Serum Proteomics Identifies Biomarkers Associated With the Pathogenesis of Idiopathic Pulmonary Fibrosis.

The heterogeneity of idiopathic pulmonary fibrosis (IPF) limits its diagnosis and treatment. The association between the pathophysiological features and the serum protein signatures of IPF currently remains unclear. The present study analyzed the specific proteins and patterns associated with the clinical parameters of IPF based on a serum proteomic dataset by data-independent acquisition using MS. Differentiated proteins in sera distinguished patients with IPF into three subgroups in signal pathways and overall survival. Aging-associated signatures by weighted gene correlation network analysis coincidently provided clear and direct evidence that aging is a critical risk factor for IPF rather than a single biomarker. Expression of LDHA and CCT6A, which was associated with glucose metabolic reprogramming, was correlated with high serum lactic acid content in patients with IPF. Cross-model analysis and machine learning showed that a combinatorial biomarker accurately distinguished patients with IPF from healthy individuals with an area under the curve of 0.848 (95% CI = 0.684-0.941) and validated from another cohort and ELISA assay. This serum proteomic profile provides rigorous evidence that enables an understanding of the heterogeneity of IPF and protein alterations that could help in its diagnosis and treatment decisions.

Downregulation of HMGCS2 mediated AECIIs lipid metabolic alteration promotes pulmonary fibrosis by activating fibroblasts.

BACKGROUND: Abnormal lipid metabolism has recently been reported as a crucial signature of idiopathic pulmonary fibrosis (IPF). However, the origin and biological function of the lipid and possible mechanisms of increased lipid content in the pathogenesis of IPF remains undetermined. METHODS: Oil-red staining and immunofluorescence analysis were used to detect lipid accumulation in mouse lung fibrosis frozen sections, Bleomycin-treated human type II alveolar epithelial cells (AECIIs) and lung fibroblast. Untargeted Lipid omics analysis was applied to investigate differential lipid species and identified LysoPC was utilized to treat human lung fibroblasts and mice. Microarray and single-cell RNA expression data sets identified lipid metabolism-related differentially expressed genes. Gain of function experiment was used to study the function of 3-hydroxy-3-methylglutaryl-Coa Synthase 2 (HMGCS2) in regulating AECIIs lipid metabolism. Mice with AECII-HMGCS2 high were established by intratracheally delivering HBAAV2/6-SFTPC- HMGCS2 adeno-associated virus. Western blot, Co-immunoprecipitation, immunofluorescence, site-directed mutation and flow cytometry were utilized to investigate the mechanisms of HMGCS2-mediated lipid metabolism in AECIIs. RESULTS: Injured AECIIs were the primary source of accumulated lipids in response to Bleomycin stimulation. LysoPCs released by injured AECIIs could activate lung fibroblasts, thus promoting the progression of pulmonary fibrosis. Mechanistically, HMGCS2 was decreased explicitly in AECIIs and ectopic expression of HMGCS2 in AECIIs using the AAV system significantly alleviated experimental mouse lung fibrosis progression via modulating lipid degradation in AECIIs through promoting CPT1A and CPT2 expression by interacting with PPARα. CONCLUSIONS: These data unveiled a novel etiological mechanism of HMGCS2-mediated AECII lipid metabolism in the genesis and development of pulmonary fibrosis and provided a novel target for clinical intervention.

NR2F2 alleviates pulmonary fibrosis by inhibition of epithelial cell senescence.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal, and aging-associated interstitial lung disease with a poor prognosis and limited treatment options, while the pathogenesis remains elusive. In this study, we found that the expression of nuclear receptor subfamily 2 group F member 2 (NR2F2), a member of the steroid thyroid hormone superfamily of nuclear receptors, was reduced in both IPF and bleomycin-induced fibrotic lungs, markedly in bleomycin-induced senescent epithelial cells. Inhibition of NR2F2 expression increased the expression of senescence markers such as p21 and p16 in lung epithelial cells, and activated fibroblasts through epithelial-mesenchymal crosstalk, inversely overexpression of NR2F2 alleviated bleomycin-induced epithelial cell senescence and inhibited fibroblast activation. Subsequent mechanistic studies revealed that overexpression of NR2F2 alleviated DNA damage in lung epithelial cells and inhibited cell senescence. Adenovirus-mediated Nr2f2 overexpression attenuated bleomycin-induced lung fibrosis and cell senescence in mice. In summary, these data demonstrate that NR2F2 is involved in lung epithelial cell senescence, and targeting NR2F2 may be a promising therapeutic approach against lung cell senescence and fibrosis.

Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot-Marie-Tooth disease and identification of H256R as a frequent mutation.

BACKGROUND AND AIMS: Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause axonal or demyelinating Charcot-Marie-Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1-related CMT in a Chinese cohort. METHODS: Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected. RESULTS: We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra-familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis. CONCLUSIONS: In this study, we conducted an analysis of clinical features of the GDAP1-related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes.

TRIOBP modulates ß-catenin signaling by regulation of miR-29b in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial-mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of ß-catenin. We concluded that the miR-29b‒TRIOBP-TRIO-ß-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis.

Catalytic Enantioselective [4+2] Cycloadditions of Salicylaldehyde Acetals with Enol Ethers.

A readily accessible conjugate-base-stabilized carboxylic acid (CBSCA) catalyst facilitates highly enantioselective [4+2] cycloaddition reactions of salicylaldehyde-derived acetals and cyclic enol ethers, resulting in the formation of polycyclic chromanes with oxygenation in the 2- and 4-positions. Stereochemically more complex products can be obtained from racemic enol ethers. Spirocyclic products are also accessible.

Single-Cell RNA Sequencing Provides New Insights into Therapeutic Roles of Thyroid Hormone in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease without an effective cure. Herein, we explore the role of 3,5,3'-triiodothyronine (T3) administration on lung alveolar regeneration and fibrosis at the single-cell level. T3 supplementation significantly altered the gene expression in fibrotic lung tissues. Immune cells were rapidly recruited into the lung after the injury; there were much more M2 macrophages than M1 macrophages in the lungs of bleomycin-treated mice; and M1 macrophages increased slightly, whereas M2 macrophages were significantly reduced after T3 treatment. T3 enhanced the resolution of pulmonary fibrosis by promoting the differentiation of Krt8+ transitional alveolar type II epithelial cells into alveolar type I epithelial cells and inhibiting fibroblast activation and extracellular matrix production potentially by regulation of Nr2f2. In addition, T3 regulated the crosstalk of macrophages with fibroblasts, and the Pros1-Axl signaling axis significantly facilitated the attenuation of fibrosis. The findings demonstrate that administration of a thyroid hormone promotes alveolar regeneration and resolves fibrosis mainly by regulation of the cellular state and cell-cell communication of alveolar epithelial cells, macrophages, and fibroblasts in mouse lungs in comprehensive ways.

Injured Endothelial Cell: A Risk Factor for Pulmonary Fibrosis.

The pathological features of pulmonary fibrosis (PF) are the abnormal activation and proliferation of myofibroblasts and the extraordinary deposition of the extracellular matrix (ECM). However, the pathogenesis of PF is still indistinct. In recent years, many researchers have realized that endothelial cells had a crucial role in the development of PF. Studies have demonstrated that about 16% of the fibroblasts in the lung tissue of fibrotic mice were derived from endothelial cells. Endothelial cells transdifferentiated into mesenchymal cells via the endothelial-mesenchymal transition (E(nd)MT), leading to the excessive proliferation of endothelial-derived mesenchymal cells and the accumulation of fibroblasts and ECM. This suggested that endothelial cells, a significant component of the vascular barrier, played an essential role in PF. Herein, this review discusses E(nd)MT and its contribution to the activation of other cells in PF, which could provide new ideas for further understanding the source and activation mechanism of fibroblasts and the pathogenesis of PF.

Clinical and molecular genetic characteristics of 24 families of hereditary neuropathy with liability to pressure palsy and literature review. / é—ä¼ æ€§åŽ‹åŠ›æ˜“æ„Ÿæ€§å‘¨å›´ç¥žç»ç— 24ä¸ªå®¶ç³»çš„ä¸´åºŠå’Œåˆ†å­é—ä¼ å­¦ç‰¹å¾åŠæ–‡çŒ®å›žé¡¾.

OBJECTIVES: Hereditary neuropathy with liability to pressure palsy (HNPP) is a rare autosomal dominant peripheral neuropathy, usually caused by heterozygous deletion mutations in the peripheral myelin protein 22 (PMP22) gene. This study aims to investigate the clinical and molecular genetic characteristics of HNPP. METHODS: HNPP patients in the Department of Neurology at Third Xiangya Hospital of Central South University from 2009 to 2023 were included in this study. The general clinical data, nervous electrophysiological and molecular genetic examination results were collected and analyzed. Molecular genetic examination was to screen for deletion of PMP22 gene using multiplex ligation-dependent probe amplification (MLPA) after extracting genomic DNA from peripheral blood; and if no PMP22 deletion mutation was detected, next-generation sequencing was used to screen for PMP22 point mutations. The related literatures of HNPP were reviewed, and the clinical and molecular genetic characteristics of HNPP patients were analyzed. RESULTS: A total of 34 HNPP patients from 24 unrelated Chinese Han families were included in this study, including 25 males and 9 females. The average age at illness onset was 22.0 years. Sixty-two point five percent of the families had a positive family history. Among them, 30 patients had symptoms of peripheral nerve paralysis. Patients often presented with paroxysmal single limb weakness with (or) numbness (25/30), and some patients had paroxysmal unilateral recurrent laryngeal nerve (vagus nerve) paralysis (2/30). Physical examination revealed muscle weakness (23/29), hypoesthesia (9/29), weakened or absent ankle reflexes (20/29), distal limb muscle atrophy (8/29) and high arched feet (5/29). Most patients (26/30) could fully recover to normal after an acute attack. Thirty-one patients in our group underwent nervous electrophysiological examination, and showed multiple demyelinating peripheral neuropathies with both motor and sensory nerves involved. Most patients showed significantly prolonged distal motor latency (DML), mild to moderate nerve conduction velocity slowing, decreased amplitude of compound muscle action potential (CMAP) and sensory nerve action potential (SNAP), and sometimes with conduction block. Nerve motor conduction velocity was (48.5±5.5) m/s, and the CMAP amplitude was (8.4±5.1) mV. Nerve sensory conduction velocity was (37.4±10.5) m/s, and the SNAP amplitude was (14.4±15.2) µV. There were 24 families, 23 of whom had the classical PMP22 deletion, the last one had a heterozygous pathogenic variant in the PMP22 gene sequence (c.434delT). By reviewing clinical data and genetic testing results of reported 1 734 HNPP families, we found that heterozygous deletion mutation of PMP22 was the most common pathogenic mutation of HNPP (93.4%). Other patients were caused by PMP22 small mutations (4.0%), PMP22 heterozygous gross deletions (0.6%), and PMP22 complex rearrangements (0.1%). Thirty-eight sorts of HNPP-related PMP22 small mutations was reported, including missense mutations (10/38), nonsense mutations (4/38), base deletion mutations (13/38), base insertion mutations (3/38), and shear site mutations (8/38). HNPP patients most often presented with episodic painless single nerve palsy. Common peroneal nerve, ulnar nerve, and brachial plexus nerve were the most common involved nerves, accounting for about 75%. Only eighteen patients with cranial nerve involved was reported. CONCLUSIONS: Heterozygous deletion mutation of PMP22 is the most common pathogenic mutation of HNPP. Patients is characterized by episodic and painless peripheral nerve paralysis, mainly involving common peroneal nerve, ulnar nerve, and other peripheral nerves. Nervous electrophysiological examination has high sensitivity and specificity for the diagnosis of HNPP, which is manifested by extensive demyelinating changes. For patients with suspected HNPP, nervous electrophysiological examination and PMP22-MLPA detection are preferred. Sanger sequencing or next generation sequencing can be considered to detect other mutations of PMP22.

TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by fibroblast activation, excessive deposition of extracellular matrix, and progressive scarring; the pathogenesis remains elusive. The present study explored the role of Tribbles pseudokinase 3 (TRIB3), a well-known stress and metabolic sensor, in IPF. TRIB3 is down-regulated in the lungs of IPF patients in comparison to control subjects. Deficiency of TRIB3 markedly inhibited A549 epithelial cells' proliferation and migration, significantly reducing wound healing. Conversely, overexpression of TRIB3 promoted A549 cell proliferation and transmigration while it inhibited its apoptosis. Meanwhile, overexpressed TRIB3 inhibited fibroblast activation and decreased ECM synthesis and deposition in MRC5 cells. TRIB3 attenuated pulmonary fibrosis by negative regulation of ATF4, while TRIB3 expression markedly inhibited ATF4 promoter-driven transcription activity and down-regulated ATF4 expression. A co-culture system showed that TRIB3 is important to maintain the normal epithelial-mesenchymal crosstalk and regulate fibroblast activation. Taken together, our data suggested that an axis of TRIB3-ATF4 is a key mediator in IPF which might be a potential target for fibroproliferative lung disease treatment.

Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation.

A Cu(II)-catalyzed diastereoselective Michael/aldol cascade approach is used to accomplish concise total syntheses of cardiotonic steroids with varying degrees of oxygenation including cardenolides ouabagenin, sarmentologenin, 19-hydroxysarmentogenin, and 5- epi-panogenin. These syntheses enabled the subsequent structure activity relationship (SAR) studies on 37 synthetic and natural steroids to elucidate the effect of oxygenation, stereochemistry, C3-glycosylation, and C17-heterocyclic ring. Based on this parallel evaluation of synthetic and natural steroids and their derivatives, glycosylated steroids cannogenol-l-α-rhamnoside (79a), strophanthidol-l-α-rhamnoside (92), and digitoxigenin-l-α-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 µM against NIH-3T3, MEF, and developing fish embryos). Further analyses indicate that these molecules show a general mode of anticancer activity involving DNA-damage upregulation that subsequently induces apoptosis.

Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

Histone 3 Trimethylation of IGFBP-7 Gene Promoter by Expression of D5 Stat5a in Breast Epithelial Cells.

As a very important transcription factor, signal transducer and activator of transcription 5a (Stat5a) has been reported to be involved in human reproductive cancers such as breast, prostate and ovarian cancer. However, up to date, the exact role of Stat5a in breast cancer is still not clear. The data reported are conflicting. D5 Stat5a is a variant of Stat5a we cloned recently. This newly cloned variant behave like its full length counterpart in terms of dimerization, being activated by prolactin and nuclear translocation, however it also behave differently in terms of effect on cell proliferation and interaction with other transcription factors. In the present study, we examined its effect on cell proliferation of cultured breast cancer cells (MCF-10A and MCF-7) by using adenovirus-mediated gene transfer and MTS technology. Also, quantitative real time polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation assay (ChIP) and Western blot were used to probe the possible changes of insulin-like growth factor binding protein-7 (IGFBP-7) expression including mRNA and protein, and the epigenetic changes with overexpression of this newly cloned variant. The results clarified that D5 Stat5a (1) behaves as a promoting factor to the cell proliferation of MCF-10A and MCF-7, (2) induces enhancer of zeste homology 2 (EZH2) expression in breast epithelial cells, as well as histone 3 trimethylation of IGFBP-7 promoter region, and (3) lower IGFBP-7 expression was detected in breast cancer tissue. Taking together, we concluded that the mitogenic effect of D5 Stat5a on breast cells is, at least partly, through up-regulation of histone methyltransferase, EZH2, and therefore inhibiting IGFBP-7 expression by increasing H3K27Me3 of IGFBP-7 promoter region.

TransVAE-DTA: Transformer and variational autoencoder network for drug-target binding affinity prediction.

BACKGROUND AND OBJECTIVE: Recent studies have emphasized the significance of computational in silico drug-target binding affinity (DTA) prediction in the field of drug discovery and drug repurposing. However, existing DTA prediction approaches suffer from two major deficiencies that impede their progress. Firstly, while most methods primarily focus on the feature representations of drug-target binding affinity pairs, they fail to consider the long-distance relationships of proteins. Furthermore, many deep learning-based DTA predictors simply model the interaction of drug-target pairs through concatenation, which hampers the ability to enhance prediction performance. METHODS: To address these issues, this study proposes a novel framework named TransVAE-DTA, which combines the transformer and variational autoencoder (VAE). Inspired by the early success of VAEs, we aim to further investigate the feasibility of VAEs for drug structure encoding, while utilizing the transformer architecture for target feature representation. Additionally, an adaptive attention pooling (AAP) module is designed to fuse the drug and target encoded features. Notably, TransVAE-DTA is proven to maximize the lower bound of the joint likelihood of drug, target, and their DTAs. RESULTS: Experimental results demonstrate the superiority of TransVAE-DTA in drug-target binding affinity prediction assignments on two public Davis and KIBA datasets. CONCLUSIONS: In this research, the developed TransVAE-DTA opens a new avenue for engineering drug-target interactions.

Hybrid energy storage configuration method for wind power microgrid based on EMD decomposition and two-stage robust approach.

Data centers are usually characterized by high energy loads, which raises increasing sustainability concerns in both academic and daily usage. To mitigate the uncertainty and high volatility of distributed wind energy generation, this paper proposes a hybrid energy storage allocation strategy by means of the Empirical Mode Decomposition (EMD) technique and the two-stage robust method. First, this paper conducts the evolution analyses for the over- and under-evaluated uncertainty of wind power fluctuation under different time scales. Second, we employ the EMD technique to configure a high-frequency flywheel energy storage device, realizing the wind power transformation from large fluctuations to small fluctuations and the convergence of the wind power fluctuation curves in minute- and hour levels. Finally, based on the hour-level wind energy stable power curves, we carry out two-stage robust planning for the equipment capacity of low-frequency cold storage tanks and lithium bromide chillers. The case study on a data center microgrid in northeastern China confirms the effectiveness of our proposed strategy.

Xiaoqinglong decoction mitigates nasal inflammation and modulates gut microbiota in allergic rhinitis mice.

Introduction: Allergic rhinitis (AR) is a respiratory immune system disorder characterized by dysregulation of immune responses. Within the context of AR, gut microbiota and its metabolites have been identified as contributors to immune modulation. These microorganisms intricately connect the respiratory and gut immune systems, forming what is commonly referred to as the gut-lung axis. Xiaoqinglong Decoction (XQLD), a traditional Chinese herbal remedy, is widely utilized in traditional Chinese medicine for the clinical treatment of AR. In this study, it is hypothesized that the restoration of symbiotic microbiota balance within the gut-lung axis plays a pivotal role in supporting the superior long-term efficacy of XQLD in AR therapy. Therefore, the primary objective of this research is to investigate the impact of XQLD on the composition and functionality of the gut microbiota in a murine model of AR. Methods: An ovalbumin-sensitized mouse model to simulate AR was utilized, the improvement of AR symptoms after medication was investigated, and high-throughput sequencing was employed to analyze the gut microbiota composition. Results: XQLD exhibited substantial therapeutic effects in AR mice, notably characterized by a significant reduction in allergic inflammatory responses, considerable alleviation of nasal symptoms, and the restoration of normal nasal function. Additionally, following XQLD treatment, the disrupted gut microbiota in AR mice displayed a tendency toward restoration, showing significant differences compared to the Western medicine (loratadine) group. Discussion: This results revealed that XQLD may enhance AR allergic inflammatory responses through the regulation of intestinal microbiota dysbiosis in mice, thus influencing the dynamics of the gut-lung axis. The proposal of this mechanism provides a foundation for future research in this area.

CCT6A alleviates pulmonary fibrosis by inhibiting HIF-1α-mediated lactate production.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive fibrotic lung disease. The development of IPF involves different molecular and cellular processes, and recent studies indicate that lactate plays a significant role in promoting the progression of the disease. Nevertheless, the mechanism by which lactate metabolism is regulated and the downstream effects remain unclear. The molecular chaperone CCT6A performs multiple functions in a variety of biological processes. Our research has identified a potential association between CCT6A and serum lactate levels in IPF patients. Herein, we found that CCT6A was highly expressed in type 2 alveolar epithelial cells (AEC2s) of fibrotic lung tissues and correlated with disease severity. Lactate increases the accumulation of lipid droplets in epithelial cells. CCT6A inhibits lipid synthesis by blocking the production of lactate in AEC2s and alleviates bleomycin-induced pulmonary fibrosis in mice. In addition, our results revealed that CCT6A blocks HIF-1α-mediated lactate production by driving the VHL-dependent ubiquitination and degradation of HIF-1α and further inhibits lipid accumulation in fibrotic lungs. In conclusion, we propose that there is a pivotal regulatory role of CCT6A in lactate metabolism in pulmonary fibrosis, and strategies aimed at targeting these key molecules could represent potential therapeutic approaches for pulmonary fibrosis.

Hibiscus manihot L. flower extract induces anticancer activity through modulation of apoptosis and autophagy in A549 cells.

Lung cancer is a major public health issue and heavy burden in China and worldwide due to its high incidence and mortality without effective treatment. It's imperative to develop new treatments to overcome drug resistance. Natural products from food source, given their wide-ranging and long-term benefits, have been increasingly used in tumor prevention and treatment. This study revealed that Hibiscus manihot L. flower extract (HML) suppressed the proliferation and migration of A549 cells in a dose and time dependent manner and disrupting cell cycle progression. HML markedly enhanced the accumulation of ROS, stimulated the dissipation of mitochondrial membrane potential (MMP) and that facilitated mitophagy through the loss of mitochondrial function. In addition, HML induced apoptosis by activation of the PTEN-P53 pathway and inhibition of ATG5/7-dependent autophagy induced by PINK1-mediated mitophagy in A549 cells. Moreover, HML exert anticancer effects together with 5-FU through synergistic effect. Taken together, HML may serve as a potential tumor prevention and adjuvant treatment for its functional attributes.

ACSS3 regulates the metabolic homeostasis of epithelial cells and alleviates pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease of unknown etiology. The emerging evidence demonstrates that metabolic homeostatic imbalance caused by repetitive injuries of the alveolar epithelium is the potential pathogenesis of IPF. Proteomic analysis identified that Acetyl-CoA synthetase short chain family member 3 (ACSS3) expression was decreased in IPF patients and mice with bleomycin-induced fibrosis. ACSS3 participated in lipid and carbohydrate metabolism. Increased expression of ACSS3 downregulated carnitine palmitoyltransferase 1A (CPT-1A) and resulted in the accumulation of lipid droplets, while enhanced glycolysis which led to an increase in extracellular lactic acid levels in A549 cells. ACSS3 increases the production of succinyl-CoA through propionic acid metabolism, and decreases the generation of acetyl-CoA and ATP in alveolar epithelial cells. Overexpression of Acss3 inhibited the excessive deposition of ECM and attenuated the ground-glass opacity which determined by micro-CT in vivo. In a nutshell, our findings demonstrate that ACSS3 decreased the fatty acid oxidation through CPT1A deficiency and enhanced anaerobic glycolysis, this metabolic reprogramming deactivate the alveolar epithelial cells by lessen mitochondrial fission and fusion, increase of ROS production, suppression of mitophagy, promotion of apoptosis, suggesting that ACSS3 might be potential therapeutic target in pulmonary fibrosis.

Identification ferroptosis-related hub genes and diagnostic model in Alzheimer's disease.

Background: Ferroptosis is a newly defined form of programmed cell death and plays an important role in Alzheimer's disease (AD) pathology. This study aimed to integrate bioinformatics techniques to explore biomarkers to support the correlation between ferroptosis and AD. In addition, further investigation of ferroptosis-related biomarkers was conducted on the transcriptome characteristics in the asymptomatic AD (AsymAD). Methods: The microarray datasets GSE118553, GSE132903, GSE33000, and GSE157239 on AD were downloaded from the GEO database. The list of ferroptosis-related genes was extracted from the FerrDb website. Differentially expressed genes (DEGs) were identified by R "limma" package and used to screen ferroptosis-related hub genes. The random forest algorithm was used to construct the diagnostic model through hub genes. The immune cell infiltration was also analyzed by CIBERSORTx. The miRNet and DGIdb database were used to identify microRNAs (miRNAs) and drugs which targeting hub genes. Results: We identified 18 ferroptosis-related hub genes anomalously expressed in AD, and consistent expression trends had been observed in both AsymAD The random forest diagnosis model had good prediction results in both training set (AUC = 0.824) and validation set (AUC = 0.734). Immune cell infiltration was analyzed and the results showed that CD4+ T cells resting memory, macrophages M2 and neutrophils were significantly higher in AD. A significant correlation of hub genes with immune infiltration was observed, such as DDIT4 showed strong positive correlation with CD4+ T cells memory resting and AKR1C2 had positive correlation with Macrophages M2. Additionally, the microRNAs (miRNAs) and drugs which targeting hub genes were screened. Conclusion: These results suggest that ferroptosis-related hub genes we screened played a part in the pathological progression of AD. We explored the potential of these genes as diagnostic markers and their relevance to immune cells which will help in understanding the development of AD. Targeting miRNAs and drugs provides new research clues for preventing the development of AD.