Sirtuin 3 (SIRT3) is a potential therapeutic target for cardiovascular, metabolic, and other aging-related diseases. In this study, we investigated the role of SIRT3 in diabetic cardiomyopathy (DCM). ...Mice were injected with streptozotocin (STZ, 60 mg/kg, ip) to induce diabetes mellitus. Our proteomics analysis revealed that SIRT3 expression in the myocardium of diabetic mice was lower than that of control mice, as subsequently confirmed by real-time PCR and Western blotting. To explore the role of SIRT3 in DCM, SIRT3-knockout mice and 129S1/SvImJ wild-type mice were injected with STZ. We found that diabetic mice with SIRT3 deficiency exhibited aggravated cardiac dysfunction, increased lactate dehydrogenase (LDH) level in the serum, decreased adenosine triphosphate (ATP) level in the myocardium, exacerbated myocardial injury, and promoted myocardial reactive oxygen species (ROS) accumulation. Neonatal rat cardiomyocytes were transfected with SIRT3 siRNA, then exposed to high glucose (HG, 25.5 mM). We found that downregulation of SIRT3 further increased LDH release, decreased ATP level, suppressed the mitochondrial membrane potential, and elevated oxidative stress in HG-treated cardiomyocytes. SIRT3 deficiency further raised expression of necroptosis-related proteins including receptor-interacting protein kinase 1 (RIPK1), RIPK3, and cleaved caspase 3, and upregulated the expression of inflammation-related proteins including NLR family pyrin domain-containing protein 3 (NLRP3), caspase 1 p20, and interleukin-1β both in vitro and in vivo. Collectively, SIRT3 deficiency aggravated hyperglycemia-induced mitochondrial damage, increased ROS accumulation, promoted necroptosis, possibly activated the NLRP3 inflammasome, and ultimately exacerbated DCM in the mice. These results suggest that SIRT3 can be a molecular intervention target for the prevention and treatment of DCM.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Dihydromyricetin (DHY), a flavonoid component isolated from Ampelopsis grossedentata, exerts versatile pharmacological activities. However, the possible effects of DHY on diabetic vascular ...endothelial dysfunction have not yet been fully elucidated. In the present study, male C57BL/6 mice, wild type (WT) 129S1/SvImJ mice and sirtuin 3 (SIRT3) knockout (SIRT3
) mice were injected with streptozotocin (STZ, 60 mg/kg/day) for 5 consecutive days. Two weeks later, DHY were given at the doses of 250 mg/kg by gavage once daily for 12 weeks. Fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) level, endothelium-dependent relaxation of thoracic aorta, reactive oxygen species (ROS) production, SIRT3, and superoxide dismutase 2 (SOD2) protein expressions, as well as mitochondrial Deoxyribonucleic Acid (mtDNA) copy number, in thoracic aorta were detected. Our study found that DHY treatment decreased FBG and HbA1c level, improved endothelium-dependent relaxation of thoracic aorta, inhibited oxidative stress and ROS production, and enhanced SIRT3 and SOD2 protein expression, as well as mtDNA copy number, in thoracic aorta of diabetic mice. However, above protective effects of DHY were unavailable in SIRT3
mice. The study suggested DHY improved endothelial dysfunction in diabetic mice via oxidative stress inhibition in a SIRT3-dependent manner.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
N-acylethanolamides (NAEs) are a class of naturally occurring lipid molecules with pleiotropic activities ranging from energy homeostasis to analgesic functioning. However, the comprehensive ...quantitation of endogenous NAEs is challenged by the sub-trace level (nM) in complex biological samples and the limited availability of stable isotope labeled internal standards (SIL-IS). Herein, a sensitive method was developed to accurately determine 20 NAEs in biological samples by chemical isotope labeling strategy coupled with liquid chromatography - tandem mass spectrometry (LC-MS/MS). A pair of efficient derivatization reagents, acetyl chloride-d0 (ACC-d0) and acetyl chloride-d3 (ACC-d3), were used to label NAEs in biological samples and NAE standard mixture, respectively. The heavily labeled NAE derivatives of the standard substances were used as one-to-one internal standards to minimize the matrix effects and potential ion suppression in MS analysis. Although no chemical moiety with high ionization capability was introduced, the detection sensitivity of the derivatized NAEs were substantially enhanced, as evidenced by 6- to 170-fold increase in LOQs, compared to non-derivatized NAEs. The derivatized NAEs provided the stable and abundant specific product ions in MS/MS spectrum, which were used as the quantitation ions for multiple reaction monitoring (MRM) analysis. The validated LC-MS/MS method was also successfully applied to determine NAEs in serum samples and liver tissues from control and alcohol-fed mice, which shown its practicability in the analysis of endogenous NAE in biological samples. Collectively, the proposed method offers a sensitive and accurate quantification of endogenous NAEs, which may facilitate the understanding of NAE metabolisms and their functions in the physiological and pathological processes.
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•A sensitive and accurate LC-MS method was developed to quantify 20 NAEs by chemical isotope labeling.•The detection sensitivity of the derivatized NAEs were substantially enhanced.•The derivatization provided the stable and abundant specific product ions for the quantitation by MRM analysis.•The proposal method was successfully applied to quantify NAEs in serum and liver tissues from alcohol-fed mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The retinoid-related orphan receptor α (RORα) is one subfamily of nuclear hormone receptors (NRs). This review summarizes the understanding and potential effects of RORα in the cardiovascular system ...and then analyzes current advances, limitations and challenges, and further strategy for RORα-related drugs in cardiovascular diseases. Besides regulating circadian rhythm, RORα also influences a wide range of physiological and pathological processes in the cardiovascular system, including atherosclerosis, hypoxia or ischemia, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, hypertension, and myocardial hypertrophy. In terms of mechanism, RORα was involved in the regulation of inflammation, apoptosis, autophagy, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial function. Besides natural ligands for RORα, several synthetic RORα agonists or antagonists have been developed. This review mainly summarizes protective roles and possible mechanisms of RORα against cardiovascular diseases. However, there are also several limitations and challenges of current research on RORα, especially the difficulties on the transformability from the bench to the bedside. By the aid of multidisciplinary research, breakthrough progress on RORα-related drugs to combat cardiovascular disorder may appear.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Postoperative delirium (POD) is a common postoperative complication, and the potential relationship between cigarette smoking and POD is still unclear. The current study evaluated the relationship ...between preoperative smoking status in patients suffering from osteoarthritic pain and POD after total knee arthroplasty (TKA).
A total of 254 patients who had undergone unilateral TKA were enrolled between November 2021 and December 2022, with no gender limitation. Preoperatively, patients' visual analog scale (VAS) scores at rest and during movement, hospital anxiety and depression (HAD) scores, pain catastrophizing scale (PCS) scores and smoking status were collected. The primary outcome was the incidence of POD, which was evaluated by the confusion assessment method (CAM).
A total of 188 patients had complete datasets for final analysis. POD was diagnosed in 41 of 188 patients (21.8%) who had complete data for analysis. The incidence of smoking was significantly higher in Group POD than in Group Non-POD (22 of 41 patients 54% vs. 47 of 147 patients 32%, p < 0.05). The postoperative hospital stays were also longer than those of Group Non-POD (p < 0.001). Multiple logistic regression analysis showed that preoperative smoking (OR: 4.018, 95% CI: 1.158-13.947, p = 0.028) was a risk factor for the occurrence of POD in patients with TKA. The length of hospital stay was correlated with the occurrence of POD.
Our findings suggest that patients who smoked preoperatively were at increased risk of developing POD following TKA.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Lung ultrasound (LUS) is a useful tool for assessing the severity of lung disease, without radiation exposure. However, there is little data on the practicality of LUS in assessing the severity of ...bronchopulmonary dysplasia (BPD) and evaluating short-term clinical outcomes. We adapted a LUS score to evaluate BPD severity and assess the reliability of mLUS score correlated with short-term clinical outcomes.
Prospective diagnostic accuracy study was designed to enroll preterm infants with gestational age < 34 weeks. Lung ultrasonography was performed at 36 weeks postmenstrual age. The diagnostic and predictive values of new modified lung ultrasound (mLUS) scores based on eight standard sections were compared with classic lung ultrasound (cLUS) scores.
A total of 128 infants were enrolled in this cohort, including 30 without BPD; 31 with mild BPD; 23 with moderate BPD and 44 with severe BPD. The mLUS score was significantly correlated with the short-term clinical outcomes, superior to cLUS score. The mLUS score well correlated with moderate and severe BPD (AUC = 0.813, 95% CI 0.739-0.888) and severe BPD (AUC = 0.801, 95% CI 0.728-0.875), which were superior to cLUS score. The ROC analysis of mLUS score to evaluate the other short-term outcomes also showed significant superiority to cLUS score. The optimal cutoff points for mLUS score were 14 for moderate and severe BPD and 16 for severe BPD.
The mLUS score correlates significantly with short-term clinical outcomes and well evaluates these outcomes in preterm infants.
Multiple pretreatment systemic inflammatory markers (SIMs) have been reported as predictors of pathological complete response (pCR) after neoadjuvant systemic therapy (NST) in patients with breast ...cancer (BC). However, the most significant SIM remains to be conclusively identified, and variations among different molecular subtypes remain unknown. The objective of the study was to identify the most significant SIM in patients with human epidermal growth factor receptor 2 (HER2) positive BC, to construct a pCR-predictive nomogram combining it with other clinicopathologic factors, and to evaluate its prognostic value on survival.
We retrospectively reviewed the findings for 240 patients with stage I-III HER2-positive BC who underwent NST and subsequent surgery at Kaohsiung and Taichung Veterans General Hospital from 2011 to 2021. Clinicopathologic factors were analyzed by stepwise logistic regression with backward selection. The data were used to construct a nomogram plot for determining the pCR probability. Kaplan-Meier curves and log-rank test were used to evaluate disease-free survival (DFS) and overall survival (OS).
Among the pretreatment SIMs, only the systemic inflammation response index (SIRI) was significantly related to pCR, with an optimal cutoff value of 1.27 × 10 9 /L. Stepwise logistic analyses indicated that clinical N stage, HER2 immunohistochemistry score, hormone receptor status, targeted therapy regimen, and SIRI were independent predictors of pCR, with an area under the curve of 0.722. The Hosmer-Lemeshow test and calibration curve revealed that the predictive ability was a good fit to actual observations. A nomogram was constructed based on the logistic model. The external validation of the model also revealed satisfactory discrimination and calibration. Kaplan-Meier analysis showed that patients with SIRI <1.27 had longer DFS and OS.
Pretreatment SIRI <1.27 is predictive of pCR, DFS, and OS in HER2-positive BC. Our nomogram could efficiently predict pCR and facilitate clinical decision-making before neoadjuvant treatment.
Serum preptin levels among subjects with different bone mineral densities (BMD) were measured and investigated to determine the correlation between BMD and bone-metabolic markers.
Approximately 52 ...elderly male patients with osteoporosis, 50 elderly men with osteopaenia, and 31 age-matched normal bone mass controls participated in the study. The serum preptin levels and bone metabolic markers were measured by enzyme-linked immunosorbent assay. The relationships between preptin levels, BMD, and metabolic parameters were also assessed.
The serum preptin level was the lowest in the osteoporosis group and positively correlated with BMD. All the bone formation markers in the osteoporosis and osteopaenia groups were significantly reduced compared with those in the normal group. Serum preptin level was positively correlated with all the bone formation markers, whereas no correlation was observed with the bone resorption marker TRACP-5b.
Serum preptin levels are decreased in osteoporosis and osteopaenia patients and positively correlated with BMD. Therefore, preptin is involved in the pathogenesis of osteoporosis, probably through bone formation rather than bone resorption.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chinese hamster ovary (CHO) cells are the predominant cell chassis for biopharmaceutical production. Engineering cellular pathways related to cell death, metabolism, and glycosylation in CHO cells is ...desired but challenging. Here, we present a novel approach that exploits CRISPR-Cas13d for gene silencing and CHO cell engineering. CRISPR-Cas13d is a burgeoning system that exploits Cas13d nuclease and guide RNA (gRNA) for RNA cleavage and gene knockdown. We first showed that CRISPR-Cas13d effectively knocked down exogenous genes in CHO cell lines (K1, DG44, and DUXB11) commonly used for recombinant protein production. We next demonstrated that CRISPR-Cas13d robustly suppressed the expression of exogenous genes and various endogenous genes involved in gene amplification, apoptosis, metabolism, and glycosylation (
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., GS, BAK, BAX, PDK1, and FUT8) in CHO cells with efficiencies ranging from 60% to 80%, simply by transient transfection. By integrating the entire CRISPR-Cas13d system with the
system and optimal gRNA design, we further improved the knockdown efficiency and rapidly generated stable cells with ≈80%-90% knockdown. With this approach, we knocked down FUT8 expression for >90% and significantly attenuated the IgG fucosylation. These data altogether implicated the potentials of CRISPR-Cas13d for gene regulation, glycoengineering, and cell engineering of CHO cells.
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IJS, KILJ, NUK, PNG, UL, UM
Heavy metal elements in particulate matter can cause adverse effects on human health, and the smaller the particle size, the greater the harm. A total of 16 heavy metal elements (Al, Si, K, Ca, V, ...Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Ba, Pb, and Cd) in PM
were continuously determined by an online heavy metal observation instrument in Zhengzhou city from January 7 to 25, 2021. The results showed that
(K) concentration was the highest during the observation period (0.62 μg·m
). According to pollutant concentration and meteorological characteristics, the observation period was divided into clean days, dust days, and haze days. The contribution of heavy metal pollution characteristics and health risk assessment in atmospheric PM
was different under different pollution processes. The US EPA health risk assessment method was used to assess the health risks of heavy metals, and the enrichment factor method and positive matrix factorization (PMF) were used to analyze the sources of heavy metals. The influence of the trans
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