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2.
Anal Chem ; 2024 May 06.
Article in English | MEDLINE | ID: mdl-38706229

ABSTRACT

The synthesis of 12α-hydroxylated bile acids (12HBAs) and non-12α-hydroxylated bile acids (non-12HBAs) occurs via classical and alternative pathways, respectively. The composition of these BAs is a crucial index for pathophysiologic assessment. However, accurately differentiating 12HBAs and non-12HBAs is highly challenging due to the limited standard substances. Here, we innovatively introduce 12α-hydroxysteroid dehydrogenase (12α-HSDH) as an enzymatic probe synthesized by heterologous expression in Escherichia coli, which can specifically and efficiently convert 12HBAs in vitro under mild conditions. Coupled to the conversion rate determined by liquid chromatography-high resolution mass spectrometry (LC-HRMS), this enzymatic probe allows for the straightforward distinguishing of 210 12HBAs and 312 non-12HBAs from complex biological matrices, resulting in a BAs profile with a well-defined hydroxyl feature at the C12 site. Notably, this enzyme-driven LC-HRMS approach can be extended to any molecule with explicit knowledge of enzymatic transformation. We demonstrate the practicality of this BAs profile in terms of both revealing cross-species BAs heterogeneity and monitoring the alterations of 12HBAs and non-12HBAs under asthma disease. We envisage that this work will provide a novel pattern to recognize the shift of BA metabolism from classical to alternative synthesis pathways in different pathophysiological states, thereby offering valuable insights into the management of related diseases.

3.
Article in English | MEDLINE | ID: mdl-38647881

ABSTRACT

Heart failure and myocardial infarction, global health concerns, stem from limited cardiac regeneration post-injury. Myocardial infarction, typically caused by coronary artery blockage, leads to cardiac muscle cell damage, progressing to heart failure. Addressing the adult heart's minimal self-repair capability is crucial, highlighting cardiac regeneration research's importance. Studies reveal a metabolic shift from anaerobic glycolysis to oxidative phosphorylation in neonates as a key factor in impaired cardiac regeneration, with mitochondria being central. The heart's high energy demands rely on a robust mitochondrial network, essential for cellular energy, cardiac health, and regenerative capacity. Mitochondria's influence extends to redox balance regulation, signaling molecule interactions, and apoptosis. Changes in mitochondrial morphology and quantity also impact cardiac cell regeneration. This article reviews mitochondria's multifaceted role in cardiac regeneration, particularly in myocardial infarction and heart failure models. Understanding mitochondrial function in cardiac regeneration aims to enhance myocardial infarction and heart failure treatment methods and insights.

4.
Clin Transl Sci ; 17(4): e13762, 2024 04.
Article in English | MEDLINE | ID: mdl-38591811

ABSTRACT

Mibavademab (previously known as REGN4461), a fully human monoclonal antibody, is being investigated for the treatment of conditions associated with leptin deficiency. Here, we report pharmacokinetics (PKs), pharmacodynamics, and immunogenicity from a phase I study in healthy participants (NCT03530514). In part A, lean or overweight healthy participants were randomized to single-ascending-dose cohorts of 0.3, 1.0, 3.0, 10, and 30 mg/kg intravenous (i.v.), or 300 and 600 mg subcutaneous doses of mibavademab or placebo. In part B, overweight or obese participants were randomized to receive multiple doses of mibavademab (15 mg/kg i.v. loading dose and 10 mg/kg i.v. at weeks 3, 6, and 9) or placebo, stratified by body mass index and baseline leptin levels: low leptin (<5 ng/mL) or relatively low leptin (5-8 ng/mL in men and 5-24 ng/mL in women). Fifty-six and 55 participants completed the single-ascending-dose and multiple-dose parts, respectively. In the single-ascending-dose cohorts, mibavademab PKs were nonlinear with target-mediated elimination, greater than dose-proportional increases in exposure, and there were no dose-dependent differences in total soluble leptin receptor (sLEPR) levels in serum over time. Following multiple-dose administration of mibavademab in participants with leptin <8 ng/mL, lower mean mibavademab concentrations, higher mean total sLEPR concentrations, and larger mean decreases in body weight than in the relatively low leptin cohorts were observed. Baseline leptin was correlated with mibavademab PKs and pharmacodynamics. No treatment-emergent anti-mibavademab antibodies were observed in any mibavademab-treated participant. Results from this study collectively inform further development of mibavademab to treat conditions associated with leptin deficiency.


Subject(s)
Leptin , Overweight , Male , Humans , Female , Leptin/pharmacokinetics , Leptin/therapeutic use , Receptors, Leptin/therapeutic use , Obesity/drug therapy , Body Mass Index , Double-Blind Method
6.
Plants (Basel) ; 13(6)2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38592923

ABSTRACT

Melanosciadium is considered a monotypic genus and is also endemic to the southwest of China. No detailed phylogenetic studies or plastid genomes have been identified in Melanosciadium. In this study, the plastid genome sequence and nrDNA sequence were used for the phylogenetic analysis of Melanosciadium and its related groups. Angelica tsinlingensis was previously considered a synonym of Hansenia forbesii. Similarly, Ligusticum angelicifolium was previously thought to be the genus Angelica or Ligusticopsis. Through field observations and morphological evidence, we believe that the two species are more similar to M. pimpinelloideum in leaves, umbel rays, and fruits. Meanwhile, we found a new species from Anhui Province (eastern China) that is similar to M. pimpinelloideum and have named it M. Jinzhaiensis. We sequenced and assembled the complete plastid genomes of these species and another three Angelica species. The genome comparison results show that M. pimpinelloideum, A. tsinlingensis, Ligusticum angelicifolium, and M. jinzhaiensis have similarities to each other in the plastid genome size, gene number, and length of the LSC and IR regions; the plastid genomes of these species are distinct from those of the Angelica species. In addition, we reconstruct the phylogenetic relationships using both plastid genome sequences and nrDNA sequences. The phylogenetic analysis revealed that A. tsinlingensis, M. pimpinelloideum, L. angelicifolium, and M. jinzhaiensis are closely related to each other and form a monophyletic group with strong support within the Selineae clade. Consequently, A. tsinlingensis and L. angelicifolium should be classified as members of the genus Melanosciadium, and suitable taxonomical treatments have been proposed. Meanwhile, a comprehensive description of the new species, M. jinzhaiensis, is presented, encompassing its habitat environment and detailed morphological traits.

7.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1164-1171, 2024 Mar.
Article in Chinese | MEDLINE | ID: mdl-38621963

ABSTRACT

Diabetic nephropathy(DN), a progressive chronic kidney disease(CKD) induced by diabetes mellitus, is the main cause of end-stage renal disease. Renal interstitial fibrosis(RIF) is an irreversible factor in the progression and deterioration of the renal function in DN. Chronic inflammation has become a key link in the pathogenesis of DN-RIF. The NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome is an important inflammatory regulator regulated by a variety of signals. It promotes the production of pro-inflammatory cytokines and induces renal inflammatory cell infiltration to participate in the process of renal fibrosis, demonstrating a complex mechanism of action. In view of the important role of NLRP3 inflammasomes in the prevention and treatment of DN-RIF, a large number of experimental studies have demonstrated that traditional Chinese medicine(TCM) can reduce the inflammation by regulating the pathways involving NLRP3 inflammasome, thereby slowing down the progression of DN-RIF and improving the renal function. This paper reviews the relationship between NLRP3 inflammasomes and DN-RIF, and the research progress in the mechanism of TCM intervention in NLRP3 inflammasomes to alleviate DN-RIF, aiming to provide new ideas for the targeted treatment of DN-RIF.


Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Humans , Inflammasomes/metabolism , Diabetic Nephropathies/drug therapy , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Medicine, Chinese Traditional , Inflammation/metabolism , Fibrosis
8.
Dalton Trans ; 53(19): 8347-8355, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38666520

ABSTRACT

A fundamental understanding of the exact structural characteristics and reaction mechanisms of interface active sites is vital to engineering an energetic metal-support boundary in heterogeneous catalysis. Herein, benefiting from a newly developed high-temperature ion trap reactor, the reverse water-gas shift (RWGS) (CO2 + H2 → CO + H2O) catalyzed by a series of compositionally and structurally well-defined RhnVO3,4- (n = 3-7) clusters were identified under variable temperatures (298-773 K). It is discovered that the Rh5-7VO3,4- clusters can function more effectively to drive RWGS at relatively low temperatures. The experimentally observed size-dependent catalytic behavior was rationalized by quantum-chemical calculations; the framework of RhnVO3,4- is constructed by depositing the Rhn clusters on the VO3,4 "support", and a sandwiched base-acid-base [Rhout--Rhin+-VO3,4-; Rhout and Rhin represent the outer and inner Rh atoms, respectively] feature in Rh5-7VO3,4- governs the adsorption and activation of reactants as well as the facile desorption of the products. In contrast, isolated Rh5-7- clusters without the electronic modification of the VO3,4 "support" can only catalyze RWGS under relatively high-temperature conditions.

9.
Light Sci Appl ; 13(1): 74, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38485915

ABSTRACT

Photonic quantum computation plays an important role and offers unique advantages. Two decades after the milestone work of Knill-Laflamme-Milburn, various architectures of photonic processors have been proposed, and quantum advantage over classical computers has also been demonstrated. It is now the opportune time to apply this technology to real-world applications. However, at current technology level, this aim is restricted by either programmability in bulk optics or loss in integrated optics for the existing architectures of processors, for which the resource cost is also a problem. Here we present a von-Neumann-like architecture based on temporal-mode encoding and looped structure on table, which is capable of multimode-universal programmability, resource-efficiency, phase-stability and software-scalability. In order to illustrate these merits, we execute two different programs with varying resource requirements on the same processor, to investigate quantum signature of chaos from two aspects: the signature behaviors exhibited in phase space (13 modes), and the Fermi golden rule which has not been experimentally studied in quantitative way before (26 modes). The maximal program contains an optical interferometer network with 1694 freely-adjustable phases. Considering current state-of-the-art, our architecture stands as the most promising candidate for real-world applications.

10.
Front Microbiol ; 15: 1359949, 2024.
Article in English | MEDLINE | ID: mdl-38500583

ABSTRACT

Diabetic retinopathy (DR) is a prevalent microvascular complication in diabetic patients that poses a serious risk as it can cause substantial visual impairment and even vision loss. Due to the prolonged onset of DR, lengthy treatment duration, and limited therapeutic effectiveness, it is extremely important to find a new strategy for the treatment of DR. Postbiotic is an emerging dietary supplement which consists of the inactivate microbiota and its metabolites. Numerous animal experiments have demonstrated that intervention with postbiotics reduces hyperglycemia, attenuates retinal peripapillary and endothelial cell damage, improves retinal microcirculatory dysfunction, and consequently delays the progression of DR. More strikingly, unlike conventional probiotics and prebiotics, postbiotics with small molecules can directly colonize the intestinal epithelial cells, and exert heat-resistant, acid-resistant, and durable for storage. Despite few clinical significance, oral administration with postbiotics might become the effective management for the prevention and treatment of DR. In this review, we summarized the basic conception, classification, molecular mechanisms, and the advances in the therapeutic implications of postbiotics in the pathogenesis of DR. Postbiotics present great potential as a viable adjunctive therapy for DR.

12.
Med Image Anal ; 93: 103098, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38320370

ABSTRACT

Characterising clinically-relevant vascular features, such as vessel density and fractal dimension, can benefit biomarker discovery and disease diagnosis for both ophthalmic and systemic diseases. In this work, we explicitly encode vascular features into an end-to-end loss function for multi-class vessel segmentation, categorising pixels into artery, vein, uncertain pixels, and background. This clinically-relevant feature optimised loss function (CF-Loss) regulates networks to segment accurate multi-class vessel maps that produce precise vascular features. Our experiments first verify that CF-Loss significantly improves both multi-class vessel segmentation and vascular feature estimation, with two standard segmentation networks, on three publicly available datasets. We reveal that pixel-based segmentation performance is not always positively correlated with accuracy of vascular features, thus highlighting the importance of optimising vascular features directly via CF-Loss. Finally, we show that improved vascular features from CF-Loss, as biomarkers, can yield quantitative improvements in the prediction of ischaemic stroke, a real-world clinical downstream task. The code is available at https://github.com/rmaphoh/feature-loss.


Subject(s)
Brain Ischemia , Stroke , Humans , Algorithms , Image Processing, Computer-Assisted/methods , Fundus Oculi
13.
Cancer Biol Ther ; 25(1): 2306674, 2024 12 31.
Article in English | MEDLINE | ID: mdl-38372700

ABSTRACT

DIRAS family GTPase 1 (DIRAS1) has been reported as a potential tumor suppressor in other human cancer. However, its expression pattern and role in cervical cancer remain unknown. Knockdown of DIRAS1 significantly promoted the proliferation, growth, migration, and invasion of C33A and SiHa cells cultured in vitro. Overexpression of DIRAS1 significantly inhibited the viability and motility of C33A and SiHa cells. Compared with normal cervical tissues, DIRAS1 mRNA levels were significantly lower in cervical cancer tissues. DIRAS1 protein expression was also significantly reduced in cervical cancer tissues compared with para-cancerous tissues. In addition, DIRAS1 expression level in tumor tissues was significantly negatively correlated with the pathological grades of cervical cancer patients. DNA methylation inhibitor (5-Azacytidine) and histone deacetylation inhibitor (SAHA) resulted in a significant increase in DIRAS1 mRNA levels in C33A and SiHa cells, but did not affect DIRAS1 protein levels. FTO inhibitor (FB23-2) significantly down-regulated intracellular DIRAS1 mRNA levels, but significantly up-regulated DIRAS1 protein levels. Moreover, the down-regulation of METTL3 and METTL14 expression significantly inhibited DIRAS1 protein expression, whereas the down-regulation of FTO and ALKBH5 expression significantly increased DIRAS1 protein expression. In conclusion, DIRAS1 exerts a significant anti-oncogenic function and its expression is significantly downregulated in cervical cancer cells. The m6A modification may be a key mechanism to regulate DIRAS1 mRNA stability and protein translation efficiency in cervical cancer.


Subject(s)
Adenine/analogs & derivatives , Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/genetics , Azacitidine/pharmacology , RNA, Messenger/genetics , Methyltransferases , GTP Phosphohydrolases , Tumor Suppressor Proteins , Alpha-Ketoglutarate-Dependent Dioxygenase FTO
14.
Eye (Lond) ; 2024 Jan 10.
Article in English | MEDLINE | ID: mdl-38200320

ABSTRACT

BACKGROUND: There are no data on pharmacokinetics, pharmacodynamics, and immunogenicity of intravitreal aflibercept in preterm infants with retinopathy of prematurity (ROP). FIREFLEYE compared aflibercept 0.4 mg/eye and laser photocoagulation in infants with acute-phase ROP requiring treatment. METHODS: Infants (gestational age ≤32 weeks or birthweight ≤1500 g) with treatment-requiring ROP in ≥1 eye were randomized 2:1 to receive aflibercept 0.4 mg or laser photocoagulation at baseline in this 24-week, randomized, open-label, noninferiority, phase 3 study. Endpoints include concentrations of free and adjusted bound aflibercept in plasma, pharmacokinetic/pharmacodynamic exploration of systemic anti-vascular endothelial growth factor effects, and immunogenicity. RESULTS: Of 113 treated infants, 75 received aflibercept 0.4 mg per eye at baseline (mean chronological age: 10.4 weeks), mostly bilaterally (71 infants), and with 1 injection/eye (120/146 eyes). Concentrations of free aflibercept were highly variable, with maximum concentration at day 1, declining thereafter. Plasma concentrations of adjusted bound (pharmacologically inactive) aflibercept increased from day 1 to week 4, decreasing up to week 24. Six infants experienced treatment-emergent serious adverse events within 30 days of treatment; aflibercept concentrations were within the range observed in other infants. There was no pattern between free and adjusted bound aflibercept concentrations and blood pressure changes up to week 4. A low-titer (1:30), non-neutralizing, treatment-emergent anti-drug antibody response was reported in 1 infant, though was not clinically relevant. CONCLUSIONS: 24-week data suggest intravitreal aflibercept for treatment of acute-phase ROP is not associated with clinically relevant effects on blood pressure, further systemic adverse events, or immunogenicity. GOV IDENTIFIER: NCT04004208.

15.
Heliyon ; 10(1): e22895, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38163172

ABSTRACT

On-dose authentication (ODA) enhances security by incorporating customized molecular or micro-tags into each pill, preventing counterfeit products in genuine packages. ODA's security relies on tag non-replication and non-reverse engineering. Combining ODA with graphical Physical Unclonable Functions (PUF) promises maximum security. PUF uses intrinsic micro or nanoscale randomness as a unique 'fingerprint'. However, current graphical PUFs have limitations like specific illumination requirements and the use of toxic materials, restricting their use in pharmaceuticals. In this study, we propose a novel approach called on-dose PUF. This method involves embedding microspheres randomly within micro biocompatible hydrogel particles. We showcase two distinct types of such on-dose PUFs. The first type utilizes randomly distributed superparamagnetic colloids (SPC) of identical diameters, while the second type utilizes vortexed sunflower oil drops of various diameters. The diameter and coordinates of the microspheres serve as input for generating cryptographic keys. A universal circle identification and binning program is used for extracting this information. One advantage of this approach is that it enables imaging using white light illumination and low-magnification microscopy, as color and signal intensity information are not crucial. This method enables patients to verify their medication by using their mobile phones from home. To assess the performance of the proposed on-dose PUF, we conducted canonical investigations on the single-diameter system. This system can only generate one layer of cryptographic keys, making it potentially more vulnerable than the multiple-diameter system. However, the single-diameter system successfully passed NIST Statistical tests and exhibited sufficient randomness, ideal bit uniformity, Hamming distance, and device uniqueness. Furthermore, we found that the encoding capacity of the single-diameter system was 9.2×1018, providing ample labeling potential.

16.
Spectrochim Acta A Mol Biomol Spectrosc ; 309: 123835, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38183734

ABSTRACT

pH plays a crucial part in numerous chemical and physiological processes. In this work, a new perylene diimide derivative that acts as a pH-sensitive dye with Bay Area Carboxylic Acid functionality. The derivative utilizes the outstanding thermal, chemical and photochemical stability found in PDI materials and has remarkable UV-visible absorption and fluorescence emission qualities. Based on these properties, a fluorescent probe (PCA) was synthesised using a perylene tetracarbodiimide (PDI) backbone for the recognition of alkaline pH. In alkaline environments where the pH values are between 10 and 14, the fluorescence intensity significantly decreases, and a blue shift occurs, which is a standard feature of alkaline pH probes. The probe demonstrates exceptional sensing ability within the pH range of 10.00-14.00, with notable stability and reversibility. Encapsulation of the probe in a thin polymer film material enhances the pH sensing capability of the system. New sensor has been developed to detect basic amino acids by utilizing the probes' pH response characteristics. this sensor has also been applied to detect the concentration of arginine.

17.
BMC Plant Biol ; 24(1): 70, 2024 Jan 24.
Article in English | MEDLINE | ID: mdl-38263006

ABSTRACT

BACKGROUND: The genus Sanicula L. is a unique perennial herb that holds important medicinal values. Although the previous studies on Sanicula provided us with a good research basis, its taxonomic system and interspecific relationships have not been satisfactorily resolved, especially for those endemic to China. Moreover, the evolutionary history of this genus also remains inadequately understood. The plastid genomes possessing highly conserved structure and limited evolutionary rate have proved to be an effective tool for studying plant phylogeny and evolution. RESULTS: In the current study, we newly sequenced and assembled fifteen Sanicula complete plastomes. Combined with two previously reported plastomes, we performed comprehensively plastid phylogenomics analyses to gain novel insights into the evolutionary history of this genus. The comparative results indicated that the seventeen plastomes exhibited a high degree of conservation and similarity in terms of their structure, size, GC content, gene order, IR borders, codon bias patterns and SSRs profiles. Such as all of them displayed a typical quadripartite structure, including a large single copy region (LSC: 85,074-86,197 bp), a small single copy region (SSC: 17,047-17,132 bp) separated by a pair of inverted repeat regions (IRs: 26,176-26,334 bp). And the seventeen plastomes had similar IR boundaries and the adjacent genes were identical. The rps19 gene was located at the junction of the LSC/IRa, the IRa/SSC junction region was located between the trnN gene and ndhF gene, the ycf1 gene appeared in the SSC/IRb junction and the IRb/LSC boundary was located between rpl12 gene and trnH gene. Twelve specific mutation hotspots (atpF, cemA, accD, rpl22, rbcL, matK, ycf1, trnH-psbA, ycf4-cemA, rbcL-accD, trnE-trnT and trnG-trnR) were identified that can serve as potential DNA barcodes for species identification within the genus Sanicula. Furthermore, the plastomes data and Internal Transcribed Spacer (ITS) sequences were performed to reconstruct the phylogeny of Sanicula. Although the tree topologies of them were incongruent, both provided strong evidence supporting the monophyly of Saniculoideae and Apioideae. In addition, the sister groups between Saniculoideae and Apioideae were strongly suggested. The Sanicula species involved in this study were clustered into a clade, and the Eryngium species were also clustered together. However, it was clearly observed that the sections of Sanicula involved in the current study were not respectively recovered as monophyletic group. Molecular dating analysis explored that the origin of this genus was occurred during the late Eocene period, approximately 37.84 Ma (95% HPD: 20.33-52.21 Ma) years ago and the diversification of the genus was occurred in early Miocene 18.38 Ma (95% HPD: 10.68-25.28 Ma). CONCLUSION: The plastome-based tree and ITS-based tree generated incongruences, which may be attributed to the event of hybridization/introgression, incomplete lineage sorting (ILS) and chloroplast capture. Our study highlighted the power of plastome data to significantly improve the phylogenetic supports and resolutions, and to efficiently explore the evolutionary history of this genus. Molecular dating analysis explored that the diversification of the genus occurred in the early Miocene, which was largely influenced by the prevalence of the East Asian monsoon and the uplift of the Hengduan Mountains (HDM). In summary, our study provides novel insights into the plastome evolution, phylogenetic relationships, taxonomic framework and evolution of genus Sanicula.


Subject(s)
Apiaceae , Sanicula , Phylogeny , Plastids , Chloroplasts
18.
Clin Pharmacol Ther ; 115(3): 422-439, 2024 03.
Article in English | MEDLINE | ID: mdl-38093583

ABSTRACT

Subcutaneous (s.c.) administration of monoclonal antibodies (mAbs) can reduce treatment burden for patients and healthcare systems compared with intravenous (i.v.) infusion through shorter administration times, made possible by convenient, patient-centric devices. A deeper understanding of clinical pharmacology principles related to efficacy and safety of s.c.-administered mAbs over the past decade has streamlined s.c. product development. This review presents learnings from key constituents of the s.c. mAb development pathway, including pharmacology, administration variables, immunogenicity, and delivery devices. Restricted mAb transportation through the hypodermis explains their incomplete absorption at a relatively slow rate (pharmacokinetic (PK)) and may impact mAb-cellular interactions and/or onset and magnitude of physiological responses (pharmacodynamic). Injection volumes, formulation, rate and site of injection, and needle attributes may affect PKs and the occurrence/severity of adverse events like injection-site reactions or pain, with important consequences for treatment adherence. A review of immunogenicity data for numerous compounds reveals that incidence of anti-drug antibodies (ADAs) is generally comparable across i.v. and s.c. routes, and complementary factors including response magnitude (ADA titer), persistence over time, and neutralizing antibody presence are needed to assess clinical impact. Finally, four case studies showcase how s.c. biologics have been clinically developed: (i) by implementation of i.v./s.c. bridging strategies to streamline PD-1/PD-L1 inhibitor development, (ii) through co-development with i.v. presentations for anti-severe acute respiratory syndrome-coronavirus 2 antibodies to support rapid deployment of both formulations, (iii) as the lead route for bispecific T cell engagers (BTCEs) to mitigate BTCE-mediated cytokine release syndrome, and (iv) for pediatric patients in the case of dupilumab.


Subject(s)
Antibodies, Monoclonal , Subcutaneous Tissue , Humans , Child , Antibodies, Monoclonal/adverse effects , Antibodies, Neutralizing , Administration, Intravenous
19.
Eur Respir J ; 63(4)2024 Apr.
Article in English | MEDLINE | ID: mdl-37973176

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. METHODS: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. RESULTS: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. CONCLUSION: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.


Subject(s)
Emphysema , Idiopathic Pulmonary Fibrosis , Pulmonary Emphysema , Humans , Pulmonary Emphysema/complications , Lung , Fibrosis , Emphysema/complications , Disease Progression , Retrospective Studies
20.
Int Urol Nephrol ; 56(1): 167-179, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37450241

ABSTRACT

As a high energy consumption organ, kidney relies on a large number of mitochondria to ensure normal physiological activities. Under specific stimulation, mitophagy and mitochondrial dynamics (fission, fusion) cooperatively regulate mitochondrial quality and participate in many life activities such as energy metabolism, inflammatory response, oxidative stress, cell senescence and death. Mitophagy plays a key role in the progression of acute kidney injury and chronic kidney disease. The early induction of oxidative stress in renal parenchyma, the activation of pro-inflammatory cytokines and TGF-ß signal pathway are closely related to renal interstitial fibrosis. Macrophage reprogramming is also considered to be an important participant in the progression of kidney fibrosis. This review summarizes the molecular mechanism of mitochondrial autophagy and its relationship with the pathway of promoting fibrosis, and discusses the possibility of restoring mitophagy balance as a pharmacological target for the treatment of renal interstitial fibrosis, so as to provide new ideas for more efficient anti-fibrosis and delay the progress of chronic kidney disease.


Subject(s)
Acute Kidney Injury , Renal Insufficiency, Chronic , Humans , Mitophagy/physiology , Kidney/pathology , Fibrosis , Acute Kidney Injury/pathology , Renal Insufficiency, Chronic/pathology
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