Biology subjects

Lv, J.

Publications and source records attributed to Lv, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Efficient recovery of transgene-free edited tobacco using the transgene self-elimination system via de novo regeneration

Elimination of integrated editing constructs remains a major challenge for generating transgene-free progeny in plant genome editing based on Agrobacterium-mediated regeneration. Here, we adapted the Transgene Killer CRISPR (TKC) concept to tobacco and established the transgene self-elimination system, in which CRISPR/Cas9 is coupled with developmentally regulated BARNASE cassettes. Three pU3TR-derived vectors carrying DLL-, OsRP3- or PHAS-driven Barnase regenerated normally after leaf-disc transformation. The DLL construct pEB138 showed the highest T editing frequency, with 56 of 69 independent T plants (81.16%) carrying mutations at one or both NtDFR target loci. Under a stringent lineage-level screen in which up to 48 T progeny were tested per T line, 36 of 43 pEB138 lineages (83.72%) yielded uniformly marker-negative progeny for the three assayed T-DNA markers, compared with 0 of 7 lineages transformed with the parental pU3TR vector. The platform also supported recovery of dfr mutants with altered flower pigmentation and NtA622-edited lines with reduced nicotine accumulation. Moreover, introduction of DLL-iBarnase into the independent pDC45 editing backbone did not impair shoot regeneration, and representative NtBBL progeny showed markedly reduced nicotine content together with loss of the selectable cassette. These results demonstrate that BARNASE-assisted transgene elimination can be integrated with Agrobacterium-mediated de novo regeneration in a dicot, enabling one-step recovery of transgene-free edited tobacco progeny.

molecular biology↗

bioRxiv2026

Assessing fish biodiversity and community structure in the Ganjiang River using eDNA metabarcoding

Hydropower development has emerged as a major driver of global environmental change, causing significant ecological damage to freshwater ecosystems and threatening aquatic biodiversity. However, the impact of cascade dams on fish communities in large river systems remains poorly understood, particularly in biodiversity hotspots such as China. Here, we used environmental DNA (eDNA) metabarcoding to assess the spatiotemporal patterns of fish diversity and community structure in the Ganjiang River, the largest tributary of the Yangtze River, in relation to cascade hydropower development. We collected water samples from 19 sites along the main stem and major tributaries in both wet and dry seasons, and analyzed the eDNA data using high-throughput sequencing and advanced bioinformatics pipelines. Our results revealed significant seasonal and spatial variations in fish diversity and community composition, with lower species richness and distinct assemblages in the impounded sections upstream of the dams compared to the downstream reaches. The fish communities were strongly influenced by environmental factors such as water temperature, pH, dissolved oxygen, and nutrients, which exhibited complex interactions with dam operation and land use practices. Spatial scale analyses further indicated that the impact of dams on fish diversity was most pronounced at the local scale, but also detectable at the regional scale. Our findings provide novel insights into the ecological consequences of cascade hydro-power development on fish communities and highlight the importance of considering spatial scales and environmental heterogeneity in assessing the impacts of human activities on freshwater biodiversity. Our study demonstrates the power of eDNA metabarcoding as a cost-effective and non-invasive tool for biodiversity assessment and conservation planning in large river systems facing multiple stressors and knowledge gaps.

ecology↗

bioRxiv2026

METTL1 regulates glioma proliferation through internal m7G methylation of EPHA2

BackgroundMethyltransferase-like 1 (METTL1) is highly expressed in organs like the pancreas but less so in the brain. The METTL1-WDR4 complex catalyzes N7-methylguanosine (m7G) methylation in tRNA, miRNA, mRNA, and rRNA, which impacts RNA stability and function. These modifications affect mRNA translation and tRNA functionality, influencing protein production and cellular activities. Such modifications can regulate tumor growth, invasion, and metabolism by selectively controlling protein expression. MethodGene expression data from public databases were analyzed to compare METTL1 expression in normal and tumor tissues. Western blot (WB) and immunohistochemistry (IHC) were used to quantify METTL1 levels in glioma samples and assess their prognostic significance. Cell viability, migration, invasion, and proliferation were evaluated using Cell Counting Kit-8 (CCK-8), wound healing, Transwell, cell cycle analysis, and colony formation assays. RNA immunoprecipitation PCR (RIP-PCR) identified m7G methylation sites on EPHA2 mRNA, and RNA stability was assessed with actinomycin D. ResultsBioinformatics analysis revealed that METTL1 is overexpressed in gliomas, correlating with poor prognosis. Knockdown of METTL1 significantly affected cell proliferation, migration, and invasion. RNA sequencing (RNA-seq) and m7G analysis identified EPHA2 as a downstream target, influencing the cell cycle via the AKT pathway. RIP and methylated RNA immunoprecipitation (MeRIP) confirmed two m7G sites on EPHA2 mRNA regulated by METTL1. Small interfering RNA (siRNA)-mediated METTL1 knockdown in EPHA2 mutants affected mRNA stability. Rescue experiments restored cell proliferation and AKT pathway gene expression. ConclusionMETTL1 methylates EPHA2 mRNA, enhancing its stability and expression, which activates the AKT signaling pathway and influences glioma cell proliferation. METTL1 could be a potential therapeutic target in glioma treatment.

cell biology↗

bioRxiv2026

Comprehensive long-read transcriptome analysis uncovers alternative RNA processing feature and isoform diversity in ovarian cancer progression

Post-transcriptional processing has a crucial yet largely unresolved dynamic change and role during the malignant progression of ovarian cancer, especially due to the limited read length of short-read RNA sequencing being insufficient to capture transcript diversity. Here, we performed Iso and RNA sequencing on paired normal, primary tumor, and metastatic samples, generating a comprehensive isoform atlas of over 41,000 full-length transcripts including many unannotated isoforms. Integrative analyses revealed extensive isoform-level remodeling across disease states that often occurred without concordant alterations at the gene level, emphasizing the importance of qualitative transcript regulation. Notably, we identified isoform-level alterations with distinct biological and clinical relevance, including differential expression of the short KRAS isoform, a tumor-specific isoform switch of TMEM201, and an alternative first-exon event in FNDC3B associated with poor survival. Together, these findings provide a high-resolution map of the ovarian cancer transcriptome and illustrate how long-read sequencing exposes multiple layers of post-transcriptional and clinical insight that remain hidden in conventional expression profiling.

bioinformatics↗

bioRxiv2026

Integrated Multi-omics Analysis Identifies Molecular Signatures of Regular Physical Activity in Human Peripheral Blood

Regular physical activity is well established to protect against metabolic disorders and bolster immunity; yet, the underlying molecular and cellular mechanisms remain incompletely understood. We integrated plasma metabolomics and lipidomics with single-cell transcriptomic and chromatin accessibility profiles to decode the systemic impact of physical activity on human immunity and metabolism. Our data reveal that regular physical activity is linked to a coordinated metabolic signature marked by enhanced fatty acid oxidation and antioxidant defense. In circulating immune cells, regularly active individuals exhibited synchronous enhancement at both the chromatin accessibility and transcriptional levels for antigen presentation-related genes in antigen-presenting cells (APCs), particularly in classical monocytes, naive B cells, and switched memory B cells. Meanwhile, cytotoxic programs in CD8+ cytotoxic T and mature NK cells showed epigenetic pre-activation of effector function regulators. Intercellular communication analysis further revealed that regular exercise enhanced MHC-I/II signaling between APCs and T cells and suppressed inflammatory signaling networks. Together, these findings elucidate molecular mechanisms underlying the health benefits of regular exercise and offer a theoretical basis for enhancing public health and preventing chronic diseases.

bioinformatics↗

bioRxiv2026

Gn1a rice promotes symbiotic fish growth via reprogramming soil microbiome

Rice-fish symbiotic ecosystems significantly contribute to world food supply. Mutation in rice (Oryza sativa) quantitative trait locus Gn1a, encoding a cytokinin oxidase/dehydrogenase (OsCKX2), leads to cytokinin accumulation in plant, which promotes tillering and panicle branching to achieved higher yield and also shows a selective effect on soil microbial composition. Given that the growth of aquatic animals can be shaped by their surrounding microbial communities, we asked whether adjusting rice cytokinin levels might synergistically boosts both rice yield and fish growth. Herein, we co-cultured common carp (Cyprinus carpio) with ckx2 rice plants to determine the effect of cytokinins on fish. Surprisingly, compared to wild-type plants, the ckx2 plants enhanced nearly 10% fish growth and improved fish antibacterial capacity against Aeromonas hydrophila and Edwardsiella tarda. In fact, the growth-promoting effect on fish requires mediation by the soil microbiota. Mechanistically, ckx2 plants secreted more cytokinins into soil to reprogram the microbial composition, which subsequently translocated to fish gut and modulated the keystone microbes in gut to facilitate short-chain fatty acid production and carbohydrate degradation. These findings provide the first evidence that rice-derived cytokinins exert a cross-kingdom growth-promoting effect on fish, providing a boosting dual-production strategy for advancing rice-fish symbiotic ecosystem.

plant biology↗

bioRxiv2025

Disentangling structure-function relationships between the human hippocampus and the whole brain using track-weighted dynamic functional connectivity.

Understanding how structural and functional connectivity shape hippocampal interactions with the rest of the brain is critical for elucidating its role in cognition. Here, we combine high-resolution diffusion MRI, a novel fibre-tracking pipeline designed to specifically probe anatomical connectivity of the in vivo human hippocampus, and track-weighted dynamic functional connectivity (TW-dFC) to investigate how direct anatomical connections between the hippocampus and the rest of the brain relate to time-varying functional interactions. In Study 1, TW-dFC maps were computed for 10 participants from the Human Connectome Project and subjected to ICA and k-means clustering to derive a data-driven parcellation of the hippocampus based on its structure-function relationships. This revealed circumscribed clusters distributed along anterior-posterior and medial-lateral axes, which broadly aligned with hippocampal subfields. In Study 2, we examined the resting-state functional connectivity profiles of each TW-dFC derived cluster in an independent sample of 100 participants. Each hippocampal cluster displayed distinct patterns of functional connectivity with specific substructures within medial temporal, parietal, frontal and occipital cortices as well as subcortical and cerebellar regions. Our findings demonstrate that TW-dFC provides a powerful framework for anatomically informed functional parcellation of the hippocampus and offers new insights into the structural-functional organisation underlying hippocampal-(sub)cortical interactions. Our approach opens new avenues for probing memory systems in health and their disruption in aging and disease.

neuroscience↗

bioRxiv2025

A Potential Beta-hydroxybutyrate Therapy for Duchenne Muscular Dystrophy in Disease Models

Duchenne muscular dystrophy (DMD) is a common and lethal muscular degenerative disorder caused by mutations in the Dystrophin gene. Patients with DMD suffer progressive motor and respiratory decline over time and exhibit mitochondria defects at the cellular level, contributing to their reduced life expectancy. Despite extensive efforts, effective treatments for DMD remain unavailable. This study aims to explore a dietary approach to treat DMD, by precisely utilizing ketone bodies, an alternative fuel and signaling molecule for the mitochondria. As the experimental design, beta-hydroxybutyrate (BHB), the ketone body that is most abundant and stable in mammals, was supplemented in the drinking water of DMD disease model mice (mdx mice) as well as wild type mice. The results show that exogenous BHB supplementation in mdx mice led to significant decreases in plasma creatine kinase (CK) levels compared to chow-fed mdx mice, indicating mitigation of muscle damages. Functional tests also show that BHB improved muscle strength and endurance in mdx mice, while histological analyses revealed muscle health restoration, evidenced in uniform fiber diameter. BHB supplementation did not adversely affect the growth and overall health in either wild type or mdx mice. These findings may provide the proof-of-principle evidence for the use of BHB as a potential dietary approach for DMD treatment.

physiology↗

bioRxiv2025

SUGP1 associates Y-box protein to regulate piRNA biogenesis in Bombyx mori

PIWI-interacting RNAs (piRNAs) are critical for transposon silencing and genome integrity, as well as gene expression regulation and antiviral immunity in metazoans, yet the molecular mechanisms governing their biogenesis remain incompletely understood. The participation of the splicing-associated process in piRNA biogenesis has been emphasized in multiple species, but the key factors and mechanisms remain elusive. Here, we identified SUGP1 (SURP and G-Patch Domain Containing 1) in BmE (a unique model cell system with a complete piRNA biogenesis pathway) as a key splicing factor that functions in piRNA biogenesis. Through CRISPR-Cas9-mediated gene knockdown in cultured cells combined with RNA-seq, small RNA-seq, and IP-mass spectrometry (IP-MS), our results reveal that SUGP1 deficiency disrupts piRNA accumulation, alters mature piRNA length distributions, and activates transposon expression. Immunofluorescence and Western blot (WB) analyses further demonstrate that SUGP1 interacts with Y-box protein (YBP), which is key regulators of RNA metabolism. Functional validation in Drosophila SUGP1-RNAi lines highlights evolutionary conserved and species-specific roles of SUGP1 in piRNA maturation. Collectively, our data uncover a dual role for silkworm SUGP1 in coordinating YBP-dependent piRNA biogenesis, thus elucidating a novel mechanistic framework for piRNA pathway regulation. Our work also underscores the silkworm as a unique model for studying non-canonical piRNA biogenesis mechanisms, with implications for treating transposon dysregulation-linked diseases. Author summaryDisruption of piRNA synthesis leads to abnormal consequences such as transposon de-repression, posing a significant threat to genomic stability. It is therefore essential to in-depth analysis of the piRNA biosynthetic mechanism. Previous studies have highlighted the involvement of splicing-related processes in piRNA biosynthesis, yet key factors and mechanisms remain poorly understood. This study employed the silkworm cell system, which possesses a complete piRNA biosynthetic pathway. Utilizing CRISPR-Cas9-mediated gene knockout technology combined with RNA sequencing, small RNA sequencing, and immunoprecipitation-mass spectrometry (IP-MS), we discovered that SUGP1 deficiency disrupts piRNA accumulation, alters the length distribution of mature piRNAs, and activates transposon expression. Furthermore, immunofluorescence and Western blot analyses confirmed an interaction between SUGP1 and Y-box proteins (YBPs), key regulators of RNA metabolism. Functional validation using Drosophila SUGP1-RNAi lines revealed that SUGP1 plays dual roles in piRNA maturation. Our study reveals that the silkworm scissor-related factor SUGP1 has dual functions in coordinating YBP-dependent piRNA biosynthesis.

molecular biology↗

bioRxiv2025

Interaction of Carbamoyl-Phosphate Synthase 1 with Agmatinase in the Liver of Torpid Bats

Mammalian torpor imposes unique metabolic constraints, yet the mechanisms of nitrogen metabolism during this state remain unclear. In this study, we show that the urea cycle is selectively regulated rather than broadly suppressed in torpid bats. A significantly increased abundance of carbamoyl-phosphate synthase 1 (CPS1) maintained its functional capacity during torpor and arousal in Myotis ricketti. Proteomic analyses and confocal microscopy identified a specific association and co-localization between CPS1 and agmatinase (AGMAT), an ATP-independent enzyme involved in nitrogen metabolism. Co-localization of CPS1 and AGMAT was also observed in torpid Rhinolophus ferrumequinum, a phylogenetically distant species. Fluorescence resonance energy transfer (FRET) further supported an indirect CPS1-AGMAT interaction. Most urea cycle enzymes exhibited stable or only moderately reduced expression during bat torpor, and metabolic profiling demonstrated sustained nitrogen flux. Together, these findings reveal a conserved adaptive mechanism that maintains urea cycle function, potentially enhancing osmotic stability and energy efficiency during prolonged fasting and water scarcity.

zoology↗

bioRxiv2025

Spatiotemporal WNT and BMP gradients orchestrate regional enteroendocrine cell diversity along the Drosophila midgut

Enteroendocrine cells (EEs) in metazoan are diversified into multiple subtypes that occupy specific regions along the digestive tract to fulfill their functions. How to establish this regional pattern of EE subtypes is unclear. Here, we investigated the complex distribution patterns of three major EE subtypes along the length of the pupal and adult Drosophila midgut, and found that regional EE patterning is regulated by WNT and BMP signaling in a spatiotemporally dependent manner. Furthermore, there are both Notch-dependent and -independent cell division modes of EE progenitors that contribute to the generation of regional EE diversity. Our findings suggest that intercalated WNT and BMP morphogen gradients emanating from compartment boundaries play a critical role, not only in establishing regional ISC identity and the resulting EE diversity during development, but also in maintaining regional EE diversity in adulthood--a paradigm that may be conserved in mammals.

developmental biology↗

bioRxiv2025

The XPF-like domain in SHOC1 required for homologous recombination and safeguarding autosome from meiotic silencing of unsynapsed chromatin

During meiosis, a group of evolutionarily conserved ZMM proteins plays essential roles in stabilizing the recombination intermediates and promoting crossover (CO) formation. In mice, SHOC1 forms a trimeric complex with the other two ZMM proteins, SPO16 and TEX11, to bind recombination intermediates after strand invasion. Although genetic variants of SHOC1 are clinically associated with meiotic arrest and male infertility, their precise molecular mechanisms and evolutionarily conserved functions in human gametogenesis remain enigmatic. Here, we delineated species-specific divergences between human and mouse SHOC1 complex, and identified a missense variant within the XPF-like domain in SHOC1 (c.A1769G:p.Q590R) that was associated with meiotic arrest and non-obstructive azoospermia (NOA). The disorder of the XPF-like domain in SHOC1 impaired DNA double-strand breaks repair by compromising its ability to bind branched DNA structures and the recruitment of M1AP, REDIC1, and ZMM factors to recombination intermediates, ultimately abolishing CO formation. Furthermore, the variant disrupted dynamic 3D chromatin structure in pachytene spermatocytes and induced defects in homologous chromosome synapsis. More importantly, the XPF-like domain in SHOC1 was revealed to prevent autosome intrusion into the sex body compartment, thereby safeguarding critical autosomal loci from meiotic silencing of unsynapsed chromatin (MSUC). Overall, our study demonstrated that the XPF-like domain in SHOC1 is required for homologous recombination and safeguarding autosome from MSUC in meiosis.

developmental biology↗

bioRxiv2025

CDK12 condensation in nuclear speckles confers sensitivity to cyclin K molecular glue degraders

Transcriptional machinery often operates in the configuration of biomolecular condensates, presenting emerging opportunities to develop therapies targeting transcriptionally addicted malignancies. In this study, we discovered that cyclin-dependent kinase 12 (CDK12), a key regulator of transcription elongation, formed dynamic liquid-like droplets within nuclear speckles, a process enhanced by high CDK12 expression and CDK12 inhibitor treatment. Recognizing this unique property, we rationally designed ZSQ253, a modular cyclin K molecular glue degrader that coupled binding moieties for both CDK12 and DDB1. By promoting phase separation-driven assembly and subsequent proteasomal degradation of the CDK12-cyclin K complex, ZSQ253 interfered with oncogenic transcription and demonstrated potent antitumor capability. Further structure-guided optimization yielded HQY1428, a derivative with a multi-site gluing effect and improved drug activity. Given the frequent genomic co-amplification of CDK12 and ERBB2 across diverse human cancers, we showed that combining HQY1428 with HER2 inhibitors provided synergistic therapeutic benefits. Collectively, our findings establish CDK12 condensation within nuclear speckles as an exploitable vulnerability, and introduce a novel mechanism of action underlying cyclin K molecular glue degraders.

cancer biology↗

bioRxiv2025

Restoration of tumor suppressor protein with enhanced activity using engineered tRNAs to induce tumor regression

Cancer develops through a gradual accumulation of mutations including nonsense mutations in tumor suppressor genes (TSGs), which drive tumor proliferation and progression due to the impairment or complete loss of tumor suppressor protein function. The ability to restore functional tumor suppressor protein from mutant driver TSGs is a longstanding aspiration in cancer therapy, however, current strategies face formidable challenges in recovering proteins harboring heterogeneous mutations and circumventing dominant-negative effects exerted by endogenous mutant proteins. Therefore, the development of therapeutic interventions that are effective and generalizable across diverse nonsense mutations in cancer, to rescue endogenous mutant tumor suppressor proteins remains an urgent yet unmet need. Here we find that engineered suppressor transfer RNA (sup-tRNA) could overcome nonsense mutations in key driver tumor suppressor genes, such as TP53, thereby avoiding the dominant-negative effects through the restoration of endogenous mutant p53 with its original functions. Optimized sup-tRNA that we named super tRNA, enabling high-fidelity incorporation of desired amino acids, can further enhanced the transcriptional activity of p53 to suppress tumor cell proliferation. Moreover, we also establish a computational model to guide super tRNAs design, and demonstrate that super tRNA could effectively inhibit tumor growth by targeted readthrough of nonsense mutations in different tumor suppressor genes. In two xenograft models harboring nonsense mutant TP53, we observed up to a 70% reduction in tumor volume after lipid nanoparticle (LNP)-based sup-tRNA treatment, along with robust recovery of p53 expression and function, and no hematological or histological abnormalities detected. Our findings demonstrate the potential of sup-tRNA as a feasible and effective strategy to rescue and enhance tumor suppressor protein function, thereby preventing cancer development. As a novel therapeutic RNA, sup-tRNA provides a flexible strategy for targeting driver mutations in cancer, thereby expanding the potential of tRNA-based therapy in precision oncology.

bioengineering↗

bioRxiv2025

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

bioRxiv2025

Extracellular stiffness regulates site-specific lung development

Extracellular matrix (ECM) stiffness plays a crucial role in regulating cell fate and maturation, but its influence on lung development is limited known. Here we utilized stiffness-tunable gelatin methacryloyl (GelMA) hydrogels to investigate how ECM stiffness influences site-specific lung development in a stem cell-derived lung organoid model. We found increased stiffness promoted NKX2-1+ lung progenitor cells (LPCs) generation. In airway organoids (hAWOs), stiff hydrogels directed proximal airway differentiation enriched with goblet, ciliated, and basal cells; whereas the decreased stiffness favored emergence of secretory cells in the proximal-distal transition zone and distal airway. In alveolar organoids (hALOs), increased stiffness enhanced AT2 and AT1 cells transition. Moreover, infection assays with Omicron BA.1.1 and Delta variants recapitulated the proximal-to-distal tropism of SARS-CoV-2 in the lung. Transcriptomic sequencing revealed ECM stiffness regulates lung development via Hippo, TGF-{beta}, HIF and Wnt pathways. These findings advance mechanism understanding of ECM stiffness on lung development and provide a novel mechanical regulation for generating site-specific lung organoids.

cell biology↗

bioRxiv2024

Potential mechanisms and effects of melatonin-regulated Nrf2/HO-1 pathway on acute lung injury due to formaldehyde exposure

Acute lung injury is a topic of great interest in critical care medicine due to its high mortality rates. The lungs are the immediate target organ for formaldehyde inhalation damage. Lung damage and fibrosis are the most important outcomes of severe and acute lung disease and pose a serious threat to human health. Melatonin (MT), a natural bioactive compound with anti-inflammatory and antioxidant properties, However, it is not clear whether MT can prevent FA-induced acute lung injury (ALI). Therefore, in this study, we aimed to evaluate the protective effects of MT and the potential mechanisms against FA-induced ALI. An environmental exposure bin was used to inhale 3 mg{middle dot}m3 FA-induced ALI, which was given intraperitoneally with different doses of MT (5/10/20 mg/kg) after successful modeling. In addition, rats were treated with Nrf2 inhibitor (ML385) to validate the signaling pathway. Lung function was measured, histopathological/morphological changes in lung tissue were assessed, and inflammatory expression and oxidation levels in lung tissue were detected. We observed that MT greatly alleviated the lung dysfunction, pathological lung injury, pulmonary edema and inflammatory response after successful modeling of FA. In additional, MT played a role in modulating the Nrf2/HO-1 signaling pathway, which effectively inhibit oxidative stress caused by FA-induced lung tissue injure. Moreover, we found that activation of the NF-{kappa}B pathway is associated with inflammation caused by this injury. Overall, our data suggest that MT inhibits the expression of oxidative stress and inflammation in lung tissue through the institutional or Nrf2/HO-1 pathway, alleviating FA-induced ALI.

developmental biology↗

bioRxiv2024

Novel derivatives of BCV and (S)-HPMPA inhibit orthopoxviruses and human adenoviruses more potently than BCV

BCV and tecovirimat are the only two chemical drugs that have been approved to treat smallpox and can be requested for Mpox treatment through a single-patient Emergency Investigational New Drug (EIND) application. Disappointedly, the efficacy of tecovirimat manifested in a recent clinical trial is far from being satisfactory, while the clinical efficacy of BCV is still inconclusive. Given that MPXV, variola and other emerging orthopoxviruses are posing serious threats to global health, it is urgent to develop better therapeutics. In this study, we tested the antiviral effects of three novel prodrugs, which were designed based on previously reported parent drugs, either (S)-HPMPC (cidofovir) or (S)-HPMPA. We found that one of the (S)-HPMPA-based prodrugs, ODE-(S)-HPMPA formate, exhibited significantly better anti-orthopoxvirus activity than BCV both in vitro and in vivo, which also inhibited human adenovirus type 2 and type 21 more efficiently than BCV. Most strikingly, the EC50 and EC90 of ODE-(S)-HPMPA formate against MPXV were more than 40-fold lower than those of BCV. In contrast, we observed that the anti-HSV-1 activities of the (S)-HPMPA-based prodrugs were less effective than those of the cidofovir-based prodrugs (BCV and BCV formate), especially in vivo. Moreover, we showed for the first time that cytidine and adenine analog combined therapies could provide mice with complete protection against lethal challenges of both vaccinia and HSV-1. Collectively, we propose that both the ODE-(S)-HPMPA formate and the BCV/ODE-(S)-HPMPA formate combination are worth further investigations for their potential clinical applications.

microbiology↗