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Background: Recently, the beneficial effects of nicotinamide adenine dinucleotide (NAD+) as an antiaging and antioxidant molecule have become a focus of research. However, the mechanisms by which NAD+ supplementation affects the associated metabolites under physiological conditions remain unclear. Specifically, although NAD+ is involved in several processes that are dysregulated in cardiovascular diseases, some effects of NAD+ precursors and NAD+ on cardiac diseases have started to gain recognition only recently. Objective: To discuss the influence of NAD+ supplementation on adverse cardiac remodeling and aging. Results: Supplementation with NAD+ precursors or nicotinamide riboside, which enhances or supplements the NAD+ metabolome, might have a protective effect on the heart. NAD+ can alleviate chronic heart failure via a mitochondrial oxidation–reduction (redox) state mechanism. Furthermore, NAD+ replenishment can improve the life span of mice. Conclusion: NAD+ exerts considerable antiaging and antioxidant effects with promising therapeutic effects. However, its effect in humans and use as a dietary supplement need to be studied further.

Context Intraoperative hemodynamic instability (HI) deteriorates surgical outcomes of patients with normotensive pheochromocytoma (NP). Objective To characterize the hemodynamics of NP and develop and externally validate a prediction model for intraoperative HI. Methods Data on 117 patients with NP (derivation cohort) and 40 patients with normotensive adrenal myelolipoma (NAM) who underwent laparoscopic adrenalectomy from January 2011 to November 2021 were retrospectively collected. Data on 22 patients with NP (independent validation cohort) were collected from another hospital during the same period. The hemodynamic characteristics of patients with NP and NAM were compared. Machine learning models were used to identify risk factors associated with HI. The final model was visualized via a nomogram. Results Forty-eight (41%) out of 117 patients experienced HI, which was significantly more than that for NAM. A multivariate logistic regression including age, tumor size, fasting plasma glucose, and preoperative systolic blood pressure showed good discrimination measured by area under curve (0.8286; 95% CI 0.6875-0.9696 and 0.7667; 95% CI 0.5386-0.9947) for predicting HI in internal and independent validation cohorts, respectively. The sensitivities and positive predictive values were 0.6667 and 0.7692 for the internal and 0.9167 and 0.6111 for the independent validations, respectively. The final model was visualized via a nomogram and yielded net benefits across a wide range of risk thresholds in decision curve analysis. Conclusion Patients with NP experienced HI during laparoscopic adrenalectomy. The nomogram can be used for individualized prediction of intraoperative HI in patients with NP.

Aging is the most important risk factor for cardiovascular diseases. Although exercise is known to be beneficial for the health of aging heart, the optimal exercise training intensity to prevent natural aging-induced cardiac damage has not been defined. In this study, we used 32-week-old male mice and randomly divided them into three groups, namely, untrained (UNT) mice, moderate-intensity exercise training (MET) mice, and high-intensity interval training (HIIT) mice. Mice in the two exercise training groups were subjected to exercise 5 days per week for 24 consecutive weeks. Metabolic characteristics, cardiac function and morphology, myocardial remodeling, myocardial fibrosis (collagen III, α-SMA, and TGF-β), oxidative stress (NRF2, HO-1, SOD, and NOX4), and apoptosis (BAX, Bak, Bcl-2, and Bcl-XL) were analyzed 24 weeks after the different treatments. MET improved cardiac function and reduced myocardial remodeling, myocardial fibrosis, and oxidative stress in the aging heart. MET treatment exerted an anti-apoptotic effect in the heart of the aging mice. Importantly, HIIT did not protect against cardiac damage during the natural aging process. These findings suggest that MET may be one of the main methods to prevent cardiac damage induced by natural aging.

Yue Liu,1,* Chenguang Yang,2,* Wenyuan Qi,1 Zuowei Pei,2 Wei Xue,1 Huolan Zhu,2 Min Dong,2 Ying Guo,2 Duanduan Cong,1 Fang Wang2 1Clinical Trial Center, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Key Laboratory of Drug Clinical Risk and Personalized Medication Evaluation, Beijing Hospital, Beijing, People’s Republic of China; 2Internal Medicine-Cardiovascular Department, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang Wang Email bjh_wangfang@163.comAbstract: Dabigatran is a novel direct oral anticoagulant agent, whose plasma concentration is closely related to bleeding risk. Genetic polymorphisms can affect the level of plasma dabigatran. The purpose of this study was to understand the relationship between dabigatran-related genes and the plasma level of dabigatran in healthy Chinese subjects after taking a single oral dose. This study was performed with a single-center, single-dose, randomized, open-label, and four-period crossover trial design under both fasting and fed conditions. A total of 106 eligible healthy subjects were enrolled in the study and 104 were genotyped. One-way analysis of variance (ANOVA) was used to compare pharmacokinetic parameters among different genotypes and linear regression was applied to explore the multiplicative interaction between variables. In this study, we found that the genotype frequencies of CES1 rs2244613 and CES1 rs8192935 were significantly different between Chinese and Caucasians, but the genotype frequencies of ABCB1 rs1045642 and ABCB1 rs4148738 were similar in both populations. CES1 rs8192935 were associated with the peak concentration of dabigatran. There was no significant gender difference in the exposure level of dabigatran. Furthermore, food significantly delayed the absorption of dabigatran but had little effect on Cmax and AUC0-∞.Keywords: anticoagulants, dabigatran, genetics, pharmacogenetics, CES1, ABCB1

The main and common treatment of renal replacement therapy (RRT) for chronic kidney disease (CKD) especially in end-stage kidney disease (ESKD) patients is hemodialysis (HD). Many reports have shown that exercise therapy is good for HD patients. This review aims to describe recent advances in exercise therapy in HD patients.Our key opinions have focused on varied types of exercise therapy and identified barriers to exercise therapy among HD patients. Exercise implementation includes aerobic exercise training, resistance exercise training, combined exercise training, and novel exercise interventions. Barriers include internal and external distress such as HD patients' restrictions and environmental problems.This review is based on the novel/ most findings in PubMed, Web of Science, Google Scholar, and MEDLINE from the inception of every database until August 2022.The systematic search strategy identified 6 articles that met the inclusion criteria. Four were specific to exercise therapy in HD and three to exercise barriers in HD. Massive evidence has demonstrated exercise therapy for HD has specific benefits and neglectful causes of exercise barriers.In this review, we aimed to summarize recent advances in individual exercise therapy recommendations (type, intensity, time, and frequency) and exercise barriers in HD patients. In conclusion, Low/moderate-intensity exercise trained for at least thirty minutes, five times per week including aerobic exercise (Walking, Jogging, Swimming, and Health Exercises), resistance training (Dumbbells, Band training, and Knee extension), and combination exercise (both) during the first 2 hours of dialysis treatment or non-dialysis days is advisable treatment recommendation.

Herbal medicines have attracted much attention in recent years and are increasingly being used as alternatives to pharmaceutical medicines. Thymoquinone (TQ) is one of the most active ingredients in

A number of metabolic disorders, including hyperlipidemia, potentially cause chronic kidney disease (CKD), one of their major chronic complications and comorbidities. Rosuvastatin is one of the widely used antiatherogenic drugs among hyperlipidemic patients. Meanwhile, sarpogrelate is not only a 5-hydroxytryptamine receptor antagonist but also an antiplatelet agent, inhibiting platelet-stimulated blood coagulation and improving peripheral circulation. In this study, a combination of sarpogrelate and/or rosuvastatin was used on CKD mice induced by a high-fat diet for 8 weeks. The mice were tested for pathological changes using histological evaluation. Tremendous alterations were found, including a remarked increase in total cholesterol and low-density lipoprotein cholesterol levels, glomerular endothelial proliferation, and mesangial expansion. Also, tubular damage and extracellular matrix accumulation occurred, namely, a marked increase in the macula densa, scattered and apoptotic loss of the apical brush border with vacuolated basophilic cytoplasm and heavily stained nuclei, and expanded Bowman’s space, which were at least partially ameliorated by sarpogrelate and/or rosuvastatin treatment. The analysis of expression profiles at both the RNA and protein levels, using real-time quantitative polymerase chain reaction and Western blot analysis, indicated that LDL-R/CD68/LOX-1-positive monocyte/macrophage-mediated enhanced proinflammatory activation, including the significant upregulation of tumor necrosis factor-α and interleukin-6, was actually attenuated by sarpogrelate and/or rosuvastatin treatment. The findings indicated that sarpogrelate and/or rosuvastatin treatment potentially ameliorates CKD progression in patients with the aforementioned comorbid metabolic disorders.

Atrial fibrillation (AF) is the most common type of persistent arrhythmia. Although its incidence has been increasing, the pathogenesis of AF in stroke remains unclear. In this study, a total of 30 participants were recruited, including 10 controls, 10 patients with AF and 10 patients with AF and stroke (AF + STROKE). Differentially expressed genes (DEGs) were identified, and functional annotation of DEGs, comparative toxicogenomic database analysis associated with cardiovascular diseases, and predictions of miRNAs of hub genes were performed. Using RT-qPCR, biological process and support vector machine neural networks, numerous DEGs were found to be related to AF. HBG1, SNCA and GYPB were found to be upregulated in the AF group. Higher expression of hub genes in AF and AF + STROKE groups was detected via RT-PCR. Upon training the biological process neural network of SNCA and GYPB for HBG1, only small differences were detected. Based on the support vector machine, the predicted value of SNCA and GYPB for HBG1 was 0.9893. Expression of the hub genes of HBG1, SNCA and GYPB might therefore be significantly correlated to AF. These genes are involved in the incidence of AF complicated by stroke, and may serve as targets for early diagnosis and treatment.

PurposeThis study is to assess the diagnostic value of noninvasive regional myocardial work (MW) by echocardiography for detecting the functional status of coronary stenosis using fractional flow reserve (FFR) as a standard criterion.MethodsA total of 84 consecutive patients were included in this study, among which 92 vessels were identified with ≥50% stenosis confirmed by invasive coronary angiography. Patients were investigated by invasive FFR and transthoracic echocardiography. Regional MW indices including myocardial work index (MWI), myocardial constructive work (MCW), myocardial wasted work, and myocardial work efficiency were calculated.ResultsMWI and MCW were significantly impaired in the FFR ≤ 0.75 group compared with the FFR > 0.75 group (both p < 0.01). There were significant positive associations between MWI and MCW with FFR. In total group, MWI ConclusionIn patients with coronary artery disease, especially those with single-vessel stenosis, the regional MW measured by echocardiography exhibited a good diagnostic value in detecting significant myocardial ischemia compared to the standard FFR approach.

Background: The potential of global and regional myocardial work (MW) parameters for detecting moderate, clinically unapparent coronary artery disease (CAD) remains unclear. This study aimed to evaluate the diagnostic power of global and regional MW to detect CAD in patients with normal left ventricular ejection fraction and wall motion. Methods: One hundred and seventy-six consecutive patients with clinically suspected CAD were prospectively included. All subjects underwent comprehensive echocardiographic evaluation and coronary angiography. Noninvasive MW indices include global work index (GWI), global work efficiency (GWE), global constructive work (GCW), global wasted work (GWW) and regional MW parameters. Results: GWI, GWE and GCW were significantly impaired in patients with CAD (stenosis ≥50%) compared with patients without CAD (all P＜0.01). An optimal GWI cutoff value of 1855.5 mmHg % (sensitivity, 71.7%; specificity, 78.0%) has been defined for predicting CAD [area under the curve (AUC) value, 0.76; P = 0.000]. GWI provided incremental value over all other echocardiographic parameters in detecting CAD, including global longitudinal strain (GLS) (P＜0.05). MW parameters in left anterior descending (LAD) segments had higher diagnostic value (AUC = 0.67-0.74, all P = 0.000) than parameters in left circumflex (LCX) (AUC = 0.64, P＜0.01) or right coronary artery (RCA) territories (AUC = 0.65-0.71, all P＜0.01).Conclusions: Global and regional MW parameters assessed at rest are of good diagnostic value for detecting CAD. GWI provides incremental value over all other echocardiographic parameters in predicting CAD, including GLS. Besides, regional MW may be a useful tool to localize and detect relevant coronary artery stenosis.

Background Hyperlipidemia is a well-established risk factor for cardiac damage, which can lead to cardiovascular diseases. Many studies have shown that Coenzyme Q10(CoQ10) protects against cardiac damage in vivo. The aim of this study was to investigate the possible protective effects of CoQ10 against cardiac damage in apolipoprotein E-deficient (ApoE−/−) mice. Methods Eight-week-old male C57BL/6 and ApoE−/− mice were randomly divided into four groups: C57BL/6 mice fed a normal diet (C57BL/6 group); C57BL/6 mice fed a normal diet + CoQ10 (C57BL/6 + CoQ10 group); ApoE−/− mice fed a high-fat diet (ApoE−/− HD group), and ApoE−/− mice fed a high-fat diet + CoQ10 (ApoE−/− HD + CoQ10 group). All groups were fed the different diets for 16 weeks. Blood samples were obtained from the inferior vena cava and collected in serum tubes. The samples were then stored at − 80 °C until used. Coronal sections of heart tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the heart tissues was snap-frozen in liquid nitrogen for mRNA or immunohistochemical analysis. Results The metabolic parameters such as total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and triglycerides (TG) levels were lower in ApoE−/−HD + CoQ10 mice than in ApoE−/− HD mice. There were significant pathophysiological changes (H&E, PAS, Masson and CD68 staining) in ApoE−/− mice in the HD group compared with those in the HD + CoQ10 group. CoQ10 reduced HD-induced cardiac tissue damage via autophagy (p62 and LC3), as evidenced by immunoblotting, immunohistochemistry, and RT-qPCR. CoQ10 also inhibited inflammation (IL-6 and TNF-α) gene expression in ApoE−/− mice. Conclusions These results indicate that CoQ10 is a potential therapeutic target for cardiac damage caused by hyperlipidemia.

Background COVID‐19 has been sweeping the world since it emerged in late December 2019. However, little is known about cardiac injury in hospitalised COVID‐19 patients. This study is to investigate the incidence and characteristics of myocardial injury in COVID‐19 patients admitted in hospital. Methods Fifty‐four COVID‐19 patients were enrolled in one ward in Tongji Hospital, Wuhan, China, and 5 were excluded caused by missing cardiac troponin I levels. Forty‐nine participants were included in the final analysis. The clinical manifestations of hospitalised patients were analysed. Patients were divided into two groups, cardiac injury group and non‐cardiac injury group, based on whether cardiac troponin I was elevated. Epidemic characteristics and laboratory test results were analysed in these two group. Results The average age of patients in the cardiac injury group was older (68.0 years old) than that in the non‐cardiac injury group (61.5 years old). The percentages of patients with diabetes and critically severe pneumonia in the cardiac injury group were 38.5% and 38.5% respectively. Lymphocytes were decreased in 53.1% of all enrolled patients, but this decrease was more prominent (76.9%) in the cardiac injury group than the non‐cardiac injury group (44.4%). Patients in the cardiac injury group also had lower platelet counts. Conclusions COVID‐19 can cause cardiac injury in many patients. It is more common in older patients and patients with diabetes and is associated with a significant decrease in lymphocytes.

Background: Hyperlipidemia, a heterogeneous group of disorders characterized by elevated levels of plasma lipids, causes serious health problems and can lead to fatty liver and nonalcoholic fatty liver disease. Thymoquinone (TQ), a major active component of Nigella sativa, can exert a vast array of biological effects. Various studies have reported that TQ protects against liver injury, and we previously reported that TQ reduces cardiac damage in mice fed a high-cholesterol diet (HD). However, few studies have evaluated the effects of TQ on hyperlipidemia-induced liver injury. The aim of this study was to investigate the possible protective effects of TQ against liver injury in hyperlipidemia-induced LDL-R-/- mice.Methods: Eight-week-old male LDL-R-/- mice were randomly divided into three groups based on diet: normal diet (ND group, which was the control), high cholesterol diet (HD group), and HD mixed with TQ (HD + TQ group). All mice were fed for 8 weeks. Blood samples were obtained from the inferior vena cava, collected in serum tubes, and stored at −80 °C to investigate the serum lipoprotein profile. Longitudinal sections of liver tissues were fixed in 10% formalin and embedded in paraffin for histological evaluation. The remainder of the liver tissues was snap-frozen in liquid nitrogen for mRNA and immunoblotting analyses.Results: TQ administration significantly reduced liver histological alterations caused by hyperlipidemia. TQ mitigated hyperlipidemia-induced liver injury, as indicated by the suppression of increases in metabolic parameters (total cholesterol, triglyceride, and low-density lipoprotein-cholesterol), hepatic biochemical parameters (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), pyroptosis indicators (nucleotide-binding oligomerization domain-like receptor 3, interleukin [IL]-1β, and IL-18), a macrophage marker (CD68-positive cells), and phosphatidylinositide 3-kinase levels induced by the HD.Conclusions: These results indicate that TQ is a potential therapeutic agent for liver injury caused by hyperlipidemia.

Hyperlipidemia causes nervous system-related diseases. Exercise training has developed into an established evidence-based treatment strategy that is beneficial for neuronal injury. This study investigated the effect of exercise on hyperlipidemia-induced neuronal injury in apolipoprotein E-deficient (ApoE-/-) mice. Male ApoE-/- mice (age: 8 weeks) were randomly divided into four groups as follows: mice fed a normal diet (ND), normal diet+swimming training (ND+S), high-fat diet (HD), and high-fat diet+swimming (HD+S). Exercise training consisted of swimming for 40 min/day, 5 days/week for 12 weeks. After 12 weeks, we measured serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c). We also evaluated glial fibrillary acidic protein (GFAP) expression levels using immunohistochemistry, real-time PCR, and immunoblotting. In addition, NLR family pyrin domain-containing 3 (NLRP3), interleukin- (IL-) 18, caspase-1, Bax, Bcl-2, and phosphorylated extracellular signal-regulated kinase (p-ERK) expression levels were measured using immunoblotting. Serum levels of TG, TC, and LDL-c were lower in ApoE-/- HD+S mice than in ApoE-/- HD mice. Immunohistochemistry, real-time PCR, and immunoblotting showed increased levels of GFAP in the ApoE-/- HD group. Immunoblotting revealed increased levels of NLRP3, IL-18, caspase-1, Bax, Bcl-2, and p-ERK in the ApoE-/- HD group; however, they were significantly suppressed in the ApoE-/- HD+S group. Therefore, exercise has protective effects against neuronal injury caused by hyperlipidemia.

Recombinant human growth hormone (rhGH), widely used in clinical studies, exerts protective effects against cardiac damage. Here, we investigated the effects and mechanisms underlying the effects of rhGH on cardiac functions in db/db mice. C57BL/6J and db/db mice were subjected to rhGH treatment. Metabolic parameters, cardiac function and morphology, oxidative stress, lipid metabolism, and apoptosis were evaluated 16 weeks after rhGH treatment. Although rhGH did not significantly affect fasting blood glucose levels in db/db mice, it protected against diabetic cardiomyopathy, by improving cardiac function and reducing oxidative stress in the heart. In addition, rhGH treatment exhibited anti-apoptotic effects in the heart of db/db mice. The rhGH treatment, besides inhibiting oxidative stress and apoptosis, ameliorated cardiac dysfunction by inhibiting lipotoxicity in mice with type 2 diabetes. These findings suggest that rhGH is a promising therapeutic agent for diabetic cardiomyopathy.

Background Hyperlipemia is a risk factor for cardiac damage and cardiovascular disease. Several studies have shown that thymoquinone (TQ) can protect against cardiac damage. The aim of this study was to investigate the possible protective effects of TQ against hyperlipemia-induced cardiac damage in low-density lipoprotein receptor deficient (LDL-R−/−) mice. Methods: Eight-week-old male LDL-R−/−mice were randomly divided into the following three groups: the control group fed a normal diet (ND group), the high fat diet (HFD) group, and the HFD mixed with TQ (HFD+TQ) group. All groups were fed the different diets for 8 weeks. Blood samples were obtained from the inferior vena cava, collected in serum tubes, and stored at -80 °C until use. Cardiac tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the cardiac tissues was snap-frozen in liquid nitrogen for mRNA preparation or immunoblotting.Results The levels of metabolism-related factors, such as total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and high-sensitivity C-reactive protein (hs-CRP), were decreased in the HFD+TQ group compared with that in the HFD group. Periodic acid-Schiff staining demonstrated that lipid deposition was lower in the HFD+TQ group than that in the HFD group. The expression of pyroptosis indicators (NOD-like receptor 3 [NLRP3], interleukin [IL]-1β, IL-18 and caspase-1), pro-inflammation factors (IL-6 and tumour necrosis factor alpha [TNF-α]), and macrophage markers (cluster of differentiation [CD]68) was significantly downregulated in the HFD+TQ group compared with that in the HFD group.Conclusions Our results indicate that TQ may serve as a potential therapeutic agent for hyperlipemia-induced cardiac damage.

Hyperlipidemia is a risk factor for cardiac damage and cardiovascular disease. Increasing evidence has shown that dyslipidemia-related cardiac damage is associated with lipid accumulation, oxidative stress, and inflammation. Thymoquinone (TQ) is the major constituent of Nigella sativa, commonly known as black seed or black cumin, and is globally used in folk (herbal) medicine for treating and preventing a number of diseases and conditions. Several studies have shown that TQ can protect against cardiac damage. This study is aimed at investigating the possible protective effects of TQ on hyperlipidemia-induced cardiac damage in low-density lipoprotein receptor-deficient (LDL-R-/-) mice. Eight-week-old male LDL-R-/- mice were randomly divided into normal diet (ND), high-fat diet (HFD), and HFD and TQ (HFD+TQ) groups and were fed the different diets for eight weeks. Blood samples were obtained from the inferior vena cava in serum tubes and stored at -80°C until use. Some cardiac tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the cardiac tissues was snap-frozen in liquid nitrogen for mRNA preparation or immunoblotting. The levels of metabolism-related factors, such as total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and high-sensitivity C-reactive protein (hs-CRP), were decreased in the HFD+TQ group compared with those in the HFD group. Periodic acid-Schiff staining demonstrated that lipid deposition was lower in the HFD+TQ group than in the HFD group. The expression of pyroptosis indicators (NOD-like receptor 3 (NLRP3), interleukin- (IL-) 1β, IL-18, and caspase-1), proinflammatory factors (IL-6 and tumor necrosis factor alpha (TNF-α)), and macrophage markers (cluster of differentiation (CD) 68) was significantly downregulated in the HFD+TQ group compared with that in the HFD group. Our results indicate that TQ may serve as a potential therapeutic agent for hyperlipidemia-induced cardiac damage.

Sepsis is a major health complication causing patient mortality and increased healthcare costs. Cardiac dysfunction, an important consequence of sepsis, affects mortality. We previously reported that thymoquinone (TQ) protected against hyperlipidemia and doxorubicin-induced cardiac damage. This study investigated the possible protective effects of TQ against cardiac damage in septic BALB/c mice. Eight-week-old male BALB/c mice were divided into four groups: control, TQ, cecal ligation and puncture (CLP), and TQ + CLP. CLP was performed after 2-week TQ gavage. After 48 h, we measured the histopathological alterations of the cardiac tissue and the plasma levels of troponin-T (cTnT) and ATP. We evaluated autophagy (p62 and beclin 1), pyroptosis (NLRP3, caspase-1, interleukin [IL]-1β, and IL-18) at the gene and protein levels and IL-6 and tumor necrosis factor-α (TNF-α) at the gene level. Our results demonstrated that TQ administration significantly reduced intestinal histological alterations. TQ inhibited plasma cTnT levels; improved ATP; significantly inhibited p62, NLRP3, caspase-1, IL-1β, IL-18, IL-6, TNF-α, and MCP-1expressions; and increased beclin 1 and IL-10 level. The phosphatidylinositide 3-kinase level was significantly decreased in the TQ + CLP group versus the CLP group. These results suggest that TQ effectively modulates autophagy, pyroptosis, and pro-inflammatory, making it important in the treatment of sepsis-induced cardiac damage.

Objective: Hypercholesterolaemia is a well-established risk factor for blood vessel damage, which can lead to cardiovascular diseases. An abundance of clinical data show that dipeptidyl peptidase-4 inhibitors protect against aortic damage in patients with diabetes. The goal of this study was to investigate the possible protective effects of teneligliptin against aortic damage in apolipoprotein E knockout (ApoE-/-) mice. Methods: Eight-week-old male ApoE-/- mice were randomly divided into 3 groups: a control group fed a normal diet, a high-cholesterol diet (HD group), and an HD diet mixed with teneligliptin (HD + Tene group), and all the groups were fed with the different treatments for 6 weeks. Results and Conclusion: The metabolic characteristics of total cholesterol, low-density lipoprotein-cholesterol, and high-sensitivity C-reactive protein were lower in ApoE-/- HD + Tene mice than in ApoE-/- HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) gene and protein expression were lower in the aortic tissue of ApoE-/- HD + Tene mice than in ApoE-/- HD mice. IL-6 and TNF-α gene expression were lower in ApoE-/- HD + Tene mice than in ApoE-/- HD mice. These results indicate that teneligliptin may provide a potential therapeutic target for the aortic damage from hypercholesterolaemia.

Hypercholesterolemia is a well-established risk factor for kidney injury that can lead to chronic kidney disease (CKD). Thymoquinone (TQ) is one of the most active ingredients in Nigella Sativa seeds. It has a variety of beneficial properties including anti-oxidative and anti-inflammatory activities. TQ exerts positive effects on DOX-induced nephropathy and ischaemia-reperfusion induced kidney injury in rats. The goal of this study was to investigate the possible protective effects of thymoquinone against kidney injury in apolipoprotein E-knockout (ApoE−/−) mice. Eight-week-old male ApoE−/− mice were randomly divided into the following 3 groups: a control group fed a normal diet (ND group), a group fed a high-cholesterol diet (HD group) and a group fed HD mixed with thymoquinone (HD + TQ group). All groups were given the diet for 8 weeks. Metabolic characteristics including total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-c) were lower in ApoE−/− HD + TQ mice than in ApoE−/− HD mice. Oil-red O staining revealed excessive lipid deposition in the kidneys of ApoE−/− HD mice; however, it was significantly suppressed in the ApoE−/− HD + TQ mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) gene and protein expression was lower in the kidney tissues of ApoE−/− HD + TQ mice than those of ApoE−/− HD mice. Furthermore, macrophages and pro-inflammatory cytokines were lower in the kidney tissues of ApoE−/− HD + TQ mice than in the ApoE−/− HD mice. These results indicate that thymoquinone may be a potential therapeutic agent for kidney damage from hypercholesterolemia.

Heart Failure (HF) is an important public health problem as a result of its high morbidity and poor prognosis [1].

Sepsis increases the risk of developing liver injury. Previous studies have demonstrated that thymoquinone (TQ) exhibits hepatoprotective properties in vivo as well as in vitro. The present study aimed to investigate the underlying mechanisms of the protective effects of TQ against liver injury in septic BALB/c mice. Male BALB/c mice (age, 8 weeks) were randomly divided into four groups, namely, the control, TQ (50 mg/kg/day) treatment, cecal ligation and puncture (CLP), and TQ + CLP groups. CLP was performed following gavage of TQ for 2 weeks. At 48 h post-CLP, the histopathological alterations in the liver tissue (LT) and plasma levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were assessed. The present study evaluated microtubule-associated protein light chain 3 (LC3), sequestosome-1 (p62) and beclin 1 protein expression by western blotting and immunostaining, as well as interleukin (IL)-6, IL-1β, IL-10, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) mRNA expression by RT-qPCR. The results of the present study indicated that administration of TQ to mice reduced the histological alterations caused by CLP in LT. TQ inhibited the plasma levels of ALT, AST and ALP in the CLP group. TQ significantly inhibited the elevation of p62, IL-1β, IL-6, MCP-1 and TNF-α levels as well as increased the LC3, beclin 1 and IL-10 levels in LT. PI3K expression in the TQ + CLP group was significantly decreased compared with that in the CLP group. TQ treatment effectively modulated the expression levels of p62, LC3, beclin 1, PI3K and proinflammatory cytokines, and may be an important agent for the treatment of sepsis-induced liver injury.

Excessive tumor necrosis factor-α (TNF-α) could enhance cell death and aggravate left ventricular remodeling and myocardial dysfunction. A disintegrin and metalloproteinase-17 (ADAM17), an important maturation regulator of TNF-α, might be involved in the aging-associated ventricular remodeling. The present study observed myocardial ADAM17 expression in young and aged rats and explored the association between cardiac structure/function and expression of ADAM17 in 6 month-old (n = 10, young group) and 24 month-old SD rats (n = 10, old group). The body, heart weight and heart weight/body weight ratio of rats in the old group were all significantly increased compared to that in the young group (P < 0.05). The left ventricular systolic end-diameter and end-diastolic diameters were significantly enlarged in the old group compared to the young group (P < 0.05), while the systolic function index including the left ventricular ejection fraction and left ventricular fractional shortening were similar between the two groups. The peak mitral flow velocity (E)/peak mitral annulus velocity (E′) ratio was significantly higher in the old group than in the young group (P < 0.05). Histological examination showed more damage of cardiomyocytes, interstitial collagen deposition and inflammatory cell infiltration in the old group. Immunohistochemistry examination showed that myocardial TNF-α expression was mainly located in cardiomyocytes and was significantly higher in the old group than in the young group (P < 0.05). The protein expression of myocardial ADAM17 detected by western blot was significantly higher in the old group than in the young group (P < 0.05), while TIMP-3 expression was similar between the two groups. The present study suggested that ADAM17 and inflammation might play an important role in aging-related myocardial remodeling through regulating TNF-α.

Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18−/− and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury.

Background Hypercholesterolemia is a well-established risk factor for cardiac damage, which can lead to cardiovascular diseases. Many studies have shown that thymoquinone protected rats from doxorubicin-induced cardiotoxicity and cardiac damage. The aim of this study was to investigate the possible protective effects of thymoquinone against cardiac damage in apolipoprotein E knockout (ApoE−/−) mice. Methods Eight-week-old male ApoE−/− mice were randomly divided into three groups: control group fed a normal diet (ND group), a high cholesterol diet (HD group) or HD mixed with thymoquinone (HD + TQ group). All groups were fed the different diets for 8 weeks. Blood samples were obtained from the inferior vena cava and collected in serum tubes. The samples were then stored at − 80 °C until used. Coronal sections of heart tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the heart tissues was snap-frozen in liquid nitrogen for mRNA or immunohistochemical analysis. Results The metabolic characteristics of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and high-sensitivity C-reactive protein (hs-CRP) were lower in ApoE−/−HD + TQ mice than in ApoE−/− HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) gene and protein expression was lower in the heart tissue of ApoE−/−HD + TQ mice than in those of ApoE−/−HD mice. Furthermore, the levels of macrophages and pro-inflammatory cytokines were lower in the cardiac tissues of ApoE−/−HD + TQ mice than in those of ApoE−/−HD mice. Conclusions These results indicate that thymoquinone may provide a potential therapeutic target for cardiac damage caused by hypercholesterolemia.

Acute kidney injury (AKI) is a severe complication of sepsis, which largely contributes to the associated high mortality rate. Fenofibrate, a peroxisome proliferator activated receptor α (PPARα) agonist, has received considerable attention because of its effects related to renal damage-related energy metabolism and inflammation. The present study investigated the effects of fenofibrate on sepsis-associated AKI in BALB/c mice subjected to caecal ligation and puncture (CLP). Eight-week-old male BALB/c mice were divided into four groups: control group, fenofibrate group, caecal ligation and puncture (CLP) group, and fenofibrate + CLP group. CLP was performed after mice were gavaged with fenofibrate for 2 weeks. After 48 hours, we measured the histopathological alterations of the kidney tissue and plasma levels of serum creatinine (CRE), neutrophil gelatinase-associated lipocalin (NGAL), reactive oxygen species (ROS), ATP, and ADP. We evaluated PPARα and P53 protein levels as well as interleukin (IL)-1β, IL-6, and tumour necrosis factor-α mRNA levels. Our results showed that administering fenofibrate significantly reduced kidney histological alterations caused by CLP. Fenofibrate inhibited the plasma levels of ROS, CRE, NGAL, and increased the ATP/ADP ratio. Fenofibrate significantly inhibited elevations in P53, IL-1β, IL-6, and tumour necrosis factor-α expression. The results suggest that fenofibrate administration effectively modulates energy metabolism and may be a novel approach to treat sepsis-induced renal damage.