liver IRI. The rTM diminished the downstream signals of TLR‐4 and also HMGB‐1 expression in liver cells, as well as release of HMGB‐1 from the liver. Interestingly, neither rTM treatment in vivo nor HMGB‐1 treatment in vitro showed any effect on TLR‐4 KO mice. Parallel in vitro studies have confirmed that rTM interfered with the interaction between HMGB‐1 and TLR‐4. Furthermore, the recombinant N‐terminal lectin‐like domain 1 (D1) subunit of TM (rTMD1) also ameliorated liver IRI to the same extent as whole rTM. Not only rTM but also rTMD1 might be a novel and useful medicine for liver transplantation. This is the first report clarifying that rTM ameliorates inflammation such as IRI in a TLR‐4 pathway–dependent manner.
Recombinant thrombomodulin suppresses high mobility group box‐1 protein expression in liver cells, as well as its release from the liver, and it ameliorates liver ischemia–reperfusion injury in a toll‐like receptor 4 pathway‐ dependent manner. See the editorial from Ke on page 7.
We have recently identified down-regulated microRNAs including miR-145 and miR-133a in bladder cancer (BC). The aim of this study is to determine the genes targeted by miR-145, which is the most ...down-regulated microRNA in BC.
We focused on fascin homologue 1 (FSCN1) from the gene expression profile in miR-145 transfectant. The luciferase assay was used to confirm the actual binding sites of FSCN1 mRNA. Cell viability was evaluated by cell growth, wound-healing, and matrigel invasion assays. BC specimens were subjected to immunohistochemistry of FSCN1 and in situ hybridisation of miR-145.
The miR-133a as well as miR-145 had the target sequence of FSCN1 mRNA by the database search, and both microRNAs repressed the mRNA and protein expression of FSCN1. The luciferase assay revealed that miR-145 and miR-133a were directly bound to FSCN1 mRNA. Cell viability was significantly inhibited in miR-145, miR-133a, and si-FSCN1 transfectants. In situ hybridisation revealed that miR-145 expression was markedly repressed in the tumour lesion in which FSCN1 was strongly stained. The immunohistochemical score of FSCN1 in invasive BC (n=46) was significantly higher than in non-invasive BC (n=20) (P=0.0055).
Tumour suppressive miR-145 and miR-133a directly control oncogenic FSCN1 in BC.
Background
Visceral obesity is one of the risk factors for clinically relevant pancreatic fistula after pancreatic resection. The objective of this study was to evaluate the impact of intraperitoneal ...lipolysis on postoperative pancreatic fistula.
Methods
The degree of intraperitoneal lipolysis was investigated by measuring the free fatty acid concentration in drain discharge in patients after pancreatic resection. An experimental pancreatic fistula model was prepared by pancreatic transection, and the impact of intraperitoneal lipolysis was evaluated by intraperitoneal administration of triolein (triglyceride) with, or without orlistat (lipase inhibitor).
Results
Thirty‐three patients were included in the analysis. The free fatty acid concentration in drain discharge on postoperative day 1 was significantly associated with the development of a clinically relevant pancreatic fistula (P = 0·004). A higher free fatty acid concentration in drain discharge was associated with more visceral adipose tissue (P = 0·009). In the experimental model that included 98 rats, intraperitoneal lipolysis caused an increased amount of pancreatic juice leakage and multiple organ dysfunction. Intraperitoneal administration of a lipase inhibitor reduced lipolysis and prevented deterioration of the fistula.
Conclusion
Intraperitoneal lipolysis significantly exacerbates pancreatic fistula after pancreatic resection. Inhibition of lipolysis by intraperitoneal administration of a lipase inhibitor could be a promising therapy to reduce clinically relevant postoperative pancreatic fistula.
Surgical relevance
Clinically, there are two types of pancreatic fistula after pancreatic resections: harmless biochemical leak and harmful clinically relevant pancreatic fistula. Visceral obesity is one of the known risk factors for clinically relevant pancreatic fistula; however, the underlying mechanisms remained to be elucidated.
Patients with clinically relevant pancreatic fistula had a higher free fatty acid concentration in the drain discharge, suggesting a relationship between intraperitoneal lipolysis and pancreatic fistula. The experimental model of pancreatic fistula demonstrated that intraperitoneal lipolysis caused deterioration in pancreatic fistula, suggesting that intraperitoneal lipolysis is one of the mechanisms that drives biochemical leakage to clinically relevant pancreatic fistula.
Intraperitoneal administration of a lipase inhibitor prevented lipolysis as well as pancreatic fistula deterioration in the experimental model, suggesting a future clinical application for lipase inhibitors in prevention of clinically relevant pancreatic fistula.
Patients with clinically relevant pancreatic fistula had a significantly higher free fatty acid concentration in drain discharge, suggesting a relationship between intraperitoneal lipolysis and pancreatic fistula. The investigation in rat pancreatic fistula models demonstrated that intraperitoneal lipolysis caused deterioration of pancreatic fistula, indicating that intraperitoneal lipolysis is one of the mechanisms that drives biochemical leakage to clinically relevant pancreatic fistula.
Potential target for prevention
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