Biology subjects

Mori, M. A.

Publications and source records attributed to Mori, M. A..

10 recordsLinked to original sources

bioRxiv2026

Organism-dependent ecotoxicological effects of transition metal-containing layered double hydroxides

Due to low environmental stability of certain molecule classes, such as phytohormones and RNA interference, layered double hydroxides (LDHs) have been investigated as nanocarriers capable of protecting and transporting molecules of interest in natural systems. Herein, the ecotoxicological effects of LDH nanoparticles composed by different transition metals (Al-Ni, Al-Co, and Al-Cu) were evaluated in maize (Zea mays), tomato (Lycopersicum esculentum), and the nematode Caenorhabditis elegans, two important crops and one soil organism found in agricultural systems. Plants were exposed to the nanoparticles through foliar spraying (5, 50, and 500 ug/mL), and physiological parameters were evaluated. In C. elegans, lethality, locomotion, larval development, and body length were analyzed. The nanoparticles exhibited high colloidal stability and characteristic lamellar morphology. The results demonstrated low phytotoxicity for all formulations, without significant changes in photochemical activity, effective quantum yield of photosystem II (psi-PSII), stomatal conductance (gs), and chlorophyll index (Chl a+b; ICF) in plants. In contrast, C. elegans exhibited greater sensitivity, showing reduced motility, developmental delay, and decreased body length, although mortality remained below 12% under all evaluated conditions. Toxicity was dependent on the metallic composition, following the order Al-Cu > Al-Ni > Al-Co. Collectively, the results indicate that LDHs exhibit high compatibility with those two crops but may cause sublethal effects in soil organisms. These findings highlight the importance of multispecies ecotoxicological assessments for the safe development of nanocarriers intended for agricultural applications.

pharmacology and toxicology↗

bioRxiv2026

Cold acclimation reprograms hepatic lipid composition toward n-3 HUFAs to uncouple adipose-derived lipid flux from steatosis

While cold exposure drives lipid flux from adipose tissue to the liver, this enhanced inter-organ crosstalk does not result in sustained hepatic steatosis during prolonged acclimation, indicating that factors beyond lipid flux shape metabolic outcome. To interrogate this adaptation, we performed integrated lipidomic and metabolic profiling across tissues and circulating lipoproteins over the course of cold acclimation. We showed that cold acclimation induces systemic reprogramming of lipid quality in mice, characterized by enrichment of n-3 highly unsaturated fatty acids (HUFAs) as a consequence of upregulation of fatty acid desaturases (FADS1 and 2) in the liver and white adipose tissue, thus increasing hepatic n-3/n-6 ratio. Cold-induced increase in n-3 HUFAs cause the suppression of SCD1-mediated desaturation, thus yielding a depletion of monounsaturated fatty acids (MUFAs) in the liver, along with the suppression of lipogenic markers. Notably, this high-HUFA/low-MUFA lipid signature is present in both hepatic free fatty acid and triglyceride pools, indicating that lipid remodeling occurs upstream of triglyceride synthesis. Lipidomic analysis revealed that the remodeled triglycerides are incorporated into very-low-density and intermediate density lipoproteins (VLDL and IDL), thereby propagating hepatic lipid reprogramming to the circulation. Thus, by selectively increasing endogenous n-3 HUFA availability, cold adaptation suppresses hepatic DNL and MUFA-driven triglyceride assembly, buffering lipid accumulation despite sustained fatty acid influx and reshaping systemic lipid distribution with potential cardiometabolic impact.

biochemistry↗

bioRxiv2025

E4BP4 Safeguards Brown Fat Mitochondria from Obesity-Induced Fragmentation via Ceramide Repression

Brown adipose tissue (BAT) counteracts obesity-related metabolic dysfunction through both thermogenic and non-thermogenic means. However, substantial evidence indicates that obesity negatively affects BAT mitochondrial morphology and oxidative capacity, impairing systemic energy homeostasis. Motivated by this apparent contradiction, we investigated the relationship between obesity and mitochondrial dynamics, as the underlying mechanisms remain incompletely understood. Here, we identified E4BP4 as a transcriptional repressor that prevents obesity-induced mitochondrial fragmentation and oxidative dysfunction by inhibiting ceramide synthesis in brown fat. Specifically, E4BP4 interacts with PRDM16 to repress Cers6 mRNA expression and consequently reduces C16:0 ceramide levels by binding to a 65 kb upstream enhancer region of the Cers6 gene. Notably, the preservation of mitochondrial integrity in BAT by E4BP4 gain-of-function improves systemic glucose homeostasis, independent of weight loss. Collectively, our findings establish E4BP4 as a molecular safeguard against obesity-induced mitochondrial fragmentation and oxidative dysfunction, primarily by suppressing ceramide synthesis in brown fat.

physiology↗

bioRxiv2024

Feasibility of intravenous injections of pig plasma extracellular particles into rats -- an acute study

BackgroundExtracellular particles (EPs), especially small extracellular vesicles (EVs), extracted from young animals are increasingly being studied in animal models as agents for regeneration and rejuvenation, with studies using EPs from one species injected into another showing no immune reaction. In this study, we aimed to investigate if the injection of Pig Plasma Extracellular Particles (PPEPs) into rats would produce an acute immune or toxic reaction. MethodsBlood from a young pig was collected, PPEPs were isolated by size exclusion chromatography and injected into young male Sprague-Dawley rats, while the control group received a sterile saline injection. After 9 days, the animals were euthanized and their organs were histologically analyzed for signs of cellular damage or immune infiltration. ResultsThe treated rats showed no signs of acute immunological reaction, behaving normally immediately after the injections and during the 9 days since the first injection. Throughout the trial period, the animals continued gaining weight normally and the histological analysis of their liver, kidney and spleen showed no signs of acute toxicity. ConclusionsPPEPs from young animals do not cause an acute immune or toxic response when injected intravenously into young male Sprague-Dawley rats.

immunology↗

bioRxiv2023

IF1 controls UCP1-dependent mitochondrial bioenergetics in brown adipocytes

While mechanisms controlling mitochondrial uncoupling protein-1 (UCP1) expression and function in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis (NST), it remains unclear whether F1Fo-ATP synthase function is regulated during NST. Here, we show that Inhibitory Factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In mice, IF1 protein content is markedly diminished in brown adipose tissue (BAT) after 5 days of cold exposure. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is higher in mitochondria isolated from cold- adapted mice compared to mice housed at room temperature. In vitro, IF1 overexpression results in an inability of mitochondria to sustain mitochondrial membrane potential upon adrenergic stimulation and this occurs in a UCP1-dependent manner. In brown adipocytes, IF1 silencing is sufficient to increase mitochondrial lipid oxidation and the cellular dependency on glycolysis to produce ATP. Conversely, IF1 overexpression blunts mitochondrial respiration without causing cellular energetic stress, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus- mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in this tissue. Taken together, our data shows that the downregulation of IF1 upon cold serves to facilitate the reverse mode of ATP synthase to enable energetic adaptation and effectively support NST in BAT. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/550888v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@16146faorg.highwire.dtl.DTLVardef@17afc1corg.highwire.dtl.DTLVardef@13da476org.highwire.dtl.DTLVardef@1f86fd3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

A multi-tissue single-cell tumor microenvironment atlas reveals myeloid-derived cell states with significant impact on clinical outcome

Tumor-associated myeloid-derived cells (MDCs) significantly impact cancer prognosis and treatment response due to their remarkable plasticity and tumorigenic behaviors. We integrated single-cell RNA-Sequencing datasets from seven different cancers, resulting in a comprehensive collection of 29 MDC subpopulations in the tumor microenvironment (TME). Distinguishing resident-tissue from monocyte-derived macrophages, we discovered a resident-tissue-like subpopulation within monocyte-derived macrophages. Additionally, hypoxia-driven macrophages emerged as a prominent TME component. Deconvolution of these profiles revealed five subpopulations as independent prognostic markers across various cancer types. Validation in large cohorts confirmed the FOLR2-expressing macrophage association with poor clinical outcomes in ovarian and triple-negative breast cancer. Moreover, the marker TREM2, commonly used to define immunosuppressive tumor-associated macrophages, cannot solely predict cancer prognosis, as different polarization states of macrophages express this marker in a context-dependent manner. This comprehensive MDC atlas offers valuable insights and a foundation for novel analyses, advancing strategies for treating solid cancers.

cancer biology↗

bioRxiv2022

Tissue-specific overexpression of the double-stranded RNA transporter SID-1 limits lifespan in C. elegans

Intertissue RNA transport has emerged as a novel signaling mechanism. In C. elegans, this is conferred by the systemic RNAi pathway, in which the limiting step is the cellular import of extracellular RNAs via SID-1. To better understand the physiological role of systemic RNAi in vivo, we modified the function of SID-1 through loss-of-function mutation and tissue-specific overexpression of sid-1 in C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were reversed by silencing the components of the systemic RNAi pathway sid-1, sid-2 and sid-5, thus implicating RNA transport. Moreover, silencing the miRNA biogenesis proteins pash-1 and dcr-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Lastly, we observed that the lifespan decrease produced by tissue-specific sid-1 overexpression was dependent on the bacterial food source. Collectively, our data support the notion that systemic RNA signaling is tightly regulated, and unbalancing that process provokes a reduction in lifespan.

molecular biology↗

bioRxiv2022

The Nuclear RNAi Pathway Regulates DAF-16/FOXO to Control C. elegans Longevity and Dauer Entry

Caenorhabditis elegans with impaired insulin/IGF-1 receptor signalling (IIS) or with germline ablation live longer and this phenomenon is entirely dependent on the transcription factor DAF-16 - the C. elegans homolog of the class O of the forkhead box transcription factors (FoxO). In a candidate RNAi screen designed to search for new modifiers of DAF-16 function among genes involved in histone modification and/or small RNA-mediated silencing pathways, we found nrde-1, wago-1, and adr-1 as positive regulators of DAF-16. We confirmed by several methods and in different models that DAF-16 translocation to the nucleus and, subsequently, its function is tightly controlled by these genes and narrowed down to components of the NRDE complex and the nuclear RNAi pathway as key DAF-16 modulators. Importantly, we found that the NRDE pathway controls DAF-16-mediated longevity and dauer entry. Our epistasis data indicate that nrde-1 interacts with akt-1 to control lifespan. We also demonstrated that NRDE-1 acts downstream of AGE-1/PI3K and partially requires mTORC2 and AKT-1 to control DAF-16 translocation. These results unveil a mechanism of regulation of dauer formation and longevity in C. elegans via nuclear RNAi-mediated modulation of DAF-16 function in a manner that involves the mTORC2-AKT axis.

genetics↗

bioRxiv2021

miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to affect muscle contractility upon proteotoxic challenge during ageing

Muscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also highly plastic, and remodelled in response to stress, growth, neural and metabolic inputs. The evolutionarily conserved muscle-enriched microRNA, miR-1, regulates distinct aspects of muscle biology during development, but whether it plays a role during ageing is unknown. Here we investigated the role of C. elegans miR-1 in muscle function in response to proteostatic stress during adulthood. mir-1 deletion results in improved mid-life muscle motility, pharyngeal pumping, and organismal longevity under conditions of polyglutamine repeat proteotoxic challenge. We identified multiple vacuolar ATPase subunits as subject to miR-1 control, and the regulatory subunit vha-13/ATP6VIA as a direct target downregulated via its 3UTR to mediate miR-1 physiology. miR-1 further regulates nuclear localization of lysosomal biogenesis factor HLH-30/TFEB and lysosomal acidification. In summary, our studies reveal that miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact muscle function and health during ageing.

genetics↗

bioRxiv2020

Senotherapeutic peptide reduces skin biological age and improves skin health

Skin aging has been primarily related to aesthetics and beauty. Therefore, interventions have focused on reestablishing skin appearance, but not necessarily skin health, function, and resilience. Recently, cellular senescence was shown to play a role in age-related skin function deterioration and influence organismal health and, potentially, longevity. In the present study, a two-step screening was performed to identify peptides capable of reducing cellular senescence in human dermal fibroblasts (HDF) from Hutchinson-Gilford Progeria (HGPS) patients. From the top four peptides of the first round of screening, we built a 764-peptide library using amino acid scanning, of which the second screen led to the identification of peptide 14. Peptide 14 effectively decreased HDF senescence induced by HGPS, chronological aging, ultraviolet-B radiation, and etoposide treatment, without inducing significant cell death, and likely by modulating longevity and senescence pathways. We further validated the effectiveness of peptide 14 using human skin equivalents and skin biopsies, where peptide 14 promoted skin health and reduced senescent cell markers, as well as the biological age of samples, according to the Skin-Specific DNA methylation clock, MolClock. Topical application of peptide 14 outperformed Retinol treatment, the current gold-standard in "anti-aging" skin care. Finally, we determined that peptide 14 is safe for long-term applications and also significantly extends both the lifespan and healthspan of C. elegans worms tested in two independent testings. This highlights the potential for geroprotective applications of the senotherapeutic compounds identified using our screening platform beyond the skin.

bioengineering↗