The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio with type 2 diabetes mellitus: recent findings from NHANES 2007-2018.

OBJECTIVE: This study aims to assess the relationship between NHHR (non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio) and Type 2 diabetes mellitus (T2DM) in US adults, using National Health and Nutrition Examination Survey (NHANES) data from 2007 to 2018. METHODS: This study explored the connection between NHHR and T2DM by analyzing a sample reflecting the adult population of the United States (n = 10,420; NHANES 2007-2018). NHHR was characterized as the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol. T2DM was defined based on clinical guidelines. This research used multivariable logistic models to examine the connection between NHHR and T2DM. Additionally, it included subgroup and interaction analyses to assess variations among different groups. Generalized additive models, smooth curve fitting, and threshold effect analysis were also employed to analyze the data further. RESULTS: The study included 10,420 subjects, with 2160 diagnosed with T2DM and 8260 without. The weighted multivariate logistic regression model indicated an 8% higher probability of T2DM for each unit increase in NHHR (OR: 1.08, 95% CI: 1.01-1.15) after accounting for all covariates. Subgroup analysis outcomes were uniform across various categories, demonstrating a significant positive relationship between NHHR and T2DM. Interaction tests showed that the positive link between NHHR and T2DM remained consistent regardless of age, body mass index, smoking status, moderate recreational activities, hypertension, or stroke history, with all interaction P-values exceeding 0.05. However, participants' sex appeared to affect the magnitude of the connection between NHHR and T2DM (interaction P-value < 0.05). Also, a nonlinear association between NHHR and T2DM was discovered, featuring an inflection point at 1.50. CONCLUSIONS: Our study suggests that an increase in NHHR may be correlated with a heightened likelihood of developing T2DM. Consequently, NHHR could potentially serve as a marker for estimating the probability of T2DM development.

A simplified herbal decoction attenuates myocardial infarction by regulating macrophage metabolic reprogramming and phenotypic differentiation via modulation of the HIF-1α/PDK1 axis.

BACKGROUND: Myocardial infarction (MI) poses a global public health challenge, often associated with elevated mortality rates and a grim prognosis. A crucial aspect of the inflammatory injury and healing process post-MI involves the dynamic differentiation of macrophages. A promising strategy to alleviate myocardial damage after MI is by modulating the inflammatory response and orchestrating the shift from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages, aiming to achieve a reduced M1/M2 ratio. Nuanxinkang (NXK), a simplified herbal decoction, has demonstrated noteworthy cardioprotective, inflammation-regulating, and myocardial energy metabolism-regulating properties. METHODS: In this study, we constructed an MI model by ligating coronary arteries to investigate the efficacy of NXK in improving ventricular remodeling and cardiac function. Mice were administered NXK (1.65 g/kg/d) or an equivalent volume of regular saline via gavage for 28 consecutive days, commencing the day after surgery. Then, we conducted echocardiography to assess the cardiac function, Masson staining to illustrate the extent of myocardial fibrosis, TUNEL staining to reveal myocardial apoptosis, and flow cytometry to analyze the polarization of M1 and M2 macrophages in the hearts. Besides, a lipopolysaccharide (LPS)-induced pro-inflammatory macrophage (M1) polarization model was implemented in RAW264.7 cells to elucidate the underlying mechanism of NXK in regulating macrophage polarization. RAW264.7 cells were pre-treated with or without NXK-containing serum. Oxidative stress was detected by MitoSox staining, followed by Seahorse energy metabolism assay to evaluate alterations in mitochondrial metabolic patterns and ATP production. Both In vivo and in vitro, HIF-1α and PDK1 were detected by fluorescent quantitative PCR and Western blotting. RESULTS: In vivo, MI mice exhibited a decline in cardiac function, adverse ventricular remodeling, and an increase in glycolysis, coupled with M1-dominant polarization mediated by the HIF-1α/PDK1 axis. Notably, robust responses were evident with high-dose NXK treatment (1.65 g/kg/day), leading to a significant enhancement in cardiac function, inhibition of cardiac remodeling, and partial suppression of macrophage glycolysis and the inflammatory phenotype in MI mice. This effect was achieved through the modulation of the HIF-1α/PDK1 axis. In vitro, elevated levels of mitochondrial ROS production and glycolysis were observed in LPS-induced macrophages. Conversely, treatment with NXK notably reduced the oxidative stress damage induced by LPS and enhanced oxidative phosphorylation (OXPHOS). Furthermore, NXK demonstrated the ability to modify the energy metabolism and inflammatory characteristics of macrophages by modulating the HIF-1α/PDK1 axis. The influence of NXK on this axis was partially counteracted by the HIF-1α agonist DMOG. And NXK downregulated PDK1 expression, curtailed glycolysis, and reversed LPS-induced M1 polarization in macrophages, similar to the PDK1 inhibitor DCA. CONCLUSION: In conclusion, NXK protects against MI-induced cardiac remodeling by inducing metabolic reprogramming and phenotypic differentiation of macrophages, achieved through the modulation of the HIF-1α/PDK1 axis. This provides a novel and promising strategy for the treatment of MI.

Ferroptosis Mediates Pulmonary Fibrosis: Implications for the Effect of Astragalus and Panax notoginseng Decoction.

Objective: To investigate the mechanism through which Astragalus and Panax notoginseng decoction (APD) facilitates the treatment of ferroptosis-mediated pulmonary fibrosis. Materials and Methods: First, the electromedical measurement systems were used to measure respiratory function in mice; the lungs were then collected for histological staining. Potential pharmacologic targets were predicted via network pharmacology. Finally, tests including immunohistochemistry, reverse transcription-quantitative polymerase chain reaction, and western blotting were used to evaluate the relative expression levels of collagen, transforming growth factor ß, α-smooth muscle actin, hydroxyproline, and ferroptosis-related genes (GPX4, SLC7A11, ACSL4, and PTGS2) and candidates involved in the mediation of pathways associated with ferroptosis (Hif-1α and EGFR). Results: APD prevented the occurrence of restrictive ventilation dysfunction induced by ferroptosis. Extracellular matrix and collagen fiber deposition were significantly reduced when the APD group compared with the model group; furthermore, ferroptosis was attenuated, expression of PTGS2 and ACSL4 increased, and expression of GPX4 and SLC7A11 decreased. In the APD group, the candidates related to the mediation of ferroptosis (Hif-1α and EGFR) decreased compared with the model group. Discussion and Conclusions. APD may ameliorate restrictive ventilatory dysfunction through the inhibition of ferroptosis. This was achieved through the attenuation of collagen deposition and inflammatory recruitment in pulmonary fibrosis. The underlying mechanisms might involve Hif-1α and EGFR.

Influence of GPRC5A-Regulated ABCB1 Expression on Lung Adenocarcinoma Proliferation.

Objective Aberrant expression of ATP binding cassette subfamily B member 1 (ABCB1) plays a key role in several cancers. However, influence of G protein coupled receptor family C group 5 type A (GPRC5A)-regulated ABCB1 expression on lung adenocarcinoma proliferation remains unclear. Therefore, this study investigated the effect of GPRC5A regulated ABCB1 expression on the proliferation of lung adenocarcinoma. Methods ABCB1 expressions in lung adenocarcinoma cell lines, human lung adenocarcinoma tissues, and tracheal epithelial cells and lung tissues of GPRC5A knockout mice and wild-type mice were analyzed with RT-PCR, Western blot, or immunohistochemical analysis. Cell counting kit-8 assay was performed to analyze the sensitivity of tracheal epithelial cells from GPRC5A knockout mice to chemotherapeutic agents. Subcutaneous tumor formation assay was performed to confirm whether down-regulation of ABCB1 could inhibit the proliferation of lung adenocarcinoma in vivo. To verify the potential regulatory relationship between GPRC5A and ABCB1, immunofluorescence and immunoprecipitation assays were performed. Results ABCB1 expression was up-regulated in lung adenocarcinoma cell lines and human lung adenocarcinoma tissues. ABCB1 expression in the tracheal epithelial cells and lung tissues of GPRC5Adeficient mice was higher than that in the wild type mice. Tracheal epithelial cells of GPRC5A knockout mice were much more sensitive to tariquidar and doxorubicin than those of GPRC5A wild type mice. Accordingly, 28 days after injection of the transplanted cells, the volume and weight of lung tumor in ABCB1knockout cell-transplanted GPRC5A-/-C57BL/6 mice were significantly smaller than those in wild type cell-transplanted mice (P= 0.0043, P= 0.0060). Furthermore, immunofluorescence and immunoprecipitation assays showed that GPRC5A regulated ABCB1 expression by direct binding.Conclusion GPRC5A reduces lung adenocarcinoma proliferation via inhibiting ABCB1 expression. The pathway by which GPRC5A regulates ABCB1 expression needs to be investigated.

Targeting iron-metabolism:a potential therapeutic strategy for pulmonary fibrosis.

Iron homeostasisis is integral to normal physiological and biochemical processes of lungs. The maintenance of iron homeostasis involves the process of intake, storage and output, dependening on iron-regulated protein/iron response element system to operate tightly metabolism-related genes, including TFR1, DMT1, Fth, and FPN. Dysregulation of iron can lead to iron overload, which increases the virulence of microbial colonisers and the occurrence of oxidative stress, causing alveolar epithelial cells to undergo necrosis and apoptosis, and form extracellular matrix. Accumulated iron drive iron-dependent ferroptosis to exacerbated pulmonary fibrosis. Notably, the iron chelator deferoxamine and the lipophilic antioxidant ferritin-1 have been shown to attenuate ferroptosis and inhibit lipid peroxidation in pulmonary fibrosis. The paper summarises the regulatory mechanisms of dysregulated iron metabolism and ferroptosis in the development of pulmonary fibrosis. Targeting iron metabolism may be a potential therapeutic strategy for the prevention and treatment of pulmonary fibrosis.

A point mutation in the meiotic crossover formation gene HEI10/TFS2 leads to thermosensitive genic sterility in rice.

Thermosensitive genic female sterility (TGFS) is a promising property to be utilized for hybrid breeding. Here, we identified a rice TGFS line, tfs2, through an ethyl methyl sulfone (EMS) mutagenesis strategy. This line showed sterility under high temperature and became fertile under low temperature. Few seeds were produced when the tfs2 stigma was pollinated, indicating that tfs2 is female sterile. Gene cloning and genetic complementation showed that a point mutation from leucine to phenylalanine in HEI10 (HEI10tfs2), a crossover formation protein, caused the TGFS trait of tfs2. Under high temperature, abnormal univalents were formed, and the chromosomes were unequally segregated during meiosis, similar to the reported meiotic defects in oshei10. Under low temperature, the number of univalents was largely reduced, and the chromosomes segregated equally, suggesting that crossover formation was restored in tfs2. Yeast two-hybrid assays showed that HEI10 interacted with two putative protein degradation-related proteins, RPT4 and SRFP1. Through transient expression in tobacco leaves, HEI10 were found to spontaneously aggregate into dot-like foci in the nucleus under high temperature, but HEI10tfs2 failed to aggregate. In contrast, low temperature promoted HEI10tfs2 aggregation. This result suggests that protein aggregation at the crossover position contributes to the fertility restoration of tfs2 under low temperature. In addition, RPT4 and SRFP1 also aggregated into dot-like foci, and these aggregations depend on the presence of HEI10. These findings reveal a novel mechanism of fertility restoration and facilitate further understanding of HEI10 in meiotic crossover formation.

Effect of high-field iMRI guided resection in cerebral glioma surgery: A randomized clinical trial.

BACKGROUND: Extent of resection (EOR) in glioma contributes to longer survival. The purpose of NCT01479686 was to prove whether intraoperative magnetic resonance imaging (iMRI) increases EOR in glioma surgery and benefit survival. METHODS: Patients were randomized (1:1) to receive the iMRI (n = 161) or the conventional neuronavigation (n = 160). The primary endpoint was gross total resection (GTR); secondary outcomes reported were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 188 high-grade gliomas (HGGs) and 133 low-grade gliomas (LGGs) were enrolled. GTR was 83.85% in the iMRI group vs. 50.00% in the control group (P < 0.0001). In 321 patients, the median PFS (mPFS) was 65.12 months in the iMRI group and 61.01 months in the control group (P = 0.0202). For HGGs, mPFS was improved in the iMRI group (19.32 vs. 13.34 months, P = 0.0015), and a trend of superior OS compared with control was observed (29.73 vs. 25.33 months, P = 0.1233). In the predefined eloquent area HGG subgroup, mPFS, and mOS were 20.47 months and 33.58 months in the iMRI vs. 12.21 months and 21.16 months in the control group (P = 0.0098; P = 0.0375, respectively). From the exploratory analyses of HGGs, residual tumor volume (TV) < 1.0 cm3 decreased the risk of survival (mPFS: 18.99 vs. 9.43 months, P = 0.0055; mOS: 29.77 vs. 18.10 months, P = 0.0042). LGGs with preoperative (pre-OP) TV > 43.1 cm3 and postoperative (post-OP) TV > 4.6 cm3 showed worse OS (P= 0.0117) CONCLUSIONS: It showed that iMRI significantly increased EOR and indicated survival benefits for HGGs, particularly eloquent HGGs. Residual TV in either HGGs or LGGs is a prognostic factor for survival.

Sniping Cancer Stem Cells with Nanomaterials.

Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.

Non-invasive brain stimulation for fibromyalgia: current trends and future perspectives.

Fibromyalgia, a common and enduring pain disorder, ranks as the second most prevalent rheumatic disease after osteoarthritis. Recent years have witnessed successful treatment using non-invasive brain stimulation. Transcranial magnetic stimulation, transcranial direct current stimulation, and electroconvulsion therapy have shown promise in treating chronic pain. This article reviews the literature concerning non-invasive stimulation for fibromyalgia treatment, its mechanisms, and establishes a scientific basis for rehabilitation, and discusses the future directions for research and development prospects of these techniques are discussed.

Study of radiochemotherapy decision-making for young high-risk low-grade glioma patients using a macroscopic and microscopic combined radiomics model.

OBJECTIVES: As a few types of glioma, young high-risk low-grade gliomas (HRLGGs) have higher requirements for postoperative quality of life. Although adjuvant chemotherapy with delayed radiotherapy is the first treatment strategy for HRLGGs, not all HRLGGs benefit from it. Accurate assessment of chemosensitivity in HRLGGs is vital for making treatment choices. This study developed a multimodal fusion radiomics (MFR) model to support radiochemotherapy decision-making for HRLGGs. METHODS: A MFR model combining macroscopic MRI and microscopic pathological images was proposed. Multiscale features including macroscopic tumor structure and microscopic histological layer and nuclear information were grabbed by unique paradigm, respectively. Then, these features were adaptively incorporated into the MFR model through attention mechanism to predict the chemosensitivity of temozolomide (TMZ) by means of objective response rate and progression free survival (PFS). RESULTS: Macroscopic tumor texture complexity and microscopic nuclear size showed significant statistical differences (p < 0.001) between sensitivity and insensitivity groups. The MFR model achieved stable prediction results, with an area under the curve of 0.950 (95% CI: 0.942-0.958), sensitivity of 0.833 (95% CI: 0.780-0.848), specificity of 0.929 (95% CI: 0.914-0.936), positive predictive value of 0.833 (95% CI: 0.811-0.860), and negative predictive value of 0.929 (95% CI: 0.914-0.934). The predictive efficacy of MFR was significantly higher than that of the reported molecular markers (p < 0.001). MFR was also demonstrated to be a predictor of PFS. CONCLUSIONS: A MFR model including radiomics and pathological features predicts accurately the response postoperative TMZ treatment. CLINICAL RELEVANCE STATEMENT: Our MFR model could identify young high-risk low-grade glioma patients who can have the most benefit from postoperative upfront temozolomide (TMZ) treatment. KEY POINTS: • Multimodal radiomics is proposed to support the radiochemotherapy of glioma. • Some macro and micro image markers related to tumor chemotherapy sensitivity are revealed. • The proposed model surpasses reported molecular markers, with a promising area under the curve (AUC) of 0.95.

Clinical observation on the treatment of displaced distal radial and ulnar fractures in children by closed manipulation combined with splinting.

Objective: The aim of this study was to investigate the clinical efficacy of closed manipulation combined with splinting in the treatment of displaced distal radial and ulnar fractures in children. Methods: A total of 82 children with displaced fractures of the distal radial and ulnar segment who met the inclusion criteria and were treated as outpatients or inpatients in the orthopedic department of Guangzhou Orthopedic Hospital, from January 2016 to June 2022 were randomly divided into an observation group and a control group: 41 children in the observation group were treated with closed manipulation combined with splint fixation; 41 children in the control group were fixed with incisional repositioning elastic nails combined with internal plates. The Anderson efficacy grading, visual analog scale (VAS) score, fracture healing time, treatment cost, hospital days, and complications were observed and compared between the two groups. Result: The efficacy was evaluated according to the Anderson forearm fracture efficacy evaluation criteria, and the results of statistical analysis showed no statistically significant differences between the two groups (P > 0.05). At 3 and 7 weeks after treatment, the VAS scores of children in both groups decreased (P < 0.05), and the VAS scores in the observation group were significantly lower than those in the control group (P < 0.05), indicating that the observation group had a significant advantage in the relief of pain after treatment. The fractures healed in both groups after treatment with the two different methods, and the difference in healing time between the two groups was not statistically significant (P > 0.05). The length of hospital stay, treatment cost, and complication ratio were significantly lower in the observation group than in the control group (P < 0.05). Conclusion: In children with displaced fractures of the distal radial and ulnar segments, treatment by manual repositioning with external splinting can achieve satisfactory results with simple operation, low cost, short hospital stay, and few complications, which is especially suitable to be promoted in primary hospitals and has good social benefits.

Tumor necrosis factor-α-induced protein 8-like 2 alleviates morphine antinociceptive tolerance through reduction of ROS-mediated apoptosis and MAPK/NF-κB signaling pathways.

Chronic morphine tolerance is a repulsive barrier to the clinical treatment of pain. Whereas the underlying molecular mechanisms of morphine tolerance remain unknown. Here, we proposed that tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is an essential control point regarding the progression of chronic morphine antinociceptive tolerance. We found that TIPE2 levels in the lumbar spinal cord were significantly downregulated in the morphine tolerance mouse model. Specifically, decreased TIPE2 by morphine tolerance was primarily expressed in spinal neurons, while increased expression of spinal TIPE2 distinctly attenuated the chronic morphine antinociceptive tolerance and tolerance-associated hyperalgesia. We also observed that increased expression of spinal TIPE2 significantly reduced morphine tolerance-induced neuronal ROS production and apoptosis, along with the activation of MAPKs and NF-κB signaling pathways. Moreover, the increased TIPE2 expression inhibited neuronal activation and glial reactivity in the spinal dorsal horn after chronic morphine exposure. Additionally, TIPE2 overexpression in cultured SH-SY5Y cells significantly suppressed ROS production and apoptosis in response to morphine challenge. Therefore, we can conclude that the upregulation of spinal TIPE2 may attenuate the morphine antinociceptive tolerance via TIPE2-dependent downregulation of neuronal ROS, inhibition of neuronal apoptosis, suppression of MAPKs and NF-κB activation. TIPE2 may be a potential strategy for preventing morphine tolerance in the future studies and clinical settings.

Aspartoacylase suppresses prostate cancer progression by blocking LYN activation.

BACKGROUND: Globally, despite prostate cancer (PCa) representing second most prevalent malignancy in male, the precise molecular mechanisms implicated in its pathogenesis remain unclear. Consequently, elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies, ultimately advancing the management of PCa. METHODS: A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University. The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa. The expression of aspartoacylase (ASPA) in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques. To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis, a comprehensive set of in vitro and in vivo assays were conducted, including orthotopic and tumor-bearing mouse models (n = 8 for each group). A combination of experimental approaches, such as Western blotting, luciferase assays, immunoprecipitation assays, mass spectrometry, glutathione S-transferase pull-down experiments, and rescue studies, were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa. The Student's t-test was employed to assess the statistical significance between two distinct groups, while one-way analysis of variance was utilized for comparisons involving more than two groups. A two-sided P value of less than 0.05 was deemed to indicate statistical significance. RESULTS: ASPA was identified as a novel inhibitor of PCa progression. The expression of ASPA was found to be significantly down-regulated in PCa tissue samples, and its decreased expression was independently associated with patients' prognosis (HR = 0.60, 95% CI 0.40-0.92, P = 0.018). Our experiments demonstrated that modulation of ASPA activity, either through gain- or loss-of-function, led to the suppression or enhancement of PCa cell proliferation, migration, and invasion, respectively. The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models. Mechanistically, ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets, JNK1/2 and C-Jun, in both PCa cells and mouse models, in an enzyme-independent manner. Importantly, the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models. Moreover, we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples, suggesting a potential regulatory role of ASPA in modulating LYN signaling. CONCLUSION: Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy.

GNPNAT1 promotes the stemness of breast cancer and serves as a potential prognostic biomarker.

Glucosamine­phosphate N­acetyltransferase 1 (GNPNAT1) is a member of the acetyltransferase superfamily, related to general control non­depressible 5 (GCN5). It has been documented that GNPNAT1 expression is increased in lung cancer, whereas its involvement in breast cancer (BC) remains to be further investigated. The present study aimed to evaluate the expression levels of GNPNAT1 in BC and its effect on BC stem cells (BCSCs). The Cancer Genome Atlas (TCGA) database was used for the analysis of the expression of GNPNAT1 and its clinical significance. Cox regression and logistic regression analyses were used to evaluate prognosis­related factors. The GNPNAT1­binding protein network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) application. The biological signaling pathways implicated in GNPNAT1 were investigated through function enrichment analysis including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis. The single­sample GSEA method was used to investigate the connection between the level of immune infiltration and GNPNAT1 expression in BC. GNPNAT1 expression was upregulated in patients with BC and was significantly associated with a poor prognosis. GNPNAT1 and its co­expressed genes were mostly enriched in nuclear transport, Golgi vesicle transport, ubiquitin­like protein transferase activity and ribonucleoprotein complex binding, as determined using functional enrichment analysis. GNPNAT1 expression was positively associated with Th2 cells and T­helper cells, and negatively associated with plasmacytoid dendritic cells, CD8+ T­cells and cytotoxic cells. Additionally, the GNPNAT1 expression levels were considerably increased in BCSCs. GNPNAT1 knockdown markedly decreased the stemness ability of SKBR3 and Hs578T cells, including the production of CSC markers and mammosphere or clone formation, while GNPNAT1 overexpression increased the stemness level. Hence, the findings of the present study demonstrate that GNPNAT1 may be exploited as a novel prognostic biomarker and therapeutic target for BC.

Meroterpenoids from Ganoderma petchii inhibiting migration of triple negative breast cancer cells.

Ganoderpetchoids A-E and (-)-dayaolingzhiol H, six undescribed meroterpenoids, were isolated from Ganoderma petchii. Their structures including the relative configurations were identified by means of spectroscopic methods and 13C NMR calculations. Chiral separation of the new racemics was performed to afford their respective enantiomers. The absolute configurations of the new isolates were clarified by computational approaches, CD comparisons and X-ray diffraction analysis. Biological studies toward triple negative breast cancer indicated that (+)-6 and (-)-6 significantly inhibit the migration of MDA-MB-231 cell line.

Lobetyolin Alleviates Ferroptosis of Skeletal Muscle in 5/6 Nephrectomized Mice via Activation of Hedgehog-GLI1 Signaling.

BACKGROUND: Muscle wasting increases morbidity and mortality and is related to chronic kidney disease (CKD) and dialysis. It is still unclear whether ferroptosis occurs during this progression and whether it is a potential intervention target for the treatment of CKD-related muscle injury. PURPOSE: The objective is to identify potential compounds for treating ferroptosis and muscle wasting and explore the potential mechanisms in vivo/in vitro. METHODS: Initially, we explored whether ferroptosis is present in the skeletal muscle of 5/6 nephrectomized (NPM) mice via RNA-Seq analysis, TUNEL staining, Oil red O staining, MDA/GSH/GSSG level detection and real-time quantitative PCR (qPCR). Subsequently, utilizing our established molecular phenotyping strategy, we screened potential traditional Chinese herb-derived compounds for alleviation of muscle wasting and ferroptosis. HE staining, Oil red O staining, TUNEL staining, immunofluorescence staining, MDA/GSH/GSSG level detection, Fe level detection, western blotting and qPCR were applied to assess the effects of the identified compound on muscle wasting and ferroptosis and explore the potential mechanism. Furthermore, RNA-Seq analysis, ChIP-Seq analysis and further experiments in vitro were performed to determine the role of Hedgehog signaling in the effect of Lobetyolin (LBT) on ferroptosis. RESULTS: In NPM mice, skeletal muscle dysfunction, lipogenesis, reduced GSH/GSSG ratio, decreased GSH content, increased MDA production and and higher levels of ferroptosis markers were observed. LBT treatment (30 mg/kg or 50 mg/kg) significantly alleviates skeletal muscle injury by inhibiting ferroptosis. Additionally, in an in vitro investigation, C2C12 cells exposed to Indolyl sulfate (IS) induced ferroptosis and LBT treatment (20 µM and 50 µM) protected C2C12 from such injury, consistent with the results from the in vivo analysis. Furthermore, it was found LBT increased the levels of protein involving Hedgehog signaling pathway (SMO and GLI1), and rescue analysis revealed that this pathway played a crucial role in the regulation of ferroptosis. Further experiments demonstrated that LBT upregulated a series of suppressors of ferroptosis by activating Gli1 transcription. CONCLUSION: LBT alleviates CKD-induced muscle injury by inhibiting ferroptosis through activation of the Hedgehog signaling pathway.

Vermicomposting of Pleurotus eryngii spent mushroom substrates and the possible mechanisms of vermicompost suppressing nematode disease caused by Meloidogyne incognita.

The mushroom industry produces a large amount of spent mushroom substrate (SMS), which requires a large geographical footprint and causes pollution. Vermicomposting is a low-cost technology for its value in recycling of organic wastes and production of beneficial organic fertilizers. In this study, the changes of physicochemical properties was characterized during vermicomposting of Pleurotus eryngii SMS with cow dung (CD) as amendment. The efficiency and possible mechanisms of vermicompost suppressing disease induced by Meloidogyne incognita was also investigated. Six combinations with different ratios of SMS and cow dung (CD) was included in the vermicomposting using Eisenia fetida. Effect of vermicompost against disease induced by M. incognita on tobacco was conducted under greenhouse condition. And the possible mechanisms of vermicompost suppressing M. incognita was investigated by evaluated the species diversity of nematode-trapping fungi (NTF) in soil, and the defense response enzymes in tobacco. The combination of 65% SMS +35% CD was more suitable for vermicomposting, in which the highest vermicompost production (57%) and earthworm biomass increment (268%) were achieved. Additionally, the reduction in pH, total organic carbon, carbon: nitrogen ratio, and the pronounced elevation in four overall nutrient status were also observed. Soil amended with vermicompost (100:1 w/w) showed 61% control efficiency against nematode disease caused by M. incognita on tobacco, which significantly higher than that of the normal compost (24%). Comparing to the normal compost, the potential mechanism of vermicompost suppressing M. incognita could be rely on promoting species diversity of NTF in soil and enhancing the activities of the defense response enzymes in tobacco plant. Our findings indicate that vermicomposting is a promising technology for recycling of P. eryngii SMS, and the resulting vermicompost as organic fertilizer can be sued for management of the diseases caused by root-knot nematodes. This study establish a sustainable avenue for P. eryngii SMS disposal and a practical manner for controlling pathogens.

Isolation and Characterization of trans-p-Hydroxycinnamoyl Meroterpenoids from Ganoderma sinensis.

Zizhines V, W, Y, Z, (±)-zizhines X, and Z1-Z3, and (±)-ganosinensol L, thirteen new compounds including four pairs of enantiomers and a known compound (-)-ganosinensol L, were isolated from the fruiting bodies of Ganoderma sinensis. Their structures were identified by spectroscopic, computational methods, and CD (circular dichroism spectroscopy) comparisons. Zizhines V-Z and Z1-Z3 are meroterpenoids consisting of the phenolic and the terpenoidal parts. All the compounds except zizhine Z3 bear a common trans-p-hydroxycinnamoyl group. Biological evaluation shows that (-)-zizhine Z1 inhibits cell migration in the MDA-MB-231 cell lines. The present study discloses the chemical profiling of G. sinensis and paves the way for its development as functional products to benefit chronic disorders.

Exosomal hsa-let-7g-3p and hsa-miR-10395-3p derived from peritoneal lavage predict peritoneal metastasis and the efficacy of neoadjuvant intraperitoneal and systemic chemotherapy in patients with gastric cancer.

BACKGROUND: The prognosis of advanced gastric cancer (GC) invading the gastric serosa remains poor, mainly owing to high incidence of peritoneal recurrence. Patients with peritoneal metastases are often treated with neoadjuvant intraperitoneal and systemic chemotherapies (NIPS). Good responders to NIPS often undergo conversion gastrectomy. This study aims to explore biomarkers predicting the occurrence of peritoneal metastasis (PM) and evaluating the efficacy of NIPS in GC patients. METHODS: We collected six peritoneal lavage (PL) samples from two patients with PM, two without PM, and two with diminished PM after NIPS via intraperitoneal access ports. We equally isolated microRNAs from exosomes derived from PL samples for deep sequencing. Two microRNAs (hsa-let-7g-3p and hsa-miR-10395-3p) were identified, and their expression levels were examined in PL samples of 99 GC patients using qRT-PCR. Moreover, we performed in vivo and in vitro functional assays to investigate effects of these microRNAs on metastasis and chemoresistance of GC cells. RESULTS: Exosomal microRNA expression profiling of six PL samples indicated that the microRNA signature in exosomes of PLs from patients with diminished PM was similar to that from patients without PM. Expression levels of hsa-let-7g-3p and hsa-miR-10395-3p were associated with PM. In vivo and in vitro functional assays confirmed that hsa-let-7g-3p and hsa-miR-10395-3p are involved in GC metastasis and chemoresistance. CONCLUSION: PL-derived exosomes in GC contain large amounts of microRNAs related to PM. Moreover, hsa-let-7g-3p and hsa-miR-10395-3p could be used as biomarkers predicting PM and NIPS efficacy and are involved in GC metastasis and chemoresistance.