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Seven undescribed 3,4-secolanostane triterpenoids, daldiconoids A-G (1-7), were isolated from the fruiting bodies of Daldinia concentrica. Daldiconoid A (1) was a highly modified 4,6,28,29-tetranorlanostane triterpenoid alkaloid featuring an unusual δ-lactam fused with a flanking cyclopentenone architecture. Their structures were determined by spectroscopic data, NMR calculations coupled with the DP4+ analysis, X-ray single-crystal diffraction, and chemical transformation. The plausible biosynthetic pathway for 1 was proposed. Compounds 1, 2, and 4-6 inhibited the expressions of IL-1ß, IL-6, and TNF-α in lipopolysaccharide stimulated RAW264.7 cells at a concentration of 10 µM. Mechanistically, Compounds 1 and 2 blocked the JAK2/STAT3 signaling pathway induced by lipopolysaccharide.
Subject(s)
Fruiting Bodies, Fungal , Lipopolysaccharides , Triterpenes , Mice , Triterpenes/chemistry , Triterpenes/pharmacology , Triterpenes/isolation & purification , Animals , RAW 264.7 Cells , Fruiting Bodies, Fungal/chemistry , Lipopolysaccharides/pharmacology , Lipopolysaccharides/antagonists & inhibitors , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Molecular Structure , Molecular Conformation , Structure-Activity Relationship , Dose-Response Relationship, DrugABSTRACT
OBJECTIVES: Despite some existing studies on the safety of high static magnetic fields (SMFs), the effects of ultra-high SMFs above 20.0 T for embryonic development in early pregnancy are absent. The objective of this study is to evaluate the influence of 16.8-22.0 T SMF on the development of zebrafish embryos, which will provide important information for the future application of ultra-high field magnetic resonance imaging (MRI). METHODS: Two-hour exposure to homogenous (0 T/m) 22.0 T SMF, or 16.8 T SMFs with 123.25 T/m spatial gradient of opposite magnetic force directions was examined in the embryonic development of 200 zebrafish. Their body length, heart rate, spontaneous tail-wagging movement, hatching and survival rate, photomotor response, and visual motor response (VMR) were analyzed. RESULTS: Our results show that these ultra-high SMFs did not significantly affect the general development of zebrafish embryos, such as the body length or spontaneous tail-wagging movement. However, the hatching rate was reduced by the gradient SMFs (p < 0.05), but not the homogenous 22.0 T SMF. Moreover, although the zebrafish larva activities were differentially affected by these ultra-high SMFs (p < 0.05), the expression of several visual and neurodevelopmental genes (p < 0.05) was generally downregulated in the eyeball. CONCLUSIONS: Our findings suggest that exposure to ultra-high SMFs, especially the gradient SMFs, may have adverse effects on embryonic development, which should cause some attention to the future application of ultra-high field MRIs. CLINICAL RELEVANCE STATEMENT: As technology advances, it is conceivable that very strong magnetic fields may be adapted for use in medical imaging. Possible dangers associated with these higher Tesla fields need to be considered and evaluated prior to human use. KEY POINTS: Ultra-High static magnetic field may affect early embryonic development. High strength gradient static magnetic field exposure impacted zebrafish embryonic development. The application of very strong magnetic fields for MR technologies needs to be carefully evaluated.
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The objective of this study was to investigate spleen pathology and immune cell subset alterations in mice exposed to acute and chronic restraint stress over various timeframes. A deeper understanding of stress-induced spleen injuries can provide new insights into the mechanisms underlying stress-induced disorders. C57BL/6N mice were restrained for different durations (1, 3, 7, 14 and 21 days) for 6-8 h daily. The control mice were observed at the same time points. Post restraint, behavioural experiments were conducted to assess spleen weight, gross morphology and microscopic histological changes. Immunohistochemical staining was used to detect changes in glucocorticoid receptor (GR) expression, immune cell subsets and cell proliferation in response to stress. Our analysis revealed significant behavioural abnormalities in the stressed mice. In particular, there was an increase in the nuclear expression of GR beginning on Day 3, and it peaked on Day 14. The spleens of stressed mice displayed a reduction in size, disordered internal tissue structure and reduced cell proliferation. NK cells and M2-type macrophages exhibited immune cell subset alterations under stress, whereas T or B cells remained unaltered. Restraint stress can lead to pathomorphological alterations in spleen morphology, cell proliferation and immune cell counts in mice. These findings suggest that stress-induced pathological changes can disrupt immune regulation during stress.
Subject(s)
Mice, Inbred C57BL , Receptors, Glucocorticoid , Restraint, Physical , Spleen , Stress, Psychological , Animals , Spleen/pathology , Spleen/metabolism , Receptors, Glucocorticoid/metabolism , Mice , Male , Stress, Psychological/immunology , Cell Proliferation , Time Factors , Killer Cells, Natural/immunology , Stress, Physiological , Macrophages/immunology , Macrophages/metabolismABSTRACT
Stress triggers a comprehensive pathophysiological cascade in organisms. However, there is a substantial gap in the research regarding the effects of stress on liver function. This study aimed to investigate the impact of restraint stress on hepatocellular damage and elucidate the underlying molecular mechanisms. An effective mouse restraint stress model was successfully developed, and liver function analysis was performed using laser speckle imaging, metabolomics and serum testing. Alterations in hepatocyte morphology were assessed using haematoxylin and eosin staining and transmission electron microscopy. Oxidative stress in hepatocytes was assessed using lipid reactive oxygen species and malondialdehyde. The methylation status and expression of GSTP1 were analysed using DNA sequencing and, real-time PCR, and the expression levels of GPX4, TF and Nrf2 were evaluated using real-time quantitative PCR, western blotting, and immunohistochemical staining. A stress-induced model was established in vitro by using dexamethasone-treated AML-12 cells. To investigate the underlying mechanisms, GSTP1 overexpression, small interfering RNA, ferroptosis and Nrf2 inhibitors were used. GSTP1 methylation contributes to stress-induced hepatocellular damage and dysfunction. GSTP1 is involved in ferroptosis-mediated hepatocellular injury induced by restraint stress via the TF/Nrf2 pathway. These findings suggest that stress-induced hepatocellular injury is associated with ferroptosis, which is regulated by TF/Nrf2/GSTP1.
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Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].
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Introduction: The mental health of university students is influenced by a variety of factors, including self-esteem and personality traits, with resilience playing a crucial role in mediating and moderating these relationships. This study investigates the intricate dynamics affecting mental well-being in Chinese university students, focusing on the roles of self-esteem, personality traits, and the interventional effects of resilience. Methods: A cross-sectional survey was conducted with 689 students, aged on average 20.3 years, between April and July 2022. The Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) was used to assess mental well-being, while resilience, personality traits, and self-esteem were evaluated using the revised Connor-Davidson Resilience Scale (CD-RISC), the Chinese version of the Big Five Inventory-2 (BFI-2), and the Texas Social Behavior Inventory (TSBI), respectively. Results: Analysis revealed significant correlations between self-esteem, personality traits, and both resilience and mental well-being. Resilience was found to partially mediate the relationship between self-esteem and mental well-being and fully mediate certain aspects of the relationship between personality traits and mental well-being. Additionally, tenacity and autonomy were identified as moderators in the link between specific personality traits and mental well-being. Discussion: The findings highlight the complex interplay between self-esteem, personality traits, resilience, and mental well-being, underscoring the critical role of resilience. This insight is pivotal for developing targeted interventions to bolster mental well-being among university students, emphasizing the need for multifaceted support strategies to enhance student mental health.
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We study the dynamics of the end monomers of a real chain confined in a spherical cavity to search for a small target on the cavity surface using Langevin dynamics simulation. The results are compared and contrasted with those of a Rouse chain to understand the influence of excluded volume interactions on the search dynamics, as characterized by the first passage time (FPT). We analyze how the mean FPT depends on the cavity size Rb, the target size a, and the degree of confinement quantified by Rg/Rb, with Rg being the polymer radius of gyration in free space. As a basic finding, the equilibrium distribution of the end monomers of a real chain in a closed spherical cavity differs from that of a Rouse chain at a given Rg/Rb, which leads to the differences between the mean FPTs of real and Rouse chains. Fitting the survival probability S(t) by a multi-exponential form, we show that the S(t) of real chains exhibits multiple characteristic times at large Rg/Rb. Our simulation results indicate that the search dynamics of a real chain exhibit three characteristic regimes as a function of Rg/Rb, including the transition from the Markovian to non-Markovian process at Rg/Rb ≈ 0.39, along with two distinct regimes at 0.39 < Rg/Rb < 1.0 and Rg/Rb > 1.0, respectively, where S(t) exhibits a single characteristic time and multiple characteristic times.
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Biochar as an agricultural soil amendment plays vital roles in mediating methane (CH4) and nitrous oxide (N2O) emissions in soils. The link between different types of biochar, bulk soil, and rhizosphere microbial communities in relation to CH4 and N2O emissions is being investigated in this study. The rice pot experiment was conducted using biochar at two temperatures (300°C and 500°C) in combination with three biochar levels (0, 2, 10% w/w). Soil properties and the abundance of genes associated with CH4 and N2O emissions from both rhizosphere and bulk soils were investigated. The study also aimed to examine the structure of microbial communities (pmoA, nosZ) in rhizosphere and bulk soils whereas CH4 and N2O emissions were monitored while growing rice. Results showed that biochar at 300°C and 10% incorporation significantly increased the CH4 emissions by up to 59% rise compared to the control group. Random Forest analysis revealed that the ratio of mcrA/pmoA along with the abundance of mcrA from both rhizosphere and bulk soils, the abundance of AOA, TN, DOC, and the community composition of pmoA-harboring microorganisms from both bulk and rhizosphere soils were important predictors of CH4 emissions. Therefore, the ratio of mcrA/pmoA in rhizosphere soil and the abundance of AOA in bulk soil were the main factors influencing CH4 emissions. Variation Partitioning Analysis (VPA) results indicated that the effects of these factors on bulk soil were 9% of CH4 emissions variations in different treatments, which contributed more than rhizosphere soils' factors. Moreover, random forest analysis results indicated that the abundance of AOB in bulk soil was the most important predictor influencing N2O emissions. The VPA result revealed that the factors in rhizosphere soil could explain more than 28% of the variations in N2O emissions. Our study highlights that rhizosphere soil has a more significant effect than bulk soil on N2O production. Our findings further the understanding of the link between bulk and rhizosphere attributes, and their impact on CH4 and N2O emissions in paddy soils. In summary, we recommend the application of biochar at 500°C and 2% incorporation rate for agricultural production in the area.
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Mitochondria are sensitive organelles that sense intrinsic and extrinsic stressors and maintain cellular physiological functions through the dynamic homeostasis of mitochondrial fusion and fission. Numerous pathological processes are associated with mitochondrial fusion and fission disorders. However, the molecular mechanism by which stress induces cardiac pathophysiological changes through destabilising mitochondrial fusion and fission is unclear. Therefore, this study aimed to investigate whether the endoplasmic reticulum stress signalling pathway initiated by the turbulence of mitochondrial fusion and fission under stressful circumstances is involved in cardiomyocyte damage. Based on the successful establishment of the classical stress rat model of restraint plus ice water swimming, we measured the content of serum lactate dehydrogenase. We used haematoxylin-eosin staining, special histochemical staining, RT-qPCR and western blotting to clarify the cardiac pathology, ultrastructural changes and expression patterns of mitochondrial fusion and fission marker proteins and endoplasmic reticulum stress signalling pathway proteins. The results indicated that mitochondrial fusion and fission markers and proteins of the endoplasmic reticulum stress JNK signalling pathway showed significant abnormal dynamic changes with the prolongation of stress, and stabilisation of mitochondrial fusion and fission using Mdivi-1 could effectively improve these abnormal expressions and ameliorate cardiomyocyte injury. These findings suggest that stress could contribute to pathological cardiac injury, closely linked to the endoplasmic reticulum stress JNK signalling pathway induced by mitochondrial fusion and fission turbulence.
Subject(s)
Mitochondrial Dynamics , Myocytes, Cardiac , Rats , Animals , Myocytes, Cardiac/metabolism , Signal Transduction , Endoplasmic Reticulum Stress/geneticsABSTRACT
Background: There is no consensus on whether intravenous rehydration must be added after preoperative phenoxybenzamine (PXB) administration for pheochromocytoma. The aim of this study is to investigate whether abandonment of intravenous volume expansion after PXB administration is associated with intraoperative hemodynamic instability. Methods: 83 Patients with pheochromocytoma received surgical treatment in the Department of Urology, Handan First Hospital, between October 2014 and July 2022. All patients were subclassified into either the hemodynamic stability group (HS group) or the hemodynamic instability group (HU group) according to whether intraoperative hemodynamic instability occurred, with 51 cases in HS group and 32 cases in HU group. Differences in data between the two groups were examined, and the risk factors for intraoperative hemodynamic instability were analyzed using logistic regression. Results: The results of the analysis showed no statistically significant differences in age, sex, location of the tumor, surgical method, body mass index (BMI) ≥ 24 kg/m2, blood and urine catecholamine test results, preoperative oral PXB followed by combined intravenous volume expansion, proportion of patients with hypertension or diabetes mellitus or coronary heart disease between the two groups (P>0.05). The size of the tumor in the HS group was smaller than that in the HU group (5.3 ± 1.9 cm vs 6.2 ± 2.4 cm P=0.010). Multivariate analyses demonstrated that abandonment of intravenous volume expansion after preoperative receipt of α-blockers in patients with adrenal pheochromocytoma was not an independent risk factor for intraoperative hemodynamic instability. Only the tumor size (P=0.025) was an independent risk factor for intraoperative hemodynamic instability. Conclusion: The purpose of general preoperative intravenous fluid expansion is to prevent hypotension after the tumor has been resected. In the current study, we indicated that preoperative management of pheochromocytomas using the α-blocker PXB in combination with intravenous volume expansion does not further reduce the risk of intraoperative hemodynamic instability or postoperative complications compared with oral PXB alone. Therefore, our study supports preoperative management of pheochromocytoma with a single α-blocker, PXB, as sufficient.
Subject(s)
Adrenal Gland Neoplasms , Pheochromocytoma , Humans , Adrenergic alpha-Antagonists/therapeutic use , Pheochromocytoma/pathology , Phenoxybenzamine/therapeutic use , Risk Factors , Hemodynamics , Adrenal Gland Neoplasms/complications , Adrenal Gland Neoplasms/surgery , Adrenal Gland Neoplasms/pathologyABSTRACT
We develop a theory for the motion of a particle grafted with inhomogeneous bead-spring Rouse chains via the generalized Langevin equation (GLE), where individual grafted polymers are allowed to take different bead friction coefficients, spring constants, and chain lengths. An exact solution of the memory kernel K(t) is obtained for the particle in the time (t) domain in the GLE, which depends only on the relaxation of the grafted chains. The t-dependent mean square displacement g(t) of the polymer-grafted particle is then derived as a function of the friction coefficient γ0 of the bare particle and K(t). Our theory offers a direct way to quantify the contributions of the grafted chain relaxation to the mobility of the particle in terms of K(t). This powerful feature enables us to clarify the effect on g(t) of dynamical coupling between the particle and grafted chains, leading to the identification of a relaxation time of fundamental importance in polymer-grafted particles, namely, the particle relaxation time. This timescale quantifies the competition between the contributions of the solvent and grafted chains to the friction of the grafted particle and separates g(t) into the particle- and chain-dominated regimes. The monomer relaxation time and the grafted chain relaxation time further divide the chain-dominated regime of g(t) into subdiffusive and diffusive regimes. Analysis of the asymptotic behaviors of K(t) and g(t) provides a clear physical picture of the mobility of the particle in different dynamical regimes, shedding light on the complex dynamics of polymer-grafted particles.
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Histone H3 is phosphorylated at Ser10 by multiple kinases, and many of them are anti-cancer targets. Here, we report the first kinase that can phosphorylate H3Ser10 in both interphase and mitosis, which we named KimH3 (kinase of interphase and mitotic Histone H3). Meta-analysis indicates that KimH3 is upregulated in a broad spectrum of human cancers and its high expression is correlated with reduced the median survival time of cancer patients. In mitosis, CDK1 phosphorylates KimH3, which then phosphorylates H3Ser10 to regulate cell cycle procession. In interphase, EGF induces KimH3 activation and H3Ser10 phosphorylation, which is involved in MAPK-ERK1/2 signaling pathway to activate immediate-early genes transcription. Consequently, a small molecule inhibitor of KimH3 significantly inhibited tumor growth in mice. This is not only consistent with the dual roles of KimH3 in both interphase and mitotic Histone H3 phosphorylation, but also reveals it as an important potential anti-cancer target.
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It is well known that alcohol consumption leads to substantially increased free radical levels and health risks, which lacks effective treatment besides alcohol abstinence. Here, we compared different static magnetic field (SMF) settings and found that a downward quasi-uniform SMF of ~0.1 to 0.2 T could effectively alleviate alcohol-induced liver damage and lipid accumulation and improve hepatic function. SMFs of two different directions can reduce the inflammation, reactive oxygen species levels, and oxidative stress in the liver, while the downward SMF had more obvious effects. Moreover, we found that the upward direction SMF of ~0.1 to 0.2 T could inhibit DNA synthesis and regeneration in hepatocytes, which caused detrimental effects on the lifespan of "heavy drinking" mice. In contrast, the downward SMF prolongs survival of "heavy drinking" mice. On one hand, our study shows that ~0.1 to 0.2 T moderate quasi-uniform SMFs with a downward direction have great promises to be developed into a physical method to reduce alcohol-induced liver damage; on the other hand, although the internationally recognized upper limit for SMF public exposure is 0.4 T, people should also pay extra attention to SMF strength, direction, and inhomogeneity that could generate harmful effects on specific severe pathological conditions.
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F-actin (filamentous actin) has been shown to be sensitive to mechanical stimuli and play critical roles in cell attachment, migration, and cancer metastasis, but there are very limited ways to perturb F-actin dynamics with low cell toxicity. Magnetic field is a noninvasive and reversible physical tool that can easily penetrate cells and human bodies. Here, we show that 0.1/0.4-T 4.2-Hz moderate-intensity low-frequency rotating magnetic field-induced electric field could directly decrease F-actin formation in vitro and in vivo, which results in decreased breast cancer cell migration, invasion, and attachment. Moreover, low-frequency rotating magnetic fields generated significantly different effects on F-actin in breast cancer vs. noncancerous cells, including F-actin number and their recovery after magnetic field retrieval. Using an intermittent treatment modality, low-frequency rotating magnetic fields could significantly reduce mouse breast cancer metastasis, prolong mouse survival by 31.5 to 46.0% (P < 0.0001), and improve their overall physical condition. Therefore, our work demonstrates that low-frequency rotating magnetic fields not only can be used as a research tool to perturb F-actin but also can inhibit breast cancer metastasis through F-actin modulation while having minimum effects on normal cells, which reveals their potential to be developed as temporal-controlled, noninvasive, and high-penetration physical treatments for metastatic cancer.
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Preconditioning with inhalative carbon monoxide (CO) at low concentrations provides protection against hypoxic and ischemic insults in the brain and heart. The present study aims to test a hypothesis that activation of mitochondrial-derived vesicles (MDVs) is a mechanism underlying the protective effect of CO preconditioning. Here we show that CO preconditioning induced mild oxidative stress and activated massive production of MDVs. Short exposure to a low concentration of carbon monoxide-releasing molecule 2 (CORM-2), a donor of carbon monoxide, prevented oligodendrocyte precursor cells (OPCs) from subsequent death induced by high doses of CO, and protected Chinese hamster ovary (CHO) cells against oxygen-glucose deprivation (OGD)-induced cell death. Furthermore, inhibition of lysosomal activity prevented degradation of MDVs, abolished MDV-mediated mitochondrial quality control, and diminished the protective effect of CO preconditioning. Altogether, our data provide direct evidence suggesting that MDV-mediated mitochondrial quality control may have a novel role in CO preconditioning.
Subject(s)
Carbon Monoxide , Mitochondria , Animals , Cricetinae , Carbon Monoxide/pharmacology , Carbon Monoxide/metabolism , CHO Cells , Cricetulus , Mitochondria/metabolism , Oxidative StressABSTRACT
The purpose of the study was to produce an algorithm and surgical procedure for optimum treatment of pedal macrodactyly. Surgery was performed on 27 feet of 26 patients with a mean age of 33 months at the time of surgery (range: 7-108 months). A multi-technique procedure based on the involved elements of the foot (soft tissue, phalanx, or metatarsal, or a combination of these) was adopted. The intermetatarsal width ratio, phalanx spread angle, and metatarsal spread angle was used to evaluate the severity of the macrodactyly and the effect of treatment. The Oxford Ankle Foot Questionnaire for Children and the Questionnaire for Foot Macrodactyly were employed to evaluate the clinical results. Under the guidelines of the treatment algorithm, all patients were successfully operated on using the multi-technique procedure; the sizes of the affected feet decreased significantly. After a mean of 33 months (range: 18-42 months) follow-up, the intermetatarsal width ratio decreased from 1.13 to 0.93 (p < 0.05), the phalanx spread angle decreased from 31.3° to 17.9° (p < 0.05), the metatarsal spread angle decreased from 33.2° to 15.8° (p < 0.05), and the mean score for the Oxford Ankle Foot Questionnaire for Children improved from 42 to 47 (p < 0.05) after surgery. The mean score for the Questionnaire for Foot Macrodactyly was 9.35 at the time of follow-up. The goal of the treatment of pedal macrodactyly is to obtain a functional and cosmetically acceptable foot. This treatment algorithm and multi-technique procedure could fully satisfy this goal.
Subject(s)
Limb Deformities, Congenital , Lower Extremity , Humans , Child , Child, Preschool , Foot/surgeryABSTRACT
Although 9.4 T magnetic resonance imaging (MRI) has been tested in healthy volunteers, its safety in diabetic patients is unclear. Furthermore, the effects of high static magnetic fields (SMFs), especially gradient vs. uniform fields, have not been investigated in diabetics. Here, we investigated the consequences of exposure to 1.0-9.4 T high SMFs of different gradients (>10 T/m vs. 0-10 T/m) on type 1 diabetic (T1D) and type 2 diabetic (T2D) mice. We found that 14 h of prolonged treatment of gradient (as high as 55.5 T/m) high SMFs (1.0-8.6 T) had negative effects on T1D and T2D mice, including spleen, hepatic, and renal tissue impairment and elevated glycosylated serum protein, blood glucose, inflammation, and anxiety, while 9.4 T quasi-uniform SMFs at 0-10 T/m did not induce the same effects. In regular T1D mice (blood glucose ≥16.7 mmol/L), the >10 T/m gradient high SMFs increased malondialdehyde ( P<0.01) and decreased superoxide dismutase ( P<0.05). However, in the severe T1D mice (blood glucose ≥30.0 mmol/L), the >10 T/m gradient high SMFs significantly increased tissue damage and reduced survival rate. In vitro cellular studies showed that gradient high SMFs increased cellular reactive oxygen species and apoptosis and reduced MS-1 cell number and proliferation. Therefore, this study showed that prolonged exposure to high-field (1.0-8.6 T) >10 T/m gradient SMFs (35-1â¯380 times higher than that of current clinical MRI) can have negative effects on diabetic mice, especially mice with severe T1D, whereas 9.4 T high SMFs at 0-10 T/m did not produce the same effects, providing important information for the future development and clinical application of SMFs, especially high-field MRI.
Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Mice , Animals , Blood Glucose , Diabetes Mellitus, Type 1/veterinary , Magnetic Fields , Diabetes Mellitus, Type 2/veterinaryABSTRACT
Nitrates can stimulate the biosynthesis of hydrophilic yellow pigments (HYPs) in Monascus ruber CGMCC 10910. To explore the molecular mechanisms whereby nitrates (NaNO3 and NH4NO3) regulate HYP production, an integrated transcriptomic and proteomic analysis was conducted in this study. Nitrate addition led to an approximately 75% higher HYP production compared with the untreated group, especially compounds Y3 and Y4. Comparative transcriptomic analysis found that mpigsA, H, K, L, and P genes involved in yellow pigment biosynthesis were significantly upregulated. In addition, pigment biosynthesis-related (carbon catabolism, amino acid metabolism, polyketide synthesis, and fatty acid metabolism) genes were upregulated to provide precursors and energy for HYP biosynthesis and cell growth. Secretion-related (cytomembrane ergosterol biosynthetic, and transport) pathways were also noticeably regulated to accelerate transmembrane transport of HYPs. Meanwhile, proteomic analysis showed that nitrates improved the protein expression of hybrid polyketide synthase-nonribosomal peptide synthetase, oxidoreductase, glucoamylase, endo-1,4-beta-xylanase, O-acetylhomoserine, and isocitrate lyase to enhance HYP production. These findings demonstrated the regulatory mechanism of nitrates for enhancing HYP production in Monascus. KEY POINTS: ⢠Nitrates stimulated the biosynthesis of Monascus hydrophilic yellow pigments (HYPs) ⢠Nitrates affected transcriptional level of pigment biosynthesis- and transport genes ⢠Increased expression of hybrid PKS-NRPS and transporters promoted production of HYPs.
Subject(s)
Monascus , Nitrates , Fermentation , Nitrates/metabolism , Pigments, Biological , Monascus/metabolism , Proteomics , TranscriptomeABSTRACT
PURPOSE: 9.4 T magnetic resonance imaging (MRI) has been initially tested on healthy human volunteers, but its future application will benefit more from experiments with animal disease models. In the meantime, high static magnetic fields (SMFs) have been shown to improve mice mental health and have anti-tumor potentials. METHODS: We compared the anti-tumor effects of 9.4 T SMF with or without a commonly used chemotherapy drug imatinib mesylate on BALB/c (Nu/Nu) mice bearing gastrointestinal stromal tumor GIST-T1 cells. The body weight, food/water consumption, complete blood count, blood biochemistry, tumor weight, HE and Ki67 stains were examined. Locomotor activity and cognitive functions were also measured by four behavior tests, including open field, elevated plus maze, three-chamber and tail suspension tests. RESULTS: We found that the tumor growth was inhibited up to 62.88% when treated with 9.4 T SMF alone for 200 h. More importantly, 9.4 T SMF combined with 20 mg/kg imatinib mesylate can result in 92.75% tumor suppression, which is close to the anti-tumor effect of high dose (80 mg/kg) imatinib. However, 80 mg/kg imatinib caused severe side effects, including significantly reduced gain of body weight, abnormal liver function and depressive behaviors in mice. In contrast, 9.4 T SMF treatment significantly reduced these side effects, especially for the depressive behaviors. CONCLUSION: Our results demonstrate that 9.4 T SMF not only has anti-tumor effects on its own, but also could improve the anti-tumor effect of imatinib mesylate, reduce its toxicity and improve the mice mental health, which unraveled the great clinical potentials of high SMF in future applications.
Subject(s)
Antineoplastic Agents , Gastrointestinal Stromal Tumors , Humans , Animals , Mice , Imatinib Mesylate/adverse effects , Antineoplastic Agents/therapeutic use , Depression , Pyrimidines/pharmacology , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/pathology , Body WeightABSTRACT
Endometrial carcinoma (EC) morbidity and mortality have been increasing in recent years. Otubain 2 (OTUB2) was shown to be upregulated in EC patients, so the aim of this study was to explore the role of OTUB2 in EC. Cell Counting Kit-8 (CCK-8), colony formation, enzyme-linked immunosorbent assay, the wound healing assay, and Transwell invasion assays were used to investigate the specific role of OTUB2 in EC tumorigenesis. Real-time polymerase chain reaction and western blot analysis were used to detect the expression of OTUB2 in EC tissues and cells. OTUB2 is upregulated in EC patients and cell lines and is associated with a poor prognosis. The overexpression of OTUB2 promoted glycolysis and induced the proliferation, migration, and invasion of endometrial cancer cells. The silencing of OTUB2 had the opposite effect. In addition, the silencing of OTUB2 significantly suppressed the expression levels of PKM2. Importantly, inhibition of the PKM2/PI3K/AKT signaling pathway significantly reversed the promoting effect of OTUB2 overexpression on EC. OTUB2 regulated the proliferation and invasion of EC cells by regulating the PKM2/PI3K/AKT signaling pathway. OTUB2 may serve as a potential prognostic and therapeutic target in EC.