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Introduction: Pulmonary fibrosis (PF) encompasses a spectrum of lung conditions characterized by the abnormal accumulation of scar tissue in the lungs, leading to impaired respiratory function. Various conditions can result in severe PF, among which viral infections have emerged as significant triggers. In addition to viral infections, exposure to toxic substances such as paraquat represents another significant risk factor for PF. Therefore, this study aimed to explore the dissimilarities and similarities between PF triggered by viral infections and chemical toxicants, using the mechanism of PF in IPF as a reference. Methods: Data-independent acquisition proteomics technology was employed to identify COVID-19 and paraquat-induced PF from the autopsy of lung tissue samples obtained from individuals who died due to PF. Bioinformatics was employed for differential protein analysis, and selected indicators were validated on pathological sections. Results: Our results showed that the differential proteins associated with the two causes of PF were enriched in similar lung fibrosis-related signaling pathways, such as the Wnt signaling pathway. However, differences were observed in proteins such as CACYBP, we verified the consistency of the results with proteomics using the IHC approach. Conclusion: This study illuminates distinct protein-level differences by investigating pulmonary fibrosis pathways in severe COVID-19 and paraquat poisoning. Although both conditions activate lung-protective and repair pathways, COVID-19 shows limited phosphorylation-independent ubiquitination of ß-catenin compared to paraquat toxicity. These findings shed light on potential therapeutic targets for PF induced via diverse factors.
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COVID-19 , Pulmón , Paraquat , Proteómica , Fibrosis Pulmonar , SARS-CoV-2 , Humanos , Paraquat/envenenamiento , COVID-19/metabolismo , COVID-19/patología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/virología , Fibrosis Pulmonar/metabolismo , Pulmón/patología , Pulmón/virología , Masculino , Persona de Mediana Edad , Femenino , AncianoRESUMEN
High-voltage dual ion battery (DIB) is promising for stationary energy storage applications owing to its cost-effectiveness, which has been a hot topic of research in rechargeable battery fields. However, it still suffers from rapid battery failure caused by the severe solvent co-intercalation and electrolyte oxidation. To address these bottlenecks, herein a functional electrolyte additive hexafluoroglutaric anhydride (HFGA) is presented based on a Helmholtz plane regulation strategy. It is demonstrated that the HFGA can precisely enter into the Helmholtz plane and positively regulate anion solvation behaviors near the graphite electrode surface owing to its considerable H-F affinity with ethyl methyl carbonate (EMC), thus alleviating EMC-related co-intercalation and oxidation decomposition during DIB charging. Meanwhile, HFGA can copolymerize with the presence of PF5 at the Helmholtz plane to participate in forming a CF2-rich CEI layer with excellent PF6- permselectivity, conducive to achieving PF6- de-solvation and simultaneously suppressing electrolyte oxidation decomposition. By virtue of such beneficial effects, the graphite cathode enables a 5.5 V DIB with a prominent capacity retention of 92% and a high average Coulombic efficiency exceeding 99% within 2000 cycles, demonstrating significantly enhanced electrochemical reversibility. The Helmholtz plane regulation strategy marks a milestone in advancing DIB technologies.
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Ependymomas are the third most common intracranial tumor in children, presenting in both the supratentorial and infratentorial compartments. They may present in infants, young children, and adolescents with symptoms depending on size, location, and the age of the patient. The ideal imaging for evaluation and treatment is MRI. This is crucial for preoperative evaluation and planning, as well as postoperative assessment and evaluating the efficacy of treatment. Essentially without exception, aggressive surgery aimed at complete resection is the initial and most important factor in the long-term outcome of all these children. Histopathologic diagnosis for intracranial pediatric ependymoma has been narrowed to grade II and grade III, no longer characterized as classic and anaplastic. Subsequent conformal photon or proton beam irradiation is an established post-surgical therapy, with solid evidence that it benefits survival and offers lower toxicity to the normal brain of the young child. Although chemotherapeutic treatment has not been generally impactful, immunotherapeutic interventions may be on the horizon. Updated molecular subgrouping of ependymoma is changing the post-resection approach of these tumors with regard to both treatment and outcome. Excluding spinal ependymoma and subependymoma, there are four subtypes that are defined by genetic characteristics, two found in the supratentorial compartment, ST-EPN-YAP1 and ST-EPN-ZFTA, and two in the posterior fossa, PF-EPN-A and PF-EPN-B. Younger children harboring ZFTA fusion-positive supratentorial and type A posterior fossa tumors, regardless of histology, tend toward the poorest outcomes. On the contrary, older children with supratentorial YAP1 fusion-positive ependymomas and type B posterior fossa tumors may survive with surgery alone. The paradigm shift regarding the behavior of the various childhood ependymoma subtypes will hopefully lead to targeted, individualized therapies and improved outcomes.
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Ependimoma , Neoplasias Infratentoriales , Neoplasias Supratentoriales , Humanos , Ependimoma/terapia , Ependimoma/diagnóstico , Ependimoma/patología , Neoplasias Infratentoriales/terapia , Neoplasias Infratentoriales/patología , Neoplasias Supratentoriales/terapia , Neoplasias Supratentoriales/patología , Neoplasias Supratentoriales/diagnóstico , Niño , AdolescenteRESUMEN
BACKGROUND: Cholestasis (CT) is a group of disorders caused by impaired production, secretion or excretion of bile. This may result in the deposition of bile components in the blood and liver, which in turn causes damage to liver cells and other tissues. If untreated, CT can progress to severe complications, including cirrhosis, liver failure, and potentially life-threatening conditions. OBJECTIVE: This research was intended to elucidate the function and mechanism of Paeoniflorin (PF) in ameliorating ANIT-induced pyroptosis in CT. METHODS: CT models were established in SD rats and HepG2 cells through ANIT treatment. Histological examination was conducted using haematoxylin and eosin (HE) staining to assess the histopathological alterations in the liver. Network pharmacology was employed to identify potential PF targets in CT treatment. To evaluate pyroptosis levels, various methods were used, including serum biochemical analysis, Enzyme-Linked Immunosorbent Assay (ELISA), immunofluorescence (IF), immunohistochemistry (IHC), Western blotting, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The HuProt™ 20K Chip was utilized to pinpoint potential PF-binding targets. PF's direct mechanisms in CT treatment were explored using molecular docking (MD), molecular dynamics simulations (MDS), Cellular Thermal Shift Assay (CETSA), and Surface Plasmon Resonance (SPR). RESULTS: PF administration was found to alleviate ANIT-induced liver pathology, enhance liver function markers, and improve cell viability. Network pharmacology and pyroptosis inhibitor studies suggested that PF might mitigate CT via the NLRP3-dependent pyroptosis pathway. This hypothesis was further supported by Western blotting, IF, and IHC analyses, which indicated PF's potential to inhibit NLRP3-dependent pyroptosis in CT. GSDMD was identified as a target through HuProt™ 20K Chip screening. The binding affinity of PF to GSDMD was validated through MD, MDS, CETSA, and SPR techniques. Additionally, the regulatory impact of GSDMD on downstream inflammatory pathways was confirmed by ELISA and IHC. CONCLUSION: PF exhibited a hepatoprotective effect in ANIT-induced CT, primarily by targeting GSDMD, thereby suppressing ANIT-induced pyroptosis and the subsequent release of inflammatory mediators.
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Advanced diagnostic materials, such as aptamers, are required due to the scarcity of efficient diagnostic antibodies and the low sensitivity of rapid diagnostic kits at detecting the malaria parasite, Plasmodium falciparum. METHODS: Two peptides M2.9 [(KPTAEQTESPELQSAPEN) and M2.17 (KILFNVYSPLGCTCECWV)] were designed using simple epitope prediction tools and modified against the merozoite surface antigen 2 of P. falciparum (Pf.MSP2) by 3-dimensional modeling based on binding affinity. Based on five prediction tools for hydropathy, M2.17 was selected as an appropriate capture peptide. A peptide-based fluorescence-linked immunosorbent assay (FLISA) and a peptide pair-based fluorescent immunochromatographic test strip (FICT) were developed to detect P. falciparum 3D7 (drug-sensitive) and P. falciparum K1 (multi drugs-resistant) strains. RESULTS: Bioinformatic analysis of two peptides demonstrated the potential binding affinity with the merozoite surface protein 2 of P. falciparum (Pf.MSP2) with a positive hydropathy value. The limit of detection (LOD) of FLISA was 10 parasites/µL and of a peptide pair-linked rapid FICT system was 5 and 200 parasites/µL for P. falciparum 3D7 and K1, respectively. Compared to commercial rapid detection systems (RDTs), a peptide pair-linked FICT system exhibited a 20-fold greater efficiency in detecting P. falciparum 3D7 and specifically discriminated another protozoan spp. CONCLUSION: A peptide pair-linked rapid diagnostic strip could be an alternative to conventional RDTs for monitoring wild-type and drug-resistant malaria parasites.
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INTRODUCTION: The Ad26.COV2·S (Janssen/Johnson & Johnson) COVID-19 vaccine, has been rarely associated with vaccine-induced immune thrombocytopenia and thrombosis (VITT). We investigated the prevalence of anti-PF4 antibody positivity, thrombocytopenia, D-dimer elevation, plasmatic thromboinflammatory markers, and platelet functional assays following Ad26.COV2·S vaccination in Rio de Janeiro, Brazil. METHODS: From July to September 2021, participants were assessed prior, 1, and 3 weeks post-vaccination. Platelet count and D-dimer were measured at each visit and anti-PF4 at week 3. A positive anti-PF4 prompted retrospective testing of the sample from week 0. Individuals with new thrombocytopenia or elevated D-dimer, positive anti-PF4, and 38 matched controls without laboratory abnormalities were evaluated for plasmatic p-selectin, tissue factor, and functional platelet activation assays. RESULTS: 630 individuals were included; 306 (48.57%) females, median age 28 years. Forty-two (6.67%) presented ≥1 laboratory abnormality in week 1 or 3. Five (0.79%) had thrombocytopenia, 31 (4.91%) elevated D-dimer, and 9 (1.57%) had positive anti-PF4 at week 3. Individuals with laboratory abnormalities and controls showed a slight increase in plasmatic p-selectin and tissue factor. Ten individuals with laboratory abnormalities yielded increased surface expression of p-selectin, and their ability to activate platelets in a FcγRIIa dependent manner was further evaluated. Two were partially inhibited by high concentrations of heparin and blockage of FcγRII with IV.3 antibody. Plasma obtained before vaccination produced similar results, suggesting a lack of association with vaccination. CONCLUSIONS: Vaccination with Ad26.COV2·S vaccine led to a very low frequency of low-titer positive anti-PF4 antibodies, elevation of D-dimer, and mild thrombocytopenia, with no associated clinically relevant increase in thromboinflammatory markers and platelet activation.
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COVID-19 , Productos de Degradación de Fibrina-Fibrinógeno , Activación Plaquetaria , Factor Plaquetario 4 , Humanos , Femenino , Masculino , Brasil/epidemiología , Adulto , Factor Plaquetario 4/inmunología , COVID-19/inmunología , COVID-19/prevención & control , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Persona de Mediana Edad , Trombocitopenia/inducido químicamente , SARS-CoV-2/inmunología , Adulto Joven , Ad26COVS1 , Recuento de Plaquetas , Vacunación , Estudios Retrospectivos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Adolescente , Trombosis/inmunología , Trombosis/prevención & controlRESUMEN
BACKGROUND: Skin flap transplantation is used to effectively reconstruct defects of the hand and foot skin and soft tissues. We here investigated the effect of the PF127/bleomycin (BLM) hydrogel on the extracellular matrix (ECM) remodeling of skin flaps and the underlying mechanism, thereby providing a new reference point for personalized flap modification and overcoming abrasion resistance- and stability-associated difficulties. METHODS: The appropriate PF127/BLM concentration was selected based on the gelation time and drug release curve. Migration assays, scratch assays, and live/dead staining were conducted to verify the effect of PF127/BLM on human skin fibroblasts (HSFs). The effects of PF127/BLM on the ECM were assessed through hematoxylin and eosin and Masson staining. Additionally, we examined the expression of ECM remodeling-related genes and proteins involved in their associated signaling pathway. Finally, the effects of PF127/BLM on organ fibrosis and toxicity to liver and kidney functions were assessed in mice. RESULTS: A 25% PF127/BLM hydrogel was selected as the study concentration. PF127/BLM augmented HSF chemotaxis and proliferation. Furthermore, PF127/BLM promoted subcutaneous ECM remodeling and fibrosis, increased the flap dermis thickness, and reduced the toxic side effects of BLM on liver/lung fibrosis and liver/kidney function. Additional studies confirmed that the PF127/BLM-mediated regulation of ECM remodeling in skin flaps was associated with TGFß-Col signaling pathway activation. CONCLUSION: The PF127/BLM hydrogel promoted subcutaneous ECM remodeling and fibrosis, which aided the construction of personalized flaps through the TGFß-Col signaling pathway, with decreased hepatic, pulmonary, and renal toxicities.
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Injectable hydrogels are promising for bone tissue engineering due to their minimally invasive application and adaptability to irregular defects. This study presents the development of pluronic grafted silk fibroin (PF-127-g-SF), a temperature-sensitive graft copolymer synthesized from SF and modified PF-127 via a carbodiimide coupling reaction. The PF-127-g-SF copolymer exhibited a higher sol-gel transition temperature (34 °C at 16 % w/v) compared to PF-127 (23 °C), making it suitable for injectable applications. It also showed improved flexibility and strength, with a yielding point increase from <10 % to nearly 30 %. Unlike PF-127 gel, which degrades within 72 h in aqueous media, the PF-127-g-SF copolymer maintained a stable gel structure for over two weeks due to its robust crosslinked hydrogel network. Incorporating hydroxyapatite nanoparticles (n-HA) into the hydrogel reduced pore size and decreased swelling and degradation rates, extending structural stability to four weeks. Increasing n-HA concentration from 0 % to 20 % reduced porosity from 80 % to 66 %. Rheological studies indicated that n-HA enhanced the scaffold's strength and mechanical properties without altering gelation temperature. Cellular studies with MG-63 cells showed that n-HA concentration influenced cell viability and mineralization, highlighting the scaffold's potential in bone tissue engineering.
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Durapatita , Fibroínas , Hidrogeles , Nanopartículas , Poloxámero , Temperatura , Ingeniería de Tejidos , Fibroínas/química , Ingeniería de Tejidos/métodos , Durapatita/química , Poloxámero/química , Nanopartículas/química , Hidrogeles/química , Hidrogeles/síntesis química , Hidrogeles/farmacología , Humanos , Huesos/efectos de los fármacos , Andamios del Tejido/química , Reología , Inyecciones , Porosidad , Materiales Biocompatibles/químicaRESUMEN
Purpose: Perception that extra-medullary fixation of these fractures are fraught with difficulties and deficiencies is becoming inappropriate. This device provides angular stable fixation retaining fracture biology with minimum interference to osseous and soft-tissue vascularity and it does not require reaming which destroys 80% of endosteal vasculature for 6-12 weeks. PFLCP averts iatrogenic fracture in lateral trochanteric wall (LTW) which is frequent with DHS, protects LTW from secondary fracture in post-operative period. Aim is to assess outcome of unstable proximal femur fracture fixation by PFLCP. Methods: Study included 64 from 2016 to 2020, divided in two groups. (A) Unstable intertrochanteric fracture and (B) subtrochanteric fracture (Seinsheimer types II-V). All fractures fixed by MIPO with PFLCP. Loss of reduction, infection, cut-out, cut-through, backing of screws, bending or breaking of plate and screw, malunion, non-union and revision were evaluated. Fracture healing and functional recovery assessed by Reborne Score and Parker Mobility Score (PMS) respectively. Results: Out of 64, 24 achieved pre-injury PMS, 32 declined by 1 point, 6 declined by 2 points and 1 by 3 points, one required revision. Using various parameters 37.5% patients had excellent results and 50% had good results, 9.38% had average and 3.12% had poor result. None reported non-union or breakage of plate. Conclusions: PFLCP provides angular stable fixation, torsional stability with high biomechanical strength to resist deforming stresses. MIPO avoids soft-tissue stripping reducing blood-loss, retains periosteal blood supply to inter-fragmentary bone fragments, enhancing fracture healing, reducing complications, such as delayed healing, nonunion, infection and implant failure.
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How to cite this article: Mishra S, Kothari N, Sharma A, Goyal S, Rathod DK, Meshram T, et al. Author Response: Beyond the Nasal Prongs: A Joust of Oxygen Delivery Methods in Post-op Hypoxemia. Indian J Crit Care Med 2024;28(6):626-627.
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Fibroblast growth factor 21 (FGF21) is a peptide hormone that is primarily expressed and secreted by the liver. The hormone is crucial for regulation of glucose homeostasis, lipid metabolism, and energy balance. Compared with natural FGF21, FGF21 analogs have become drug candidates for the treatment of cardiovascular and metabolic diseases owing to their long half-life and greater stability in vitro. Apolipoprotein E (Apoe)-knockout (Apoe -/-) mice exhibit progressive disruptions in lipid metabolism in vivo and develop further atherosclerosis pathological features owing to Apoe deletion. Therefore, this study used an Apoe -/- mouse model to investigate the effects of a long-acting FGF21 analog (PF-05231023) on lipid metabolism and related parameters. Eighteen Apoe -/- female mice were fed a Western diet equivalent for 12 weeks, and then randomly assigned to intraperitoneally receive either physiological saline (the control group) or 10 mg/kg PF-05231023 (the treatment group) three times a week for seven consecutive weeks. Body composition, glucose tolerance, blood and liver cholesterol, triglyceride levels, liver vacuolization levels, peri-ovarian white adipocyte hypertrophy, aortic atherosclerotic plaque formation, and the expression of genes related to lipid metabolism in adipose tissue were subsequently assessed before and after treatment. The aortic atherosclerotic plaque area was reduced in mice in the PF-05231023 treatment group compared with that in the saline group. Although the effect of PF-05231023 on the plasma biochemical indexes of mice was small, it significantly reduced lipid levels and lipid droplet accumulation in the liver, and reduced adipocyte hypertrophy in white adipose tissue. Transcriptome analysis of adipose tissue showed that PF-05231023 treatment downregulated the expression of lipid synthesis-related genes and inhibited the sterol regulatory element binding transcription factor 1 gene, thereby improving lipid deposition. PF-05231023 effectively improved the lipid metabolism of Apoe -/- mice, demonstrating an anti-atherosclerotic effect and providing a scientific basis and experimental foundation for the clinical treatment of cardiovascular diseases by using long-acting FGF21 analogs.
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Background: Pregnancy-associated fulminant type 1 diabetes (PF) occurs during pregnancy or within 2 weeks of delivery. Although it occurs infrequently, it is associated with high fetal mortality rate. Few studies have examined whether PF is associated with gestational diabetes mellitus (GDM). Case Description: A 29-year-old woman diagnosed with GDM at 24 weeks of gestation developed a fever, sore throat, nausea and vomiting at 29 weeks of gestation. Ketoacidosis was considered based on her blood ketone and glucose levels and the results of a blood gas analysis. Since the patient's islet function declined rapidly, fluid replacement, insulin therapy, and other treatments were administered. The patient was ultimately diagnosed with PF, and has required ongoing insulin therapy. She delivered a healthy baby girl by elective cesarean section at 37-week gestation. Her blood glucose has been satisfactorily controlled over the 12 months since her acute presentation. Conclusions: PF is characterized by poor maternal and infant outcomes and a high stillbirth rate. Blood glucose should be regularly monitored in pregnant women with GDM. A sudden increase in blood glucose may indicate the possibility of PF, which needs to be managed in a timely manner to avoid adverse pregnancy outcomes.
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Vitiligo is a common chronic autoimmune disease characterized by white macules and patches of the skin, having a negative impact on patients' life, and without any definitive cure at present. Identification of new compounds to reverse depigmentation is therefore a pressing need for this disease. The pharmacologic compounds phosphodiesterase-4 inhibitors (PDE4i) are small molecules with immunomodulatory properties, used for treatment of inflammatory dermatoses. PDE4i have shown repigmentation effects in vitiligo patients, in some case reports. We characterized the proliferative and melanogenic potential of two known PDE4i, crisaborole and roflumilast, and of a more recently designed compound, PF-07038124. We used two in vitro model systems, the primary human melanocyte culture and a 3D co-cultured skin model (MelanoDermTM), with an exploratory testing platform composed of complementary assays (spectrophotometry, melanin and proliferation assays, immunostaining, Fontana-Masson staining, qRT-PCR, western blot and whole transcriptome RNA-Sequencing). We identified that the treatment with PDE4i was associated with increased melanocyte proliferation and melanization in both in vitro models, and with increase in the melanogenic genes and proteins expression in cultured melanocytes. These effects were found to be enhanced by addition of α-MSH. Our findings support the further evaluation of PDE4i with or without α-MSH agonists in vitiligo trials.
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The bacterial membrane vesicles (MVs) are non-replicative, nanoscale structures that carry specific cargos and play multiple roles in microbe-host interactions. An appropriate MV isolation method that mimics complex pathogen infections in vivo is needed. After bacterial MVs extraction, flagella or pili can be frequently observed along with MVs by transmission electron microscope (TEM). Recently, MVs from Pseudomonas aeruginosa were found to coexist with Pf4 phages, and this MV-phages complex exhibited a different impact on host cell innate immunity compared with MVs or phages solely. The presence of this MVs-phages complex simulates the real condition of complex pathogen infections within the host. This protocol outlines the extraction of the MVs and Pf4 phages complex of P. aeruginosa PAO1, including the respective isolation and qualification approaches. Our step-by-step bacterial MVs-phages complex extraction protocol provides valuable insights for further studying microbe-host cell interactions and the development of novel phage therapies. Key features ⢠Detailed density gradient extraction procedures of MVs-phages complex ⢠TEM, plaque assay, and PCR to verify the coexistence of MVs and phages ⢠The obtained MVs-phages complex can be used for exploring phage-microbe-host cell interactions Graphical overview.
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Aim: Heparin-induced thrombocytopenia (HIT) is a rare, life-threatening, immune-mediated adverse effect of heparin administration. This study compares frequently used laboratory assays in terms of their effectiveness in HIT diagnosis.Materials & methods: Fifty patients with suspected HIT were tested by gel immunoassay and solid phase PF4/heparin antibody ELISA. On positive results, platelet activation markers P-selectin and Annexin V were assayed using flow cytometry.Results: Thirty/50 patients were negative for both immunoassays. Flow cytometry was performed in the 20 immunoassay positive patients. Platelet activation was observed in 7/20 in the presence of low heparin concentration (0.2 IU/ml).Conclusion: The results are in accordance with the currently available literature and flow cytometry seems a promising alternative in HIT laboratory investigation.
[Box: see text].
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Citometría de Flujo , Heparina , Factor Plaquetario 4 , Trombocitopenia , Heparina/inmunología , Heparina/efectos adversos , Citometría de Flujo/métodos , Humanos , Factor Plaquetario 4/inmunología , Trombocitopenia/inducido químicamente , Trombocitopenia/inmunología , Trombocitopenia/diagnóstico , Femenino , Anticuerpos/inmunología , Masculino , Persona de Mediana Edad , Ensayo de Inmunoadsorción Enzimática/métodos , Inmunoensayo/métodos , Anciano , Activación Plaquetaria/efectos de los fármacos , AdultoRESUMEN
INTRODUCTION: Clinical practice guidelines recommend autoimmune serological testing in patients newly diagnosed with interstitial lung disease of apparently unknown cause who may have idiopathic pulmonary fibrosis (IPF), in order to exclude connective tissue disease (CTD). Autoantibody positivity has been associated with unique patient profiles and prognosis in patients with IPF who otherwise lack a CTD diagnosis. METHODS: This post-hoc analysis of patients with IPF from the Phase III ASCEND trial (NCT01366209) evaluated the association of antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) status with baseline disease characteristics, disease progression [percent predicted forced vital capacity (%FVC), forced vital capacity (FVC) volume and progression-free survival (PFS)], and treatment outcomes with pirfenidone and placebo (%FVC, FVC and PFS). RESULTS: Of 555 participants, 244/514 (47.5%) were ANA positive (ANA+), 83/514 (16.1%) had high ANA+ (ANA titre ≥ 1:160 or positive nucleolar- or centromere-staining patterns), 60/555 (10.8%) were RF positive (RF+) and/or anti-CCP positive (anti-CCP+) and 270/514 (52.5%) were autoantibody negative (AAb-). Baseline demographics and characteristics were generally comparable between autoantibody subgroups. Although not statistically significant, more placebo-treated participants with ANA+ or high ANA+ had a decline from baseline to Week 52 of ≥ 10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb- group (%FVC or death: 42.0%; FVC volume or death: 42.0%). The RF+ and/or anti-CCP+ group was similar to AAb-. No differences were observed in PFS. A treatment benefit for pirfenidone versus placebo was observed regardless of autoantibody status [PFS: ANA+ HR (95% CI): 0.56 (0.37 to 0.86), P = 0.007; AAb- HR (95% CI): 0.50 (0.32 to 0.78), P = 0.002]. CONCLUSION: IPF disease course did not differ by autoantibody status in ASCEND. Pirfenidone had a treatment benefit regardless of the presence of ANA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01366209.
People with idiopathic pulmonary fibrosis sometimes have abnormal antibodies, called autoantibodies, in their blood. Uncommonly, autoantibodies may mistakenly target the person's own tissues, including the lungs. It is unknown whether these autoantibodies cause idiopathic pulmonary fibrosis or make it worse. This analysis looked at data from the ASCEND clinical trial in people with idiopathic pulmonary fibrosis, who were split randomly into two groups to receive tablets of either a medicine called pirfenidone or a placebo for 52 weeks. One goal was to see whether people with certain autoantibodies called antinuclear antibodies ('ANA' for short), rheumatoid factor ('RF') and anti-cyclic citrullinated peptide ('anti-CCP') had different traits from people without autoantibodies, such as age, race or smoking history. Other goals were to see if autoantibodies affected (1) how well people's lungs worked during the trial, (2) how quickly people's idiopathic pulmonary fibrosis got worse or they died and (3) how well pirfenidone worked. The analysis showed that most traits were similar in people with and without autoantibodies. In people who received placebo, the change in lung function during the trial was not different for people with ANA, RF or anti-CCP compared with people with no autoantibodies. People who received pirfenidone were less likely to have worsening lung function, or die, than people who received placebo, regardless of whether or not they had autoantibodies. Doctors evaluating patients with idiopathic pulmonary fibrosis should consider the impact of autoantibodies and feel confident that pirfenidone is effective regardless of whether or not autoantibodies are present.
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As individuals age, there is a gradual decline in cardiopulmonary function, often accompanied by cardiac pump dysfunction leading to increased pulmonary vascular resistance (PVR). Our study aims to investigate the changes in cardiac and pulmonary vascular function associated with aging. Additionally, we aim to explore the impact of phosphodiesterase 9A (PDE9A) inhibition, which has shown promise in treating cardiometabolic diseases, on addressing left ventricle (LV) dysfunction and elevated PVR in aging individuals. Young (3 months old) and aged (32 months old) male C57BL/6 mice were used. Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days. LV function was evaluated using cardiac ultrasound, and PVR was assessed in isolated, ventilated lungs perfused under a constant flow condition. Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP). PDE9A protein expression was measured by Western blots. Our results demonstrate the development of LV diastolic dysfunction and increased PVR in aged mice. The aged mice exhibited diminished decreases in PVR in response to both bradykinin and SNP compared to the young mice. Moreover, the lungs of aged mice showed an increase in PDE9A protein expression. Treatment of aged mice with PF04447943 had no significant effect on LV systolic or diastolic function. However, PF04447943 treatment normalized PVR and SNP-induced responses, though it did not affect the bradykinin response. These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction.
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Envejecimiento , Ratones Endogámicos C57BL , Resistencia Vascular , Animales , Masculino , Envejecimiento/fisiología , Resistencia Vascular/efectos de los fármacos , Ratones , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Disfunción Ventricular Izquierda/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/farmacología , Western BlottingRESUMEN
In this study, we report on the ability of DMTMM PF6 to improve the amidation reaction. The on-DNA amidation reaction using DMTMM PF6 demonstrates higher conversion rates than those using HATU or DMTMM Cl, particularly with challenging sterically hindered amines and carboxylic acids. The developed method enables the expansion of available building blocks and the efficient synthesis of high-purity DNA-encoded libraries.
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Amidas , ADN , Amidas/química , Amidas/síntesis química , ADN/química , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Biblioteca de GenesRESUMEN
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD405] of 0.93 (SD = 1.21) units, and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD405 ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody-negative patients. We observed statistical differences between antibody-positive and -negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody-positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including in vitro binding studies and larger observational cohorts.
Asunto(s)
Anticoagulantes , Heparina , Factor Plaquetario 4 , Trombocitopenia , Humanos , Factor Plaquetario 4/inmunología , Trombocitopenia/inducido químicamente , Trombocitopenia/inmunología , Trombocitopenia/sangre , Trombocitopenia/diagnóstico , Femenino , Heparina/efectos adversos , Heparina/inmunología , Persona de Mediana Edad , Masculino , Anciano , Anticoagulantes/efectos adversos , Anticoagulantes/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Recuento de Plaquetas , Autoanticuerpos/sangre , Adulto , Metales , Biomarcadores/sangreRESUMEN
PF11_0189 is a putative insulin degrading enzyme present in Plasmodium falciparum genome. The catalytic domain of PF11_0189 is about 27 kDa. Substrate specificity study shows PF11_0189 acts upon different types of proteins. The substrate specificity is found to be highest when insulin is used as a substrate. Metal dependency study shows highest dependency of PF11_0189 towards zinc metal for its proteolytic activity. Chelation of zinc metal with EDTA shows complete absence of PF11_0189 activity. Peptide inhibitors, P-70 and P-121 from combinatorial peptide library prepared against PF11_0189 show inhibition with an IC50 value of 4.8 µM and 7.5 µM respectively. A proven natural anti-malarial peptide cyclosporin A shows complete inhibition against PF11_0189 with an IC50 value of 0.75 µM suggesting PF11_0189 as a potential target for peptide inhibitors. The study implicates that PF11_0189 is a zinc metalloprotease involved in catalysis of insulin. The study gives a preliminary insight into the mechanism of complications arising from glucose abnormalities during severe malaria.