Excessive alcohol consumption induces intestinal dysbiosis of the gut microbiome and reduces gut epithelial integrity. This often leads to portal circulation–mediated translocation of gut-derived ...microbial products, such as lipopolysaccharide (LPS), to the liver, where these products engage Toll-like receptor 4 (TLR4) and initiate hepatic inflammation, which promotes alcoholic liver disease (ALD). Although the key self-destructive process of autophagy has been well-studied in hepatocytes, its role in macrophages during ALD pathogenesis remains elusive. Using WT and myeloid cell–specific autophagy-related 7 (Atg7) knockout (Atg7ΔMye) mice, we found that chronic ethanol feeding for 6 weeks plus LPS injection enhances serum alanine aminotransferase and IL-1β levels and augments hepatic C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) expression in WT mice, a phenotype that was further exacerbated in Atg7ΔMye mice. Atg7ΔMye macrophages exhibited defective mitochondrial respiration and displayed elevated mitochondrial reactive oxygen species production and inflammasome activation relative to WT cells. Interestingly, compared with WT cells, Atg7ΔMye macrophages also had a drastically increased abundance and nuclear translocation of interferon regulatory factor 1 (IRF1) after LPS stimulation. Mechanistically, LPS induced co-localization of IRF1 with the autophagy adaptor p62 and the autophagosome, resulting in subsequent IRF1 degradation. However, upon p62 silencing or Atg7 deletion, IRF1 started to accumulate in autophagy-deficient macrophages and translocated into the nucleus, where it induced CCL5 and CXCL10 expression. In conclusion, macrophage autophagy protects against ALD by promoting IRF1 degradation and removal of damaged mitochondria, limiting macrophage activation and inflammation.
Periodontitis is a progressive disease of the periodontium with a complex, polymicrobial etiology. Recent Next-Generation Sequencing (NGS) studies of the microbial diversity associated with ...periodontitis have revealed strong, community-level differences in bacterial assemblages associated with healthy or diseased periodontal sites. In this study, we used NGS approaches to characterize changes in periodontal pocket bacterial diversity after standard periodontal treatment. Despite consistent changes in the abundance of certain taxa in individuals whose condition improved with treatment, post-treatment samples retained the highest similarity to pre-treatment samples from the same individual. Deeper phylogenetic analysis of periodontal pathogen-containing genera Prevotella and Fusobacterium found both unexpected diversity and differential treatment response among species. Our results highlight how understanding interpersonal variability among microbiomes is necessary for determining how polymicrobial diseases respond to treatment and disturbance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Certolizumab pegol (CZP) is an Fc‐free, PEGylated anti‐tumour necrosis factor biologic.
Objectives
To report 3‐year safety data from three phase III trials of CZP in adults with ...plaque psoriasis.
Methods
Data were pooled from CIMPASI‐1 (NCT02326298), CIMPASI‐2 (NCT02326272) and CIMPACT (NCT02346240). Included patients had moderate‐to‐severe plaque psoriasis of ≥ 6 months’ duration; had been randomized to CZP 200 mg every 2 weeks (Q2W) (400 mg at weeks 0, 2 and 4) or CZP 400 mg Q2W; and had received at least one dose of CZP with up to 144 weeks of exposure. Treatment‐emergent adverse events (TEAEs) were classified using MedDRA v18·1. Reported incidence rates (IRs) are incidence of new cases per 100 patient‐years (PY).
Results
Over 144 weeks, 995 patients received at least one dose of CZP (exposure: 2231·3 PY); 731 and 728 received at least one dose of CZP 200 mg Q2W (1211·4 PY) and/or 400 mg Q2W (1019·9 PY), respectively. The IR 95% confidence interval (CI) of TEAEs was 144·9 (135·3–155·0) for all patients, 134·1 (123·2–145·7) for CZP 200 mg Q2W and 158·3 (145·5–171·9) for CZP 400 mg Q2W. The IR (95% CI) of serious TEAEs for all patients was 7·5 (6·4–8·8); the IRs were 6·7 (5·2–8·3) and 8·7 (6·9–10·8) for CZP 200 mg and 400 mg Q2W, respectively. Overall, 3·2% of patients reported serious infections (2·2% within each of the CZP 200 and 400 mg Q2W groups). Overall, there was one case of active tuberculosis, 16 malignancies in 14 patients and seven deaths (two considered treatment‐related). The cumulative IR of TEAEs did not increase over time.
Conclusions
No new safety signals were identified compared with previously reported data. Risk did not increase with longer or higher CZP exposure.
What is already known about this topic?
Certolizumab pegol is an Fc‐free, PEGylated, anti‐tumour necrosis factor biologic approved for adults with moderate‐to‐severe plaque psoriasis.
Safety data from phase III trials in plaque psoriasis have found the incidence of adverse events to be generally similar over 16 weeks of treatment between the evaluated certolizumab pegol doses 200 mg and 400 mg every 2 weeks and placebo.
Additionally, the safety profile was in line with the class over 48 weeks.
What does this study add?
Plaque psoriasis is a chronic disease for which patients require lifetime management; long‐term safety data are important to understand the benefits and risks of prolonged treatment.
Here, 3‐year data from a pooled analysis of three phase III trials of certolizumab pegol in plaque psoriasis are presented, representing 2231·3 patient‐years of exposure.
No new safety signals were identified and the risk of treatment‐emergent adverse events did not increase with longer or higher certolizumab pegol exposure.
RATIONALE:Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the ...result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis.
OBJECTIVE:The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise.
METHODS AND RESULTS:We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity.
CONCLUSIONS:These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
Summary
Background The anti‐interleukin‐12/23p40 monoclonal antibody briakinumab has been shown in a phase II study to be effective psoriasis treatment.
Objectives The aim of the current study was ...to assess the efficacy, safety and tolerability of briakinumab compared with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis.
Methods In this phase III, 12‐week study (M10‐114, NCT00691964), 347 patients were randomized in a 2 : 2 : 1 ratio to receive 200 mg briakinumab at weeks 0 and 4 followed by 100 mg briakinumab at week 8 (n = 138); 50 mg of etanercept twice weekly 3–4 days apart at weeks 0–11 (n = 141); or placebo injections matching active treatment (n = 68). The co‐primary efficacy endpoints were the proportion of patients achieving a Physician’s Global Assessment (PGA) of 0/1 at week 12, and the proportion of patients achieving a Psoriasis Area and Severity Index (PASI) 75 response at week 12.
Results Of the briakinumab‐treated patients, 71·0% achieved a PGA of 0/1 at week 12 as compared with 39·7% of etanercept‐treated patients and 2·9% of placebo‐treated patients, (P < 0·001, for both comparisons). Of the briakinumab‐treated patients 81·9% achieved a PASI 75 response at week 12 as compared with 56·0% of etanercept‐treated and 7·4% of placebo‐treated patients (P < 0·001, for both comparisons). Serious adverse event rates were reported in four (2·9%) patients receiving briakinumab, one (0·7%) patient receiving etanercept and one (1·5%) placebo‐treated patient.
Conclusions In patients with moderate to severe psoriasis, briakinumab had superior efficacy to both placebo and etanercept at 12 weeks as administered in this study.
Summary
Background
Secukinumab has shown sustained efficacy and safety in several manifestations of psoriasis.
Objectives
GESTURE investigated the long‐term (2·5‐year) safety and efficacy of 150 mg ...and 300 mg subcutaneous secukinumab in 205 patients with moderate‐to‐severe palmoplantar psoriasis.
Methods
GESTURE was a randomized, double‐blind, placebo‐controlled, multicentre, phase IIIb trial conducted across 15 countries. The study was 140 weeks long and consisted of four periods: screening (up to 4 weeks), treatment period 1 (16 weeks), treatment period 2 (116 weeks) and post‐treatment follow‐up (8 weeks). Eligible patients were aged ≥ 18 years with moderate‐to‐severe palmoplantar psoriasis and at least one plaque outside of the palms and soles. Efficacy was assessed via a palmoplantar Investigator's Global Assessment (ppIGA) and the palmoplantar Psoriasis Area and Severity Index (PASI).
Results
The primary end point, a ppIGA score of 0 or 1, was met at week 16. The effect was sustained over 2·5 years with 59% 95% confidence interval (CI) 43·5–74·1 and 53% (95% CI 35·1–69·6) of patients in the secukinumab 300 mg and 150 mg groups, respectively, achieving clear or almost clear palms and soles (ppIGA 0 or 1). At 2·5 years, the mean palmoplantar PASI percentage was reduced in both the secukinumab 300 mg group (−74·7%) and the secukinumab 150 mg group (−61·6%). A total of 17% (secukinumab 300 mg group) and 18% (secukinumab 150 mg group) of patients experienced no difficulty in hands and feet functionality, as indicated by the palmoplantar quality of life instrument overall scores. The safety profile was favourable.
Conclusions
GESTURE revealed that secukinumab provides a strong and sustained response over 2·5 years in challenging‐to‐treat palmoplantar psoriasis.
What's already known about this topic?
Palmoplantar psoriasis is a common type of plaque psoriasis and is associated with significant disability and discomfort.
It is difficult to treat and requires continuous treatment for an extended period of time.
No long‐term phase III studies dedicated to patients with moderate‐to‐severe palmoplantar psoriasis have been done before.
What does this study add?
GESTURE is the first long‐term, phase IIIb, double‐blind randomized trial specifically dedicated to patients with moderate‐to‐severe palmoplantar psoriasis.
Around 60% of patients treated with secukinumab 300 mg showed clear or almost clear palms and soles over a period of 2·5 years.
The improvement in skin lesions was mirrored by a significant improvement in quality of life, as well as in activities of daily living.
Plain language summary available online
Coxsackievirus B3 (CVB3), a member of the picornavirus family and enterovirus genus, causes viral myocarditis, aseptic meningitis, and pancreatitis in humans. We genetically engineered a unique ...molecular marker, "fluorescent timer" protein, within our infectious CVB3 clone and isolated a high-titer recombinant viral stock (Timer-CVB3) following transfection in HeLa cells. "Fluorescent timer" protein undergoes slow conversion of fluorescence from green to red over time, and Timer-CVB3 can be utilized to track virus infection and dissemination in real time. Upon infection with Timer-CVB3, HeLa cells, neural progenitor and stem cells (NPSCs), and C2C12 myoblast cells slowly changed fluorescence from green to red over 72 hours as determined by fluorescence microscopy or flow cytometric analysis. The conversion of "fluorescent timer" protein in HeLa cells infected with Timer-CVB3 could be interrupted by fixation, suggesting that the fluorophore was stabilized by formaldehyde cross-linking reactions. Induction of a type I interferon response or ribavirin treatment reduced the progression of cell-to-cell virus spread in HeLa cells or NPSCs infected with Timer-CVB3. Time lapse photography of partially differentiated NPSCs infected with Timer-CVB3 revealed substantial intracellular membrane remodeling and the assembly of discrete virus replication organelles which changed fluorescence color in an asynchronous fashion within the cell. "Fluorescent timer" protein colocalized closely with viral 3A protein within virus replication organelles. Intriguingly, infection of partially differentiated NPSCs or C2C12 myoblast cells induced the release of abundant extracellular microvesicles (EMVs) containing matured "fluorescent timer" protein and infectious virus representing a novel route of virus dissemination. CVB3 virions were readily observed within purified EMVs by transmission electron microscopy, and infectious virus was identified within low-density isopycnic iodixanol gradient fractions consistent with membrane association. The preferential detection of the lipidated form of LC3 protein (LC3 II) in released EMVs harboring infectious virus suggests that the autophagy pathway plays a crucial role in microvesicle shedding and virus release, similar to a process previously described as autophagosome-mediated exit without lysis (AWOL) observed during poliovirus replication. Through the use of this novel recombinant virus which provides more dynamic information from static fluorescent images, we hope to gain a better understanding of CVB3 tropism, intracellular membrane reorganization, and virus-associated microvesicle dissemination within the host.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gating the mechanical channel Piezo1 Gottlieb, Philip A.; Bae, Chilman; Sachs, Frederick
Channels (Austin, Tex.),
07/2012, Letnik:
6, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Piezo1 is a eukaryotic cation-selective mechanosensitive ion channel. To understand channel function in vivo, we first need to analyze and compare the response in the whole cell and the patch. In ...patches, Piezo1 inactivates and the current is fit well by a 3-state model with a single pressure-dependent rate. However, repeated stimulation led to an irreversible loss of inactivation. Remarkably, the loss of inactivation did not occur on a channel-by-channel basis but on all channels at the same time. Thus, the channels are in common mechanical domain. Divalent ions decreased the unitary conductance from ~68 pS to ~37 pS, irrespective of the cation species. Mg and Ca did not affect inactivation rates, but Zn caused a 3-fold slowing. CytochalasinD (cytoD) does not alter inactivation rates or the transition to the non-inactivating mode but does reduce the steady-state response. Whole-cell currents were similar to patch currents but also had significant differences. In contrast to the patch, cytoD inhibited the current suggesting that the activating forces were transmitted through the actin cytoskeleton. Hypotonic swelling that prestressed the cytoskeleton and the bilayer greatly increased the sensitivity of both control and cytoD cells so there are two pathways to transmit force to the channels. In contrast to patch, removing divalent ions decreased the whole-cell current. The difference between whole cell and patch properties provide new insights into our understanding of the Piezo1 gating mechanisms and cautions against generalization to in situ behavior.
Summary
Tumour necrosis factor (TNF)‐α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo ...by exploring its pro‐ and anti‐inflammatory properties and examine the effects of blocking its actions with TNF‐α antagonist therapeutics in reports available in the literature. We found that TNF‐α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF‐α inhibition has proven useful for patients with progressive vitiligo, where TNF‐α inhibition is able to quash cytotoxic T‐cell‐mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.
What's already known about this topic?
Increased levels of tumour necrosis factor (TNF)‐α are present in active vitiligo lesions.
Upon TNF‐α inhibition in vitiligo, anti‐TNF‐α agents have been labelled as ineffective, as repigmentation was not achieved.
What does this study add?
In patients with progressive disease, TNF‐α inhibition may provide a means to halt depigmentation in vitiligo.
Summary
Background
Certolizumab pegol (CZP) is an Fc‐free, PEGylated anti‐tumour necrosis factor biologic.
Objectives
To report the 3‐year efficacy of CZP in plaque psoriasis, pooled from the ...CIMPASI‐1 (NCT02326298) and CIMPASI‐2 (NCT02326272) phase III trials.
Methods
Adults with moderate‐to‐severe psoriasis for ≥ 6 months were randomized 2 : 2 : 1 to CZP 200 mg, CZP 400 mg or placebo, every 2 weeks (Q2W) for up to 48 weeks. Patients entering the open‐label period (weeks 48–144) from double‐blinded CZP initially received CZP 200 mg Q2W. Patients not achieving ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 16 entered an open‐label CZP 400 mg Q2W escape arm (weeks 16–144). Dose adjustments based on PASI response were permitted during open‐label treatment. Outcomes included PASI 75, PASI 90 and Physician’s Global Assessment (PGA) 0/1 responder rates, based on a logistic regression model (missing data imputed using Markov Chain Monte Carlo methodology).
Results
In total, 186 patients were randomized to CZP 200 mg Q2W and 175 to CZP 400 mg Q2W. At week 48, PASI 75/90 was achieved by 72·7%/51·3% of patients randomized to CZP 200 mg and 84·4%/62·7% randomized to CZP 400 mg. Patients entering the open‐label period at week 48, from blinded treatment, received CZP 200 mg Q2W. At week 144, PASI 75/90 was achieved by 70·6%/48·7% patients randomized to CZP 200 mg and 72·9%/42·7% randomized to CZP 400 mg. At week 16, 72 placebo‐randomized patients entered the CZP 400 mg Q2W escape arm; 75.7%/58.5% achieved PASI 75/90 at week 144.
Conclusions
Both CZP 200 mg and 400 mg Q2W demonstrated sustained, durable efficacy, with numerically higher responses for some outcomes with 400 mg Q2W.
What is already known about this topic?
Certolizumab pegol is an Fc‐free, PEGylated, anti‐tumour necrosis factor biologic approved for adults with moderate‐to‐severe plaque psoriasis.
Efficacy data from the first 48 weeks of phase III trials have shown significant improvements in the signs and symptoms of psoriasis with certolizumab pegol dosed at either 400 mg or 200 mg every 2 weeks.
Numerically greater improvements were observed for patients treated with the higher dose.
What does this study add?
Plaque psoriasis is a chronic, systemic disease that requires long‐term management and sustained efficacy of therapies.
Three‐year efficacy data pooled from the CIMPASI‐1 and CIMPASI‐2 phase III trials demonstrate a sustained and durable response to certolizumab pegol dosed at either 400 mg or 200 mg every 2 weeks.
Additional long‐term clinical benefits may be obtained from the higher dose.
Linked Comment: Johnson et al. Br J Dermatol 2021; 184:588–589.
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