Potential Loss Research Articles

Enhanced Therapeutic Efficacy Against Melanoma through Exosomal Delivery of Hesperidin.

Melanoma, characterized as the most aggressive and metastatic form of skin cancer, currently has limited treatment options, predominantly chemotherapy and radiation therapy. However, the drawbacks associated with parenterally administered chemotherapy underscore the urgent need for alternative compounds to combat melanoma effectively. Hesperidin (HES), a flavonoid present in various citrus fruits, exhibits promising anticancer activity. Nevertheless, the clinical utility of HES is hindered by challenges such as poor water solubility, a short half-life, and low oral bioavailability. In response to these limitations, we introduced a novel approach by formulating HES-loaded exosomes (Exo-HES). Isolation of exosomes was achieved through the ultracentrifugation method, and HES was efficiently loaded using the sonication method. The resulting formulations displayed a desirable particle size (∼106 nm) and exhibited a spherical morphology, as confirmed by scanning electron and atomic force microscopy. In vitro studies conducted on B16F10 cell lines demonstrated higher cytotoxicity of Exo-HES compared to free HES, supported by enhanced cellular uptake validated through coumarin-6-loaded exosomes. This superior cytotoxicity was further evidenced by DNA fragmentation, increased generation of free radicals (ROS), loss of mitochondrial membrane potential, and effective inhibition of colony formation. The antimetastatic properties of Exo-HES were confirmed through wound healing and transwell migration assays. Oral pharmacokinetics studies revealed a remarkable increase of approximately 2.5 times in oral bioavailability and half-life of HES when loaded into exosomes. Subsequent in vivo experiments utilizing a B16F10-induced melanoma model in Swiss mice established that Exo-HES exhibited superior anticancer activity compared to HES after oral administration. Importantly, no biochemical, hematological, or histological toxicities were observed in tumor-bearing mice treated with Exo-HES. These findings suggest that exosomes loaded with HES represent a promising nanocarrier strategy to enhance the therapeutic effectiveness of hesperidin in melanoma treatment.

Carbon carrying capacity in primary forests shows potential for mitigation achieving the European Green Deal 2030 target

Carbon accounting in the land sector requires a reference level from which to calculate past losses of carbon and potential for gains using a stock-based target. Carbon carrying capacity represented by the carbon stock in primary forests is an ecologically-based reference level that allows estimation of the mitigation potential derived from protecting and restoring forests to increase their carbon stocks. Here we measured and collated tree inventory data at primary forest sites including from research studies, literature and forest inventories (7982 sites, 288,262 trees, 27 countries) across boreal, temperate, and subtropical Global Ecological Zones within Europe. We calculated total biomass carbon stock per hectare (above- and below-ground, dead biomass) and found it was 1.6 times larger on average than modelled global maps for primary forests and 2.3 times for all forests. Large trees (diameter greater than 60 cm) accounted for 50% of biomass and are important carbon reservoirs. Carbon stock foregone by harvesting of 12–52% demonstrated the mitigation potential. Estimated carbon gain by protecting, restoring and ongoing growth of existing forests equated to 309 megatons carbon dioxide equivalents per year, additional to, and higher than, the current forest sink, and comparable to the Green Deal 2030 target for carbon dioxide removals.

Obeticholic Acid Inhibit Mitochondria Dysfunction Via Regulating ERK1/2-DRP Pathway to Exert Protective Effect on Lipopolysaccharide-Induced Myocardial Injury.

Farnesoid X receptor (FXR) plays critical regulatory roles in cardiovascular physiology/pathology. However, the role of FXR agonist obeticholic acid (OCA) in sepsis-associated myocardial injury and underlying mechanisms remain unclear. C57BL/6J mice are treated with OCA before lipopolysaccharide (LPS) administration. The histopathology of the heart and assessment of FXR expression and mitochondria function are performed. To explore the underlying mechanisms, H9c2 cells, and primary cardiomyocytes are pre-treated with OCA before LPS treatment, and extracellular signal-regulated protein kinase (ERK) inhibitor PD98059 is used. LPS-induced myocardial injury in mice is significantly improved by OCA pretreatment. Mechanistically, OCA pretreatment decreased reactive oxygen species (ROS) levels and blocked the loss of mitochondrial membrane potential (ΔΨm) in cardiomyocytes. The expression of glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF-2) increased in the case of OCA pretreatment. In addition, OCA improved mitochondria respiratory chain with increasing Complex I expression and decreasing cytochromeC (Cyt-C) diffusion. Moreover, OCA pretreatment inhibited LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway. FXR agonist OCA inhibits LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway to protect mice against LPS-induced myocardial injury.

Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H2O2-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H2O2-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.

First Report of Neoscytalidium dimidiatum causing leaf zonate spot disease of Aloe vera L. in China.

In February 2022, leaf zonate spot disease afflicted Aloe vera L. in Yunnan, China, endangering the $39 billion industry with 0.33ha under cultivation (Wan 2015). The disease manifested with watery spots progressing into oval or circular necrosis lesions, characterized by a dark center surrounded by a gray-brown zone. In the late stage of the disease, lesions regress in size and several small dark picnidia dots appeared on the gray-brown zone. The disease incidence ranged from 10% to 15% in three commercial plantations. If left uncontrolled, the disease could diminish the commercial value of Aloe vera plants. Eighteen symptomatic leaf samples underwent morphological and genetic identification. The samples were carefully washed with distilled water and 1×1 cm2 sections of tissue were excised using a sterile scalpel. The sections underwent surface-disinfection with 3% NaOCl for 3 min and 75% ethanol for 30 s. After three sterile water rinses the sections were air-dried. Subsequently, they were transferred to potato dextrose agar (PDA) before being incubated at 25 ℃ in the dark. Of the 18 samples, eight produced the colonies with similar morphological characteristics, named LH7. Isolate LH7 had downy to woolly aerial mycelia, initially pinkish white on the surface, and gradually turned greenish-olivaceous from the middle, and eventually turned dark brown to black after seven days. The fungus formed arthric chains in the aerial mycelium on PDA but did not produce conidiomata. The conidia, which occurred in arthric chains were 5.50-9.9 × 4.08-7.51 μm (mean 7.09× 5.26 μm, n=50) in size, cylindrical, brown, and 0-1 septate. To ascertain LH7's pathogenicity, three healthy one-year old aloe plants were surface-sanitized with a 1% aqueous chlorine solution, rinsed with sterile water, and dried. Three leaves from each plant were punctuated and inoculated using conidial suspension (100 μl of 1x 106 conidial mL-1), while three control plants were inoculated with sterile distilled water. The pathogenicity tests were repeated twice. The inoculated plants were kept at 25 ℃ with a 12-hour light/12-hour dark cycle. After seven days, symptoms observed in the field appeared in the plants, while no disease occurred in the control plants. After 21 days, conidiomata formed on the inoculated leaves, averaging 116.92 μm (n=20) in diameter. These conidiomata were globose to subglobose, and brown to sub-brown. The fungus was successfully re-isolated from symptomatic tissue and the resulting colonies were morphologically consistent with isolate LH7. Based on the characteristics, the fungus was identified as Neoscytalidium dimidiatum (Philips et al. 2013). The specimen was deposited in China Center for Type Culture Collection ( CCTCC AF 2024001). This identification was confirmed through sequencing of ITS gene region of rDNA using ITS1/ITS4 (Imran et al. 2022). The sequence was submitted into GenBank database (ON878059). BLAST analysis of the LH7's ITS amplicon showed 100% similarity with that of JN093303.1. A phylogenetic tree constructed using the maximum likelihood method revealed that ON878059 was clustered with JN093303.1. Previous studies have documented that pathogens such as Colletotrichum gloeosporioides (Penz.), Fusarium spp. and Rhizopus oryzae can also cause diseases in A. vera in China (Zhou et al. 2008; Ding et al. 2015). Additinonally, Cladosporium sphaerospermum, Pseudopestalotiopsis theae, and Lasiodiplodia theobromae have been identified as causal agents of aloe leaf spot diseases in India, Bangladesh and Malaysia (Avasthi et al. 2016; Ahmmed et al. 2022; Khoo et al. 2022). To our knowledge, this is the first report of N. dimidiatum causing leaf necrosis of aloe in China. Vigilant surveillance and disease control measures are imperative to mitigate potential losses in this region.

Targeted inhibition of branched-chain amino acid metabolism drives apoptosis of glioblastoma by facilitating ubiquitin degradation of Mfn2 and oxidative stress

Glioblastoma is one of the most challenging malignancies with high aggressiveness and invasiveness and its development and progression of glioblastoma highly depends on branched-chain amino acid (BCAA) metabolism. The study aimed to investigate effects of inhibition of BCAA metabolism with cytosolic branched-chain amino acid transaminase (BCATc) Inhibitor 2 on glioblastoma, elucidate its underlying mechanisms, and explore therapeutic potential of targeting BCAA metabolism. The expression of BCATc was upregulated in glioblastoma and BCATc Inhibitor 2 precipitated apoptosis both in vivo and in vitro with the activation of Bax/Bcl2/Caspase-3/Caspase-9 axis. In addition, BCATc Inhibitor 2 promoted K63-linkage ubiquitination of mitofusin 2 (Mfn2), which subsequently caused lysosomal degradation of Mfn2, and then oxidative stress, mitochondrial fission and loss of mitochondrial membrane potential. Furthermore, BCATc Inhibitor 2 treatment resulted in metabolic reprogramming, and significant inhibition of expression of ATP5A, UQCRC2, SDHB and COX II, indicative of suppressed oxidative phosphorylation. Moreover, Mfn2 overexpression or scavenging mitochondria-originated reactive oxygen species (ROS) with mito-TEMPO ameliorated BCATc Inhibitor 2-induced oxidative stress, mitochondrial membrane potential disruption and mitochondrial fission, and abrogated the inhibitory effect of BCATc Inhibitor 2 on glioblastoma cells through PI3K/AKT/mTOR signaling. All of these findings indicate suppression of BCAA metabolism promotes glioblastoma cell apoptosis via disruption of Mfn2-mediated mitochondrial dynamics and inhibition of PI3K/AKT/mTOR pathway, and suggest that BCAA metabolism can be targeted for developing therapeutic agents to treat glioblastoma.

First report of the damaging pest Meloidogyne enterolobii parasitizing mulberry (Morus alba L.) in Vietnam.

Mulberry (Morus alba L.) is highly important crop in Vietnam, playing a key role in the country's economy through sericulture, food supply, pharmaceuticals, and beverage industries (Nguyen et al., 2018; Rohela et al., 2020). Recently, many mulberry-growing areas in Lam Dong, Vietnam have reported severe symptoms associated with nematode infection, including yellowing leaves, stunted growth, and severe root galling, leading to a significant decline in mulberry productivity. From April to December 2022, twenty soil and root samples from mulberry-growing areas in Lam Dong (Da Teh: 11°28'48.11"N; 107°28'23.74"E elevation: 133m; Lam Ha 11°48'25.13"N; 108°14'7.13"E elevation: 848m) were collected to uncover the presence of Meloidogyne enterolobii parasitizing mulberry in Vietnam. One nematode population was randomly selected for characterizing in this study among analyzed nematode populations. Females were extracted from heavily galled roots (Fig. S1) from a single mulberry tree in Lam Dong, Vietnam, using a needle and forceps (Subbotin et al., 2021). The perineal patterns of adult females (n = 10) have an oval shape, with clearly visible phasmids, along with a prominently high and squared dorsal arch. The striae are smooth and coarse, while the perivulval region remains devoid of striae. The lateral lines appear indistinct, and the tail tip is easily observable. Morphometric measurements were as follows: body length = 585 ± 78 (464-724) µm, body width = 367 ± 75 (271-529) µm, neck length = 221.5 ± 30.7 (167-269.6) µm, stylet length = 13.1 ± 1.2 (11.4-15.1) µm, vulva-slit length 16.3±2.3 (10.4-18) µm, vulva-anus distance = 16.8±3.0 (11.4-18) µm, anus-tail tip distance = 10.3±2.1 (6.9-14.2) µm, interphasmidial distance = 15.9 ± 3.7 (10.3-23.4) µm. The morphology of this nematode population is highly in agreement with the original description of M. enterolobii (Yang & Eisenback, 1983). This population was also identified using the D2-D3 of 28S rRNA and 18S rRNA (Powers et al., 2017; Subbotin et al., 2006) regions. The D2-D3 of 28S rRNA sequences from this study (accession numbers: OR889633) exhibited 99.5-99.8% similarity to the sequences of M. enterolobii from GenBank (accession numbers: OR214950 and ON496981). While the 18S rRNA sequences (accession numbers: OR896547) showed 99.2-99.3% similarity to the sequences of M. enterolobii from GenBank (accession numbers: MZ955995, MZ531901, and MW488150). To carry out Koch's postulates, 2000 J2s from collected M. enterolobii egg masses (initial population) were inoculated on two-month-old plantlets of mulberry (n = 6), planted on 2L pots within a screenhouse, non-inoculated plantlets (n=6) served as negative controls. After 90 days post-inoculation, nematode reproduction factors (RF = final density (nematodes were extracted from the whole root system and corresponding soil samples (Subbotin et al., 2021)) / initial population) and root damage symptoms were evaluated. The inoculated plantlets exhibited consistent yellowing leaves, stunting, and root galling symptoms (Fig. S1), mirroring observations from the field, with an average RF of 11.5. Control plants displayed no symptoms. Root-knot nematodes extracted from the roots were identified as M. enterolobii through molecular analyses of D2-D3 of 28S and 18S rRNA regions (GenBank accession numbers: OR889634 (D2-D3 of 28S) and OR896548 (18S)), thereby confirming that mulberry acts as a host for M. enterolobii. Currently, this nematode has been reported to be associated with two different host plants, including guava (Trinh et al., 2022) and pomelo (Le et al., 2023). Our discovery marks the first documented case of Meloidogyne enterolobii parasitizing mulberry in Vietnam. While the impact on mulberry productivity remains to be really important for sericulture food supply, pharmaceuticals, and beverage industries; the aggressive nature of M. enterolobii, as observed in the field and confirmed by the screenhouse tests, raises concerns about potential economic losses in mulberry production. Therefore, further investigations are needed to assess the extent of M. enterolobii infestation in mulberry orchards and to develop effective control measures to safeguard the sustainability of mulberry cultivation in Vietnam.

Abstract PO3-06-08: Epithelial to Mesenchymal Transition Confers Sensitivity to Cytotoxic Agent Ophiobolin A via Alterations in Mitochondrial Function and Metabolic Pathways

Abstract Epithelial to Mesenchymal Transition Confers Sensitivity to Cytotoxic Agent Ophiobolin A via Alterations in Mitochondrial Function and Metabolic Pathways Haleigh Parker1, Kayla Haberman1, Alexander Kornienko2, Antonio Evidente3, Daniel Romo4, Benny Abraham Kaipparettu5,6, Joseph Taube1,6 1 Department of Biology, Baylor University, Waco, TX, USA 2 Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, USA 3 Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario Monte Sant’Angelo, Naples, Italy 4 Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 6 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA Background Metastatic progression in patients with triple negative breast cancer (TNBC) occurs in approximately half of all patients, reducing median overall survival. Metastasis may be facilitated through the epithelial to mesenchymal transition (EMT), which generates cancer cells with enhanced metastatic capacity and resistance to chemotherapeutics, features which are partially mediated by alterations in metabolic pathways and mitochondrial function. Here, we show a drug-like small molecule possesses EMT-specific cytotoxic activity via EMT-imparted variations in metabolic and mitochondrial functions. The fungus-derived sesterterpenoid, Ophiobolin A (OpA), possesses nanomolar cytotoxic activity and a high therapeutic index, though its target and mechanism of action remain unknown. Objectives The objectives of this study are to characterize alterations in metabolic pathways and mitochondrial function in the context of EMT, determine OpA induced alterations in specific metabolic pathways involved in metastasis and identify metabolic targets for the treatment of chemotherapeutic-resistant, metastatic triple negative breast cancer. Methods This study identifies distinct, novel metabolic alterations associated with EMT status and specific changes in mitochondrial and metabolic function associated with OpA treatment via analysis of intermediate metabolites, rates of oxidative phosphorylation and glycolysis, metabolic pathway capacity and dependency, protein expression, iron localization, reactive oxygen species accumulation and transmission electron microscopy. Results Our analysis indicates that OpA acts in a mitochondria-specific manner to cause a loss of membrane potential in EMT-positive, but not EMT-negative, cells with specific effects on complex III of the electron transport chain and oxidative phosphorylation as a whole. Furthermore, distinct shifts in glycolysis not only support previous data, but also provides insight as to mitochondrial functionality. Cells were also found to have distinct metabolic pathway capacities/dependencies and ROS and iron accumulation, depending on EMT status and OpA treatment. Finally, specific morphological alterations were uncovered via TEM image analysis. Therefore, we conclude that EMT imparts alterations in mitochondrial function and metabolic pathways, conferring sensitivity to the cytotoxic effects of OpA. Citation Format: Haleigh Parker, Kayla Haberman, Joseph Taube, Alexander Kornienko, Antonio Evidente, Daniel Romo, Benny Kaipparettu. Epithelial to Mesenchymal Transition Confers Sensitivity to Cytotoxic Agent Ophiobolin A via Alterations in Mitochondrial Function and Metabolic Pathways [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-08.

Topological phase transitions in the non-Hermitian SSH model with long-range hopping terms induced by gains and losses

The latest progress in the one-dimensional chain SSH model provide the basic understanding of non-Hermitian topological phases. By periodically introducing the gains and losses of imaginary potential ig,-ig,-ig,ig with anti-PT symmetry, we have investigated the topological property of non-Hermitian SSH model with long-range hopping terms. We find that the gains and losses of imaginary potential causes the model to exhibit non-Hermiticity, and the non-Hermiticity induces system to undergo topological phase transitions from topologically trivial phase with non-Hermitian winding number 0 to topologically nontrivial phase with non-Hermitian winding number 1 and −1. The introduction of gains and losses greatly broadens the topological non-trivial region and play a non-trivial role in the model. We fully characterize the topological phase transitions by the band gap closing-reopening, the non-Hermitian winding numbers v and the hidden Chern number C.

L-theanine abates oxidative stress and mitochondrial dysfunction in myocardial ischemia-reperfusion injury by positively regulating the antioxidant response

L-theanine (L-THE), a non-protein amino acid isolated from Camelia sinensis, has antioxidant properties that could prevent oxidative damage and mitochondrial dysfunction generated by myocardial ischemia and reperfusion (I/R) injury. The present study aimed to identify the effects of pretreatment with L-THE in rat hearts undergoing I/R. Wistar rats received vehicle or 250 mg/Kg L-THE intragastrically for 10 days. On day 11, hearts were removed under anesthesia and exposed to I/R injury in the Langendorff system. Measurement of left ventricular developed pressure and heart rate ex vivo demonstrates that L-THE prevents I/R-induced loss of cardiac function. Consequently, the infarct size of hearts subjected to I/R was significantly decreased when L-THE was administered. L-THE also mitigated I/R-induced oxidative injury in cardiac tissue by decreasing reactive oxygen species and malondialdehyde levels, while increasing the activity of antioxidant enzymes, SOD and CAT. Additionally, L-THE prevents oxidative phosphorylation breakdown and loss of inner mitochondrial membrane potential caused by I/R, restoring oxygen consumption levels, increasing respiratory control and phosphorylation efficiency, as well as buffering calcium overload. Finally, L-THE modifies the expression of genes involved in the antioxidant response through the overexpression of SOD1, SOD2 and CAT; as well as the transcriptional factors PPARα and Nrf2 in hearts undergoing I/R. In conclusion, L-THE confers cardioprotection against I/R injury by preventing oxidative stress, protecting mitochondrial function, and promoting overexpression of antioxidant genes. More studies are needed to place L-THE at the forefront of cardiovascular research and recommend its therapeutic use.

Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh3, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh3 exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC50 value of 4.0 μM. Ru-TPE-PPh3 could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh3 also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.

M2 macrophage-derived TGF-β induces age-associated loss of adipogenesis through progenitor cell senescence

ObjectivesAdipose tissue is an endocrine and energy storage organ composed of several different cell types, including mature adipocytes, stromal cells, endothelial cells, and a variety of immune cells. Adipose tissue aging contributes to the pathogenesis of metabolic dysfunction and is likely induced by crosstalk between adipose progenitor cells (APCs) and immune cells, but the underlying molecular mechanisms remain largely unknown. In this study, we revealed the biological role of p16high senescent APCs, and investigated the crosstalk between each cell type in the aged white adipose tissue. MethodsWe performed the single-cell RNA sequencing (scRNA-seq) analysis on the p16high adipose cells sorted from aged p16-CreERT2/Rosa26-LSL-tdTomato mice. We also performed the time serial analysis on the age-dependent bulk RNA-seq datasets of human and mouse white adipose tissues to infer the transcriptome alteration of adipogenic potential within aging. ResultsWe show that M2 macrophage-derived TGF-β induces APCs senescence which impairs adipogenesis in vivo. p16high senescent APCs increase with age and show loss of adipogenic potential. The ligand–receptor interaction analysis reveals that M2 macrophages are the donors for TGF-β and the senescent APCs are the recipients. Indeed, treatment of APCs with TGF-β1 induces senescent phenotypes through mitochondrial ROS-mediated DNA damage in vitro. TGF-β1 injection into gonadal white adipose tissue (gWAT) suppresses adipogenic potential and induces fibrotic genes as well as p16 in APCs. A gWAT atrophy is observed in cancer cachexia by APCs senescence, whose induction appeared to be independent of TGF-β induction. ConclusionsOur results suggest that M2 macrophage-derived TGF-β induces age-related lipodystrophy by APCs senescence. The TGF-β treatment induced DNA damage, mitochondrial ROS, and finally cellular senescence in APCs.

Spatiotemporal Analysis of Soil Quality Degradation and Emissions in the State of Iowa (USA)

The concept of soil quality (SQ) is defined as the soil's capacity to function, which is commonly assessed at the field scale. Soil quality is composed of inherent (soil suitability) and dynamic (soil health, SH) SQ, which can also be analyzed using geospatial tools as a SQ continuum (SQC). This study proposes an innovative spatiotemporal analysis of SQ degradation and emissions from land developments using the state of Iowa (IA) in the United States of America (USA) as a case study. The SQ degradation was linked to anthropogenic soil (SD) and land degradation (LD) in the state. More than 88% of land in IA experienced anthropogenic LD primarily due to agriculture (93%). All six soil orders were subject to various degrees of anthropogenic LD: Entisols (75%), Inceptisols (94%), Histosols (59%), Alfisols (79%), Mollisols (93%), and Vertisols (98%). Soil and LD have primarily increased between 2001 and 2016. In addition to agricultural LD, there was also SD/LD caused by an increase in developments often through urbanization. All land developments in IA can be linked to damages to SQ, with 8385.9 km2 of developed area, causing midpoint total soil carbon (TSC) losses of 1.7 × 1011 kg of C and an associated midpoint of social cost of carbon dioxide emissions (SC-CO2) of $28.8B (where B = billion = 109, USD). More recently developed land area (398.5 km2) between 2001 and 2016 likely caused the midpoint loss of 8.0 × 109 kg of C and a corresponding midpoint of $1.3B in SC-CO2. New developments are often located near urban areas, for example, near the capital city of Des Moines, and other cities (Sioux City, Dubuque). Results of this study reveal several different kinds of SQ damage from developments: loss of potential for future C sequestration in soils, soil C loss, and “realized” soil C social costs (SC-CO2). The state of IA has very limited potential land (2.0% of the total state area) for nature-based solutions (NBS) to compensate for SD and LD. The results of this study can be used to support pending soil health-related legislation in IA and monitoring towards achieving the Sustainable Development Goals (SDGs) developed by the United Nations (UN) by providing a landscape-level perspective on LD to focus field-level initiatives to reduce soil loss and improve SQ. Future technological innovations will provide higher spatial and temporal remote sensing data that can be fused with field-level direct sensing to track SH and SQ changes.

Quercetin prevents methylmercury-induced mitochondrial dysfunction in the cerebral cortex of mice

Methylmercury (MeHg) exposure can cause nerve damage and mitochondrial dysfunction. Mitochondrial dysfunction is mainly mediated by mitochondrial biogenesis and mitochondrial dynamics disorders. Quercetin (QE) plays an important role in activating silencing information regulator 2 related enzyme 1 (SIRT1), and SIRT1 activates peroxisome-proliferator-activated receptor-γ co-activator 1α (PGC-1α), which can regulate mitochondrial biogenesis and mitochondrial dynamics. The main purpose of this study was to explore the alleviating effects of QE on MeHg-induced nerve damage and mitochondrial dysfunction. The results showed that QE could reduce the excessive production of reactive oxygen species (ROS) and the loss of membrane potential induced by MeHg. Meanwhile, QE activated SIRT1 activity and SIRT1/PGC-1α signaling pathway, improved mitochondrial biogenesis and fusion and reduced mitochondrial fission. In summary, we hypothesized that QE prevents MeHg-induced mitochondrial dysfunction by activating SIRT1/PGC-1α signaling pathway.

Boom-bust population dynamics drive rapid genetic change

Increasing environmental threats and more extreme environmental perturbations place species at risk of population declines, with associated loss of genetic diversity and evolutionary potential. While theory shows that rapid population declines can cause loss of genetic diversity, populations in some environments, like Australia's arid zone, are repeatedly subject to major population fluctuations yet persist and appear able to maintain genetic diversity. Here, we use repeated population sampling over 13 y and genotype-by-sequencing of 1903 individuals to investigate the genetic consequences of repeated population fluctuations in two small mammals in the Australian arid zone. The sandy inland mouse (Pseudomys hermannsburgensis) experiences marked boom-bust population dynamics in response to the highly variable desert environment. We show that heterozygosity levels declined, and population differentiation (FST) increased, during bust periods when populations became small and isolated, but that heterozygosity was rapidly restored during episodic population booms. In contrast, the lesser hairy-footed dunnart (Sminthopsis youngsoni), a desert marsupial that maintains relatively stable population sizes, showed no linear declines in heterozygosity. These results reveal two contrasting ways in which genetic diversity is maintained in highly variable environments. In one species, diversity is conserved through the maintenance of stable population sizes across time. In the other species, diversity is conserved through rapid genetic mixing during population booms that restores heterozygosity lost during population busts.

Centella asiatica mitigates the detrimental effects of Bisphenol-A (BPA) on pancreatic islets

Bisphenol-A (BPA) is widely used in food packaging and household products, leading to daily human exposure and potential health risks including metabolic diseases like type 2 diabetes mellitus (T2DM). Understanding BPA's mechanisms and developing intervention strategies is urgent. Centella asiatica, a traditional herbal medicine containing pentacyclic triterpenoids, shows promise due to its antioxidant and anti-inflammatory properties, utilized for centuries in Ayurvedic therapy. We investigated the effect of Centella asiatica (CA) ethanol extract on BPA-induced pancreatic islet toxicity in male Swiss albino mice. BPA administration (10 and 100 μg/kg body weight, twice daily) for 21 days caused glucose homeostasis disturbances, insulin resistance, and islet dysfunction, which were partially mitigated by CA supplementation (200 and 400 mg/kg body weight). Additionally, heightened oxidative stress, elevated levels of proinflammatory cytokines, loss of mitochondrial membrane potential (MMP), abnormal cell cycle, and increased apoptosis were implicated in the detrimental impact of BPA on the endocrine pancreas which were effectively counteracted by CA supplementation. In summary, CA demonstrated a significant ability to mitigate BPA-induced apoptosis, modulate redox homeostasis, alleviate inflammation, preserve MMP, and regulate the cell cycle. As a result, CA emerged as a potent agent in neutralizing the diabetogenic effects of BPA to a considerable extent.

Geochemical Properties and Gas-Bearing Analysis of Lower Cambrian Black Shale in Western Hunan Province

Western Hunan province and its surrounding areas are significant targets for shale gas exploration and development in southern China, where the black shale of the lower Cambrian Niutitang Formation and Wunitang Formation is extensively distributed. Geochemical analysis was conducted on the lower Cambrian black shale from a new exploration well of XAD1 located at the southeast margin of the Yangtze paraplatform, followed by a discussion on gas-bearing properties using molecular dynamics simulation. The geochemical characteristics indicate that the black shale in well XAD1 was primarily deposited in a strongly reducing marine environment, with organic matter predominantly composed of type I kerogen derived from algae. Currently, it has reached a stage of high to over maturity with limited potential for liquid hydrocarbon generation. The recovery of the original hydrocarbon generation potential shows that they are excellent source rocks and have completed the main hydrocarbon generation evolution. Despite the favorable conditions for shale gas formation observed in well XAD1, the low measured gas content within the Niutitang Formation suggests that other geological factors may have contributed to a substantial loss of shale gas. Gas adsorption simulation reveals that the maximum methane adsorption capacity (15.77 m3/t) was achieved by Niutitang shale during the late Silurian period when there was an abundant source of natural gas without any influence from CO2, H2O or other molecules. However, due to a lack of natural gas replenishment and subsequent tectonic uplift and subsidence causing variations in temperature and pressure, the methane adsorption capacity gradually decreased (to 6.56 m3/t). Furthermore, water occurrence within the shale reservoir further reduced the methane adsorption capacity (below 2 m3/t), while tectonic activities exacerbated the loss of shale gas potential within this study area. The findings indicate that the dynamic alteration of gas-bearing properties in shale reservoirs due to tectonic movements is a crucial factor influencing the success rate of shale gas exploration in the study area, provided that there are sufficient gas resources and superior reservoir conditions.

Timing of intraoperative neurophysiological monitoring (IONM) recovery and clinical recovery after termination of pediatric spinal deformity surgery due to loss of IONM signals

Background ContextIntraoperative neurophysiological monitoring (IONM) is used to reduce the risk of spinal cord injury during pediatric spinal deformity surgery. Significant reduction and/or loss of IONM signals without immediate recovery may lead the surgeon to acutely abort the case. The timing of when monitorable signals return remains largely unknown. PurposeThe goal of this study was to investigate the correlation between IONM signal loss, clinical examination, and subsequent normalization of IONM signals after aborted pediatric spinal deformity surgery to help determine when it is safe to return to the operating room. Study Design/SettingThis is a multicenter, multidisciplinary, retrospective study of pediatric patients (< 18 years old) undergoing spinal deformity surgery whose surgery was aborted due to a significant reduction or loss of IONM potentials. Patient SampleSixty-six patients less than 18 years old who underwent spinal deformity surgery that was aborted due to IONM signal loss were enrolled into the study. Outcome MeasuresIONM data, operative reports, and clinical examinations were investigated to determine the relationship between IONM loss, clinical examination, recovery of IONM signals, and clinical outcome. MethodsInformation regarding patient demographics, deformity type, clinical history, neurologic and ambulation status, operative details, IONM information (e.g., quality of loss [SSEPs, MEPs], laterality, any recovery of signals, etc.), intra-operative wake-up test, post-operative neurologic exam, post-operative imaging, and time to return to the operating were all collected. All factors were analyzed and compared with univariate and multivariate analysis using appropriate statistical analysis. ResultsSixty-six patients were enrolled with a median age of 13 years [IQR 11-14], and the most common sex was female (42/66, 63.6%). Most patients had idiopathic scoliosis (33/66, 50%). The most common causes of IONM loss were screw placement (27/66, 40.9%) followed by rod correction (19/66, 28.8%). All patients had either complete bilateral (39/66, 59.0%), partial bilateral (10/66, 15.2%) or unilateral (17/66, 25.8%) MEP loss leading to termination of the case. Overall, when patients were returned to the operating room two weeks postoperatively, nearly 75% (40/55) had monitorable IONM signals. Univariate analysis demonstrated that bilateral SSEP loss (p = 0.019), bilateral SSEP and MEP loss (p = 0.022) and delayed clinical neurologic recovery (p = 0.008) were significantly associated with having unmonitorable IONM signals at repeat surgery. Multivariate regression analysis demonstrated that delayed clinical neurologic recovery (> 72 hours) was significantly associated with unmonitorable IONM signals when returned to the operating room (p=0.006). All patients ultimately made a full neurologic recovery. ConclusionsIn children whose spinal deformity surgery was aborted due to intraoperative IONM loss, there was a strong correlation between combined intraoperative SSEP/MEP loss, the magnitude of IONM loss, the timing of clinical recovery, and the time of electrophysiological IONM recovery. The highest likelihood of having a prolonged postoperative neurological deficit and undetectable IONM signals upon return to the OR occurs with bilateral complete loss of SSEPs and MEPs.

Bortezomib suppresses acute myelogenous leukaemia stem-like KG-1a cells via NF-κB inhibition and the induction of oxidative stress.

Acute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating that a critical strategy for overcoming chemoresistance in AML therapy is to eradicate LSCs. In this work, we investigated the anti-AML activity of bortezomib (BTZ), emphasizing its anti-LSC potential, using KG-1a cells, an AML cell line with stem-like properties. BTZ presented potent cytotoxicity to both solid and haematological malignancy cells and reduced the stem-like features of KG-1a cells, as observed by the reduction in CD34- and CD123-positive cells. A reduction in NF-κB p65 nuclear staining was observed in BTZ-treated KG-1a cells, in addition to upregulation of the NF-κB inhibitor gene NFΚBIB. BTZ-induced DNA fragmentation, nuclear condensation, cell shrinkage and loss of transmembrane mitochondrial potential along with an increase in active caspase-3 and cleaved PARP-(Asp 214) level in KG-1a cells. Furthermore, BTZ-induced cell death was partially prevented by pretreatment with the pancaspase inhibitor Z-VAD-(OMe)-FMK, indicating that BTZ induces caspase-mediated apoptosis. BTZ also increased mitochondrial superoxide levels in KG-1a cells, and BTZ-induced apoptosis was partially prevented by pretreatment with the antioxidant N-acetylcysteine, indicating that BTZ induces oxidative stress-mediated apoptosis in KG-1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45-positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG-1a cells with tolerable toxicity. Taken together, these data indicate that the anti-LSC potential of BTZ appears to be an important strategy for AML treatment.

Loss aversion predicts cigarette smoking status across levels of sociodemographic characteristics.

Loss aversion (LA) is a tendency to be more sensitive to potential losses relative to similar gains. Low LA is associated with increased risk for cigarette smoking and use of other substances. Previous studies of LA and smoking risk controlled for potentially confounding influences of sociodemographic characteristics associated with smoking risk. The present study replicates these earlier observations while also examining the generality of the association between low LA and smoking risk within different levels of each of the five sociodemographic risk factors for smoking (age, educational attainment, gender, income, race/ethnicity). Parallel analyses were conducted using delay discounting (DD) as a positive control; DD is a decision-making bias regarding the rate at which rewards lose value with increasing delay to receipt. Participants were recruited using standard crowdsourcing methods and completed a sociodemographics questionnaire, a hypothetical gamble task measure of LA, and a monetary choice measure of DD. Low LA was associated with increased risk of cigarette smoking after accounting for the influence of sociodemographic characteristics and DD. Similarly, high DD was associated with increased risk of cigarette smoking after accounting for the influence of sociodemographic characteristics and LA. Further analyses showed that associations of LA with smoking risk or DD with smoking risk generally although not always remained significant within varying levels of the sociodemographic characteristics of interest. These results provide support for low LA as a reliable risk factor for smoking that has generality within and across sociodemographic characteristics and closely parallels associations observed with DD and smoking risk. (PsycInfo Database Record (c) 2024 APA, all rights reserved).