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DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.
Bildik, G, Gray, JP, Mao, W, Yang, H, Ozyurt, R, Orellana, VR, De Wever, O, Carey, MS, Bast, RC, Lu, Z
Autophagy. 2024;(3):675-691
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and low-grade ovarian cancer (LGSOC) are characterized by the prevalence of KRAS oncogene mutations. DIRAS3 is the first endogenous non-RAS protein that heterodimerizes with RAS, disrupts RAS clustering, blocks RAS signaling, and inhibits cancer cell growth. Here, we found that DIRAS3-mediated KRAS inhibition induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations, but not in cells with wild-type KRAS, by downregulating NFE2L2/Nrf2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective macroautophagy/autophagy that may protect mutant KRAS cancer cells from oxidative stress, by inhibiting mutant KRAS, activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27 localization, and inducing autophagic gene expression. Treatment with chloroquine or the novel dimeric chloroquine analog DC661 significantly enhances DIRAS3-mediated inhibition of mutant KRAS tumor cell growth in vitro and in vivo. Taken together, our study demonstrates that DIRAS3 plays a critical role in regulating mutant KRAS-driven oncogenesis in PDAC and LGSOC.Abbreviations: AFR: autophagic flux reporter; ATG: autophagy related; CQ: chloroquine; DCFDA 2'-7'-dichlorodihydrofluorescein diacetate; DIRAS3: DIRAS family GTPase 3; DOX: doxycycline; KRAS KRAS proto-oncogene, LGSOC low-grade serous ovarian cancer; MiT/TFE: microphthalmia family of transcription factors; NAC: N-acetylcysteine; PDAC pancreatic ductal adenocarcinoma; ROS: reactive oxygen species; TFEB transcription factor EB.
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Cardiac Metabolism, Reprogramming, and Diseases.
Wang, H, Shen, M, Shu, X, Guo, B, Jia, T, Feng, J, Lu, Z, Chen, Y, Lin, J, Liu, Y, et al
Journal of cardiovascular translational research. 2024;(1):71-84
Abstract
Cardiovascular diseases (CVD) account for the largest bulk of deaths worldwide, posing a massive burden on societies and the global healthcare system. Besides, the incidence and prevalence of these diseases are on the rise, demanding imminent action to revert this trend. Cardiovascular pathogenesis harbors a variety of molecular and cellular mechanisms among which dysregulated metabolism is of significant importance and may even proceed other mechanisms. The healthy heart metabolism primarily relies on fatty acids for the ultimate production of energy through oxidative phosphorylation in mitochondria. Other metabolites such as glucose, amino acids, and ketone bodies come next. Under pathological conditions, there is a shift in metabolic pathways and the preference of metabolites, termed metabolic remodeling or reprogramming. In this review, we aim to summarize cardiovascular metabolism and remodeling in different subsets of CVD to come up with a new paradigm for understanding and treatment of these diseases.
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Basal metabolic rate and the risk of urolithiasis: a two-sample Mendelian randomization study.
Lu, Z, Chen, Y, Tang, Z, Zhang, J, Li, Z, Tang, F, He, Z
World journal of urology. 2024;(1):235
Abstract
OBJECTIVE Few studies have investigated the impact of basal metabolic rate (BMR) on the development of urolithiasis, and the causal relationship is yet to be established. In this study, a two-sample Mendelian randomization (MR) analysis was utilized to identify the causal relationship between BMR and risk of urolithiasis. METHOD Genetic instruments for BMR were drawn from a public genome-wide association study (GWAS). Summary dates on BMR and urolithiasis were obtained from a GWAS meta-analysis with sample sizes of 454,874 and 212,453, respectively. The inverse-variance weighted (IVW) method was provided as the main approach to estimate the causal relationship. The weighted-median method and the MR-Egger method were used as supplements to the IVW method. In addition, we conducted sensitivity analyses, including heterogeneity tests, pleiotropy tests and leave-one-out analysis, to assess the robustness of the outcomes. Furthermore, the funnel plot asymmetry was visually inspected to evaluate possible bias. RESULTS The inverse-variance weighted data revealed that genetically predicted BMR significantly decreased the risk of urolithiasis [beta coefficient (beta): - 0.2366, odds ratio (OR): 0.7893, 95% confidence interval (CI) 0.6504-0.9579, p = 0.0166]. CONCLUSIONS BMR has causal effects on urolithiasis in an MR study, and the risk of urolithiasis in patients with lower levels of BMR is higher.
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Preparation and thermostability of a Si/P/N synergistic flame retardant containing triazine ring structure for cotton fabrics.
Wang, Z, Wang, S, Chen, H, Chen, C, Luan, J, Dong, C, Lu, Z
International journal of biological macromolecules. 2024;(Pt 1):129497
Abstract
A new synergistic flame retardant named Bisiminopropyl trimethoxysilane-1,3,5-triazine-O-bicyclic pentaerythritol phosphate (BTPODE) was synthesized, which is a type of Si/P/N flame retardant. This was accomplished by grafting aminopropyl trimethoxysilane and bicyclic pentaerythritol phosphate onto a triazine ring structure, serving as an intermediate. The structure of BTPODE was determined using nuclear magnetic resonance (1H NMR, 13C NMR, and 31P NMR) and Fourier transform infrared spectroscopy (FT-IR). SEM was used to detect the surface morphology of cotton fabrics, which suggested that BTPODE had been resoundingly stick to cotton fabrics. The flame retardant properties of cotton fabrics were evaluated by measuring the limiting oxygen index (LOI) and conducting vertical flammability experiments. Cotton fabrics with a weight gain of 20.73 % achieved an LOI value of 32.5 %. Thermogravimetric (TG) experiments demonstrated the samples' good thermostability. Furthermore, under nitrogen conditions, the char residue of cotton fabric with a weight gain of 20.73 % was 36.85 %. The cone calorimetry test (CONE) showed a significant reduction in the TSP value, indicating a certain level of smoke suppression performance. Finally, based on the obtained experimental results, the fire-retardant mechanism principle of the flame retardant was deduced.
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Efficacy of acupotomy combined with sodium hyaluronate versus sodium hyaluronate alone in the treatment of knee osteoarthritis: A meta-analysis.
Wu, Q, Wu, Z, Lu, Z
Medicine. 2023;(37):e34930
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Abstract
BACKGROUND The efficacy of acupotomy combined with hyaluronic sodium acid in the treatment of knee osteoarthritis (KOA) is unclear. Therefore, this meta-analysis aims to evaluate the efficacy of acupotomy combined with hyaluronic sodium acid compared with hyaluronic sodium acid alone in the treatment of KOA. METHODS Studies from 8 Online databases were searched on KOA treatment using acupotomy combined with sodium hyaluronate until May 2022. The primary outcome indicator was clinical effectiveness, and the secondary outcome indicators included the visual analogue scale scores and Lysholm scores. We calculated the weighted mean difference (WMD) or relative risk for all relevant outcomes. RESULTS Nine studies were identified, involving 644 cases. The results showed that acupotomy combined with intra-articular sodium hyaluronate injection for KOA was superior to sodium hyaluronate injection alone in terms of clinical effectiveness (relative risk = 1.17, 95% confidence interval [CI]: 1.09-1.25, P < .001) and visual analogue scale (WMD = -2.1, 95% CI: -2.25 to 1.95, P < .001), Lysholm score (WMD = 13.83, 95% CI: 3.47-24.19, P = .009). CONCLUSION Acupotomy combined with intra-articular sodium hyaluronate injection for KOA is superior to sodium hyaluronate injection alone. Limited by the number and quality of included studies, this conclusion still needs to be verified by more high-quality Research. INPLASY REGISTRATION NUMBER INPLASY202350029.
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RAGE plays key role in diabetic retinopathy: a review.
Lu, Z, Fan, B, Li, Y, Zhang, Y
Biomedical engineering online. 2023;(1):128
Abstract
RAGE is a multiligand receptor for the immunoglobulin superfamily of cell surface molecules and is expressed in Müller cells, vascular endothelial cells, nerve cells and RPE cells of the retina. Diabetic retinopathy (DR) is a multifactorial disease associated with retinal inflammation and vascular abnormalities and is the leading cause of vision loss or impairment in older or working-age adults worldwide. Therapies aimed at reducing the inflammatory response and unnecessary angiogenesis can help slow the progression of DR, which in turn can save patients' vision. To maximize the efficacy and minimize the side effects, treatments that target key players in the pathophysiological process of DR need to be developed. The interaction between RAGE and its ligands is involved in a variety of cytopathological alterations in the retina, including secretion of inflammatory factors, regulation of angiogenesis, oxidative stress, structural and functional changes, and neurodegeneration. In this review, we will summarize the pathologic pathways mediated by RAGE and its ligand interactions and discuss its role in the progression of diabetic retinopathy to explore potential therapeutic targets that are effective and safe for DR.
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Effects of Vitamin D Supplementation on Children with Autism Spectrum Disorder: A Systematic Review and Meta-analysis.
Zhang, M, Wu, Y, Lu, Z, Song, M, Huang, X, Mi, L, Yang, J, Cui, X
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology. 2023;(2):240-251
Abstract
The effect of vitamin D supplementation on individuals with autism spectrum disorder (ASD) is inconclusive. We aimed to conduct a meta-analysis of the available randomized controlled trials (RCTs) to explore whether vitamin D supplementation can improve core symptoms and coexisting conditions in children with ASD. Data were obtained by searching the PubMed, Embase, Web of Science, CINAHL and Cochrane Library databases up to February 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using a random-effects model, mean differences with 95% confidence intervals (CIs) were calculated through a meta-analysis. There were eight RCTs with 266 children with ASD in the present review, among which six RCTs were included in the meta-analysis. Children who received vitamin D supplementation showed a significant improvement in stereotypical behavior scores (pooled mean difference (MD): -1.39; 95% CI: -2.7, -0.07; P = 0.04) with low heterogeneity (I2 = 34%), and there was a trend toward decreased total scores on the Social Responsiveness Scale (SRS) and Childhood Autism Rating Scale (CARS, P = 0.05); however, there were no other significant differences in the core symptoms of ASD and coexisting conditions between groups as measured by the Aberrant Behavior Checklist (ABC). Vitamin D supplementation appears to improve stereotypical behaviors but does not improve other core symptoms and coexisting conditions. Further randomized controlled trials with large sample sizes and individualized doses are needed.
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Integration of circulating microRNAs and transcriptome signatures identifies early-pregnancy biomarkers of preeclampsia.
Mirzakhani, H, Handy, DE, Lu, Z, Oppenheimer, B, Litonjua, AA, Loscalzo, J, Weiss, ST
Clinical and translational medicine. 2023;(11):e1446
Abstract
BACKGROUND MicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case-control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures related to preeclampsia and vitamin D status (≤30 ng/mL) during gestation from 10 to 18 weeks, using differential expression analysis. METHODS Using quantitative PCR arrays, we conducted profiling of circulating miRNAs at 10-18 weeks of gestation in the same VDAART cohort to identify differentially expressed (DE) miRNAs associated with preeclampsia and vitamin D status. For the validation of the expression of circulating miRNA signatures in the placenta, the HTR-8/SVneo trophoblast cell line was used. Targets of circulating miRNA signatures in the preeclampsia mRNA signatures were identified by consensus ranking of miRNA-target prediction scores from four sources. The connected component of target signatures was identified by mapping to the protein-protein interaction (PPI) network and hub targets were determined. As experimental validation, we examined the gene and protein expression of IGF1R, one of the key hub genes, as a target of the DE miRNA, miR-182-5p, in response to a miR-182-5p mimic in HTR-8/SVneo cells. RESULTS Pregnant women with preeclampsia had 16 circulating DE miRNAs relative to normal pregnancy controls that were also DE under vitamin D insufficiency (9/16 = 56% upregulated, FDR < .05). Thirteen miRNAs (13/16 = 81.3%) were detected in HTR-8/SVneo cells. Overall, 16 DE miRNAs had 122 targets, of which 87 were unique. Network analysis demonstrated that the 32 targets of DE miRNA signatures created a connected subnetwork in the preeclampsia module with CXCL8, CXCL10, CD274, MMP9 and IGF1R having the highest connectivity and centrality degree. In an in vitro validation experiment, the introduction of an hsa-miR-182-5p mimic resulted in significant reduction of its target IGF1R gene and protein expression within HTR-8/SVneo cells. CONCLUSIONS The integration of the circulating DE miRNA and mRNA signatures associated preeclampsia added additional insights into the subclinical molecular signature of preeclampsia. Our systems and network biology approach revealed several biological pathways, including IGF-1, that may play a role in the early pathophysiology of preeclampsia. These pathways and signatures also denote potential biomarkers for the early stages of preeclampsia and suggest possible preventive measures.
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Normalization of the H3K9me2/H3K14ac-ΔFosB pathway in the nucleus accumbens underlying the reversal of morphine-induced behavioural and synaptic plasticity by Compound 511.
Wang, Q, Qin, F, Wang, Y, Wang, Z, Lin, W, Li, Z, Liu, Q, Mu, X, Wang, H, Lu, S, et al
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2023;:154467
Abstract
BACKGROUND Although opioid agonist-based treatments are considered the first-line treatment for opioid use disorders, nonopioid alternatives are urgently needed to combat the inevitable high relapse rates. Compound 511 is a formula derived from ancient traditional Chinese medical literature on opiate rehabilitation. Previously, we observed that Compound 511 could effectively prevent the acquisition of conditioned place preference (CPP) during early morphine exposure. However, its effects on drug-induced reinstatement remain unclear. PURPOSE This study aims to estimate the potential of Compound 511 for the therapeutic intervention of opioid relapse in rodent models and explore the potential mechanisms underlying the observed actions. STUDY DESIGN/METHODS The CPP and locomotor sensitization paradigm were established to evaluate the therapeutic effect of Compound 511 treatment on morphine-induced neuroadaptations, followed by immunofluorescence and western blot (WB) analysis of the synaptic markers PSD-95 and Syn-1. Furthermore, several addiction-associated transcription factors and epigenetic marks were examined by qPCR and WB, respectively. Furthermore, the key active ingredients and targets of Compound 511 were further excavated by network pharmacology approach and experimental validation. RESULTS The results proved that Compound 511 treatment during abstinence blunted both the reinstatement of morphine-evoked CPP and locomotor sensitization, accompanied by the normalization of morphine-induced postsynaptic plasticity in the nucleus accumbens (NAc). Additionally, Compound 511 was shown to exert a selectively repressive influence on morphine-induced hyperacetylation at H3K14 and a reduction in H3K9 dimethylation as well as ΔFosB activation and accumulation in the NAc. Finally, two herbal ingredients of Compound 511 and six putative targets involved in the regulation of histone modification were identified. CONCLUSION Our findings indicated that Compound 511 could block CPP reinstatement and locomotor sensitization predominantly via the reversal of morphine-induced postsynaptic plasticity through epigenetic mechanisms. Additionally, 1-methoxy-2,3-methylenedioxyxanthone and 1,7-dimethoxyxanthone may serve as key ingredients of Compound 511 by targeting specific epigenetic enzymes. This study provided an efficient nonopioid treatment against opioid addiction.
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Transformation from acute promyelocytic leukemia in pregnancy to acute myeloid leukemia with MLL-AF9 fusion gene: A case report and literature review.
Gao, Y, Han, N, Jiang, Y, Lu, Z
Medicine. 2023;(48):e36403
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Abstract
RATIONALE Because there are few evidence-based guidelines and an extremely low incidence rate, managing and treating patients who have transitioned from acute promyelocytic leukemia (APL), which was diagnosed during pregnancy, to acute myeloid leukemia (AML), can be difficult. PATIENT CONCERNS In this case, a 34-year-old pregnant patient was diagnosed with APL in medium-risk group in June 2017. After the all-trans retinoic acid and arsenic trioxide-based full-course treatment, the patients achieved complete remission (CR) and were well-tolerated. After 5 years, the patient complained of fatigue for 3 months. DIAGNOSIS Bone marrow examination revealed hypercellularity with approximately 50% immunophenotypic abnormal myeloblasts with MLL-AF9 fusion gene. Based on the AML diagnosis criteria of the World Health Organization, the patient was eventually diagnosed with a rare transformation from APL to AML. INTERVENTIONS The patient was treated with two cycles of induction chemotherapy and an allogeneic hematopoietic stem cell transplantation (allo-HSCT). OUTCOMES Until now, the patient is in continuous remission with no signs of APL and AML. LESSIONS Despite the rarity of APL to AML transformation, it is crucial to track the disease's progress and administer treatment on time. It remains uncertain whether the risk stratification and clinical outcomes of secondary AML with MLL-AF9 are equivalent to those of de novo AML with MLL-AF9. The management and treatment of these patients should be personalized and require further observation.