Lethal Disease Research Articles

WITHDRAWAL: Quantitative modeling of approved and emerging therapeutics for modifying TTR levels in patients with Transthyretin Amyloid Cardiomyopathy.

Withdrawal: McGirr, K., Sarkar, S., Subramanian, K. (2023) "Quantitative modeling of approved and emerging therapeutics for modifying TTR levels in patients with Transthyretin Amyloid Cardiomyopathy" CPT: Pharmacometrics & Systems Pharmacology. https://doi.org/10.1002/psp4.13078. The above article, published online on November 6, 2023, in Wiley Online Library (http://wileyonlinelibrary.com), has been withdrawn by agreement between the authors, journal Editor-in-Chief, France Mentré, the American Society for Clinical Pharmacology and Therapeutics (ASCPT), and Wiley Periodicals LLC. The withdrawal has been agreed to at the authors' request due to a disagreement over the ownership of some data contained therein.

Nano-Assembled Polyphosphazene Delivery System Enables Effective Intranasal Immunization with Nipah Virus Subunit Vaccine.

The ultimate vaccine against infections caused by Nipah virus should be capable of providing protection at the respiratory tract─the most probable port of entry for this pathogen. Intranasally delivered vaccines, which target nasal-associated lymphoid tissue and induce both systemic and mucosal immunity, are attractive candidates for enabling effective vaccination against this lethal disease. Herein, the water-soluble polyphosphazene delivery vehicle assembles into nanoscale supramolecular constructs with the soluble extracellular portion of the Hendra virus attachment glycoprotein─a promising subunit vaccine antigen against both Nipah and Hendra viruses. These supramolecular constructs signal through Toll-like receptor 7/8 and promote binding interactions with mucin─an important feature of effective mucosal adjuvants. High mass contrast of phosphorus-nitrogen backbone of the polymer enables a successful visualization of nanoconstructs in their vitrified state by cryogenic electron microscopy. Here, we characterize the self-assembly of polyphosphazene macromolecule with biologically relevant ligands by asymmetric flow field flow fractionation, dynamic light scattering, fluorescence spectrophotometry, and turbidimetric titration methods. Furthermore, a polyphosphazene-enabled intranasal Nipah vaccine candidate demonstrates the ability to induce immune responses in hamsters and shows superiority in inducing total IgG and neutralizing antibodies when benchmarked against the respective clinical stage alum adjuvanted vaccine. The results highlight the potential of polyphosphazene-enabled nanoassemblies in the development of intranasal vaccines.

Diet and Tumor Genetics Conspire to Promote Prostate Cancer Metabolism and Shape the Tumor Microenvironment.

Obesity has been linked to prostate cancer in a stage-dependent manner, having no association with cancer initiation but correlating with disease progression in men with prostate cancer. Given the rising obesity rate and its association to aggressive prostate cancer, there is a growing need to understand the mechanisms underlying this relationship to identify patients at increased risk of lethal disease and inform therapeutic approaches. In this issue of Cancer Research, Boufaied and colleagues describe how diets high in saturated fatty acids promote MYC-driven prostate cancer. Leveraging MYC-expressing genetically engineered and allograft mouse models fed either a control low-fat or high-fat diet (HFD) enriched in saturated fatty acids, the authors found using digital pathology that HFD-fed mice exhibited increased tumor invasion. Metabolomics, transcriptomics, immunoblotting, and positron emission tomography of tumors from these mice demonstrated that a HFD promoted a metabolic shift in the tumors towards glycolysis. These preclinical data were supported by findings from two large clinical cohorts revealing that men diagnosed with prostate cancer and who consumed high levels of saturated fatty acids possessed tumors bearing glycolytic signatures. Deconvolution analyses and immunohistochemistry validation showed that these tumors also displayed increased angiogenesis and infiltration of immunosuppressive macrophages and regulatory T cells, the latter of which was also correlated with high saturated fat intake-associated glycolytic signatures in patient tumors. Together, these findings suggest that diets rich in saturated fatty acids, rather than obesity alone, accelerate MYC-driven prostate cancers through shifting tumor metabolism and shaping the tumor microenvironment. See related article by Boufaied et al., p. 1834.

Impact of preoperative respiratory distress on outcomes of slide tracheoplasty.

Children with congenital tracheal stenosis born in the developing world face a high risk of mortality due to limited access to proper treatment. Patients who required preoperative respiratory support were suspected to have poor survival after slide tracheoplasty; however, this was not clearly demonstrated in the previous studies. This study aims to investigate the impact of preoperative respiratory conditions on outcomes of slide tracheoplasty. From 2016 to 2022, children who underwent slide tracheoplasty were retrospectively reviewed. Patients with respiratory distress requiring emergency operations (group A) were compared with patients in stable condition who were scheduled for surgery (group B). Perioperative results revealed that group A (n = 43) had a longer bypass time (P < 0.001), operation time (P = 0.01), postoperative ventilation time (P < 0.001) and length of intensive care unit stay (P = 0.00125) than group B (n = 60). The early mortality rate was 7.8%, and the actuarial 5-year survival rate was 85.3%. The cumulative incidence test revealed that group A was highly significant for overall mortality [sudistribution (SHR) 4.5; 95% confidence interval (CI) 1.23-16.4; P = 0.023]. Risk factors for overall mortality were prolonged postoperative ventilation time (hazard ratio 3.86; 95% CI 1.20-12.48; P = 0.024), bronchial stenosis (hazard ratio 5.77; 95% CI 1.72-19.31; P = 0.004), and preoperative tracheal mucositis (hazard ratio 5.67; 95% CI 1.51-21.31; P = 0.01). Four patients needed reintervention during a follow-up of 28.4 months (interquartile range 15.3-47.3). Preoperative respiratory distress negatively affected the outcomes of patients who required slide tracheoplasty. Therefore, early detection of congenital tracheal stenosis and aggressive slide tracheoplasty are crucial and obligatory to enhance long-term survival in this lethal congenital airway disease.

Phase separation-competent FBL promotes early pre-rRNA processing and translation in acute myeloid leukaemia.

RNA-binding proteins (RBPs) are pivotal in acute myeloid leukaemia (AML), a lethal disease. Although specific phase separation-competent RBPs are recognized in AML, the effect of their condensate formation on AML leukaemogenesis, and the therapeutic potential of inhibition of phase separation are underexplored. In our in vivo CRISPR RBP screen, fibrillarin (FBL) emerges as a crucial nucleolar protein that regulates AML cell survival, primarily through its phase separation domains rather than methyltransferase or acetylation domains. These phase separation domains, with specific features, coordinately drive nucleoli formation and early processing of pre-rRNA (including efflux, cleavage and methylation), eventually enhancing the translation of oncogenes such as MYC. Targeting the phase separation capability of FBL with CGX-635 leads to elimination of AML cells, suggesting an additional mechanism of action for CGX-635 that complements its established therapeutic effects. We highlight the potential of PS modulation of critical proteins as a possible therapeutic strategy for AML.

Identification of potential biomarkers for sepsis based on neutrophil extracellular trap-related genes

Sepsis is a highly lethal disease that poses a serious threat to human health. Increasing evidence indicates that neutrophil extracellular traps (NETs) are key factors in the pathological progression of sepsis. This study aims to screen potential biomarkers for sepsis and delve into their regulatory function in the pathogenesis. We downloaded 6 microarray datasets from the Gene Expression Omnibus (GEO) database, with 4 as the training sets and 2 as the validation sets. NETs-related genes (NRGs) were obtained from relevant literature. Differential expression analysis was performed on four training sets separately. We intersected differentially expressed genes (DEGs) from the four training sets and NRGs, finally resulting in 19 NETs-related sepsis genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) unearthed that NETs-related sepsis genes were majorly abundant in functions and pathways such as defense response to bacterium and Neutrophil extracellular trap formation. Using the PPI network, the MCC algorithm, and the MCODE algorithm in the CytoHubba plugin, 7 sepsis hub genes (ELANE, TLR4, MPO, PADI4, CTSG, MMP9, S100A12) were identified. ROC curve for each Hub gene in the training and validation sets were plotted, which revealed that the Area Under Curve (AUC) values are all greater than 0.6, indicating good classification ability. A total of 349 miRNAs targeting Hub genes were predicted in the mirDIP database, and 620 lncRNAs targeting miRNAs were predicted in the ENCORI database. The ceRNA regulatory network was constructed using Cytoscape software. Finally, we employed the cMAP database to predict small molecular complexes as potentially effective drugs for the treatment of sepsis, such as chloroquine, harpagoside, and PD-123319. In conclusion, this project successfully identified 7 core genes, which may serve as promising candidates for novel sepsis biomarkers. Meanwhile, we constructed a related ceRNA network and predicted potential targeted drugs, providing potential therapeutic targets and treatment strategies for sepsis patients.

A SIMPLE, QUICK, AND ECONOMICAL METHOD FOR IN VITRO CULTIVATION OF ECHINOCOCCUS MULTILOCULARIS METACESTODE AND GENERATION OF PRIMARY CELLS.

Alveolar echinococcosis is considered to be one of the most potentially lethal parasitic zoonotic diseases. However, the molecular mechanisms by which Echinococcus multilocularis interacts with hosts are poorly understood, hindering the prevention and treatment of this disease. Due to the great advantages of cell culture systems for molecular research, numerous attempts have been made to establish primary cell cultures for E. multilocularis. In this study we developed a simple, rapid, and economical method that allows E. multilocularis metacestode tissue blocks to generate daughter vesicles without the continuous presence of host feeder cells in a regular medium. We performed anaerobic, hypoxic (1% O2), normoxic, and semi-anaerobic (in sealed tubes) cultures and found that E. multilocularis metacestode tissues can produce daughter vesicles only in the sealed tubes after 4 wk of incubation. The daughter vesicles cultivated in this system were remarkably enlarged under anaerobic conditions after 8 days of culture, whereas vesicles cultured under hypoxic (1% O2) and normoxic conditions showed only a mild increase in volume. Our in vitro cultivated vesicles showed strong viability and could be used to test antiparasitic drugs, isolate primary cells, and infect animals.

The low-density lipoprotein receptor and apolipoprotein E associated with CCHFV particles mediate CCHFV entry into cells

The Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging pathogen of the Orthonairovirus genus that can cause severe and often lethal hemorrhagic diseases in humans. CCHFV has a broad tropism and can infect a variety of species and tissues. Here, by using gene silencing, blocking antibodies or soluble receptor fragments, we identify the low-density lipoprotein receptor (LDL-R) as a CCHFV entry factor. The LDL-R facilitates binding of CCHFV particles but does not allow entry of Hazara virus (HAZV), another member of the genus. In addition, we show that apolipoprotein E (apoE), an exchangeable protein that mediates LDL/LDL-R interaction, is incorporated on CCHFV particles, though not on HAZV particles, and enhances their specific infectivity by promoting an LDL-R dependent entry. Finally, we show that molecules that decrease LDL-R from the surface of target cells could inhibit CCHFV infection. Our study highlights that CCHFV takes advantage of a lipoprotein receptor and recruits its natural ligand to promote entry into cells.

Wnt/β-catenin signaling is a therapeutic target in anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that has consistently shown Wnt/β-catenin (canonical) signaling activation in various study populations. There are currently no targetable treatments for BRAF-wildtype ATC and a lack of effective treatment for BRAFV600EATC. Our aim is to identify whether Wnt inhibitors could be potential therapeutic agents for ATC patients with limited treatment options. In this Institutional Review Board-approved study, we utilize a cohort of 32 ATCs and 20 non-neoplastic multinodular goiters (MNG). We also use 4 ATC spheroid cell lines (THJ-16T, THJ-21T, THJ-29T, and THJ-11T) and two primary patient-derived ATC organoid cultures (VWL-T5 and VWL-T60). Finally, we use a murine xenograft mouse model of ATC for in vivo treatment studies. Using a large patient cohort, we demonstrate that this near-universal Wnt signaling activation is associated with ligand expression- rather than being mutationally-driven. We show that pyrvinium pamoate, a potent Wnt inhibitor, exhibits in vitro efficacy against both ATC cell lines and primary patient-derived ATC organoids VWL-T5 (p < 0.05) and VWL-T60 (p < 0.01) Finally, using a murine xenograft model of ATC, we show that pyrvinium significantly delays the growth of ATC tumors in THJ-16T (p < 0.005) and THJ-21T (p < 0.001). We tested Wnt inhibitor treatment, both in vitro and in vivo, as a potential novel therapy for this highly lethal disease. Future large-scale studies utilizing multiple Wnt inhibitors will lay the foundation for the development of these novel therapies for patients with ATC.

Bioinformatics Characteristics and Genomic Patterns of the Envelope Glycoproteins of the Crimean-congo Hemorrhagic Fever Viruses

Background: Rodents and many wild and domestic animals, including cattle, donkeys, goats, hares, ostriches, and sheep, spread the Crimean-Congo Hemorrhagic Fever Virus (CCHFV), acting as hosts for infected ticks primarily of the Hyalomma genus, which serve as vectors and reservoirs of the virus. CCHF is a severe, potentially lethal, and widespread disease, making it a serious public health issue. Environmental changes impacting rodent populations affect their global distribution and, therefore, play a role in the spread of CCHFV. Objective: This study aims togain a deeper understanding of the envelope glycoproteins expressed by the CCHFV. Methods: Multiple computational algorithms determined the Intrinsic Disorder Predisposition (PIDP), Polarity Index, and genomic profiles of each sequence of the glycoproteins. Results: When examining the Polarity Index Method Profile, 3.0v profile, and the PIDP profile, the envelope glycoproteins of the CCHFV showed different patterns. With these patterns, it was possible to identify structural and morphological similarities. Conclusion: With the PIM 3.0v profile, our computer programs were able to identify isolated CCHFV envelope glycoproteins. We believe that this research provides a deeper understanding of this virus. conclusion: Using the PIM 3.0v profile, our computer programs were able to identify isolates of the CCHFV envelope glycoproteins. We believe that this research contributes to a deeper understanding of this emerging virus.

An mRNA-LNP-based Lassa virus vaccine induces protective immunity in mice.

The mammarenavirus Lassa virus (LASV) causes the life-threatening hemorrhagic fever disease, Lassa fever. The lack of licensed medical countermeasures against LASV underscores the urgent need for the development of novel LASV vaccines, which has been hampered by the requirement for a biosafety level 4 facility to handle live LASV. Here, we investigated the efficacy of mRNA-lipid nanoparticle (mRNA-LNP)-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or nucleoprotein (LCMnp) of the prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), in mice. Two doses of LASgpc- or LCMnp-mRNA-LNP administered intravenously (i.v.) protected C57BL/6 mice from a lethal challenge with a recombinant (r) LCMV expressing a modified LASgpc (rLCMV/LASgpc2m) inoculated intracranially. Intramuscular (i.m.) immunization with two doses of LASgpc- or LCMnp-mRNA-LNP significantly reduced the viral load in C57BL/6 mice inoculated i.v. with rLCMV/LASgpc2m. High levels of viremia and lethality were observed in CBA mice inoculated i.v. with rLCMV/LASgpc2m, which were abrogated by i.m. immunization with two doses of LASgpc-mRNA-LNP. The protective efficacy of two i.m. doses of LCMnp-mRNA-LNP was confirmed in a lethal hemorrhagic disease model of FVB mice i.v. inoculated with wild-type rLCMV. In all conditions tested, negligible and high levels of LASgpc- and LCMnp-specific antibodies were detected in mRNA-LNP-immunized mice, respectively, but robust LASgpc- and LCMnp-specific CD8+ T cell responses were induced. Accordingly, plasma from LASgpc-mRNA-LNP-immunized mice did not exhibit neutralizing activity. Our findings and surrogate mouse models of LASV infection, which can be studied at a reduced biocontainment level, provide a critical foundation for the rapid development of mRNA-LNP-based LASV vaccines.IMPORTANCELassa virus (LASV) is a highly pathogenic mammarenavirus responsible for several hundred thousand infections annually in West African countries, causing a high number of lethal Lassa fever (LF) cases. Despite its significant impact on human health, clinically approved, safe, and effective medical countermeasures against LF are not available. The requirement of a biosafety level 4 facility to handle live LASV has been one of the main obstacles to the research and development of LASV countermeasures. Here, we report that two doses of mRNA-lipid nanoparticle-based vaccines expressing the LASV glycoprotein precursor (LASgpc) or nucleoprotein (LCMnp) of lymphocytic choriomeningitis virus (LCMV), a mammarenavirus genetically closely related to LASV, conferred protection to recombinant LCMV-based surrogate mouse models of lethal LASV infection. Notably, robust LASgpc- and LCMnp-specific CD8+ T cell responses were detected in mRNA-LNP-immunized mice, whereas no virus-neutralizing activity was observed.

Creatine Kinase-MM/Proto-oncogene Tyrosine-Protein Kinase Receptor as a Sensitive Indicator for Duchenne Muscular Dystrophy Carriers.

Duchenne muscular dystrophy (DMD), a lethal X-linked recessive genetic disease, is characterized by progressive muscle wasting which will lead to premature death by cardiorespiratory complications in their late twenties. And 2.5-19% DMD carriers that also suffer from skeletal muscle damage or dilated cardiomyopathy when diagnosed as soon as possible is meaningful for prenatal diagnosis and advance warning for self-health. The current DMD carrier screening mainly relies on detecting serum creatine kinase activity, covering only 50-70% DMD carriers which will cause many false negatives and require the discovery of highly effective biomarker and simple detection procedure for DMD carriers. In this article, we have compiled a comprehensive summary of all documented biomarkers associated with DMD and categorized them based on their expression patterns. We specifically pinpointed novel DMD biomarkers, previously unreported in DMD carriers, and conducted further investigations to explore their potential. Compared to creatine kinase activity alone in DMD carriers, creatine kinase-MM can improve the specificity from 73 to 81%. And our investigation revealed another promising protein: proto-oncogene tyrosine-protein kinase receptor (RET). When combined with creatine kinase-MM (creatine kinase-MM/RET ratio), it significantly enhances the specificity (from 81 to 83%) and sensitivity (from71.4 to 93%) of detecting DMD carriers in serum. Moreover, we successfully devised an efficient method for extracting RET from dried blood spots. This breakthrough allowed us to detect both creatine kinase-MM and RET using dried blood spots without compromising the detection rate.

Molecular Identification and Characterization of Novel Taxonomic Subgroups and New Host Plants in 16SrI and 16SrII Group Phytoplasmas and Their Evolutionary Diversity on Hainan Island, China.

Phytoplasmas are a group of plant prokaryotic pathogens distributed worldwide. To comprehensively reveal the diversity of the pathogens and the diseases they cause on Hainan, a tropical island with abundant biodiversity in China, a survey of phytoplasmal diseases was performed from 2009 to 2022. Herein, molecular identification and genetic analysis were conducted based on the conserved genes of phytoplasmas. The results indicated that phytoplasmas could be detected in 138 samples from 18 host plants among 215 samples suspected to be infected by the pathogens. The phytoplasma strains from 27 diseased samples of 4 host plants belonged to the 16SrI group and the strains from 111 samples of 14 hosts belonged to the 16SrII group. Among them, 12 plants, including important tropical cash crops such as Phoenix dactylifera, cassava, sugarcane, and Piper nigrum, were first identified as hosts of phytoplasmas on Hainan Island. Based on BLAST and iPhyClassifier analyses, seven novel 16Sr subgroups were proposed to describe the relevant phytoplasma strains, comprising the 16SrI-AP, 16SrI-AQ, and 16SrI-AR subgroups within the 16SrI group and the 16SrII-Y, 16SrII-Z, 16SrII-AB, and 16SrII-AC subgroups within the 16SrII group. Genetic variation and phylogenetic analysis indicated that the phytoplasma strains identified in this study and those reported previously on Hainan Island mainly belong to four 16Sr groups (including I, II, V, and XXXII) and could infect 44 host plants, among which the 16SrI and 16SrII groups were the prevalent 16Sr groups associated with 43 host plant species. The diversity of host plants infected by the phytoplasmas made it difficult to monitor and control their related diseases. Therefore, strengthening inspection and quarantine during the introduction and transit of the related phytoplasmal host crops would effectively curb the spread and prevalence of the phytoplasmas and their related lethal diseases.

NUP43 promotes PD-L1/nPD-L1/PD-L1 feedback loop via TM4SF1/JAK/STAT3 pathway in colorectal cancer progression and metastatsis

Programmed cell death-ligand 1 (PD-L1) has a significant role in tumor progression and metastasis, facilitating tumor cell evasion from immune surveillance. PD-L1 can be detected in the tumor cell nucleus and exert an oncogenic effect by nuclear translocation. Colorectal cancer (CRC) progression and liver metastasis (CCLM) are among the most lethal diseases worldwide, but the mechanism of PD-L1 nuclear translocation in CRC and CCLM remains to be fully understood. In this study, using CRISPR-Cas9-based genome-wide screening combined with RNA-seq, we found that the oncogenic factor NUP43 impacted the process of PD-L1 nuclear translocation by regulating the expression level of the PD-L1 chaperone protein IPO5. Subsequent investigation revealed that this process could stimulate the expression of tumor-promoting factor TM4SF1 and further activate the JAK/STAT3 signaling pathway, which ultimately enhanced the transcription of PD-L1, thus establishing a PD-L1-nPD-L1-PD-L1 feedback loop that ultimately promoted CRC progression and CCLM. In conclusion, our study reveals a novel role for nPD-L1 in CRC, identifies the PD-L1-nPD-L1-PD-L1 feedback loop in CRC, and provides a therapeutic strategy for CRC patients.

Exploring the recent pioneering developments of small molecules in antimalarial drug armamentarium: A chemistry prospective appraisal.

Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug-resistant strains. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

The Role of TLR-2 in Lethal COVID-19 Disease Involving Medullary and Resident Lung Megakaryocyte Up-Regulation in the Microthrombosis Mechanism.

The aim of this study was to study the expression of platelet glycoprotein IIIa (CD61), playing a critical role in platelet aggregation, together with TRL-2 as a marker of innate immune activation. A total of 25 patients were investigated, with the majority (24/25, 96%) having co-morbidities and dying from a fatal form of SARS-CoV-2(+) infection (COVID-19+), with 13 men and 12 females ranging in age from 45 to 80 years. When compared to a control group of SARS-CoV-2 (-) negative lungs (COVID-19-), TLR-2 expression was up-regulated in a subset of patients with deadly COVID-19 fatal lung illness. The proportion of Spike-1 (+) patients found by PCR and ISH correlates to the proportion of Spike-S1-positive cases as detected by digital pathology examination. Furthermore, CD61 expression was considerably higher in the lungs of deceased patients. In conclusion, we demonstrate that innate immune prolonged hyperactivation is related to platelet/megakaryocyte over-expression in the lung. Microthrombosis in deadly COVID-19+ lung disease is associated with an increase in the number of CD61+ platelets and megakaryocytes in the pulmonary interstitium, as well as their functional activation; this phenomenon is associated with increased expression of innate immunity TLR2+ cells, which binds the SARS-CoV-2 E protein, and significantly with the persistence of the Spike-S1 viral sequence.

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.

Comprehensive analysis of gene signatures associated with aging in human aortic dissection

BackgroundAortic dissection (AD) is a lethal aortic disease with limited effective therapeutic strategies. Aging increases the risk of AD, yet the underlying mechanisms remain unclear. This study aims to analyze the association of aging-related genes (Args) and AD using bioinformatic analysis. This helps provide novel insights into AD pathogenesis and contributes to developing novel therapeutic strategies. MethodsmRNA (GSE52093, GSE153434), miRNA (GSE98770) and single-cell RNA-sequencing (scRNA-seq, GSE213740) datasets of AD were downloaded from GEO database. Args were downloaded from Aging Atlas database. Differentially-expressed Args were determined by intersecting Args and differentially-expressed mRNAs of two mRNA datasets. Cytoscape was used to identify hub genes and construct hub gene regulatory networks related to miRNAs. Seurat and clusterProfiler R package were used for investigating expression patterns of hub genes at single-cell level, and functional analysis, respectively. To validate the cellular expression pattern of hub genes, the same analysis was applied to our own scRNA-seq data. Drugs targeting hub Args were determined using the DGIdb database. ResultsHGF, CXCL8, SERPINE1, HIF1A, TIMP1, ESR1 and PLAUR were identified as aging-related hub genes in AD. miR-221-3p was predicted to interact with ESR1. A decreased ESR1 expression in smooth muscle cell subpopulation 4 (SMC4) was observed in AD versus normal aortic tissues, which was validated by sequencing 197,605 aortic cells from 13 AD patients. Additionally, upregulated genes of SMC4 in AD tissues were enriched in the “cellular senescence” pathway. These data indicated that decreased ESR1 might promote SMC4 aging during AD formation. Eleven existing drugs targeting hub genes were identified, including ruxolitinib and filgrastim, which are associated with AD. ConclusionsBy sequencing transcriptomic data, this study revealed aging-related hub genes and regulatory network involved in AD formation. Additionally, this study proposed a noteworthy hypothesis that downregulated ESR1 may exacerbate AD by promoting SMC aging, which requires further investigation.

Carvacrol and Thymol Hybrids: Potential Anticancer and Antibacterial Therapeutics

Cancer is ranked among lethal diseases globally, and the increasing number of cancer cases and deaths results from limited access to effective therapeutics. The use of plant-based medicine has been gaining interest from several researchers. Carvacrol and its isomeric compound, thymol, are plant-based extracts that possess several biological activities, such as antimalarial, anticancer, antifungal, and antibacterial. However, their efficacy is compromised by their poor bioavailability. Thus, medicinal scientists have explored the synthesis of hybrid compounds containing their pharmacophores to enhance their therapeutic efficacy and improve their bioavailability. Hence, this review is a comprehensive report on hybrid compounds containing carvacrol and its isomer, thymol, with potent anticancer and antibacterial agents reported between 2020 and 2024. Furthermore, their structural activity relationship (SAR) and recommended future strategies to further enhance their therapeutic effects will be discussed.

Construction of An Orthotopic Xenograft Model of Non-small Cell Lung Cancer Mimicking Disease Progression and Predicting Drug Activities.

Non-small cell lung cancer (NSCLC) is a highly lethal disease with a complex and heterogeneous tumor microenvironment. Currently, common animal models based on subcutaneous inoculation of cancer cell suspensions do not recapitulate the tumor microenvironment in NSCLC. Herein we describe a murine orthotopic lung cancer xenograft model that employs the intrapulmonary inoculation of three-dimensional multicellular spheroids (MCS). Specifically, fluorescent human NSCLC cells (A549-iRFP) were cultured in low-attachment 96-well microplates with collagen for 3 weeks to form MCS, which were then inoculated intercostally into the left lung of athymic nude mice to establish the orthotopic lung cancer model. Compared with the original A549 cell line, MCS of the A549-iRFP cell line responded similarly to anticancer drugs. The long-wavelength fluorescent signal of the A549-iRFP cells correlated strongly with common markers of cancer cell growth, including spheroid volume, cell viability, and cellular protein level, thus allowing dynamic monitoring of the cancer growth in vivo by fluorescent imaging. After inoculation into mice, the A549-iRFP MCS xenograft reliably progressed through phases closely resembling the clinical stages of NSCLC, including the expansion of the primary tumor, the emergence of neighboring secondary tumors, and the metastases of cancer cells to the contralateral right lung and remote organs. Moreover, the model responded to the benchmark antilung cancer drug, cisplatin with the anticipated toxicity and slower cancer progression. Therefore, this murine orthotopic xenograft model of NSCLC would serve as a platform to recapitulate the disease's progression and facilitate the development of potential anticancer drugs.