BACKGROUND: Cardiac arrest (CA) induced by electric shock is a rare occurrence, particularly in cases of prolonged CA. Currently, there is limited literature on similar incidents, and we present a relevant case report. CASE SUMMARY: A 27-year-old Asian male man, experiencing respiratory CA due to electric shock, was successfully restored to sinus rhythm after 50 min of cardiopulmonary resuscitation and 8 electrical defibrillation sessions. In the subsequent stages, the patient received multiple organ function protection measures, leading to a successful recovery and eventual discharge from the hospital. CONCLUSION: Prolonging resuscitation time can enhance the chances of survival for patients, this study provide valuable insights into the management of electric shock-induced CA.
Acetamiprid is a neonicotinoid commonly detected in aquatic ecosystems, with residual concentrations of up to 0.41 mg/L in surface water, posing a threat to the health of nontarget aquatic organisms. However, studies on the potential toxicity and underlying mechanisms of action of acetamiprid on nontarget aquatic organisms are limited. This study investigated the acute and short-term toxicity of acetamiprid to Xenopus laevis tadpoles. A 96-h acute toxicity test determined the LC50 of acetamiprid to be 32.1 mg/L. After 28 days of exposure to 1/10 and 1/100 LC50 concentrations, tadpole samples were collected for bioconcentration elimination analysis, biochemical analyses, transcriptomics, and metabolomics studies to comprehensively evaluate the toxic effects of acetamiprid and its underlying mechanisms. The results, indicating bioconcentration factors (BCFs) < 1, suggest that acetamiprid has a low bioconcentration in tadpoles. Additionally, oxidative stress was observed in treated Xenopus laevis tadpoles. Transcriptomic and nontargeted metabolomic analyses identified 979 differentially expressed genes (DEGs) and 95 differentially metabolites in the 0.321 mg/L group. The integrated analysis revealed that disruption of purine and amino acid metabolic pathways potentially accounts for acetamiprid-induced toxic effects in tadpoles. The disruptive effects of acetamiprid on valine, leucine and isoleucine biosynthesis; and aminoacyl-tRNA biosynthesis metabolic pathways in tadpoles were validated through targeted metabolomics analysis. These findings are crucial for assessing the risk of acetamiprid to nontarget aquatic organisms.
OBJECTIVE: Proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to vascular remodeling. Asprosin, a newly discovered protein hormone, is involved in metabolic diseases. Little is known about the roles of asprosin in cardiovascular diseases. This study focused on the role and mechanism of asprosin on VSMC proliferation and migration, and vascular remodeling in a rat model of hypertension. METHODS AND RESULTS: VSMCs were obtained from the aortic media of 8-week-old male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Asprosin was upregulated in the VSMCs of SHR. For in vitro studies, asprosin promoted VSMC proliferation and migration of WKY and SHR, and increased Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, NOX1/2/4 protein expressions and superoxide production. Knockdown of asprosin inhibited the proliferation, migration, NOX activity, NOX1/2 expressions and superoxide production in the VSMCs of SHR. The roles of asprosin in promoting VSMC proliferation and migration were not affected by hydrogen peroxide scavenger, but attenuated by superoxide scavenger, selective NOX1 or NOX2 inhibitor. Toll-like receptor 4 (TLR4) was upregulated in SHR, TLR4 knockdown inhibited asprosin overexpression-induced proliferation, migration and oxidative stress in VSMCs of WKY and SHR. Asprosin was upregulated in arteries of SHR, and knockdown of asprosin in vivo not only attenuated oxidative stress and vascular remodeling in aorta and mesentery artery, but also caused a subsequent persistent antihypertensive effect in SHR. CONCLUSIONS: Asprosin promotes VSMC proliferation and migration via NOX-mediated superoxide production. Inhibition of endogenous asprosin expression attenuates VSMC proliferation and migration, and vascular remodeling of SHR.
This research addresses the pH-dependency limitation in electrocatalytic hydrogen evolution reactions (HER) by creating heterostructures through the chemical bonding between 2D-dichalcogenides and V4C3Tx (T = OH, O) planes. The one-step solvothermal synthesis employed in this study constructs a synergistically interacted 1T phase of, e.g., MoS2 and V4C3Tx MXene, demonstrating an omnidirectional improvement on catalytic stability, active site exposure, surface area enlargement, electrical conductivity, and hence enhancement of water dissociation activities. Despite the notable progress in creating hydrogen production catalysts with ground breaking performances, a significant gap remains in the availability of catalysts capable of functioning effectively under high current densities. The catalyst 1T MoS2@V4C3Tx shows remarkable activities under the current density of 1000 mA cm-2, which require overpotentials of 16, 24, and 37 mV in 0.5 m H2SO4, 1 m KOH, and 0.1 m PBS electrolytes, respectively at 10 mA cm-2, and exhibits excellent HER performance with small overpotentials of 103.16 and 138 mV to achieve current densities of 500 and 1000 mA cm-2, respectively, with outstanding stability for 1000 cylic voltammetric cycle HER test without degradation in acidic media. Enhanced HER performance has also been observed in other 2D-dichalcogenides/V4C3Tx heterostructures, providing prospects for phase-engineered dichalcogenides/fluorine-free V4C3Tx composites for pH-universal HER.
Double perovskites (DPs) have attracted attention in the field of luminescence due to their inherent broadband emission of self-trapping excitons. In this work, we choose [(CH3)3NCH2CHCH2]+ and [CH3CHOHCH2NH2]+ as organic cations to synthesize two new organic-inorganic hybrid DPs, [(CH3)3NCH2CHCH2]2KInCl6 (1) and [CH3CHOHCH2NH2]2KInCl6 (2). The [KCl6]3- and [InCl6]3- octahedra are interchangeably connected by sharing two opposite faces, forming a one-dimensional coordination chain. Each K atom coordinates with six chlorine atoms in 1, while it coordinates with two oxygen atoms in addition to the six chlorine atoms in 2. The coordination between ions K and O in compound 2 may have significantly reduced its luminescence. As a result, compound 1 shows bright-yellow light with a quantum yield of more than 90%, while 2 shows weak blue light with a quantum yield of only 0.98%. In addition, different from no phase transition found in 2, 1 undergoes a reversible phase transition at 324/307 K in the heating-cooling cycle. Through structural and spectral analysis and density functional theory calculation, we conclude that the larger degree of [InCl6]3- octahedral distortion and the larger anion distance (In···In) also cause the PLQY of compound 1 to be higher than that of compound 2.
INTRODUCTION: Colorectal cancer (CRC) remains a significant public health concern. This study aims to provide a comprehensive understanding of the effectiveness of fecal immunochemical test (FIT) screening on CRC incidence and mortality, leveraging the scale of over 1.5 million randomly selected Taiwanese and more than 11.7 million person-years of follow-up. METHODS: This prospective cohort study merges data from 3 robust Taiwanese health databases: the CRC screening program, cancer registration, and death registration databases. Incidence and mortality rates of CRC were calculated based on age, sex, urbanization, and past screening status. Cox proportional hazard models were used to assess the association between screening statuses and CRC incidence or mortality, adjusting for age, sex, and urbanization levels. Statistical analysis of the data was conducted in 2021-2022. RESULTS: FIT screening was associated with a 33% reduction in CRC incidence and a 47% reduction in mortality. The study identified a dose-response relationship between the fecal hemoglobin concentration (f-HbC) levels and CRC risk. Participants with consistent FIT-negative results had significantly reduced CRC incidence and mortality risks, while those with one or more positive FIT results faced increased risks. Notably, compliance with follow-up examinations after a positive FIT significantly lowered mortality risk. CONCLUSIONS: This large-scale study validates the efficacy of FIT screening in reducing CRC incidence and mortality. It offers a nuanced understanding of how various screening statuses impact CRC risks, thus providing valuable insights for public health strategies aimed at CRC prevention.
Nasopharyngeal carcinoma is a significant health challenge that is particularly prevalent in Southeast Asia and North Africa. MRI is the preferred diagnostic tool for NPC due to its superior soft tissue contrast. The accurate segmentation of NPC in MRI is crucial for effective treatment planning and prognosis. We conducted a search across PubMed, Embase, and Web of Science from inception up to 20 March 2024, adhering to the PRISMA 2020 guidelines. Eligibility criteria focused on studies utilizing DL for NPC segmentation in adults via MRI. Data extraction and meta-analysis were conducted to evaluate the performance of DL models, primarily measured by Dice scores. We assessed methodological quality using the CLAIM and QUADAS-2 tools, and statistical analysis was performed using random effects models. The analysis incorporated 17 studies, demonstrating a pooled Dice score of 78% for DL models (95% confidence interval: 74% to 83%), indicating a moderate to high segmentation accuracy by DL models. Significant heterogeneity and publication bias were observed among the included studies. Our findings reveal that DL models, particularly convolutional neural networks, offer moderately accurate NPC segmentation in MRI. This advancement holds the potential for enhancing NPC management, necessitating further research toward integration into clinical practice.
Human cytochrome P450 1B1 enzyme (hCYP1B1), a member of hCYP1 subfamily, plays a crucial role in multiple diseases by participating in many metabolic pathways. Although a suite of potent hCYP1B1 inhibitors have been previously reported, most of them also act as aryl hydrocarbon receptor (AhR) agonists that can up-regulate the expression of hCYP1B1 and then counteract their inhibitory potential in living systems. This study aimed to develop novel efficacious hCYP1B1 inhibitors that worked well in living cells but without AhR agonist effects. For these purposes, a series of 1,8-naphthalimide derivatives were designed and synthesized, and their structure-activity relationships (SAR) as hCYP1B1 inhibitors were analyzed. Following three rounds SAR studies, several potent hCYP1B1 inhibitors were discovered, among which compound 3n was selected for further investigations owing to its extremely potent anti-hCYP1B1 activity (IC50 = 0.040 nM) and its blocking AhR transcription activity in living cells. Inhibition kinetic analyses showed that 3n potently inhibited hCYP1B1 via a mix inhibition manner, showing a Ki value of 21.71 pM. Docking simulations suggested that introducing a pyrimidine moiety to the hit compound (1d) facilitated 3n to form two strong interactions with hCYP1B1/heme, viz., the C-Brâ¯π halogen bond and the N-Fe coordination bond. Further investigations demonstrated that 3n (5 µM) could significantly reverse the paclitaxel (PTX) resistance in H460/PTX cells, evidenced by the dramatically reduced IC50 values, from 632.6 nM (PTX alone) to 100.8 nM (PTX plus 3n). Collectively, this study devised a highly potent hCYP1B1 inhibitor (3n) without AhR agonist effect, which offered a promising drug candidate for overcoming hCYP1B1-associated drug resistance.
Cytochrome P-450 CYP1B1 , Drug Design , Naphthalimides , Humans , Structure-Activity Relationship , Naphthalimides/pharmacology , Naphthalimides/chemistry , Naphthalimides/chemical synthesis , Cytochrome P-450 CYP1B1/antagonists & inhibitors , Cytochrome P-450 CYP1B1/metabolism , Molecular Structure , Dose-Response Relationship, Drug
Environmental factors in early life have been demonstrated to increase the risk of neurodevelopmental disorders in offspring, especially the deficiency of the cognitive ability. Leptin has emerged as a key hormone that conveys information on energy stores, but there is growing appreciation that leptin signaling may also play an important role in neurodevelopment. The present study aimed to investigate whether maternal HFD exposure impairs the offspring learning and memory through the programming of central leptin system. We observed that hippocampus-dependent learning and memory were impaired in male but not female offspring from HFD-fed maternal ancestors (C57BL/6 mice), as assessed by novel object recognition and Morris water maze tests. Moreover, the chromatin immunoprecipitation results revealed the maternal HFD consumption led to the increasement in the binding of the histone marker H3K9me3 in male offspring, which mediates gene silencing in the leptin receptor promoter region. Furthermore, there was an increase in the expression of the histone methylase SUV39H1 in male but not female offspring, which regulates H3K9me3. Additionally, it has been observed that IL-6 and IL-1 also could lead to similar alternations when acting on cultured hippocampal neurons in vitro. Taken together, our data suggest that maternal HFD consumption influences male offspring hippocampal cognitive performance in a sex-specific manner, and central leptin signaling may serve as the cross-talk between maternal diet and cognitive impairment in offspring.
Diet, High-Fat , Hippocampus , Leptin , Mice, Inbred C57BL , Prenatal Exposure Delayed Effects , Signal Transduction , Spatial Learning , Animals , Female , Male , Hippocampus/metabolism , Leptin/metabolism , Diet, High-Fat/adverse effects , Mice , Spatial Learning/physiology , Prenatal Exposure Delayed Effects/metabolism , Pregnancy , Signal Transduction/physiology , Sex Characteristics , Neurons/metabolism , Histones/metabolism , Receptors, Leptin/metabolism , Receptors, Leptin/genetics
This study aims to identify FDA-approved drugs that can target the kappa-opioid receptor (KOR) for the treatment of demyelinating diseases. Demyelinating diseases are characterized by myelin sheath destruction or formation that results in severe neurological dysfunction. Remission of this disease is largely dependent on the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLGs) in demyelinating lesions. KOR is an important regulatory protein and drug target for the treatment of demyelinating diseases. However, no drug targeting KOR has been developed due to the long clinical trials for drug discovery. Here, a structure-based virtual screening was applied to identify drugs targeting KOR among 1843 drugs of FDA-approved drug libraries, and famotidine was screen out by its high affinity cooperation with KOR as well as the clinical safety. We discovered that famotidine directly promoted OPC maturation and remyelination using the complementary in vitro and in vivo models. Administration of famotidine was not only effectively enhanced CNS myelinogenesis, but also promoted remyelination. Mechanically speaking, famotidine promoted myelinogenesis or remyelination through KOR/STAT3 signaling pathway. In general, our study provided evidence of new clinical applicability of famotidine for the treatment of demyelinating diseases for which there is currently no effective therapy.
Cell Differentiation , Famotidine , Receptors, Opioid, kappa , Remyelination , STAT3 Transcription Factor , Signal Transduction , Famotidine/pharmacology , STAT3 Transcription Factor/metabolism , Animals , Signal Transduction/drug effects , Cell Differentiation/drug effects , Remyelination/drug effects , Receptors, Opioid, kappa/metabolism , Oligodendrocyte Precursor Cells/drug effects , Oligodendrocyte Precursor Cells/metabolism , Oligodendrocyte Precursor Cells/cytology , Central Nervous System/drug effects , Central Nervous System/metabolism , Mice , Rats , Oligodendroglia/drug effects , Oligodendroglia/metabolism , Oligodendroglia/cytology , Myelin Sheath/metabolism , Myelin Sheath/drug effects , Demyelinating Diseases/drug therapy , Demyelinating Diseases/metabolism , Humans
Current guidelines encourage large studies in a diverse population to establish normal reference ranges for three-dimensional (3D) echocardiography for different ethnic groups. This study was designed to establish the normal values of 3D-left ventricular (LV) and left atrial (LA) volume and function in a nationwide, population-based cohort of healthy Han Chinese adults. A total of 1117 healthy volunteers aged 18-89 years were enrolled from 28 collaborating laboratories in China. Two sets of 3D echocardiographic instruments were used, and full-volume echocardiographic images were recorded and transmitted to a core laboratory for image analysis with a vendor-independent off-line workstation. Finally, 866 volunteers (mean age of 48.4 years, 402 men) were qualified for final analysis. Most parameters exhibited substantial differences between different sex and age groups, even after indexation by body surface area. The normal ranges of 3D-LV and 3D-LA volume and function differed from those recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines, presented by the World Alliance Societies of Echocardiography (WASE) study, and from the 2D values in the EMINCA study. The normal reference values of 3D echocardiography-derived LV and LA volume and function were established for the first time in healthy Han Chinese adults. Normal ranges of 3D-LV and 3D-LA echocardiographic measurements stratified with sex, age, and race should be recommended for clinical applications.
Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren's syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg-1·d-1) or hydroxychloroquine (50 mg·kg-1·d-1) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg-1·d-1) was more effective than hydroxychloroquine (50 mg·kg-1·d-1). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.
Squamosa Promoter Binding Protein-Like (SPL) plays a crucial role in regulating plant development and combating stress, yet its mechanism in regulating resistance to Cd toxicity remains unclear. In this study, we cloned a nuclear-localized transcription factor, NtSPL4a, from the tobacco cultivar TN90. Transient co-expression results showed that miR156 significantly reduced the expression of NtSPL4a by binding to the 3'-UTR of its transcript. We obtained transgenic tobacco overexpressing NtSPL4a (including the 3'-UTR) and NtSPL4aΔ (lacking the 3'-UTR) through Agrobacterium-mediated genetic transformation. Compared to the wild type (WT), overexpression of NtSPL4a/NtSPL4aΔ shortened the flowering time and exhibited a more developed root system. The transgenic tobacco showed significantly reduced Cd content, being 85.1% (OE-NtSPL4a) and 46.7% (OE-NtSPL4aΔ) of WT, respectively. Moreover, the upregulation of NtSPL4a affected the mineral nutrient homeostasis in transgenic tobacco. Additionally, overexpression of NtSPL4a/NtSPL4aΔ effectively alleviated leaf chlorosis and oxidative stress induced by Cd toxicity. One possible reason is that the overexpression of NtSPL4a/NtSPL4aΔ can effectively promote the accumulation of non-enzymatic antioxidants. A comparative transcriptomic analysis was performed between transgenic tobacco and WT to further unravel the global impacts brought by NtSPL4a. The tobacco overexpressing NtSPL4a had 183 differentially expressed genes (77 upregulated, 106 downregulated), while the tobacco overexpressing NtSPL4aΔ had 594 differentially expressed genes (244 upregulated, 350 downregulated) compared to WT. These differentially expressed genes mainly included transcription factors, metal transport proteins, flavonoid biosynthesis pathway genes, and plant stress-related genes. Our study provides new insights into the role of the transcript factor SPL in regulating Cd tolerance.
Cadmium , Gene Expression Regulation, Plant , Nicotiana , Plant Proteins , Plants, Genetically Modified , Nicotiana/genetics , Nicotiana/metabolism , Nicotiana/drug effects , Cadmium/toxicity , Cadmium/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
BACKGROUND: Regular physical activity during childhood and adolescence is beneficial to bone development, as evidenced by the ability to increase bone density and peak bone mass by promoting bone formation. AIM: To investigate the effects of exercise on bone formation in growing mice and to investigate the underlying mechanisms. METHODS: 20 growing mice were randomly divided into two groups: Con group (control group, n = 10) and Ex group (treadmill exercise group, n = 10). Hematoxylin-eosin staining, immunohistochemistry, and micro-CT scanning were used to assess the bone formation-related indexes of the mouse femur. Bioinformatics analysis was used to find potential miRNAs targets of long non-coding RNA H19 (lncRNA H19). RT-qPCR and Western Blot were used to confirm potential miRNA target genes of lncRNA H19 and the role of lncRNA H19 in promoting osteogenic differentiation. RESULTS: Compared with the Con group, the expression of bone morphogenetic protein 2 was also significantly increased. The micro-CT results showed that 8 wk moderate-intensity treadmill exercise significantly increased bone mineral density, bone volume fraction, and the number of trabeculae, and decreased trabecular segregation in the femur of mice. Inhibition of lncRNA H19 significantly upregulated the expression of miR-149 and suppressed the expression of markers of osteogenic differentiation. In addition, knockdown of lncRNA H19 significantly downregulated the expression of autophagy markers, which is consistent with the results of autophagy-related protein changes detected in mouse femurs by immunofluorescence. CONCLUSION: Appropriate treadmill exercise can effectively stimulate bone formation and promote the increase of bone density and bone volume in growing mice, thus enhancing the peak bone mass of mice. The lncRNA H19/miR-149 axis plays an important regulatory role in osteogenic differentiation.
Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti-IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23-driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes.
Interleukin-23 , Humans , Interleukin-23/antagonists & inhibitors , Interleukin-23/immunology , Interleukin-23/metabolism , Animals , Signal Transduction , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/therapy , Psoriasis/immunology , Psoriasis/drug therapy , Arthritis, Psoriatic/immunology , Arthritis, Psoriatic/drug therapy
Advance care planning (ACP) has the potential to improve the outcomes of end-of-life care for residents in nursing homes. The aim of this study was to determine whether an ACP program was beneficial for nursing home residents by assessing end-of-life indicators. An experimental study with a retrospective chart review was conducted. In total, 37 residents in the intervention group participated in an institutional advance care planning program for 1 year, and their chart data over 1 year were collected following the completion of the program; 33 residents in the control group had died within 1 year before the start date of program, and their chart data were reviewed retrospectively. Chi-square and t tests were used to examine four indicators of the quality of end-of-life care. Compared with the control group, the intervention group had a higher proportion of do-not-resuscitate directives, hospice care before death, and deaths in the nursing home, and fewer hospitalizations and deaths in an emergency department. ACP programs may improve the quality of end-of-life care for nursing home residents in Taiwan. Further research across different long-term care facilities is warranted.
Safflopentsides A-C (1-3), three highly oxidized rearranged derivatives of quinochalcone C-glycosides, were isolated from the safflower yellow pigments. Their structures were determined based on a detailed spectroscopic analysis (UV, IR, HR-ESI-MS, 1D and 2D NMR), and the absolute configurations were confirmed by the comparison of experimental ECD spectra with calculated ECD spectra. Compounds 1-3 have an unprecedented cyclopentenone or cyclobutenolide ring A containing C-glucosyl group, respectively. The plausible biosynthetic pathways of compounds have been presented. At 10 µM, 2 showed strong inhibitory activity against rat cerebral cortical neurons damage induced by glutamate and oxygen sugar deprivation.
Carthamus tinctorius , Glycosides , Oxidation-Reduction , Glycosides/chemistry , Glycosides/pharmacology , Glycosides/isolation & purification , Animals , Carthamus tinctorius/chemistry , Rats , Molecular Structure , Neurons/drug effects , Structure-Activity Relationship , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/isolation & purification , Dose-Response Relationship, Drug , Cerebral Cortex/drug effects , Chalcones/pharmacology , Chalcones/chemistry , Chalcones/isolation & purification
MicroRNA-29a (miR-29a) has been suggested to serve a potential protective function against Parkinson's disease (PD); however, the exact molecular mechanisms remain elusive. This study explored the protective role of miR-29a in a cellular model of PD using SH-SY5Y cell lines through iTRAQ-based quantitative proteomic and biochemistry analysis. The findings showed that using a miR-29a mimic in SH-SY5Y cells treated with 1-methyl-4-phenylpyridinium (MPP+) significantly decreased cell death and increased mitochondrial membrane potential. It also reduced mitochondrial reactive oxygen species (ROS) and the production of α-synuclein. Subsequent heatmap analysis using iTRAQ-based quantitative proteomics revealed remarkably contrasting protein expression profiles for 882 genes when comparing the groups treated with miR-29a mimic plus MPP + against the control group treated solely with MPP+. The KEGG pathway analysis of these 882 genes indicated the substantial role of miR-29a in the PD pathway (P = 1.58x10-5) and highlighted its function in mitochondrial genes. Furthermore, treatment with a miR-29a mimic in SH-SY5Y cells reduced the levels of GSK-3ß, phosphorylated GSK-3ß, and cleaved caspase-7 following exposure to MPP+. The miR-29a mimic also upregulated the expressions of α-synuclein clearance proteins FYCO1 and Rab7 in this cellular PD model, thereby inhibiting the production of α-synuclein. Luciferase activity analysis confirmed the specific binding of miR-29a to the 3' untranslated region (3'UTR) of GSK-3ß, leading to its repression. Our findings demonstrated miR-29a's neuroprotective role in mitochondrial function and highlighted its potential to inhibit ROS and α-synuclein production, offering possible therapeutic avenues for PD treatment.
Glycogen Synthase Kinase 3 beta , MicroRNAs , Parkinson Disease , Reactive Oxygen Species , alpha-Synuclein , MicroRNAs/genetics , MicroRNAs/metabolism , Humans , alpha-Synuclein/genetics , alpha-Synuclein/metabolism , Reactive Oxygen Species/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3 beta/genetics , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology , Cell Line, Tumor , Mitochondria/metabolism , Mitochondria/drug effects , Membrane Potential, Mitochondrial/drug effects , 1-Methyl-4-phenylpyridinium/toxicity
BACKGROUND: The World Health Organization aims for the global elimination of cervical cancer, necessitating modeling studies to forecast long-term outcomes. OBJECTIVE: This paper introduces a macrosimulation framework using age-period-cohort modeling and population attributable fractions to predict the timeline for eliminating cervical cancer in Taiwan. METHODS: Data for cervical cancer cases from 1997 to 2016 were obtained from the Taiwan Cancer Registry. Future incidence rates under the current approach and various intervention strategies, such as scaled-up screening (cytology based or human papillomavirus [HPV] based) and HPV vaccination, were projected. RESULTS: Our projections indicate that Taiwan could eliminate cervical cancer by 2050 with either 70% compliance in cytology-based or HPV-based screening or 90% HPV vaccination coverage. The years projected for elimination are 2047 and 2035 for cytology-based and HPV-based screening, respectively; 2050 for vaccination alone; and 2038 and 2033 for combined screening and vaccination approaches. CONCLUSIONS: The age-period-cohort macrosimulation framework offers a valuable policy analysis tool for cervical cancer control. Our findings can inform strategies in other high-incidence countries, serving as a benchmark for global efforts to eliminate the disease.
Papillomavirus Infections , Uterine Cervical Neoplasms , Humans , Female , Benchmarking , Cohort Studies , Taiwan
