Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Acute Myocardial Infarction With or Without Type 2 Diabetes: A Systematic Review and Meta-analysis.

ABSTRACT: Recent studies have revealed the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure patients. However, their effects on acute myocardial infarction (AMI) remain uncertain. Therefore, we conducted this meta-analysis to assess the effectiveness of SGLT2i in patients with AMI with or without diabetes. We conducted a comprehensive search of PubMed, Embase, and Cochrane Library encompassing data from inception until November 30, 2023. Relevant studies comparing SGLT2i with placebo or non-SGLT2i in patients with AMI were included. The mean difference and/or odds ratio (OR) with 95% confidence intervals were pooled using a fixed-effects model when the heterogeneity statistic (I2) was less than 50%; otherwise, a random-effects model was employed. Four randomized controlled trials and 4 observational studies involving 9397 patients with AMI were included in this meta-analysis. Patients treated with SGLT2i exhibited a significantly lower rate of hospitalization for heart failure (OR = 0.50, 95% CI: 0.32-0.80) and all-cause death (OR = 0.65, 95% CI: 0.44-0.95) compared with those treated with placebo or non-SGLT2i. Furthermore, the use of SGLT2i was associated with a significant increase in left ventricular ejection fraction (mean difference = 1.90, 95% CI: 1.62-2.17) and a greater reduction of N-terminal prohormone of brain natriuretic peptide (OR = 0.88, 95% CI 0.82-0.94). Subgroup analysis revealed that in patients with diabetes, SGLT2i exhibited similar effects. The present meta-analysis provided evidence indicating the effectiveness of SGLT2i in patients with AMI; SGLT2i may serve as an additional therapeutic option for patients with AMI, regardless of the presence or absence of diabetes.

Photocatalytic Hydrosilylation over Pt@UiO-66-NH2: Enhanced Activity and Polymerization Kinetics.

Metal-organic frameworks (MOFs) have shown great research and application value in various types of hydrosilylation reactions. However, studies on photocatalysis-induced hydrosilylation using MOFs are extremely rare. Metal nanoparticles (MNPs)@MOFs are extensively studied for their excellent structural tunability and photocatalytic activity, but there are few reports on their application in photocatalytic hydrosilylation. Here, a novel photocatalyst consisting of platinum (Pt) nanoparticles immobilized in a MOF framework is synthesized and used for photocatalytic hydrosilylation. The effects of various factors on hydrosilylation conversion are investigated, including catalyst concentration, substrate ratio, and irradiation intensity. Furthermore, the photoreactivity of the synthesized Pt catalyst is evaluated in the presence of different concentrations of 2-chlorothixanthone as a photosensitizer. It is noteworthy that the conversion of the reaction increases with increasing catalyst concentration or photosensitizer concentration, whereas increasing the polymethylhydrosiloxane content does not lead to a significant increase in conversion. This study demonstrates the potential of MNPs@MOFs as efficient photocatalysts for photoinduced hydrosilylation reactions and paves the way for future applications in this area.

Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions.

BACKGROUND: Compromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer's disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA's long-term treatment of AD and mechanisms of action are unknown. METHODS: We addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches. RESULTS: Long-term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aß) and tau pathologies and enhanced long-term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA-induced therapeutic effects on AD. CONCLUSIONS: Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA. HIGHLIGHTS: Long-term urolithin A (UA) treatment improved learning, memory, and olfactory function in Alzheimer's disease (AD) mice. UA restored lysosomal functions in part by regulating cathepsin Z (Ctsz) protein. UA modulates immune responses and AD-specific pathophysiological pathways.

Discrimination and prediction of Qingzhuan tea storage year using quantitative chemical profile combined with multivariate analysis: Advantages of MRMHR based targeted quantification metabolomics.

The duration of storage significantly influences the quality and market value of Qingzhuan tea (QZT). Herein, a high-resolution multiple reaction monitoring (MRMHR) quantitative method for markers of QZT storage year was developed. Quantitative data alongside multivariate analysis were employed to discriminate and predict the storage year of QZT. Furthermore, the content of the main biochemical ingredients, catechins and alkaloids, and free amino acids (FAA) were assessed for this purpose. The results show that targeted marker-based models exhibited superior discrimination and prediction performance among four datasets. The R2Xcum, R2Ycum and Q2cum of orthogonal projection to latent structure-discriminant analysis discrimination model were close to 1. The correlation coefficient (R2) and the root mean square error of prediction of the QZT storage year prediction model were 0.9906 and 0.63, respectively. This study provides valuable insights into tea storage quality and highlights the potential application of targeted markers in food quality evaluation.

Interactions between mitochondrial dysfunction and other hallmarks of aging: Paving a path toward interventions that promote healthy old age.

Current research on human aging has largely been guided by the milestone paper "hallmarks of aging," which were first proposed in the seminal 2013 paper by Lopez-Otin et al. Most studies have focused on one aging hallmark at a time, asking whether the underlying molecular perturbations are sufficient to drive the aging process and its associated phenotypes. More recently, researchers have begun to investigate whether aging phenotypes are driven by concurrent perturbations in molecular pathways linked to not one but to multiple hallmarks of aging and whether they present different patterns in organs and systems over time. Indeed, preliminary results suggest that more complex interactions between aging hallmarks must be considered and addressed, if we are to develop interventions that successfully promote healthy aging and/or delay aging-associated dysfunction and diseases. Here, we summarize some of the latest work and views on the interplay between hallmarks of aging, with a specific focus on mitochondrial dysfunction. Indeed, this represents a significant example of the complex crosstalk between hallmarks of aging and of the effects that an intervention targeted to a specific hallmark may have on the others. A better knowledge of these interconnections, of their cause-effect relationships, of their spatial and temporal sequence, will be very beneficial for the whole aging research field and for the identification of effective interventions in promoting healthy old age.

Salidroside promotes healthy longevity by interfering with HSP90 activity.

Aging is a risk factor for human health and quality of life. Screening and development of novel supplements and medications to combat aging and delay the incidence of age-related diseases are of great significance. In this study, salidroside (SA), a primary natural small molecule from Rhodiola rosea, was investigated regarding its effects on life and healthspan and the underlying molecular mechanism(s) of anti-aging and antioxidation. Our results showed that SA effectively prolonged lifespan and exhibited anti-aging and antioxidative properties. Computer-assisted methods, label-free interaction analysis, and in vitro assays showed that SA directly bound heat shock protein 90 (HSP90). Furthermore, SA significantly inhibited the ATPase activity of HSP90, affecting the interaction between HSP90 and its interacting proteins and the expression of downstream genes to regulate lifespan and the oxidative stress response. Our findings provided new insights into the pharmacological properties of SA across multiple species and its potential as an anti-aging drug.

Structural Engineering of Co-Metal-Organic Frameworks via Ce Incorporation for Improved Oxygen Evolution.

The rational design of metal-organic framework (MOF)-based electrocatalysts plays a key role in achieving high-efficiency oxygen evolution reaction (OER). Herein, a synergetic morphology and electronic structure engineering strategy are proposed to design a Co-MOF nanoflower grown on carbon paper via rare-earth cerium doping (CoCe-MOF/CP). Compared with Co-MOF/CP, the developed CoCe-MOF/CP exhibited superior OER performance with a low overpotential of 267 mV at 10 mA cm-2 and outstanding long-term stability over 100 h. Theoretical calculations show that the unique 4f valence electron structure of Ce induced charge redistribution of the Co-MOF surface through the strong Co 3d-O 2p-Ce 4f orbital electronic coupling below the Fermi level. Ce-doped plays a key role in the engineering of the electronic states of the Co sites to endow them with the optimal free energy landscape for enhanced OER catalytic activity. This work provides new insights into comprehending the RE-enhanced mechanism of electrocatalysis and provides an effective strategy for the design of MOF-based electrocatalysts.

Revealing the chemical differences and their application in the storage year prediction of Qingzhuan tea by SWATH-MS based metabolomics analysis.

It's generally believed that the longer the storage, the better the quality of dark tea, but the chemical differences of Qingzhuan tea (QZT) with different storage years is still unclear. Herein, in this work, an untargeted metabolomic approach based on SWATH-MS was established to investigate the differential compounds of QZT with 0-9 years' storage time. These QZT samples were roughly divided into two categories by principal component analysis (PCA). After orthogonal projections to latent structures discriminant analysis (OPLS-DA), 18 differential compounds were putatively identified as chemical markers for the storage year variation of QZT. Heatmap visualization showed that the contents of catechins, fatty acids, and some phenolic acids significantly reduced, flavonoid glycosides, triterpenoids, and 8-C N-ethyl-2-pyrrolidinone-substituted flavan-3-ols (EPSFs) increased with the increase of storage time. Furthermore, these chemical markers were verified by the peak areas corresponding to MS2 ions from SWATH-MS. Based on the extraction chromatographic peak areas of MS and MS2 ions, a duration time prediction model was built for QZT with correlation coefficient R2 of 0.9080 and 0.9701, and RMSEP value of 0.85 and 1.24, respectively. This study reveals the chemical differences of QZT with different storage years and provides a theoretical basis for the quality evaluation of stored dark tea.

Polyphenols in Oral Health: Homeostasis Maintenance, Disease Prevention, and Therapeutic Applications.

Polyphenols, a class of bioactive compounds with phenolic structures, are abundant in human diets. They have gained attention in biomedical fields due to their beneficial properties, including antioxidant, antibacterial, and anti-inflammatory activities. Therefore, polyphenols can prevent multiple chronic or infectious diseases and may help in the prevention of oral diseases. Oral health is crucial to our well-being, and maintaining a healthy oral microbiome is essential for preventing various dental and systemic diseases. However, the mechanisms by which polyphenols modulate the oral microbiota and contribute to oral health are still not fully understood, and the application of polyphenol products lies in different stages. This review provides a comprehensive overview of the advancements in understanding polyphenols' effects on oral health: dental caries, periodontal diseases, halitosis, and oral cancer. The mechanisms underlying the preventive and therapeutic effects of polyphenols derived from dietary sources are discussed, and new findings from animal models and clinical trials are included, highlighting the latest achievements. Given the great application potential of these natural compounds, novel approaches to dietary interventions and oral disease treatments may emerge. Moreover, investigating polyphenols combined with different materials presents promising opportunities for developing innovative therapeutic strategies in the treatment of oral diseases.

Rev1 deficiency induces a metabolic shift in MEFs that can be manipulated by the NAD+ precursor nicotinamide riboside.

Replication stress, caused by Rev1 deficiency, is associated with mitochondrial dysfunction, and metabolic stress. However, the overall metabolic alterations and possible interventions to rescue the deficits due to Rev1 loss remain unclear. Here, we report that loss of Rev1 leads to intense changes in metabolites and that this can be manipulated by NAD + supplementation. Autophagy decreases in Rev1-/- mouse embryonic fibroblasts (MEFs) and can be restored by supplementing the NAD+ precursor nicotinamide riboside (NR). The abnormal mitochondrial morphology in Rev1-/- MEFs can be partially reversed by NR supplementation, which also protects the mitochondrial cristae from rotenone-induced degeneration. In nematodes rev-1 deficiency causes sensitivity to oxidative stress but this cannot be rescued by NR supplementation. In conclusion, Rev1 deficiency leads to metabolic dysregulation of especially lipid and nucleotide metabolism, impaired autophagy, and mitochondrial anomalies, and all of these phenotypes can be improved by NR replenishment in MEFs.

Pooled analysis of frontal lobe transcriptomic data identifies key mitophagy gene changes in Alzheimer's disease brain.

Background: The growing prevalence of Alzheimer's disease (AD) is becoming a global health challenge without effective treatments. Defective mitochondrial function and mitophagy have recently been suggested as etiological factors in AD, in association with abnormalities in components of the autophagic machinery like lysosomes and phagosomes. Several large transcriptomic studies have been performed on different brain regions from AD and healthy patients, and their data represent a vast source of important information that can be utilized to understand this condition. However, large integration analyses of these publicly available data, such as AD RNA-Seq data, are still missing. In addition, large-scale focused analysis on mitophagy, which seems to be relevant for the aetiology of the disease, has not yet been performed. Methods: In this study, publicly available raw RNA-Seq data generated from healthy control and sporadic AD post-mortem human samples of the brain frontal lobe were collected and integrated. Sex-specific differential expression analysis was performed on the combined data set after batch effect correction. From the resulting set of differentially expressed genes, candidate mitophagy-related genes were identified based on their known functional roles in mitophagy, the lysosome, or the phagosome, followed by Protein-Protein Interaction (PPI) and microRNA-mRNA network analysis. The expression changes of candidate genes were further validated in human skin fibroblast and induced pluripotent stem cells (iPSCs)-derived cortical neurons from AD patients and matching healthy controls. Results: From a large dataset (AD: 589; control: 246) based on three different datasets (i.e., ROSMAP, MSBB, & GSE110731), we identified 299 candidate mitophagy-related differentially expressed genes (DEG) in sporadic AD patients (male: 195, female: 188). Among these, the AAA ATPase VCP, the GTPase ARF1, the autophagic vesicle forming protein GABARAPL1 and the cytoskeleton protein actin beta ACTB were selected based on network degrees and existing literature. Changes in their expression were further validated in AD-relevant human in vitro models, which confirmed their down-regulation in AD conditions. Conclusion: Through the joint analysis of multiple publicly available data sets, we identify four differentially expressed key mitophagy-related genes potentially relevant for the pathogenesis of sporadic AD. Changes in expression of these four genes were validated using two AD-relevant human in vitro models, primary human fibroblasts and iPSC-derived neurons. Our results provide foundation for further investigation of these genes as potential biomarkers or disease-modifying pharmacological targets.

Juvenile hormone suppresses the FoxO-takeout axis to shorten longevity in male silkworm.

Juvenile hormone (JH) plays a crucial endocrine regulatory role in insect metamorphosis, reproduction, and longevity in multiple organisms, such as flies, honeybees, and migratory monarch butterflies. However, the molecular mechanism of JH affecting longevity remains largely unknown. In this study, we showed that JH III and its analog methoprene shortened the survival days significantly in the adulthood of male silkworm. At the same time, the allatostatin, a neuropeptide that inhibits the secretion of JH by the corpora allata, could extend the survival days dramatically after adult eclosion in male silkmoth. Interestingly, a central pro-longevity FoxO transcription factor was reduced upon JH stimulation in silkworm individuals and BmN-SWU1 cells. Furthermore, the analysis of the upstream sequence of the FoxO gene identified a JH response element which suggested that FoxO might be regulated as a target of JH. Surprisingly, we identified a Bmtakeout (BmTO) gene that encodes a JH-binding protein and contains a FoxO response element. As expected, FoxO overexpression and knockdown up- and down-regulated the expression of BmTO respectively, indicating that BmTO functions as a FoxO target. BmTO overexpression could release the inhibitory effect of JH on the BmFoxO gene by reducing JH bioavailability to block its signal transduction. Collectively, these results may provide insights into the mechanism of the JH-FoxO-TO axis in aging research and pest control.

Coumarinacyl Anilinium Salt: A Versatile Visible and NIR Photoinitiator for Cationic and Step-Growth Polymerizations.

A coumarinacyl anilinium (CAA) salt, facilely synthesized via a one-pot reaction, is shown to be a versatile visible and NIR photoinitiator for cationic and step-growth polymerizations. CAA salt exhibits superior photoinitiation performance as compared to commercial iodonium salt in cationic polymerization. Upon visible-light irradiation, this salt undergoes hemolytic and heterolytic cleavage and subsequent electron transfer and hydrogen abstraction reactions, forming reactive species capable of initiating cationic polymerization of epoxides and vinyl monomers. After a short irradiation period, polymerization also proceeds in the dark due to the non-nucleophilic nature of the counteranion. NIR-induced polymerizations were successfully conducted based on upconversion photochemistry. CAA salt can also initiate step-growth polymerization of N-ethyl carbazole (NEC) by oxidation of the monomer by the photochemically formed anilium radical cations. Subsequent proton release and radical coupling reactions essentially yield polycarbazole. CAA salt, featuring straightforward synthesis and long-wavelength sensitivity as well as versatile photoinitiating performance, has great potential in various applications.

Shift in the Mode of Carbon Cycling Recorded by Biomarkers and Carbon Isotopic Compositions in the Yanchang Formation, Ordos Basin: Autotrophy vs Heterotrophy.

Organic-rich shales and mudstones have long been investigated regarding the control of source, environment, climate, etc. on the enrichment of organic carbon. However, little is documented about how autotrophy and heterotrophy influence organic carbon cycling/export. Here, we show molecular and carbon isotopic compositional changes of the shale or mudstone source rocks from the Chang 3 to 7 members of the Yanchang Formation. The Chang 7 member source rocks have higher quality (480-500 mg/g) and total organic carbon (TOC) (15.3% on average) than other member source rocks; the sterane/hopane ratio and the δ13C of organic carbon and kerogen decrease from the Chang 3 to 7 members, but Δδ ([average δ13C of n-C17 + n-C18] - [average δ13C of pristane + phytane]) increases, and no aryl isoprenoids and C40 aromatic carotenoids (e.g., isorenieratane) were observed. These low maturity biomarker features suggest that there were no water stratification, photic zone euxinia (PZE), and no obvious change in the organic matter source, and the water column is generally anoxic. A comparison of the δ13C of Pr and Ph with the δ13C of the n-C17 and n-C18 alkanes reveals a shift in the mode of carbon cycling/export (autotrophy versus heterotrophy) in the Yanchang Formation and that there was dominant heterotrophic bacterial activity or bacterial biomass in the Chang 7 member. The TOC spike in the Chang 7 member may result from boosted carbon cycling/export that improves organic carbon preservation than other members. Possible external forcings on the shift are abundant hydrothermal- or volcanic-derived metal salts as electron acceptors in the palaeowater, which is a reasonable explanation for enhanced heterotrophic bacterial activity. This finding improves our understanding of heterotrophic bacterial activity control on organic matter (OM) preservation and may be a significant supplement for understanding the ecological or environmental forcings in the Yanchang Formation, Ordos Basin.

The impact of unified discharge standards on the clinical efficacy and prognosis of hemiarthroplasty in elderly patients with hip fractures.

OBJECTIVES: The aim of this study was to investigate the impact of unified discharge standards on the clinical efficacy and prognosis of hemiarthroplasty in elderly patients with hip fractures. METHODS: Retrospective study of 158 elderly patients with hip fractures who underwent artificial femoral head replacement in our hospital from March 2016 to July 2019 were enrolled. According to the unified discharge standards, patients were divided into the observation (65 cases who met discharge criteria) and control group (93 cases who failed to meet all discharge criteria). Histopathological feature, operation status, postoperative Harris Hip score, therapeutic outcome, postoperative complications, readmission and mortality rate were compared between the two groups. RESULTS: Surgery duration and intraoperative blood loss exhibited no difference between the two groups, while transfusion volume and length of hospital stay were significantly increased in the observation group. There was no significant difference in the Harris Hip score between the two groups 12 months postoperatively. The incidence of postoperative complications during the follow-up period was notably lower in the observation group. In addition, the three-month readmission rate and one-year mortality rate were significantly lower in the observation group. CONCLUSIONS: For elderly patients with hip fractures undergoing artificial femoral head replacement, the incidence of postoperative complications and postoperative readmission/mortality rate could be reduced through the establishment of unified discharge standards, which should be used in future clinical practice.

Lycium barbarum polysaccharide improves dopamine metabolism and symptoms in an MPTP-induced model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal models and medications await development to elucidate the aetiology of PD and attenuate the symptoms, respectively. METHODS: A neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was used in the current study to establish a PD pathologic model in silkworms. The time required to complete specific behaviours was recorded. Dopamine content was detected by ultra-performance liquid chromatography (UPLC). The activity of insect tyrosine hydroxylase (TH) was determined using a double-antibody sandwich method. Oxidative stress was assessed by changes in antioxidant enzyme activity and the content of oxidative products. RESULTS: MPTP-treated silkworms were characterized by impaired motor ability, reduced dopamine content, and elevated oxidative stress level. The expression of TH, a dopamine biosynthetic enzyme within dopaminergic neurons in the brain, was significantly reduced, indicating that dopaminergic neurons were damaged. Moreover, MPTP-induced motility impairment and reduced dopamine level in the silkworm PD model could be rescued after feeding a combination of levodopa (L-dopa [LD]) and carbidopa (CD). MPTP-induced oxidative damage was also alleviated, in ways consistent with other PD animal models. Interestingly, administration of Lycium barbarum polysaccharide (LBP) improved the motor ability, dopamine level, and TH activity, and the oxidative damage was concomitantly reduced in the silkworm PD model. CONCLUSIONS: This study provides a promising animal model for elucidating the pathogenesis of PD, as well as a relevant preliminary drug screening (e.g., LBP) and evaluation.

New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.

Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.

Degradation of iopamidol by UV365/NaClO: Roles of reactive species, degradation mechanism, and toxicology.

The degradation of iopamidol (IPM) was investigated using a UV365/NaClO system. The reactive species (HO·, ClO·, ozone, Cl·, and Cl2-·) in the system were identified, and the changing trends of the percentage contributions of these reactive species to IPM removal under various conditions were systematically evaluated. The results showed that ClO· and HO· played the most significant roles in the apparent pseudo-first-order rate constants of IPM degradation (kobs, min-1) in the control experiment, and their percentage contributions to kobs were 41.31% and 34.45%, respectively. In addition, Cl· and Cl2-· together contributed 22% to the kobs. Furthermore, the contribution of ozone to the IPM removal could be neglected. The concentrations of these species increased significantly when the concentration of NaClO was increased from 50 µM to 200 µM, while the percentage contribution of ClO· to kobs was greatly increased. The concentrations and percentage contributions of HO· and ClO· decreased significantly as the solution pH increased from 5 to 9, with Cl2-· playing a greater role in the degradation of IPM under alkaline conditions. While Cl- or HCO3-/CO32- significantly promoted the generation of Cl2-· or CO3-·, neither had an obvious effect on kobs, suggesting that Cl2-· and CO3-· should have a certain reactivity with IPM. Compared with that of Cl2-·, the percentage contribution of ClO· and Cl· to kobs was more likely to be inhibited by NOM. In addition, the organic and inorganic oxidation products of IPM were detected. The oxidation mechanisms of IPM degradation in the UV365/NaClO system, such as the H-extraction reaction, deiodination, substitution reaction, amide hydrolysis, and amine oxidation, were proposed according to the obtained 15 organic products. No effect on acute toxicity towards Vibrio fischeri and Photobacterium phosphoreum was detected during the oxidation of IPM by the UV365/NaClO system. Furthermore, the engineering feasibility of the oxidation system was demonstrated, by the effective degradation of IPM in actual water. However, HOI rapidly accumulated during the removal of IPM in the UV365/NaClO system, which poses certain environmental risks and will needs to be investigated.

Role of BLACAT1 in IL-1ß-Induced Human Articular Chondrocyte Apoptosis and Extracellular Matrix Degradation via the miR-149-5p/ HMGCR Axis.

BACKGROUND: Osteoarthritis (OA) is an inflammatory joint disorder with high incidence rates. Long non-coding RNAs (LncRNAs) influence OA development. OBJECTIVES: In this research, we attempt to figure out the functions of lncRNA BLACAT1 in human articular chondrocyte (HAC) apoptosis and extracellular matrix (ECM) degradation in OA. METHODS: Interleukin (IL)-1ß was employed to induce HAC damage. Cell viability and apoptosis were detected, with expression patterns of lncRNA BLACAT1, miR-149-5p, and HMGCR, and levels of Caspase-3, Caspase-9, BAX, Bcl-2, COL2A1, and SOX9 determined. Then, lncRNA BLACAT1 was silenced in IL-1ß-treated HACs to analyze its role in HAC damage. The target relations of lncRNA BLACAT1 and miR-149-5p and miR-149-5p and HMGCR were verified. In addition, combined experiments were performed as a miR-149-5p inhibitor or HMGCR overexpression was injected into cells with lncRNA BLACAT1 silencing. RESULTS: In IL-1ß-treated HACs, lncRNA BLACAT1 and HMGCR were overexpressed while miR- 149-5p was poorly expressed, along with reduced cell viability, enhanced apoptosis, elevated Caspase-3 and Caspase-9 activities, increased BAX level, decreased Bcl-2 level, and declined levels of COL2A1 and SOX9, which were reversed by lncRNA BLACAT1 silencing. LncRNA BLACAT1 targeted miR-149-5p, and miR-149-5p targeted HMGCR. miR-149-5p knockout or HMGCR overexpression annulled the inhibitory role of lncRNA BLACAT1 silencing in HAC apoptosis and ECM degradation. CONCLUSION: LncRNA BLACAT1 was overexpressed in IL-1ß-treated HACs, and the lncRNA BLACAT1/miR-149-5p/HMGCR ceRNA network promoted HAC apoptosis and ECM degradation.

High-Mobility Group Box 1 Inhibitor BoxA Alleviates Neuroinflammation-Induced Retinal Ganglion Cell Damage in Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) is a significant cause of vision loss and irreversible blindness worldwide. It is defined as retinal ganglion cell death and axon degeneration caused by injury. Optic nerve crush (ONC), a well-validated model of TON, activates retinal microglia and initiates neuroinflammation. High-mobility group box 1 (HMGB1), a non-histone chromosomal binding protein in the nucleus of eukaryotic cells, is an important inducer of microglial activation and pro-inflammatory cytokine release. The purpose of this study was to examine the protective effects and mechanism of the HMGB1 inhibitor BoxA to neuroinflammation-induced retinal ganglion cells (RGCs) damage in traumatic optic neuropathy. For that purpose, an optic nerve crush model was established in C57BL/6J mice at 10-12 weeks. Model mice received an intravitreal injection of PBS and the HMGB1 inhibitor BoxA. Our data demonstrated that HMGB1 expression increased after optic nerve crush. Retinal ganglion cell function and morphology were damaged, and retinal ganglion cell numbers were reduced after optic nerve crush. Intravitreal injection of BoxA after ONC can alleviate damage. Furthermore, BoxA reduced microglial activation and expression levels of nuclear factor κB (NF-kB), nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC) in experimental ONC mice. In summary, HMGB1 mediates NLRP3 inflammasome via NF-kB to participate in retinal inflammatory injury after ONC. Thus, intravitreal injection of BoxA has potential therapeutic benefits for the effective treatment of RGC death to prevent TON.