ACSL1 positively regulates adipogenic differentiation.

Aberrant adipogenic differentiation is strongly associated with obesity and related metabolic diseases. Elucidating the key factors driving adipogenesis is an effective strategy for identifying novel therapeutic targets for treating metabolic diseases represented by obesity. In this study, transcriptomic techniques were employed to investigate the functional genes that regulate adipogenic differentiation in OP9 cells and 3T3-L1 cells. The findings indicated a notable upregulation of Acsl1 expression throughout the adipogenic differentiation process. Knocking down Acsl1 led to a decrease in the expression of genes associated with adipogenesis and a reduction in triglyceride accumulation. Additionally, Acsl1 overexpression promoted adipocyte differentiation and adipose-specific overexpression of Acsl1 markedly aggravated steatosis induced by a high-fat diet. Mechanistically, Cyp2f2, Dusp23 and Gstm2 are the crucial genes implicated in Acsl1-induced adipogenic differentiation. The findings of this study indicate that Acsl1 promotes adipogenesis and could serve as a potential therapeutic target for treating obesity and related metabolic disorders.

Abdominal obesity and CKD: A potential mediating role of serum metabolites in the UK Biobank population.

BACKGROUND: It is generally known that although a connection between abdominal obesity and chronic kidney disease (CKD) is well-established, there is a lack of systematic research investigating the specific roles of serum metabolites, including lipid metabolites, amino acid metabolites, carbohydrate metabolites and inflammatory substances in explaining this associations. METHODS: We included 118,020 general patients with data of serum metabolites from UK Biobank. We defined abdominal obesity and CKD based on waist circumference and ICD-10 criteria. The serum metabolites were assessed by a high-throughput nuclear magnetic resonance (NMR) based metabolic biomarker profiling platform. We conducted mediation analysis by R software and used the proportion of mediation to quantify the mediation effect. RESULTS: This study demonstrated that lipid metabolites played a more important role in mediating the relationship between abdominal obesity and CKD than amino acid metabolites and carbohydrate metabolites. And Glycoprotein Acetyls (GlycA) was the strongest mediator for the correlation between abdominal obesity and CKD, accounting for 26.4 %. And In the mediation analysis stratified by sex, we found that the mediating effects of lipid metabolites were mostly higher in men than in women, while GlycA accounted for the largest proportion of the mediation association in both two groups (31.0 % for women and 19.8 % for men). CONCLUSION: Among lipid metabolites, amino acid metabolites, carbohydrate metabolites and inflammatory substances, our study showed that infammation marker GlycA was the novel and key mediator for the correlation between abdominal obesity and CKD.

TMEM56 deficiency impairs the haem metabolism and cell cycle progression during human erythropoiesis.

TMEM56, a gene coding a transmembrane protein, is abundantly expressed in erythroid cells. Despite this, its role in erythropoiesis has not been well characterized. In this study, we sought to clarify the function of TMEM56 in erythroid development, focusing specifically on its involvement in haem biosynthesis and cell cycle progression. To do this, we used CD34+ haematopoietic stem cells derived from umbilical cord blood and differentiated them into erythroid cells in an ex vivo model. Our results indicate that the loss of TMEM56 disrupts haem biosynthesis and impairs erythroid differentiation. Furthermore, deletion of Tmem56 in the erythroid lineage in murine models using erythropoietin receptor (EpoR)-Cre revealed defects in erythroid progenitors within the bone marrow under both normal conditions and during haemolytic anaemia. These observations underscore the regulatory role of TMEM56 in maintaining erythroid lineage homeostasis. Taken together, our results unveil a previously unrecognized function of TMEM56 in erythroid differentiation and suggest its potential as an unfounded target for therapeutic strategies in the treatment of erythropoietic disorders.

Primer exchange reaction assisted CRISPR/Cas9 cleavage for detection of dual microRNAs with electrochemistry method.

An electrochemical sensor assisted by primer exchange reaction (PER) and CRISPR/Cas9 system (PER-CRISPR/Cas9-E) was established for the sensitive detection of dual microRNAs (miRNAs). Two PER hairpin (HP) were designed to produce a lot of extended PER products, which could hybridize with two kinds of hairpin probes modified on the electrode and initiate the cleavage of two CRISPR/Cas9 systems guided by single guide RNAs (sgRNAs) with different recognition sequences. The decrease of the two electrochemical redox signals indicated the presence of dual-target miRNAs. With the robustness and high specificity of PER amplification and CRISPR/Cas9 cleavage system, simultaneous detection of two targets was achieved and the detection limits for miRNA-21 and miRNA-155 were 0.43 fM and 0.12 fM, respectively. The developed biosensor has the advantages of low cost, easy operation, and in-situ detection, providing a promising platform for point-of-care detection of multiple miRNAs.

Protective effects of a novel bicyclic γ-butyrolactone compound against H2O2 or corticosterone-induced neural cell apoptosis.

Oxidative stress plays a pivotal role in various neurological disorders, encompassing both neurodegenerative diseases such as Alzheimer's and Parkinson's, and mood disorders like depression. The balance between the generation of reactive oxygen species (ROS) and the cell's antioxidant defenses, when disrupted, can lead to neuronal damage and neurologic dysfunction. In this study, we focused on the pathogenic role of oxidative stress in various neurologic disease models in vitro and investigated the neuroprotective capabilities of some novel bicyclic γ-butyrolactone compounds, with particular emphasis on the compound designated as 'bd'. Our investigation leveraged the HT22 and SH-SY5Y cells to model oxidative stress induced by H2O2 or corticosterone (CORT), common triggers of neuronal damage in neurodegenerative and mood disorders. We discovered that compound bd robustly reduced ROS production and suppressed neuronal apoptosis, suggesting its potential in treating a wider array of neurological conditions influenced by oxidative stress. In conclusion, our research underscores the importance of addressing oxidative stress in the context of diverse neurological disorders. The identification of compound bd as a neuroprotective agent with potential efficacy against ROS-induced apoptosis in neural cells opens new horizons for therapeutic development, offering hope for patients suffering from neurodegenerative diseases, depression, and other stress-related neurological conditions.

Generation and Characterization of Induced Pluripotent Stem Cells Carrying An ASXL1 Mutation.

Additional sex combs-like 1 (ASXL1) is an epigenetic modulator frequently mutated in myeloid malignancies, generally associated with poor prognosis. Current models for ASXL1-mutated diseases are mainly based on the complete deletion of Asxl1 or overexpression of C-terminal truncations in mice models. However, these models cannot fully recapitulate the pathogenesis of myeloid malignancies. Patient-derived induced pluripotent stem cells (iPSCs) provide valuable disease models that allow us to understand disease-related molecular pathways and develop novel targeted therapies. Here, we generated iPSCs from a patient with myeloproliferative neoplasm carrying a heterozygous ASXL1 mutation. The iPSCs we generated exhibited the morphology of pluripotent cells, highly expressed pluripotent markers, excellent differentiation potency in vivo, and normal karyotype. Subsequently, iPSCs with or without ASXL1 mutation were induced to differentiate into hematopoietic stem/progenitor cells, and we found that ASXL1 mutation led to myeloid-biased output and impaired erythroid differentiation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that terms related to embryonic development, myeloid differentiation, and immune- and neural-related processes were most enriched in the differentially expressed genes. Western blot demonstrated that the global level of H2AK119ub was significantly decreased when mutant ASXL1 was present. Chromatin Immunoprecipitation Sequencing showed that most genes associated with stem cell maintenance were upregulated, whereas occupancies of H2AK119ub around these genes were significantly decreased. Thus, the iPSC model carrying ASXL1 mutation could serve as a potential tool to study the pathogenesis of myeloid malignancies and to screen targeted therapy for patients.

SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway.

High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.

Naturally sourced amphiphilic peptides as paclitaxel vehicles for breast cancer treatment.

The marketed paclitaxel (PTX) formulation Taxol relies on the application of Cremophor EL as a solubilizer. The major drawback of Taxol is its hypersensitivity reactions and a pretreatment of anti-allergic drugs is a necessity. Therefore, developing an efficient and safe delivery vehicle is a solution to increase PTX treatment outcomes with minimal adverse effects. In this work, we prepared the amphiphilic peptides (termed AmP) from soybean proteins using a facile two-step method. AmP could efficiently solubilize PTX by self-assembling into mixed micelles with D-α-tocopherol polyethylene glycol succinate (TPGS), a common pharmaceutical expedient (PTX@TPGS-AmP). The intravenously administrated PTX@TPGS-AmP exhibited a slow clearance (0.24 mL·(min·kg)-1) and an enhanced AUC (41.4 µg.h/mL), manifesting a 3.6-fold increase compared to Taxol. In a murine 4T1 tumor model, PTX@TPGS-AmP displayed a superior antitumor effect over Taxol. Importantly, safety assessment showed a high biocompatibility of AmP and an i.v. dose up to 2500 mg/kg led to no observable abnormalities in the mice. In summary, the AmP presents a new green and easily-prepared amphiphilic biomaterial, with promising potential as a pharmaceutical excipient for drug delivery.

Metabolite and protein shifts in mature erythrocyte under hypoxia.

As the only cell type responsible for oxygen delivery, erythrocytes play a crucial role in supplying oxygen to hypoxic tissues, ensuring their normal functions. Hypoxia commonly occurs under physiological or pathological conditions, and understanding how erythrocytes adapt to hypoxia is fundamental for exploring the mechanisms of hypoxic diseases. Additionally, investigating acute and chronic mountain sickness caused by plateaus, which are naturally hypoxic environments, will aid in the study of hypoxic diseases. In recent years, increasingly developed proteomics and metabolomics technologies have become powerful tools for studying mature enucleated erythrocytes, which has significantly contributed to clarifying how hypoxia affects erythrocytes. The aim of this article is to summarize the composition of the cytoskeleton and cytoplasmic proteins of hypoxia-altered erythrocytes and explore the impact of hypoxia on their essential functions. Furthermore, we discuss the role of microRNAs in the adaptation of erythrocytes to hypoxia, providing new perspectives on hypoxia-related diseases.

Nickel-induced transcriptional memory in lung epithelial cells promotes interferon signaling upon nicotine exposure.

Exposure to nickel, an environmental respiratory toxicant, is associated with lung diseases including asthma, pulmonary fibrosis, bronchitis and cancers. Our previous studies have shown that a majority of the nickel-induced transcriptional changes are persistent and do not reverse even after the termination of exposure. This suggested transcriptional memory, wherein the cell 'remembers' past nickel exposure. Transcriptional memory, due to which the cells respond more robustly to a previously encountered stimulus has been identified in a number of organisms. Therefore, transcriptional memory has been described as an adaptive mechanism. However, transcriptional memory caused by environmental toxicant exposures has not been well investigated. Moreover, how the transcriptional memory caused by an environmental toxicant might influence the outcome of exposure to a second toxicant has not been explored. In this study, we investigated whether nickel-induced transcriptional memory influences the outcome of the cell's response to a second respiratory toxicant, nicotine. Nicotine, an addictive compound in tobacco, is associated with the development of chronic lung diseases including chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. Our results show that nicotine exposure upregulated a subset of genes only in the cells previously exposed to nickel. Furthermore, our analyses indicate robust activation of interferon (IFN) signaling in these cells. IFN signaling is a driver of inflammation, which is associated with many chronic lung diseases. Therefore, our results suggest that nicotine exposure of lung cells that retain the transcriptional memory of previous nickel exposure could result in increased susceptibility to developing chronic inflammatory lung diseases.

The Regulation of Phosphorus Release by Penicillium chrysogenum in Different Phosphate via the TCA Cycle and Mycelial Morphology.

Phosphate-solubilizing fungi (PSF) efficiently dissolve insoluble phosphates through the production of organic acids. This study investigates the mechanisms of organic acid secretion by PSF, specifically Penicillium chrysogenum, under tricalcium phosphate (Ca3(PO4)2, Ca-P) and ferric phosphate (FePO4, Fe-P) conditions. Penicillium chrysogenum exhibited higher phosphorus (P) release efficiency from Ca-P (693.6 mg/L) than from Fe-P (162.6 mg/L). However, Fe-P significantly enhanced oxalic acid (1193.7 mg/L) and citric acid (227.7 mg/L) production by Penicillium chrysogenum compared with Ca-P (905.7 and 3.5 mg/L, respectively). The presence of Fe-P upregulated the expression of genes and activity of enzymes related to the tricarboxylic acid cycle, including pyruvate dehydrogenase and citrate synthase. Additionally, Fe-P upregulated the expression of chitinase and endoglucanase genes, inducing a transformation of Penicillium chrysogenum mycelial morphology from pellet to filamentous. The filamentous morphology exhibited higher efficiency in oxalic acid secretion and P release from Fe-P and Ca-P. Compared with pellet morphology, filamentous morphology enhanced P release capacity by > 40% and > 18% in Ca-P and Fe-P, respectively. This study explored the strategies employed by PSF to improve the dissolution of different insoluble phosphates.

Raman and fourier transform infrared spectroscopy techniques for detection of coronavirus (COVID-19): a mini review.

Coronavirus pandemic has been a huge jeopardy to human health in various systems since it outbroke, early detection and prevention of further escalation has become a priority. The current popular approach is to collect samples using the nasopharyngeal swab method and then test for RNA using the real-time polymerase chain reaction, which suffers from false-positive results and a longer diagnostic time scale. Alternatively, various optical techniques, namely, optical sensing, spectroscopy, and imaging shows a great promise in virus detection. In this mini review, we briefly summarize the development progress of vibrational spectroscopy techniques and its applications in the detection of SARS-CoV family. Vibrational spectroscopy techniques such as Raman spectroscopy and infrared spectroscopy received increasing appreciation in bio-analysis for their speediness, accuracy and cost-effectiveness in detection of SARS-CoV. Further, an account of emerging photonics technologies of SARS-CoV-2 detection and future possibilities is also explained. The progress in the field of vibrational spectroscopy techniques for virus detection unambiguously show a great promise in the development of rapid photonics-based devices for COVID-19 detection.

Serum cell division cycle 42 in advanced hepatocellular carcinoma patients: Linkage with clinical characteristics and immune checkpoint inhibitor-related treatment outcomes.

OBJECTIVE: Cell division cycle 42 (CDC42) facilitates immune escape and drug resistance towards immunotherapy in several malignancies. This prospective study aimed to explore the predictive value of serum CDC42 for immune checkpoint inhibitor (ICI)-treatment response and survival in advanced hepatocellular carcinoma (HCC) patients. METHODS: Thirty advanced HCC patients scheduled for ICI or ICI-based treatment were enrolled in this prospective study, whose serum CDC42 was determined via enzyme-linked immunosorbent assay before therapy initiation. RESULTS: The median (interquartile range) of serum CDC42 level was 766.5 (605.0-1329.5) pg/mL. Serum CDC42 was related to increased tumor size but decreased programmed death-ligand 1 combined positive score (PD-L1 CPS). With respect to ICI or ICI-based treatment outcomes, elevated serum CDC42 was associated with decreased disease control rate, but did not link with objective response rate. Patients with high serum CDC42 (vs. low, cut by its median level) had shortened progression-free survival (PFS), while overall survival (OS) only disclosed a reduced trend (lacked statistical significance) in patients with high serum CDC42 (vs. low). In detail, the median (95%CI) PFS and OS were 3.0 (0.0-6.0) months and 11.7 (2.7-20.7) months in patients with high serum CDC42, while they were 11.1 (6.6-15.6) months and 19.3 (14.5-24.1) months in patients with low CDC42. After adjusted by multivariate cox regression analysis, high serum CDC42 (vs. low) was independently associated with shortened PFS, but not OS. CONCLUSIONS: Elevated serum CDC42 possesses a potential value in predicting worse ICI or ICI-based treatment outcomes in advanced HCC.

Lead remediation is promoted by phosphate-solubilizing fungi and apatite via the enhanced production of organic acid.

Lead (Pb) is one of the most common heavy metal pollutants in the environment, which can indirectly or directly threaten human health. Lead immobilization by apatite can reduce the effectiveness of Pb cations via the formation of pyromorphite (Pyro). However, the formation of Pyro is always depending on the release of phosphorus (P) from apatite. Phosphate-solubilizing fungi (PSF) can secrete large amounts of organic acid to promote the release of P from apatite. Although the combination of PSF and apatite has shown a huge potential in Pb remediation, this pathway needs to be more attention, especially for organic acid secretion by PSF. This research mainly reviews the possible pathway to strengthen Pb immobilization by PSF and apatite. Meanwhile, the limitation of this approach is also reviewed, with the aim of a better stabilizing effect of Pb in the environment and promoting the development of these remediation technologies.

Lower Limb Arterial Ischemia: An Independent Risk Factor of Sudomotor Dysfunction in Type 2 Diabetes.

Background: As an early manifestation of diabetic peripheral neuropathy (DPN), sudomotor dysfunction significantly increases the risk of diabetic foot ulcer. The pathogenesis of sudomotor dysfunction is still unclear. Lower limb ischemia may be related to sudomotor dysfunction, but few studies have explored it. The purpose of this study is to explore the relationship between sudomotor function and comprehensive lower limb arterial ischemia including large arteries, small arteries and microvascular in type 2 diabetes mellitus (T2DM). Patients and Methods: 511 T2DM patients were enrolled in this cross-sectional study. Sudomotor function was assessed qualitatively and quantitatively by Neuropad. Lower limb arterial ischemia was defined as any abnormality of the ankle brachial index (ABI), toe brachial index (TBI) or transcutaneous oxygen tension (TcPO2). Results: In this study, 75.1% of patients had sudomotor dysfunction. Compared with normal sudomotor function, patients with sudomotor dysfunction had a higher incidence of lower limb arterial ischemia (51.2% vs 36.2%, p = 0.004). Similarly, compared with the non-arterial ischemia group, the proportion of sudomotor disorders was higher in the arterial ischemia group (p = 0.004). Low TBI and low TcPO2 groups also had a higher proportion of sudomotor disorders (all p < 0.05).Compare with normal groups, low ABI, low TBI, and low TcPO2 groups had lower Slop4 which quantitatively reflecting Neuropad discoloration. Arterial ischemia was an independent risk factor for sudomotor dysfunction [OR = 1.754, p = 0.024]. Low TcPO2 also independently increased the risk of sudomotor disorders [OR = 2.231, p = 0.026]. Conclusion: Lower limb arterial ischemia is an independent risk factor of sudomotor dysfunction. Especially below the ankle (BTA) small arteries and microvascular ischemia may also be involved in the occurrence of sudomotor disorders.

An NIR light-responsive "on-off-on" photoelectrochemical aptasensor for carcinoembryonic antigen assay based on Y-shaped DNA.

This work develops a novel photoelectrochemical sensor for the detection of carcinoembryonic antigen (CEA) based on the composite of UCNPs with semiconductors and conformational changes in the DNA structure. Firstly, SnS2, ZnIn2S4 and UCNPs were assembled on the surface of the ITO electrode. Then Au NPs were dropped, which could facilitate the coupling of CdSe NPs modified DNA1 via Au-S bond, giving an ITO/SnS2/ZnIn2S4/UCNPs/CdSe heterojunction structure. When irradiated with 980 nm near-infrared (NIR) light, the UV-visible light emitted by the UCNPs could excite the nanocomposite, producing an enhanced photoelectric reaction. Subsequently, CEA aptamer and DNA2-modified SiO2 were added to form a Y-shaped DNA structure. At this time, the photocurrent was significantly reduced by the combination of the light-blocking effect of SiO2 and the departure of CdSe NPs from the electrode surface. When the target CEA was added, the recognition between CEA and the aptamer led to the collapse of the Y-shaped DNA structure, the restoration of hairpin DNA and the proximity of CdSe to the electrode. Accordingly, the photocurrent signals enhanced again. Under optimal experimental conditions, the detection limit as low as 0.3 pg mL-1 was obtained with good selectivity, achieving a sensitive "on-off-on" photoelectrochemical sensor for CEA detection.