Quercetin as a therapeutic agent activate the Nrf2/Keap1 pathway to alleviate lung ischemia-reperfusion injury.

Lung ischemia-reperfusion injury (LIRI) causes oxidative stress, inflammation, and immune system activation. The Nrf2/Keap1/HO-1 pathway is important in cellular defense against these effects. Quercetin, a flavonoid with antioxidant, anti-inflammatory, and anti-cancer properties, has been investigated. Our aim in this study was to investigate the effect of quercetin on preventing lung ischemia-reperfusion injury and the role of the Nrf2/Keap1/HO-1 pathway. Sixty-four male Wistar rats were divided into four distinct groups(n = 16). Sham, lung ischemia-reperfusion (LIR), Saline + LIR, Quercetin + LIR (30 mg/kg i.p for a week before LIR). LIR groups were subjected to 60 min of ischemia (left pulmonary artery, vein, and bronchus) and 120 min of reperfusion. Our assessment encompassed a comprehensive analysis of various factors, including the evaluation of expression Nrf2, Keap1, and Heme Oxygenase-1 (HO-1) levels and NF-κB protein. Furthermore, we examined markers related to inflammation (interleukin-1ß and tumor necrosis factor alpha), oxidative stress (malondialdehyde, total oxidant status, superoxide dismutase, glutathione peroxidase, total antioxidant capacity), lung edema (Wet/dry lung weight ratio and total protein concentration), apoptosis (Bax and Bcl2 protein), and histopathological alterations (intra-alveolar edema, alveolar hemorrhage, and neutrophil infiltration). Our results show that ischemia-reperfusion results in heightened inflammation, oxidative stress, apoptosis, lung edema, and histopathological damage. Quercetin showed preventive effects by reducing these markers, acting through modulation of the Nrf2/Keap1 pathway and inhibiting the NF-κB pathway. This anti-inflammatory effect, complementary to the antioxidant effects of quercetin, provides a multifaceted approach to cell protection that is important for developing therapeutic strategies against ischemia-reperfusion injury and could be helpful in preventive strategies against ischemia-reperfusion.

Evaluation of the Safety and Efficacy of Curcumin-Synthesized Silver Nanoparticles in Rats Exposed to Chlorpyrifos During Puberty Development.

BACKGROUND: Silver nanoparticles (Ag-NPs) have garnered significant attention in recent years due to their therapeutic effects. Curcumin (CUR) has been utilized as a coating agent for synthesizing Ag-NPs, intended to act as a potential drug. OBJECTIVE: This study was designed to evaluate the safety and efficacy of curcuminsynthesized silver nanoparticles on rats exposed to chlorpyrifos (CPF) during their pubertal development. METHODS: Forty-two male Wistar rats, 23 days old, were selected and randomly divided into 7 groups (n=6) as follows: positive control, negative control, CPF (5 mg/kg), silver nanoparticles synthesized using curcumin at 40 µg/kg (CUR-Ag-NPs 40), CUR-Ag-NPs 80, CPF+ CUR-Ag-NPs 40, CPF+ CUR-AgNPs 80. All treatments were administered via gavage for 30 days. At the end of the study, rats were anesthetized using ketamine (50 mg/kg), and xylazine, (10 mg/kg) and blood was collected from the heart for serum analysis of liver enzymes, urea, and creatinine. RESULTS: Liver and kidney tissues were isolated for histopathological analysis. No significant differences were observed in serum levels of AST, ALT, and ALP enzymes as well as urea and creatinine levels among the different groups. Light microscopy observation revealed multifocal inflammatory mononuclear cell subsets in liver tissue associated with mild inflammatory mononuclear cell infiltration in the portal region in CPF, CUR-Ag-NPs 40, CUR-Ag-NPs 80, CPF+CUR-Ag-NPs 40, and CPF+CUR-Ag- NPs 80 groups. Histological examination of kidney tissue showed degenerative changes in the tubular epithelium, congestion, and mild infiltration of mononuclear inflammatory cells in the renal interstitial tissue in the CPF group, CUR-Ag-NPs 40, CUR-Ag-NPs 80, CPF+CUR-Ag-NPs 40 and CPF+CUR-Ag-NPs 80 groups. CONCLUSION: This study failed to establish the safety and efficacy of CUR-Ag-NP at 40 and 80 µg/kg in prepubertal rats exposed to CPF. However, further studies should be conducted to thoroughly characterize the efficacy of CUR-Ag-NP in developmental animal models.

Antioxidants Hydroxytyrosol and Thioredoxin-Mimetic Peptide CB3 Protect Irradiated Normal Tissue Cells.

Reducing side effects in non-cancerous tissue is a key aim of modern radiotherapy. Here, we assessed whether the use of the antioxidants hydroxytyrosol (HT) and thioredoxin-mimetic peptide CB3 (TMP) attenuated radiation-induced normal tissue toxicity in vitro. We used primary human umbilical vein endothelial cells (HUVECs) and human epidermal keratinocytes (HaCaT) as normal tissue models. Cells were treated with HT and TMP 24 h or immediately prior to irradiation. Reactive oxygen species (ROS) were assessed via luminescent- and fluorescence-based assays, migration was investigated using digital holographic microscopy, and clonogenic survival was quantified by colony formation assays. Angiogenesis and wound healing were evaluated via time-dependent microscopy. Secreted cytokines were validated in quantitative polymerase chain reaction (qPCR) studies. Treatment with HT or TMP was well tolerated by cells. The application of either antioxidant before irradiation resulted in reduced ROS formation and a distinct decrease in cytokines compared to similarly irradiated, but otherwise untreated, controls. Antioxidant treatment also increased post-radiogenic migration and angiogenesis while accelerating wound healing. HT or TMP treatment immediately before radiotherapy increased clonogenic survival after radiotherapy, while treatment 24 h before radiotherapy enhanced baseline proliferation. Both antioxidants may decrease radiation-induced normal tissue toxicity and deserve further pre-clinical investigation.

Myosin light chain phosphatase is a downstream target of Rho-kinase in endothelin-1-induced transactivation of the TGF-ß receptor.

BACKGROUND: Rho-kinase (ROCK) regulates actomyosin contraction, coronary vasospasm, and cytoskeleton dynamics. ROCK and of NADPH oxidase (NOX) play an essential role in cardiovascular disease and proteoglycan synthesis, which promotes atherosclerosis by trapping low density lipoprotein. ROCK is activated by endothelin-1 (ET1) and transactivates the transforming growth factor beta receptor (TGFßR1), intensifying Smad signaling and proteoglycan production. This study aimed to identify the role of myosin light chain phosphatase (MLCP) as a downstream target of ROCK in TßR1 transactivation. METHODS: Vascular smooth muscle cells were treated with ET1 and inhibitors of ROCK and MLCP were added. The phosphorylation levels of Smad2C, myosin light chain (MLC), and MLCP were monitored by western blot, and the mRNA expression of chondroitin 4-O-sulfotransferase 1 (C4ST1) was assessed by quantitative real-time PCR. RESULTS: We examined ROCK's role in ET1-induced TGFßR1 activation. ROCK phosphorylated MLCP at the MYPT1 T853 residue, blocked by the ROCK inhibitor Y27632. ROCK also increased MLC phosphorylation and actomyosin contraction in response to ET1, enhanced by the phosphatase inhibitor Calyculin A. Calyculin A also increased C4ST1 expression, GAG-chain synthesizing enzymes. CONCLUSIONS: This work suggests that ROCK is involved in ET1-mediated TßR1 activation through increased MLCP phosphorylation, which leads to Smad2C phosphorylation and stimulates C4ST1 expression.

Factors influencing smoking cessation attempts and success in Iranian male adults: national survey data.

BACKGROUND: Smoking cessation is a dynamic process that often involves a series of unsuccessful quit attempts before long-term abstinence is achieved. To implement interventions that lead to long-term abstinence, it will be necessary to understand the determinants of smoking cessation. Therefore, the main objective of the present study was to determine the effect of factors influencing both smoking cessation attempts and successful smoking cessation in the general population of Iran. METHODS: The data of 1293 participants whose information was obtained through a national cross-sectional study entitled "Survey of Risk Factors of Noncommunicable Diseases in 2016" were analyzed. There were three response levels: "quit attempt and successful quit", "quit attempt and unsuccessful quit", and "no quit attempt and unsuccessful quit". A multinomial logistic regression model was used to assess the effect of covariates on response. RESULTS: The mean (sd) age of all participants was 47.21 (13.65) years. According to the results, 883 people (68.29%) did not attempt to quit smoking, and of those who attempted to quit smoking, only 64 (15.61%) men were successful. The factors of living in an urban area (OR = 1.71) and past smoking intensity (OR = 1.967) were associated with no quit attempt and unsuccessful quitting. In addition, physician recommendation to quit smoking was a protective factor for no quit attempt and unsuccessful quit (OR = 0.599). Alcohol consumption was also a protective factor against successful quitting for both attempters (OR = 0.351) and nonattempters (OR = 0.359). CONCLUSIONS: Tobacco control programs should be implemented with a greater focus on heavy smokers and alcohol users. In addition, the role of health professionals in encouraging smokers to quit smoking should not be ignored.

Changes in the hippocampal level of tau but not beta-amyloid may mediate anxiety-like behavior improvement ensuing from exercise in diabetic female rats.

BACKGROUND: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. METHODS: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of VMax, 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aß) and Tau were also assessed using Western blot. RESULTS: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. CONCLUSIONS: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.

Mixture effects of trace element levels on cardiovascular diseases and type 2 diabetes risk in adults using G-computation analysis.

There is an increasing concern about the health effects of exposure to a mixture of pollutants. This study aimed to evaluate the associations between serum levels of heavy/essential metals ([Arsenic (As), Cadmium (Cd), Mercury (Hg), Lead (Pb), Nickel (Ni), Chromium (Cr), Copper (Cu), Iron (Fe), and Zinc (Zn)]) and the risk of developing cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2D). Data were collected from 450 participants (150 with CVDs, 150 with T2D, and 150 healthy subjects) randomly selected from the Ravansar Non-Communicable Disease (RaNCD) cohort in Western Iran, covering the years 2018-2023. Trace element levels in the serum samples were assayed using ICP-MS. Logistic regression was performed to estimate the adjusted risk of exposure to single and multi-metals and CVD/T2D. Odds ratios were adjusted for age, sex, education, residential areas, hypertension, and BMI. The mixture effect of exposure to multi-metals and CVD/T2D was obtained using Quantile G-computation (QGC). In the logistic regression model, chromium, nickel, and zinc levels were associated with CVD, and significant trends were observed for these chemical quartiles (P < 0.001). Arsenic, chromium, and copper levels were also associated with T2D. The weight quartile sum (WQS) index was significantly associated with both CVD (OR 4.17, 95% CI 2.16-7.69) and T2D (OR 11.96, 95% CI 5.65-18.26). Cd, Pb, and Ni were the most heavily weighed chemicals in these models.The Cd had the highest weight among the metals in the CVD model (weighted at 0.78), followed by Hg weighted at 0.197. For T2D, the serum Pb (weighted at 0.32), Ni (weighted at 0.19), Cr (weighted at 0.17), and Cd (weighted at 0.14) were the most weighted in the G-computation model. The results showed the significant role of toxic and essential elements in CVDs and T2D risk. This association may be driven primarily by cadmium and mercury for CVDs and Pb, Ni, Cr, and Cd for T2D, respectively. Prospective studies with higher sample sizes are necessary to confirm or refute our preliminary results as well as to determine other important elements.

Design and computational analysis of an effective multi-epitope vaccine candidate using subunit B of cholera toxin as a build-in adjuvant against urinary tract infections.

Introduction: Urinary tract infection (UTI) is one of the most common infections, usually caused by uropathogenic Escherichia coli (UPEC). However, antibiotics are a usual treatment for UTIs; because of increasing antibiotic-resistant strains, vaccination can be beneficial in controlling UTIs. Using immunoinformatics techniques is an effective and rapid way for vaccine development. Methods: Three conserved protective antigens (FdeC, Hma, and UpaB) were selected to develop a novel multi-epitope vaccine consisting of subunit B of cholera toxin (CTB) as a mucosal build-in adjuvant to enhance the immune responses. Epitopes-predicted B and T cells and suitable linkers were used to separate them and effectively increase the vaccine's immunogenicity. The vaccine protein's primary, secondary, and tertiary structures were evaluated, and the best 3D model was selected. Since CTB is the TLR2 ligand, molecular docking was made between the vaccine protein and TLR2. Molecular dynamic (MD) simulation was employed to evaluate the stability of the vaccine protein-TLR2 complex. The vaccine construct was subjected to in silico cloning. Results: The designed vaccine protein has multiple properties in the analysis. The HADDOCK outcomes show an excellent interaction between vaccine protein and TLR2. The MD results confirm the stability of the vaccine protein- TLR2 complex during the simulation. In silico cloning verified the expression efficiency of our vaccine protein. Conclusion: The results of this study suggest that our designed vaccine protein could be a promising vaccine candidate against UTI, but further in vitro and in vivo studies are needed.

Lactate-induced autophagy activation: unraveling the therapeutic impact of high-intensity interval training on insulin resistance in type 2 diabetic rats.

Impaired autophagy is a hallmark of diabetes. The current study proposed to investigate if high intensity interval training (HIIT) induced lactate accumulation could stimulate autophagy in type 2 diabetic male rats. 28 male Wistar rats were randomly assigned into four groups: Healthy Control (CO), Diabetes Control (T2D), Exercise (EX), and Diabetes + Exercise (T2D + EX). Diabetes was induced by feeding high-fat diet and administrating single dose of streptozotocin (35 mg/kg). After becoming diabetic, the animals in the exercise groups (EX and T2D + EX) performed an eight-week HIIT (4-10 interval, 80-100% Vmax, 5 days per week). Serum levels of lactate, glucose and insulin as well as the levels of lactate, pyruvate, lactate transporter monocarboxylate transporter 1 (MCT1), phosphorylated mitogen-activated protein kinases (p-MAP 1 and 2), phosphorylated extracellular signal-regulated protein kinases 1 and 2 (p-ERK 1 and 2), mammalian target of rapamycin (p-mTOR), ribosomal protein S6 kinase beta-1 (p-70S6k), p90 ribosomal S6 kinases (p-90RSK), autophagy related 7 (ATG7), Beclin-1, microtubule-associated protein 1A/1B, and 2A/2B -light chain 3 levels (LC3-I), (LC3- II), (LC3I/LC3II) in soleus muscle were measured. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and serum glucose was lower in T2D + EX compared to T2D group (P < 0.0001). While serum and soleus muscle levels of lactate was not different between T2D and T2D + Ex, the levels of Pyruvate (P < 0.01), MCT1, p-ERK1/2, p-mTOR, p70S6k, P-90RSK, ATG7, LC3-II, and LC3-II/LC3I ratios were higher in T2D + EX compared to T2D group (P < 0.0001). We concluded that eight weeks of high-intensity interval training could activated ERK/P90SRK while inhibiting mTOR/P70S6K signaling pathway in lactate dependent manner. It means increased autophagy which resulted in improve insulin resistance (IR) and reduce blood glucose.

Evaluation of Cognitive Impairment in Refractory Temporal Lobe Epilepsy Patients Concerning Structural Brain Lesions.

Introduction: Temporal lobe epilepsy (TLE) is the most prevalent form of drug-resistant epilepsy with concurrent cognitive impairment. Prevention, earlier diagnosis, and personalized management of cognitive deficits in TLE require more understanding of underlying structural and functional brain Ialterations. No study has evaluated the performance of TLE patients in different cognitive domains based on their structural brain lesions. Methods: In this study, 69 refractory TLE patients underwent magnetic resonance imaging (MRI) epilepsy protocol and several neuropsychological tests, consisting of the Wechsler adult intelligence scale-revised, Rey-Osterrieth complex figure test, verbal fluency test, digit span test, spatial span test, Wechsler memory scale-III, design fluency test, Rey visual design learning test, auditory-verbal learning test, and trail making test. MRI findings were classified into the following groups: Focal cortical dysplasia, gliosis, atrophy, mesial temporal sclerosis (MTS), tumor, vascular malformation, and other lesions or normal. Results of neuropsychological tests were compared between MRI groups using a generalized linear model with gamma distribution and log link. Results: Patients with MTS showed better performance in general intellectual functioning, working memory, attentional span, and auditory-verbal learning compared to patients with non-MTS MRI lesions. Atrophy and focal cortical dysplasia had the largest differences from MTS. Conclusion: Cognitive performance of refractory TLE patients varies concerning structural brain alterations. Further neuroimaging studies of TLE lead to prevention and more accurate management of cognitive decline in clinical settings. Highlights: Cognitive status in temporal lobe epilepsy (TLE) varies concerning structural brain alterations.Patients with mesial temporal sclerosis (MTS) show better cognitive performance than those with non-MTS lesions.Among non-MTS findings, patients with atrophy have more severe cognitive deficits. Plain Language Summary: Temporal lobe epilepsy (TLE) is the most common form of epilepsy which does not respond to anti-seizure drugs and needs surgery of the brain lesions. One of the most important issues of TLE patients is their cognitive impairment. Cognition refers to the mental processes for thinking, understanding, and perception of the environment such as attention, memory, learning, language, etc. Prevention, earlier diagnosis, and treatment of cognitive deficits in TLE patients need more understanding of their brain changes. No study has evaluated the cognition of TLE patients in detail based on their brain lesions. In this study, 69 drug-resistant TLE patients have undergone brain magnetic resonance imaging (MRI) and several neuropsychological tests that assess cognition, consisting of the Wechsler adult intelligence scale-revised, Rey-Osterrieth complex figure test, verbal fluency test, digit span test, spatial span test, Wechsler memory scale-III, design fluency test, Rey visual design learning test, auditory-verbal learning test, and trail making test. MRI findings were classified into the following groups based on the type of brain lesion by an expert: Focal cortical dysplasia, gliosis, atrophy, mesial temporal sclerosis (MTS), tumor, vascular malformation, and other lesions or normal. Results of neuropsychological tests were compared between MRI groups using appropriate statistical methods. Patients with MTS, as the most common lesion in TLE, showed better results compared to patients with lesions other than MTS in intelligence, memory, attention, and learning tests. Patients with atrophy and focal cortical dysplasia had the largest differences from those with MTS. These results suggest that the cognitive performance of drug-resistant TLE patients is different based on their structural brain changes. As imaging, in particular brain MRI, is the most available technique in the clinic for the assessment of epilepsy, further brain imaging studies can lead to prevention and better management of cognitive decline in TLE.

High prevalence of antibiotic resistance and biofilm formation in Salmonella Gallinarum.

Background and Objectives: Antibiotic resistance is an indicator of the passively acquired and circulating resistance genes. Salmonella Gallinarum significantly affects the poultry food industry. The present study is the first study of the S. Gallinarum biofilm in Iran, which is focused on the characterization of the S. Gallinarum serovars and their acquired antibiotic resistance genes circulating in poultry fields in central and northwestern Iran. Materials and Methods: Sixty isolates of S. Gallinarum serovar were collected from feces of live poultry. The bacteria were isolated using biochemical tests and confirmed by Multiplex PCR. Biofilm formation ability and the antibacterial resistance were evaluated using both phenotypic and genotypic methods. The data were analyzed using SPSS software. Results: According to Multiplex PCR for ratA, SteB, and rhs genes, all 60 S. Gallinarum serovars were Gallinarum biovars. In our study, the antibiotic resistance rate among isolated strains was as follows: Penicillin (100%), nitrofurantoin (80%), nalidixic acid (45%), cefoxitin (35%), neomycin sulfate (30%), chloramphenicol (20%), and ciprofloxacin (5%). All isolates were susceptible to imipenem, ertapenem, ceftriaxone, ceftazidime, and ceftazidime+clavulanic acid. All sixty isolates did not express the resistance genes IMP, VIM, NDM, DHA, blaOXA48, and qnrA. On the other hand, they expressed GES (85%), qnrB (75%), Fox M (70%), SHV (60%), CITM (20%), KPC (15%), FOX (10%), MOXM (5%), and qnrS (5%). All S. Gallinarum isolates formed biofilm and expressed sdiA gene. Conclusion: Considering that the presence of this bacteria is equal to the death penalty to the herd, the distribution of resistance genes could be a critical alarm for pathogen monitoring programs in the region. This study showed a positive correlation between biofilm formation and 50% of tested resistance genes. Also, it was found that the most common circulating S. gallinarum biovars are multidrug-resistant.

High Intensity Interval Training can Ameliorate Hypothalamic Appetite Regulation in Male Rats with Type 2 Diabetes: The Role of Leptin.

Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1).

Impact of modifiable risk factors on prediction of 10-year cardiovascular disease utilizing framingham risk score in Southwest Iran.

BACKGROUND: This cohort study was conducted to examine the association between modifiable risk factors, including hypertension, smoking, physical activity, diabetes, cholesterol, and high-density lipoprotein with Framingham risk score in the prediction of 10-year-risk of cardiovascular diseases (CVD) between men and women in an Arab community of Southwest Iran, Hoveyzeh. MATERIALS AND METHODS: A total of 8,526 people aged 35-70 participated in this cohort study. Framingham was used to estimate the 10-year risk of CVD. Also, the linear regression models were used to assess the relationship between modifiable risk factors and the 10-year risk of CVD. Finally, the area under the receiver operating characteristic curve (AUC) was used to measure the ability of modifiable risk factors to predict the 10-year risk of CVD. RESULTS: Our results of linear regression models showed that hypertension, smoking, PA, diabetes, cholesterol, and HDL were independently associated with the CVD risk in men and women. Also, AUC analysis showed that hypertension and diabetes have the largest AUC in men 0.841; 0.778 and in women 0.776; 0.715, respectively. However, physical activity had the highest AUC just in women 0.717. CONCLUSION: Hypertension and diabetes in both gender and physical activity in women are the most important determinant for the prediction of CVD risk in Hoveyzeh. Our cohort study may be useful for adopting strategies to reduce CVD progression through lifestyle changes.

Leptin Signaling Could Mediate Hippocampal Decumulation of Beta-Amyloid and Tau Induced by High-Intensity Interval Training in Rats with Type 2 Diabetes.

Leptin (LEP) can cross the blood-brain barrier and facilitate cross-talk between the adipose tissue and central nerve system (CNS). This study aimed to investigate the effect of 8-week high-intensity interval training (HIIT) on the LEP signaling in the hippocampus of rats with type 2 diabetes. 20 rats were randomly divided into four groups: (i) control (Con), (ii) type 2 diabetes (T2D), (iii) exercise (EX), and (iv) type 2 diabetes + exercise (T2D + EX). The rats in the T2D and T2D + EX were fed a high-fat diet for two months, then a single dose of STZ (35 mg/kg) was injected to induce diabetes. The EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of Vmax. Serum and hippocampal levels of LEP as well as hippocampal levels of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), activated protein kinase (AMP-K), proxy zoster receptor α (PGC-1α), beta-secretase 1 (BACE1), Beta-Amyloid (Aß), Phosphoinositide 3-kinases (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), Glycogen Synthase Kinase 3 Beta (GSK3ß), and hyperphosphorylated tau proteins (TAU) were measured. One-way ONOVA and Tukey post-hoc tests were used to analyze the data. Serum and hippocampal levels of LEP as well as hippocampal levels of LEP-R, JAK-2, STAT-3, AMP-K, PGC1α, PI3K, AKT, and mTOR were increased while hippocampal levels of BACE1, GSK3B, TAU, and Aß were decreased in T2D + EX compared with T2D group. Serum LEP and hippocampal levels of LEP, LEP-R, JAK-2, STAT-3, AMP-K, PGC1α, PI3K, AKT, and mTOR were decreased. Conversely hippocampal levels of BACE1, GSK3B, TAU, and Aß were increased in T2D group compared with CON group. HIIT could improve LEP signaling in the hippocampus of rats with type 2 diabetes and decrease the accumulation of Tau and Aß, which may reduce the risk of memory impairments.

In silico design and in vivo evaluation of two multi-epitope vaccines containing build-in adjuvant with chitosan nanoparticles against uropathogenic Escherichia coli.

BACKGROUND: Urinary pathogenic Escherichia coli (UPEC) is one of the most important bacterial causes of urinary tract infections (UTIs). Rising antimicrobial resistance and serious clinical challenges such as persistent and recurrent UTIs make it a serious public health concern. Therefore, preventative approaches such as vaccinations are required. METHODS: In this study, we selected three conserve and protective antigens (FdeC, Hma and UpaB) and also subunit B of cholera toxin (as build-in adjuvant) to design two multi-epitope vaccines (construct B containing B cell epitopes and construct T containing T epitopes) using different bioinformatics methods. The expression of the recombinant protein was performed using the BL21(DE3)/pET28 expression system and purified through a Ni-NTA column. Vaccine proteins were encapsulated in chitosan nanoparticles (CNP) based on ionic gelation via a microfluidic system. Mice were immunized intranasally with different vaccine formulations. Antibody responses and also cytokine expression (IFN-γ and IL-4) were measured by ELISA and real-time PCR respectively. The effectiveness of immune responses was assessed by bladder challenge. RESULTS: Based on the in silico study, construct B and construct T have high confidence value and stable structure in vivo. High yield expression of both constructs was confirmed by SDS-PAGE and western blot assay. Immunization of mice with construct B induced strong Th2 (IgG1 and IL4) responses and construct T shift immune responses to Th1 (IFNγ and IgG2a). Vaccine protein-encapsulated CNP elicited higher levels of antibodies and cell-mediated responses than the vaccine proteins alone. CONCLUSIONS: The results of this study suggest that intranasal administration of the construct B has the potential to enhance humoral immunity and construct T has the potential to stimulate cellular immunity. In addition, the combination of CTB as a build-in adjuvant and CNP can be proposed as a potent adjuvant for the development of a novel vaccine against UTI.

Effect of Magnesium Status on Microalbuminuria in Type 2 Diabetic Patients.

BACKGROUND: There are several controversies regarding the association between serum magnesium depletion and microalbuminuria in type 2 diabetic patients. OBJECTIVE: Therefore, this study aimed to assess serum magnesium concentrations in Type 2 diabetic patients with microalbuminuria and normoalbuminuria in Birjand, Iran, in 2019. METHODS: In this cross-sectional study, 25 type 2 diabetes patients with microalbuminuria were enrolled as the case group and 25 type 2 diabetes patients with normoalbuminuria as the control group. Both groups were matched for age, sex, hypertension, and dyslipidemia. Blood samples were obtained for serum magnesium measurement. RESULTS: Our findings showed no significant difference between serum magnesium concentration in the case and control groups (mean serum magnesium concentration for case group: 2.34 ± 0.35 mg/dl and control group: 2.27 ± 0.33 mg/dl). Pearson correlation coefficient analysis did not show any correlation between serum magnesium levels and urine albumin levels in patients with microalbuminuria versus patients with normoalbuminuria (r = 0.06, p = 0.67). CONCLUSION: This study did not indicate a correlation between serum magnesium concentrations and microalbuminuria in Type 2 diabetic patients.

High-Intensity Interval Training-Induced Hippocampal Molecular Changes Associated with Improvement in Anxiety-like Behavior but Not Cognitive Function in Rats with Type 2 Diabetes.

(1) Background: Exercise exerts many neuroprotective effects in diabetes-induced brain disorders. In this study, we investigated the effect of high-intensity interval training (HIIT) on brain molecular changes and cognitive and anxiety-like behaviors in rats with type 2 diabetes. (2) Methods: Twenty-eight adult male rats were divided into four groups (n = 7): control (C), exercise + control (C+EX), diabetes (DM), and diabetes + exercise (DM+EX). Diabetes was induced using a two-month high-fat diet and a single dose of streptozotocin (35 mg/kg) in the DM and DM+EX groups. After, the C+EX and DM+EX groups performed HIIT for eight weeks (five sessions per week, running at 80-100% of VMax, 4-10 intervals) on a motorized treadmill. Then, the elevated plus maze (EPM) and open field test (OFT) were performed to evaluate anxiety-like behaviors. The Morris water maze (MWM) and shuttle box were used to assess cognitive function. The hippocampal levels of beta-amyloid and tau protein were also assessed using Western blot. (3) Results: The hippocampal levels of beta-amyloid and tau protein were increased in the DM group, but HIIT restored these changes. While diabetes led to a significant decrease in open arm time percentage (%OAT) and open arm enters percentage (%OAE) in the EPM, indicating anxiety-like behavior, HIIT restored them. In the OFT, grooming was decreased in diabetic rats, which was restored by HIIT. No significant difference between groups was seen in the latency time in the shuttle box or for learning and memory in the MWM. (4) Conclusions: HIIT-induced hippocampal molecular changes were associated with anxiety-like behavior improvement but not cognitive function in rats with type 2 diabetes.

Reducing Proteoglycan Synthesis and NOX Activity by ROCK Inhibitors: Therapeutic Targets in Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arteries characterized by the accumulation of inflammatory cells in the arterial wall. Hypertension, dyslipidemia, and hyperglycemia are major risk factors of atherosclerosis. Rho-associated protein kinase (ROCK), a serine/threonine kinase, is a downstream effector of the small GTPase RhoA. ROCK is involved in different stages of atherosclerosis. Accumulating evidence has demonstrated that ROCK signaling plays vital roles in various cellular functions, such as contraction, migration, and proliferation of smooth muscle cells. Dysregulation of the ROCK pathway is associated with atherosclerosis and hypertension. Experimental studies have shown that ROCK inhibitors may have favorable effects in ameliorating atherosclerosis. ROCK signaling has a role in proteoglycan synthesis through transactivation of the TGF-ß receptor Type I (TßRI) mediated by G-protein-coupled receptor (GPCR) agonists (endothelin-1, angiotensin II and …), and ROCK inhibitors could decrease proteoglycan synthesis and atherosclerotic plaque formation. Based on the hypothesis that targeting ROCK pathway may be effective in ameliorating atherosclerosis, we suggest that ROCK inhibitors may have a potential therapeutic role in inhibition or slowing atherogenesis. However, for this hypothesis more research is needed.

A redox-dependent thiol-switch and a Ca2+ binding site within the hinge region hierarchically depend on each other in α7ß1 integrin regulation.

Integrin-mediated cell contacts with the extracellular matrix (ECM) are essential for cellular adhesion, force transmission, and migration. Several effectors, such as divalent cations and redox-active compounds, regulate ligand binding activities of integrins and influence their cellular functions. To study the role of the Ca2+ binding site within the hinge region of the integrin α7 subunit, we genetically abrogated it in the α7hiΔCa mutant. This mutant folded correctly, associated with the ß1 subunit and was exposed on the cell surface, but showed reduced ligand binding and weaker cell adhesion to laminin-111. Thus, it resembles the α7hiΔSS mutant, in which the redox-regulated pair of cysteines, closeby to the Ca2+ binding site within the hinge, was abrogated. Comparing both mutants in adhesion strength and cell migration revealed that both Ca2+ complexation and redox-regulation within the hinge interdepend on each other. Moreover, protein-chemical analyses of soluble integrin ectodomains containing the same α7 hinge mutations suggest that integrin activation via the subunit α hinge is primed by the formation of the cysteine pair-based crosslinkage. Then, this allows Ca2+ complexation within the hinge, which is another essential step for integrin activation and ligand binding. Thus, the α hinge is an allosteric integrin regulation site, in which both effectors, Ca2+ and redox-active compounds, synergistically and hierarchically induce far-ranging conformational changes, such as the extension of the integrin ectodomain, resulting in integrin activation of ECM ligand binding and altered integrin-mediated cell functions.