PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury.

Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.

Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction.

Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial.

Saturated fatty acids increase LPI to reduce FUNDC1 dimerization and stability and mitochondrial function.

Ectopic lipid deposition and mitochondrial dysfunction are common etiologies of obesity and metabolic disorders. Excessive dietary uptake of saturated fatty acids (SFAs) causes mitochondrial dysfunction and metabolic disorders, while unsaturated fatty acids (UFAs) counterbalance these detrimental effects. It remains elusive how SFAs and UFAs differentially signal toward mitochondria for mitochondrial performance. We report here that saturated dietary fatty acids such as palmitic acid (PA), but not unsaturated oleic acid (OA), increase lysophosphatidylinositol (LPI) production to impact on the stability of the mitophagy receptor FUNDC1 and on mitochondrial quality. Mechanistically, PA shifts FUNDC1 from dimer to monomer via enhanced production of LPI. Monomeric FUNDC1 shows increased acetylation at K104 due to dissociation of HDAC3 and increased interaction with Tip60. Acetylated FUNDC1 can be further ubiquitinated by MARCH5 for proteasomal degradation. Conversely, OA antagonizes PA-induced accumulation of LPI, and FUNDC1 monomerization and degradation. A fructose-, palmitate-, and cholesterol-enriched (FPC) diet also affects FUNDC1 dimerization and promotes its degradation in a non-alcoholic steatohepatitis (NASH) mouse model. We thus uncover a signaling pathway that orchestrates lipid metabolism with mitochondrial quality.

Does PM1 exposure during pregnancy impact the gut microbiota of mothers and neonates?

BACKGROUND: Ambient air pollutant exposure can change the composition of gut microbiota at 6-months of age, but there is no epidemiological evidence on the impacts of exposure to particulate matter with an aerodynamic diameter ≤1 µm (PM1) during pregnancy on gut microbiota in mothers and neonates. We aimed to determine if gestational PM1 exposure is associated with the gut microbiota of mothers and neonates. METHODS: Leveraging a mother-infant cohort from the central region of China, we estimated the exposure concentrations of PM1 during pregnancy based on residential address records. The gut microbiota of mothers and neonates was analyzed using 16 S rRNA V3-V4 gene sequences. Functional pathway analyses of 16 S rRNA V3-V4 bacterial communities were conducted using Tax4fun. The impact of PM1 exposure on α-diversity, composition, and function of gut microbiota in mothers and neonates was evaluated using multiple linear regression, controlling for nitrogen dioxide (NO2) and ozone (O3). Permutation multivariate analysis of variance (PERMANOVA) was used to analyze the interpretation degree of PM1 on the sample differences at the OTU level using the Bray-Curtis distance algorithm. RESULTS: Gestational PM1 exposure was positively associated with the α-diversity of gut microbiota in neonates and explained 14.8% (adj. P = 0.026) of the differences in community composition among neonatal samples. In contrast, gestational PM1 exposure had no impact on the α- and ß-diversity of gut microbiota in mothers. Gestational PM1 exposure was positively associated with phylum Actinobacteria of gut microbiota in mothers, and genera Clostridium_sensu_stricto_1, Streptococcus, Faecalibacterium of gut microbiota in neonates. At Kyoto Encyclopedia of Genes and Genomes pathway level 3, the functional analysis results showed that gestational PM1 exposure significantly down-regulated Nitrogen metabolism in mothers, as well as Two-component system and Pyruvate metabolism in neonates. While Purine metabolism, Aminoacyl-tRNA biosynthesis, Pyrimidine metabolism, and Ribosome in neonates were significantly up-regulated. CONCLUSIONS: Our study provides the first evidence that exposure to PM1 has a significant impact on the gut microbiota of mothers and neonates, especially on the diversity, composition, and function of neonatal meconium microbiota, which may have important significance for maternal health management in the future.

Evaluation of the Anti-Diabetic Activity of Polysaccharide from Cordyceps cicadae in Experimental Diabetic Rats.

Cordyceps cicadae is a medicinal fungus used in treating night sweat, childhood convulsions, vision improvement and pain. This study was designed to evaluate the anti-diabetic activity of the crude polysaccharide (SHF) from the mycelium and body portion of C. cicadae. Diabetes mellitus was induced in the rat with a single intravenous injection of alloxan monohydrate (150 mg/kg). In other to evaluate the anti-diabetic effects of C. cicadae polysaccharide in alloxan-induced diabetic rats, the crude polysaccharide (SHF at 100, 200 and 400 mg/kg body weight) and glibenclamide were administered orally to diabetic rats for 30 days. Blood glucose level, total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphate (ALP), creatinine (CREA), urea, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH) were determined. SHF showed significant reduction in blood glucose in diabetic rats. Treatment of diabetic rats also resulted an improvement in body weights, increased HDL, SOD and GSH, as well as decreased TC, TG, LDL, MDA, urea, CREA, ALT, AST and ALP. These results suggested that C. cicadae polysaccharide displayed anti-hyperglycemic, anti-hyperlipidemic and antioxidant activities and could be a promising therapeutic source in managing diabetes mellitus and its associated complications.

Prenatal Gut Microbiota Predicts Temperament in Offspring at 1-2 Years.

The purpose of this study was to explore whether prenatal gut microbiota (GM) and its functions predict the development of offspring temperament. A total of 53 mothers with a 1-year-old child and 41 mothers with a 2-year-old child were included in this study using a mother-infant cohort from central China. Maternal fecal samples collected during the third trimester were analyzed using 16S rRNA V3-V4 gene sequences. Temperament of the child was measured by self-reported data according to the primary caregiver. The effects of GM in mothers on offspring's temperament were evaluated using multiple linear regression models. The results demonstrated that the alpha diversity index Simpson of prenatal GM was positively associated with the activity level of offspring at 1 year (adj. P = .036). Bifidobacterium was positively associated with high-intensity pleasure characteristics of offspring at 1 year (adj. P = .031). Comparatively, the presence of Bifidobacterium found in the prenatal microbiome was associated with low-intensity pleasure characteristics in offspring at 2 years (adj. P = .031). There were many significant associations noted among the functional pathways of prenatal GM and temperament of offspring at 2 years. Our findings support the maternal-fetal GM axis in the setting of fetal-placental development with subsequent postnatal neurocognitive developmental outcomes, and suggest that early childhood temperament is in part associated with specific GM in the prenatal setting.

Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome.

Sepsis-induced acute respiratory distress syndrome (ARDS) causes significant fatalities worldwide and lacks pharmacological intervention. Alveolar fluid clearance (AFC) plays a pivotal role in the remission of ARDS and is markedly impaired in the pathogenesis of ARDS. Here, we demonstrated that erythropoietin could effectively ameliorate lung injury manifestations and lethality, restore lung function and promote AFC in a rat model of lipopolysaccharide (LPS)-induced ARDS. Moreover, it was proven that EPO-induced restoration of AFC occurs through triggering the total protein expression of ENaC and Na,K-ATPase channels, enhancing their protein abundance in the membrane, and suppressing their ubiquitination for degeneration. Mechanistically, the data indicated the possible involvement of EPOR/JAK2/STAT3/SGK1/Nedd4-2 signaling in this process, and the pharmacological inhibition of the pathway markedly eliminated the stimulating effects of EPO on ENaC and Na,K-ATPase, and subsequently reversed the augmentation of AFC by EPO. Consistently, in vitro studies of alveolar epithelial cells paralleled with that EPO upregulated the expression of ENaC and Na,K-ATPase, and patch-clamp studies further demonstrated that EPO substantially strengthened sodium ion currents. Collectively, EPO could effectively promote AFC by improving ENaC and Na,K-ATPase protein expression and abundance in the membrane, dependent on inhibition of ENaC and Na,K-ATPase ubiquitination, and resulting in diminishing LPS-associated lung injuries.

Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance.

Acquired drug resistance is a major challenge for cancer therapy and is the leading cause of cancer mortality; however, the mechanisms of drug resistance are diverse and the strategy to specifically target drug-resistant cancer cells remains an unmet clinical issue. Here, we established a colorectal cancer-derived organoid biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies revealed that chemoresistant cancer-derived organoids exhibited elevated expression of LGR4 and activation of the Wnt signaling pathway. Further, we generated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4-Wnt signaling and found that treatment with LGR4-mAb notably sensitized drug-induced ferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augments ferroptosis when co-administrated with chemotherapeutic agents, demonstrating a potential opportunity to fight refractory and recurrent cancers.

Effects of cognitive stimulation therapy on patients with dementia: An umbrella review of systematic reviews and meta-analyses.

BACKGROUND: Dementia is characterized by significant cognitive decline that results in disturbance of daily activities. Increasing number of meta-analyses has examined the efficacy of cognitive stimulation therapy (CST) for dementia. However, there is a lack of comprehensive reports that specifically discuss the strength of evidence to support CST for dementia. PURPOSE: This study aimed to summarize evidence regarding the efficacy of CST on people with dementia. DESIGN: Umbrella review of systematic reviews and meta-analyses. METHODS: We searched Cochrane Library, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, China Biology Medicine disc (CBMdisc), and VIP databases from inception to December 31, 2022. The methodological quality of the identified studies was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2). Studies scoring 9-12 (moderate quality) points or higher were further analyzed using Grades of Recommendations Assessment, Development and Evaluation (GRADE) principles. RESULTS: A total of 14 systematic reviews and meta-analyses were included in the umbrella review. The methodological quality of most included reviews was rated as moderate according to AMSTAR 2 rating system. In these studies, we summarized the characteristics of the content, providers, frequency, period and setting of CST, and examined eight health outcomes related to CST, including cognition, depression, behavioral symptoms, quality of life (QoL), activities of daily living (ADL), language and communication, anxiety, and memory. Eleven studies with low to high rating of overall confidence (OC) consistently reported that CST could significantly improve cognition of people with dementia, including high-quality supporting evidence. However, the effect of CST on other health outcomes for people with dementia (e.g., depression, behavioral symptoms, QoL, ADL) is inconsistent, with low- to moderate-quality evidence ratings. Compared with the above results, few studies have reported the effects of CST on communication, anxiety, and memory for people with dementia. CONCLUSIONS: In the future, the design and reporting of systematic reviews and meta-analyses should incorporate high-quality research metrics in accordance with AMSTAR 2 criteria. The current review supports CST as an effective treatment for improving cognitive function in patients with dementia. Multi-component interventions are more effective than single-component interventions and need to be delivered regularly. REGISTRATION: The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022364259).

Dynamic O-GlcNAcylation coordinates ferritinophagy and mitophagy to activate ferroptosis.

Ferroptosis is a regulated iron-dependent cell death characterized by the accumulation of lipid peroxidation. A myriad of facets linking amino acid, lipid, redox, and iron metabolisms were found to drive or to suppress the execution of ferroptosis. However, how the cells decipher the diverse pro-ferroptotic stress to activate ferroptosis remains elusive. Here, we report that protein O-GlcNAcylation, the primary nutrient sensor of glucose flux, orchestrates both ferritinophagy and mitophagy for ferroptosis. Following the treatment of ferroptosis stimuli such as RSL3, a commonly used ferroptosis inducer, there exists a biphasic change of protein O-GlcNAcylation to modulate ferroptosis. Pharmacological or genetic inhibition of O-GlcNAcylation promoted ferritinophagy, resulting in the accumulation of labile iron towards mitochondria. Inhibition of O-GlcNAcylation resulted in mitochondria fragmentation and enhanced mitophagy, providing an additional source of labile iron and rendering the cell more sensitive to ferroptosis. Mechanistically, we found that de-O-GlcNAcylation of the ferritin heavy chain at S179 promoted its interaction with NCOA4, the ferritinophagy receptor, thereby accumulating labile iron for ferroptosis. Our findings reveal a previously uncharacterized link of dynamic O-GlcNAcylation with iron metabolism and decision-making for ferroptosis, thus offering potential therapeutic intervention for fighting disease.

High prevalence of thyroid carcinoma in patients with insulin resistance: a meta-analysis of case-control studies.

The association between insulin resistance and thyroid carcinoma is controversial. We conducted this meta-analysis of association between insulin resistance and thyroid carcinoma. There were 14 studies included in this meta-analysis. Random-effect model was used to merge the weighted mean difference value of fasting serum insulin level and the pooled effect shows that the level of fasting serum insulin is higher in patients with thyroid carcinoma than those of controls (1.88, 95% CI 0.87 to 2.90, P=0.0003). Random-effect model was used to estimate the pooled weighted mean difference and it shows that thyroid carcinoma patients have a higher level of homeostasis model assessment of insulin resistance (HOMA-IR) than patients without thyroid carcinoma (0.54, 95% CI 0.29 to 0.78, P<0.0001). Fixed-effect model with the odds ratio of insulin resistance shows that insulin resistance could increase the risk of thyroid carcinoma 216% compared with participants without insulin resistance (3.16, 95% CI 2.09 to 4.77, P<0.0001). In conclusion, insulin resistance might be a risk factor for thyroid carcinoma.

Ghrelin Alleviates Endoplasmic Reticulum Stress in MC3T3E1 Cells by Inhibiting AMPK Phosphorylation.

Ghrelin is a gastric endocrine peptide that has been found to be involved in the process of energy homeostasis and bone physiology in recent years. To explore the effects of ghrelin on endoplasmic reticulum stress (ERS) in MC3T3E1 cells and its possible mechanism, an ERS model was induced by tunicamycin (TM) in the osteoblast line MC3T3E1. TM at 1.5 µg/mL was selected as the experimental concentration found by CCK8 assay. Through the determination of apoptosis, reactive oxygen species production, and endoplasmic reticulum stress-related gene expression, we found that ERS induced by TM can be relieved by ghrelin in a concentration-dependent manner (P < 0.001). Compared with the TM group, ghrelin reduced the expression of ERS-related marker genes induced by TM. Compared with the GSK621 + TM group without ghrelin pretreatment, the mRNA expression of genes in the ghrelin pretreatment group decreased significantly (P < 0.001). The results of protein analysis showed that the levels of BIP, p-AMPK, and cleaved-caspase3 in the TM group increased significantly, while the levels decreased after ghrelin pretreatment. In group GSK621 + TM compared with group GSK621 + ghrelin+TM, ghrelin pretreatment significantly reduced the level of p-AMPK, which is consistent with the trend of the ERS-related proteins BIP and cleaved-caspase3. In conclusion, ghrelin alleviates the ERS induced by TM in a concentration-dependent manner and may or at least partly alleviate the apoptosis induced by ERS in MC3T3E1 cells by inhibiting the phosphorylation of AMPK.

The different hypoglycemic effects between East Asian and non-Asian type 2 diabetes patients when treated with SGLT-2 inhibitors as an add-on treatment for metformin: a systematic review and meta-analysis of randomized controlled trials.

AIMS: To investigate the efficacy and safety of SGLT-2 inhibitors as an add-on treatment for metformin between Asian and non-Asian T2DM. METHODS: A systematic literature search of PubMed, EMBASE, and the Cochrane Library was performed through August 2020 with the following keywords: Sodium-Glucose Transporter 2 Inhibitors, Sodium Glucose Transporter 2 Inhibitors, SGLT2 inhibitor, SGLT-2 inhibitors, type 2 diabetes, and randomized controlled trials. Double-blinded RCTs comparing SGLT-2 inhibitors as an add-on treatment for metformin and metformin monotherapy in adults with type 2 diabetes were included. A random effects model was used to calculate overall effect sizes. RESULTS: 5 RCTs with 1193 Asian patients and 7 RCTs with 2098 non-Asian patients were investigated. The improvement in HbA1c and fasting blood glucose in the Asian patients (WMD, -0.73%; 95% CI, -1.01% to -0.46%, p < 0.01; WMD, -1.51; 95% CI, -1.81 to -1.21, p < 0.01, respectively) were both significantly better than in the non-Asians (WMD, -0.45%; 95% CI, -0.62% to -0.29%, p < 0.01; WMD, -1.03; 95% CI, -1.27 to -0.78, p < 0.01, respectively). The effect of weight loss was similar in the non-Asian patients and Asian patients. There was little difference in the improvement of systolic blood pressure between them. The risk of serious adverse events was not significantly increased between the Asian and non-Asian patients. CONCLUSION: SGLT-2 inhibitors as an add-on treatment for metformin are more efficacious in East Asian T2DM patients than in non-Asian T2DM patients without an additional risk of severe adverse events.

Optimization method of fatigue maintenance for cable-beam anchorage zone of suspension bridge.

The cable-beam anchorage zone is the vital load-bearing component in suspension bridge. For maintenance of such structure, a method of probabilistic optimization was proposed by combining linear elastic fracture mechanics, structural reliability and life cycle cost analysis. In this method, the optimal maintenance time is obtained by determining the relative proportion between the costs under the condition that the structural reliability is higher than the minimum allowable reliability. While, the minimum total maintenance cost is obtained by determining the maintenance interval. Then, an example is presented to verify this method, with the following conclusions: the reliability index is inversely proportional to the failure probability, the change of maintenance cost and failure cost affects the optimal maintenance time, the optimal maintenance time will be ahead of time when consider the risk cost. And finally, when the maintenance time interval is determined, the optimal maintenance cost is affected by the maintenance probability and the failure probability.