Search

Prior research has demonstrated an association between sodium-glucose cotransporter 2 (SGLT2) inhibitor and a reduced incidence of atrial fibrillation (AF). Given the established link between mitochondrial dysfunction and AF, this study aimed to explore the impact of SGLT2 inhibitors on AF burden and plausible antiarrhythmic mechanisms in patients with cardiovascular implantable electronic devices (CIEDs). Patients with atrial high-rate episodes (AHREs) detected by CIEDs were randomized to receive either 10 mg of dapagliflozin or a placebo for 3 months. AF burdens were quantified via CIEDs interrogations as AHREs duration, percentage, and number of episodes at baseline and after 3 months of treatment. Mitochondrial parameters, cellular oxidative stress, and norepinephrine levels were measured in peripheral blood mononuclear cells (PBMCs). A total of 54 patients with CIEDs were enrolled in the study. Among them, 36 patients (66.7%) had a history of clinical AF, and 9 patients (16.7%) had diabetes mellitus. After 3 months of the assigned treatment, the median longest AHRE duration decreased similarly in both the dapagliflozin and placebo groups (-77.0 vs. -162.0 min, p = 0.442). Clinical AF, as opposed to subclinical AF, was independently linked to decreased basal respiration and adenosine triphosphate (ATP) production. Although the changes in AHREs burden over the 3 months did not significantly differ between the dapagliflozin and placebo groups, dapagliflozin significantly decreased the number of AHREs per month by 2.2 episodes among patients with clinical AF, whereas the placebo group experienced an increase of 0.6 episodes (p = 0.048). Additionally, dapagliflozin significantly reduced cellular oxidative stress (from 26840 to 18164 arbitrary units, p = 0.049) and improved mitochondrial spare respiratory capacity (SRC) percentage (from 166 to 202%, p = 0.016) in patients with clinical AF. Dapagliflozin did not significantly reduce the longest AHRE duration in patients with CIED. However, in the subgroup of patients with clinical AF, dapagliflozin reduced the number of AHREs potentially via reduction of cellular oxidative stress and enhancement of mitochondrial function.The study protocol was registered at the Thai Clinical Trials Registry (TCTR identification number TCTR20210315003) on March 15, 2021., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate The study protocol was approved by the Research Ethics Committee, Chiang Mai University (certificate of approval No.041/2021). The investigations were carried out in accordance with the Declaration of Helsinki. The informed consent was obtained from all subjects and/or their legal guardian(s)., (© 2024. The Author(s).)

Iron overload causes cognitive impairment in thalassemia patients. The gut-brain axis plays an important role in cognitive function. However, the association between gut/blood microbiome, cognition, and iron burden in thalassemia patients has not been thoroughly investigated. We aimed to determine those associations in thalassemia patients with different blood-transfusion regimens. Sixty participants: healthy controls, transfusion-dependent thalassemia (TDT) patients, and non-transfusion-dependent (NTDT) patients, were recruited to evaluate iron overload, cognition, and gut/blood microbiome. TDT patients exhibited greater iron overload than NTDT patients. Most thalassemia patients developed gut dysbiosis, and approximately 25% of the patients developed minor cognitive impairment. Increased Fusobacteriota and Verrucomicrobiota with decreased Fibrobacterota were observed in both TDT and NTDT groups. TDT patients showed more abundant beneficial bacteria: Verrucomicrobia. Iron overload was correlated with cognitive impairment. Increased Butyricimonas and decreased Paraclostridium were associated with higher cognitive function. No trace of blood microbiota was observed. Differences in blood bacterial profiles of thalassemia patients and controls were insignificant. These findings suggest iron overload plays a role in the imbalance of gut microbiota and impaired cognitive function in thalassemia patients. Harnessing probiotic potential from those microbes could prevent the gut-brain disturbance in thalassemia patients., (© 2024. The Author(s).)

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial anomalies. Abnormal Alu methylation in DNA of the pregnant mother may influence the abnormal development of the child. This study aimed to examine Alu methylation and cellular senescence in NSCL/P patients and their mothers as well as the correlation with the severity of NSCL/P. A total of 39 patients with NSCL/P and 33 mothers were enrolled. Of these patients, 6 were cleft lip only (CLO), 9 were cleft palate only (CPO), and 24 were cleft lip and palate (CLP). Alu methylation and senescence markers were determined in the white blood cells of NSCL/P patients, their mothers, and in the lip and palatal tissues of patients at the time of cheiloplasty and palatoplasty. Total Alu methylation was not significantly different between groups. However, a decrease in Alu hypermethylation, increased partial Alu methylation, RAGE, and p16 expression were shown in CLP, the most severe cleft type. Alu methylation in tissues did not differ between groups. In mothers, an increase in Alu methylation was observed only in the CLP. Therefore, the pathogenesis of NSCL/P may be related to Alu methylation of the mother promoting loss of Alu methylation and subsequently senescence in the children., (© 2024. The Author(s).)

Pediatric sepsis is a serious issue globally and is a significant cause of illness and death among infants and children. Refractory septic shock and multiple organ dysfunction syndrome are the primary causes of mortality in children with sepsis. However, there is incomplete understanding of mechanistic insight of sepsis associated organ dysfunction. Biomarkers present during the body's response to infection-related inflammation can be used for screening, diagnosis, risk stratification/prognostication, and/or guidance in treatment decision-making. Research on biomarkers in children with sepsis can provide information about the risk of poor outcomes and sepsis-related organ dysfunction. This review focuses on clinically used biomarkers associated with immune dysregulation and organ dysfunction in pediatric sepsis, which could be useful for developing precision medicine strategies in pediatric sepsis management in the future. IMPACT: Sepsis is a complex syndrome with diverse clinical presentations, where organ dysfunction is a key factor in morbidity and mortality. Early detection of organ complications is vital in sepsis management, and potential biomarkers offer promise for precision medicine in pediatric cases. Well-designed studies are needed to identify phase-specific biomarkers and improve outcomes through more precise management., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Metabolic alterations play an essential role in ovarian carcinogenesis. The flexibility of mitochondrial functions facilitates cellular adaptation to the tough environment associated with carcinogenesis. An understanding of the differences in mitochondrial functions in normal ovaries and cancers could provide a basis for further exploration of future mitochondria-based screening, diagnosis, prognostic prediction, and targeted therapy for epithelial ovarian cancers. The main objective of this study was to assess mitochondrial function profiles measured from PBMCs and ovarian tissues of epithelial ovarian cancers in comparison with normal ovaries. A total of 36 patients were recruited for the study, all of whom underwent primary surgical treatment for malignant epithelial ovarian neoplasm. Of these, 20 patients were in the early stage and 16 patients were in the advanced stage. Additionally, 21 patients who had pelvic surgery for benign gynecologic conditions, with normal ovaries incidentally removed, were recruited as controls. At the time of surgery, a blood sample was collected from each participant for PBMC isolation, and ovarian tissue was retained for molecular studies. These studies included the examination of oxidative stress, mitochondrial mass, mitochondrial respiration, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes, and mitochondrial swelling. Clinical and histopathological data were also collected and compared between different stages of epithelial ovarian cancers: early-stage (group 1), advanced-stage (group 2), and normal ovaries (group 3). The levels of cellular oxidative stress, mitochondrial mass, and mitochondrial biogenesis in the peripheral blood mononuclear cells (PBMCs) of participants with ovarian cancer were significantly lower than those of the control group. However, the mitochondrial respiratory parameters measured from the PBMCs were similar across all three groups. Furthermore, mitochondrial membrane depolarization and mitochondrial swelling were observed in ovarian tissues of both early-stage and advanced-stage cancer groups. We demonstrated the dynamic nature of mitochondrial ROS production, biogenesis, and respiratory function in response to epithelial ovarian carcinogenesis. The flexibility of mitochondrial functions under diverse conditions may make it a challenging therapeutic target for ovarian cancer., (© 2024. The Author(s).)

Gut microbiota play an important role in the health and disease of Asian elephants, however, its characteristics at each stage of life have not been thoroughly investigated in maintaining and regulating health of elephants. This study, therefore, aimed to characterize the profiles of the gut microbiota of captive Asian elephants from infants to the elderly. Gut microbiota were identified by 16S rRNA sequencing from the feces of captive Asian elephants with varying age groups, including infant calves, suckling calves, weaned calves, subadult and adult elephants, and geriatric elephants. The diversity of the gut microbiota was lowest in infants, stable during adulthood, and slightly decreased in the geriatric period. The gut microbiota of the infant elephants was dominated by milk-fermenting taxa including genus Bifidobacterium of family Bifidobacteriaceae together with genus Akkermansia. The fiber-fermenting taxa such as Lachnospiraceae_NK3A20_group were found to be increased in suckling elephants in differential abundance analysis by Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC). The gut microbiota profiles after weaning until the adult period has been uniform as indicated by no significant differences in beta diversity between groups. However, the composition of the gut microbiota was found to change again in geriatric elephants. Understanding of the composition of the gut microbiota of captive Asian elephants at various life stages could be beneficial for promoting good health throughout their lifespan, as well as ensuring the welfare of captive elephants., (© 2024. The Author(s).)

Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies., (© 2023. Springer Nature Limited.)

Aberrant activation of NLRP3 inflammasome causes the progression of various inflammation-related diseases, but the small-molecule inhibitors of NLRP3 are not currently available for clinical use. Tabersonine (Tab) is a natural product derived from a traditional Chinese herb Catharanthus roseus that is usually used as an anti-tumor agent. In this study we investigated the anti-inflammatory effects and molecular targets of Tab. We first screened 151 in-house natural compounds for their inhibitory activity against IL-1β production in BMDMs. We found that Tab potently inhibited NLRP3-mediated IL-1β production with an IC 50 value of 0.71 μM. Furthermore, we demonstrated that Tab suppressed the assembly of NLRP3 inflammasome, especially the interaction between NLRP3 and ASC. Interestingly, we found that Tab directly bound to NLRP3 NACHT domain, thereby reducing the self-oligomerization of NLRP3. In addition, we showed that administration of Tab significantly ameliorated NLRP3-driven diseases, such as peritonitis, acute lung injury, and sepsis in mouse models. The preventive effects of Tab were not observed in the models of NLRP3 knockout mouse. In conclusion, we have identified Tab as a natural NLRP3 inhibitor and a lead compound for the design and discovery of novel NLRP3 inhibitors., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The fate of osteoprogenitor cells along with the progression of type 2 diabetes (T2DM) and factors determining the fate of those cells remains to be elucidated. This cross-sectional study included 18 normoglycemic, 27 prediabetic, and 73 T2DM to determine osteogenic differentiation across the continuum of dysglycemia and to construct a model to predict the fate of osteoprogenitor cells. This study demonstrated a preserved osteogenic differentiation ability of peripheral blood-derived mononuclear cells (PBMC) isolated from normoglycemic and prediabetic but a progressive decline in their osteogenic differentiation during the progression of T2DM. The rate of osteogenic differentiation rapidly declined by 4-7% annually during the first 10 years of diabetes and then slowed down. A predictive model composed of three independent risk factors, including age, duration of diabetes, and glomerular filtration rate, demonstrated an AuROC of 0.834. With a proposed cut-off of 21.25, this model had 72.0% sensitivity, 87.5% specificity, and 78.9% accuracy in predicting the fate of osteoprogenitor cells. In conclusion, this study provided a perspective on the osteogenic differentiation ability of the osteoprogenitor cells across a continuum of dysglycemia and a predictive model with good diagnostic performance for the prediction of the fate of osteoprogenitor cells in patients with T2DM., (© 2023. The Author(s).)

We aimed to compare the time-course effect of D-galactose (D-gal)-induced aging, obesity, and their combined effects on bone homeostasis. Male Wistar rats were fed with either a normal diet (ND; n = 24) or a high-fat diet (HFD; n = 24) for 12 weeks. All rats were then injected with either vehicle or 150 mg/kg/day of D-gal for 4 or 8 weeks. Blood was collected to measure metabolic, aging, oxidative stress, and bone turnover parameters. Bone oxidative stress and inflammatory markers, as well as bone histomorphometry were also evaluated. Additionally, RAW 264.7 cells were incubated with either D-gal, insulin, or D-gal plus insulin to identify osteoclast differentiation capacity under the stimulation of receptor activator of nuclear factor κB ligand. At week 4, D-gal-induced aging significantly elevated serum malondialdehyde level and decreased trabecular thickness in ND- and HFD-fed rats, when compared to the control group. At week 8, D-gal-induced aging further elevated advanced glycation end products, increased bone inflammation and resorption, and significantly impaired bone microarchitecture in HFD-fed rats. The osteoclast number in vitro were increased in the D-gal, insulin, and combined groups to a similar extent. These findings suggest that aging aggravates bone dyshomeostasis in the obese condition in a time-dependent manner., (© 2022. The Author(s).)

The association between Lipocalin-2 (LCN2) and cognition in patients with metabolic syndrome (MetS) has not been thoroughly investigated. We aimed to evaluate whether serum LCN2 levels are associated with the alteration of cognitive function in patients with MetS. The total of 191 non-demented participants with MetS were enrolled onto the study in 2015, and a cohort study was conducted in a subpopulation in 2020. After adjustment for sex, age, waist circumference, creatinine levels, and HbA1C, an association between the higher serum LCN2 levels and the lower Montreal cognitive assessment (MoCA) scores was observed (B = - 0.045; 95%CI - 0.087, - 0.004; p 0.030). A total of 30 participants were followed-up in 2020. Serum LCN2 levels were decreased in correlation with age (23.31 ± 12.32 ng/ml in 2015 and 15.98 ± 11.28 ng/ml in 2020, p 0.024), while other metabolic parameters were unchanged. Magnetic resonance imaging studies were conducted on a subsample of patients in 2020 (n = 15). Associations between high serum LCN2 levels from 2015 and 2020 and changes in brain volume of hippocampus and prefrontal cortex from 2020 have been observed. These findings suggest a relationship between changes of the level of circulating LCN2, cognitive impairment, and changes in brain volume in patients with MetS. However, further investigation is still needed to explore the direct effect of circulating LCN2 on the cognition of MetS patients., (© 2022. The Author(s).)

Mitochondria are extraordinarily dynamic organelles that have a variety of morphologies, the status of which are controlled by the opposing processes of fission and fusion. Our recent study shows that inhibition of excessive mitochondrial fission by Drp1 inhibitor (Mdivi-1) leads to a reduction in infarct size and left ventricular (LV) dysfunction following cardiac ischemia-reperfusion (I/R) injury in high fat-fed induced pre-diabetic rats. In the present study, we investigated the cardioprotective effects of a mitochondrial fusion promoter (M1) and a combined treatment (M1 and Mdivi-1) in pre-diabetic rats. Wistar rats were given a high-fat diet for 12 weeks to induce prediabetes. The rats then subjected to 30 min-coronary occlusions followed by reperfusion for 120 min. These rats were intravenously administered M1 (2 mg/kg) or M1 (2 mg/kg) combined with Mdivi-1 (1.2 mg/kg) prior to ischemia, during ischemia or at the onset of reperfusion. We showed that administration of M1 alone or in combination with Mdivi-1 prior to ischemia, during ischemia or at the onset of reperfusion all significantly attenuated cardiac mitochondrial ROS production, membrane depolarization, swelling and dynamic imbalance, leading to reduced arrhythmias and infarct size, resulting in improved LV function in pre-diabetic rats. In conclusion, the promotion of mitochondrial fusion at any time-points during cardiac I/R injury attenuated cardiac mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and improved LV function in pre-diabetic rats., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are known as the common causes of respiratory failure in critically ill patients. Myeloid differentiation 2 (MD2), a co-receptor of toll like receptor 4 (TLR4), plays an important role in LPS-induced ALI in mice. Since MD2 inhibition by pharmacological inhibitors or gene knockout significantly attenuates ALI in animal models, MD2 has become an attractive target for the treatment of ALI. In this study we identified two chalcone-derived compounds, 7w and 7x, as new MD2 inhibitors, and investigated the therapeutic effects of 7x and 7w in LPS-induced ALI mouse model. In molecular docking analysis we found that 7w and 7x, formed pi-pi stacking interactions with Phe 151 residue of the MD2 protein. The direct binding was confirmed by surface plasmon resonance analysis (with KD value of 96.2 and 31.2 μM, respectively) and by bis-ANS displacement assay. 7w and 7x (2.5, 10 μM) also dose-dependently inhibited the interaction between lipopolysaccharide (LPS) and rhMD2 and LPS-MD2-TLR4 complex formation. In mouse peritoneal macrophages, 7w and 7x (1.25-10 μM) dose-dependently inhibited LPS-induced inflammatory responses, MAPKs (JNK, ERK and P38) phosphorylation as well as NF-κB activation. Finally, oral administration of 7w or 7x (10 mg ·kg -1 per day, for 7 days prior LPS challenge) in ALI mouse model significantly alleviated LPS-induced lung injury, pulmonary edema, lung permeability, inflammatory cells infiltration, inflammatory cytokines expression and MD2/TLR4 complex formation. In summary, we identify 7w and 7x as new MD2 inhibitors to inhibit inflammatory response both in vitro and in vivo, proving the therapeutic potential of 7w and 7x for ALI and inflammatory diseases., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Cognitive impairment has been reported in patients with myocardial infarction despite a successful reperfusion therapy. Several modes of cell death are involved in brain damage during cardiac ischemia/reperfusion (I/R) injury. Although apoptosis, necroptosis, and ferroptosis inhibitors provided neuroprotection against cerebral I/R injury, the effects of these cell death inhibitors on the brain following cardiac I/R injury have never been investigated. We hypothesized that apoptosis, necroptosis, and ferroptosis inhibitors attenuate brain damage following cardiac I/R injury. One-hundred and twenty-six male rats were used: 6 rats were assigned to sham operation and 120 rats were subjected to 30-min regional cardiac ischemia and 120-min reperfusion. Rats in cardiac I/R group were pretreated with either vehicle (n = 12) or one of cell death inhibitors. Rats treated with apoptosis, necroptosis, or ferroptosis inhibitor were subdivided into three different doses including low (L), medium (M), and high (H) doses (n = 12/group). Z-VAD, necrostatin-1 (Nec-1), and ferrostatin-1 (Fer-1) were used as apoptosis, necroptosis, and ferroptosis inhibitor, respectively. Rats were sacrificed at the end of reperfusion, and the brain was used to analyze dendritic spine density, Alzheimer's disease (AD)-related proteins, blood-brain barrier (BBB) tight junction proteins, mitochondrial function, inflammation, and cell death. Our data showed that cardiac I/R led to brain damage and only apoptosis occurred in the hippocampus after cardiac I/R injury. In the cardiac I/R group, treatment with M-Z-VAD and all doses of Nec-1 decreased hippocampal apoptosis and amyloid beta aggregation, thereby reducing dendritic spine loss. M- and H-Fer-1 also reduced dendritic spine loss by suppressing ACSL4, TNF-α, amyloid beta, and tau hyperphosphorylation. Moreover, Bax/Bcl-2 was decreased in all treatment regimen except L-Z-VAD. Additionally, M-Z-VAD and M-Fer-1 partially attenuated mitochondrial dysfunction. Only L-Nec-1 preserved BBB proteins. In conclusion, cell death inhibitors prevented hippocampal dendritic spine loss caused by cardiac I/R injury through different mechanisms., (© 2021. The Author(s).)

Although an increased fibroblast growth factor 21 (FGF21) level was related to mild cognitive impairment (MCI) in metabolic syndrome patients, any association regarding FGF21 and MCI in thalassemia patients as well as mechanistic insight are questionable. Therefore, the objectives of this study were: (1) to investigate the prevalence and associative risk factors of MCI in thalassemia patients, (2) to evaluate the association between levels of FGF21 and MCI in thalassemia patients, and (3) to investigate brain FGF21 signaling in iron-overload thalassemia. Thalassemia patients were enrolled onto the study (n = 131). Montreal cognitive assessment (MoCA) was used to determine cognitive performance. Plasma FGF21 level was determined in all patients. Iron-overload β-thalassemic (HT) mice were used to investigate brain FGF21 level and signaling, the expression of synaptic proteins, and Alzheimer's like pathology. We found that 70% of thalassemia patients developed MCI. FGF21 level was positively correlated with the MCI. Interestingly, brain FGF21 resistance, as indicated by increased brain FGF21 levels with impaired FGF21 signaling, was found in iron-overload HT mice. The reduced synaptic protein expression and increased Alzheimer's like pathology were also observed. These suggest that FGF21 may play a role in MCI in thalassemia patients.

Cognitive impairment is commonly found in the elderly population. Evidence suggests that mitochondrial function in lymphocytes are potential biomarkers in the progression of neurodegeneration, as peripheral mitochondrial function is associated with mild cognitive impairment (MCI) in the elderly population. Therefore, we hypothesize that impaired mitochondrial ATP production and oxidative stress in peripheral blood mononuclear cells (PBMCs) are associated with cognitive impairment in the elderly population. Data were collected from 897 participants from the EGAT (The Electricity Generating Authority of Thailand) cohort. The participants were classified to be in the normal cognition group (n = 428) or mild cognitive impairment group (n = 469), according to their MoCA score. The association of mitochondrial function and cognitive status was analyzed by binary logistic regression analysis. MCI participants had higher age, systolic blood pressure, waist/hip ratio, and lower plasma high- and low-density lipoprotein cholesterol levels, when compared to the normal cognition group. In addition, estimated glomerular filtration rate were lower in the MCI group than those in the normal cognition group. Collectively, MCI is associated with mitochondrial dysfunction in PBMCs as indicated by decreasing mitochondrial ATP production, increasing proton leak, and oxidative stress, in the elderly population, independently of the possible confounding factors in this study.

Metabolic syndrome (MetS) has become a worldwide health issue. Recent studies reveal that the human gut microbiota exerts a significant role in the pathogenesis of this disease. While drug treatments may greatly improve metabolic symptoms, little is known about the gut microbiota composition of these treated MetS patients. This study aimed to characterize the gut microbiota composition of treated-MetS patients and analyse the possibility of using gut microbiota as an indicator of metabolic conditions. 16S rRNA metagenomic sequencing approach was used to profile gut microbiota of 111 treated MetS patients from The Cohort of patients at a high Risk of Cardiovascular Events (CORE)-Thailand registry. Our results show that the gut microbiota profiles of MetS patients are diverse across individuals, but can be classified based on their similarity into three groups or enterotypes. We also showed several associations between species abundance and metabolic parameters that are enterotype specific. These findings suggest that information on the gut microbiota can be useful for assessing treatment options for MetS patients. In addition, any correlations between species abundance and human properties are likely specific to each microbial community.

Increased fibroblast growth factor 21 (FGF21) levels have been found in patients with metabolic syndrome (MetS). MetS is also associated with cognitive decline. However, the correlation between FGF21 and cognitive decline in elderly and nonelderly MetS patients has not been investigated. 116 non-elderly patients (age <65 years old) and 96 elderly patients (≥65 years old) with MetS were enrolled. Blood samples for FGF21 were collected from all participants after 12-hour fasting. Cognitive function was assessed using the Montreal cognitive assessment (MoCA) test. The MoCA score was negatively associated with age and was different among different levels of education in these MetS patients. In the non-elderly group, body mass index (BMI) showed positively correlated with MoCA score while, FGF21 level and HbA1C were negatively associated with the MoCA score in non-elderly MetS patients. BMI was the only factor which showed a negative correlation with the MoCA score in elderly MetS patients. This study demonstrated that FGF21 level was independently associated with cognitive impairment in non-elderly patients but not in elderly patients. The possible role of FGF21 level in cognitive impairment in non-elderly should be confirmed in a prospective study.

Hyperglycemia-induced oxidative stress is usually found in diabetic condition. 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, statins, are widely used as cholesterol-lowering medication with several "pleiotropic" effects in diabetic patients. This study aims to evaluate whether the protective effects of atorvastatin and insulin on renal function and renal organic anion transporter 3 (Oat3) function involve the modulation of oxidative stress and pancreatic function in type 1 diabetic rats. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin (50 mg/kg BW). Atorvastatin and insulin as single or combined treatment were given for 4 weeks after diabetic condition had been confirmed. Diabetic rats demonstrated renal function and renal Oat3 function impairment with an increased MDA level and decreased SOD protein expression concomitant with stimulation of renal Nrf2 and HO-1 protein expression. Insulin plus atorvastatin (combined) treatment effectively restored renal function as well as renal Oat3 function which correlated with the decrease in hyperglycemia and oxidative stress. Moreover, pancreatic inflammation and apoptosis in diabetic rats were ameliorated by the combined drugs treatment. Therefore, atorvastatin plus insulin seems to exert the additive effect in improving renal functionby alleviating hyperglycemiaand the modulation of oxidative stress, inflammation and apoptosis.

Intracellular calcium [Ca 2+ ] i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca 2+ ] i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca 2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca 2+ ]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca 2+ ]i homeostasis, only DFP + NAC restored cardiac [Ca 2+ ]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca 2+ ] i homeostasis, leading to restored myocardial contractility in iron-overloaded rats.

Estrogen deprivation aggravates cardiac injury after myocardial ischemia and reperfusion (I/R) injury. Although either estrogen or the dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, reduces myocardial damage following cardiac I/R, their effects on the heart in obese-insulin resistant and estrogen deprived conditions remain unknown. Ovariectomized (O) rats (n = 36) were divided to receive either normal diet (NDO) or high-fat diet (HFO) for 12 weeks, followed by treatment with a vehicle, estrogen or vildagliptin for 4 weeks. The setting of in vivo cardiac I/R injury, 30-min ischemia and 120-min reperfusion, was performed. At 12 weeks after ovariectomy, both NDO and HFO rats exhibited an obese-insulin resistant condition. Both NDO and HFO rats treated with estrogen and vildagliptin showed reduced fasting plasma glucose, insulin and HOMA index. Both treatments improved cardiac function indicated by restoration of heart rate variability and increased %left ventricular ejection fraction (%LVEF). The treatments similarly protected cardiac mitochondrial function against I/R injury, leading to a reduction in the infarct size, oxidative stress and apoptosis in the ischemic myocardium. These findings demonstrate that vildagliptin effectively improves metabolic status, and shares similar efficacy to estrogen in reducing myocardial infarction and protecting cardiac mitochondrial function against I/R injury in estrogen-deprived obese-insulin resistant rats.

Vagus nerve stimulation (VNS) therapy was shown to improve peripheral insulin sensitivity. However, the effects of chronic VNS therapy on brain insulin sensitivity, dendritic spine density, brain mitochondrial function, apoptosis and cognition in obese-insulin resistant subjects have never been investigated. Male Wistar rats (n = 24) were fed with either a normal diet (n = 8) or a HFD (n = 16) for 12 weeks. At week 13, HFD-fed rats were divided into 2 groups (n = 8/group). Each group was received either sham therapy or VNS therapy for an additional 12 weeks. At the end of treatment, cognitive function, metabolic parameters, brain insulin sensitivity, brain mitochondrial function, brain apoptosis, and dendritic spines were determined in each rat. The HFD-fed with Sham therapy developed brain insulin resistance, brain oxidative stress, brain inflammation, and brain apoptosis, resulting in the cognitive decline. The VNS group showed an improvement in peripheral and brain insulin sensitivity. VNS treatment attenuated brain mitochondrial dysfunction and cell apoptosis. In addition, VNS therapy increased dendritic spine density and improved cognitive function. These findings suggest that VNS attenuates cognitive decline in obese-insulin resistant rats by attenuating brain mitochondrial dysfunction, improving brain insulin sensitivity, decreasing cell apoptosis, and increasing dendritic spine density.

Long-term high-fat diet (HFD) consumption leads to not only obese-insulin resistance, but also impaired left ventricular (LV) function. Vagus nerve stimulation (VNS) has been shown to exert cardioprotection. However, its effects on the heart and metabolic parameters under obese-insulin resistant condition is not known. We determined the effects of VNS on metabolic parameters, heart rate variability (HRV) and LV function in obese-insulin resistant rats. Male Wistar rats were fed with HFD for 12 weeks, and were randomly divided into sham and VNS groups. VNS was applied for the next 12 weeks. Echocardiography, blood pressure and HRV were examined. Blood samples were collected for metabolic parameters. At the end, the heart was removed for determination of apoptosis, inflammation, oxidative stress, and cardiac mitochondrial function. VNS for 12 weeks significantly decreased plasma insulin, HOMA index, total cholesterol, triglyceride, LDL and visceral fat. Serum adiponectin was significantly increased in the VNS group. VNS also significantly decreased blood pressure, improved HRV and LV function, decreased cardiac MDA, TNF-α and Bax levels, and improved cardiac mitochondrial function. VNS improves metabolic and hemodynamic parameters, and the LV function via its ability against apoptosis, inflammation and oxidative stress, and preserved cardiac mitochondrial function in obese-insulin resistant rats.