A machine learning approach for predicting and localizing the failure and damage point in sewer networks due to pipe properties.

As a basic infrastructure, sewers play an important role in the innards of every city and town to remove unsanitary water from all kinds of livable and functional spaces. Sewer pipe failures (SPFs) are unwanted and unsafe in many ways, as the disturbance that they cause is undeniable. Sewer pipes meet manholes frequently, unlike water distribution systems, as in sewers, water movement is due to gravity and manholes are needed in every intersection as well as through pipe length. Many studies have been focused on sewer pipe failures and so on, but few investigations have been done to show the effect of manhole proximity on pipe failure. Predicting and localizing the sewer pipe failures is affected by different parameters of sewer pipe properties, such as material, age, slope, and depth of the sewer pipes. This study investigates the applicability of a support vector machine (SVM), a supervised machine learning (ML) algorithm, for the development of a prediction model to predict sewer pipe failures and the effects of manhole proximity. The results show that SVM with an accuracy of 84% can properly approximate the manhole effects on sewer pipe failures.

Modeling the structural relationships between trauma exposure with substance use tendency, depression symptoms, and suicidal thoughts in individuals with earthquake trauma experience: the mediatory role of peritraumatic dissociation and experiential avoidance.

BACKGROUND: Despite the fact that studies indicate that earthquake trauma is associated with numerous psychological consequences, the mediating mechanisms leading to these outcomes have not been well-studied. Therefore, this study investigates the relationship between trauma exposure with substance use tendency, depression, and suicidal thoughts, with the mediating role of peritraumatic dissociation and experiential avoidance. METHODS: The descriptive-correlational approach was employed in this study. The participants were people who had experienced the Kermanshah earthquake in 2017. A total of 324 people were selected by convenient sampling method. The Traumatic Exposure Severity Scale, the Peritraumatic Dissociative Experiences Questionnaire, the Acceptance and Action Questionnaire, the Iranian Addiction Potential Scale, Beck's Depression Inventory [BDI-II], and Beck's Suicidal Thoughts Scale were used to collect data. The gathered data was analyzed| using structural equation modeling in |SPSS Ver. 24 and LISREL Ver. 24. RESULTS: The study findings indicated that the intensity of the trauma exposure is directly and significantly associated with depression symptoms, peritraumatic dissociation, and experiential avoidance. The severity of exposure to trauma had a significant indirect effect on the tendency to use substances through experiential avoidance. This is while the severity of the trauma experience did not directly correlate with substance use and suicidal thoughts. In addition, peritraumatic dissociation did not act as a mediator in the relationship between the severity of trauma exposure with substance use, depression, and suicidal thoughts. CONCLUSIONS: The severity of exposure to the earthquake was associated with symptoms of depression and these findings indicate the importance of experiential avoidance in predicting the tendency to use drugs. Hence, it is essential to design and implement psychological interventions that target experiential avoidance to prevent drug use tendencies and to establish policies that lower depression symptoms following natural disasters.

The Lawson-loaded ß-cyclodextrin nanocarriers (LB-NCs) a novel targeted cancer cell in stomach and breast cancer as a drug delivery system.

Applying nanotechnology to design drug delivery systems is a promising turning point in cancer treatment strategies. In the current study, Lawson, a nonpolar anticancer phytochemical, was entrapped into ß-cyclodextrin polymer to evaluate its selective cytotoxicity in several types of human cancer cell lines including MCF-7, AGS, A549, and PC3. The Lawson-loaded ß-cyclodextrin nanocarriers (LB-NCs) were produced by applying a high-energy ultrasound-mediated homogenization technique. The LB-NCs were characterized by applying dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), zeta potential, and field emission scanning electron microscopy (FESEM) analysis. Also, the selective cytotoxic impact of the LB-NCs was studied by conducting the MTT assay on human MCF-7, AGS, A549, and PC3 cancer cell lines. Finally, the type of cellular death was evaluated by measuring the cell cycle status and apoptotic gene expression profile of the treated MCF-7 cells by conducting flow cytometry and Q-PCR methods, respectively. The synthesized negatively charged (- 23.8 mV) nanoparticles (348.12 nm) exhibited apoptotic activity in the human breast MCF-7 cancer cells by upregulating the apoptotic gene expression profile (Caspase 3, 8, and 9). The LB-NCs exhibited a significant selective cytotoxic effect on the human cancer cell lines compared with the normal HUVEC cells. However, variable toxic intensities were detected depending on the cancer cell type. Selective cancer cell-depended anticancer activity of the produced LB-NCs has the potential to be considered their safe efficient targeted anticancer activity. However, studying the animal cancer models has to be conducted to verify their selective toxicity and clarify the cellular death mechanism.

Preparation of the Myricetin-Loaded PEGylated Niosomes and Evaluation of their in†vitro Anti-Cancer Potentials.

Several edible plants contain flavonoids, including myricetin (Myr), which perform a wide range of biological activities. Myr has antitumor properties against various tumor cells. In this study Myr-loaded PEGylated niosomes (Myr-PN) were prepared and their anti-cancer activities were evaluated in vitro. Myr-PNs were prepared as a tool for drug delivery to the tumor site. Myr-PN was characterized in terms of size, zeta potential, and functional groups using dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), and field emission scanning electron microscopy (SEM). The Myr-PN size was 241 nm with a polydispersity index (PDI) of 0.20, and zeta potential -32.7±6.6 mV. Apoptotic properties of Myr-PN against normal and cancer cell lines were determined by flow cytometry and real-time quantitative PCR. Cancer cells showed higher cytotoxicity when treated with Myr-PN compared with normal cells, indicating that the synthesized nanoparticles pose no adverse effects. Apoptosis was induced in cells treated with 250 µg/mL of Myr-PN, in which 45.2 % of cells were arrested in subG1, suggesting that Myr-PN can induce apoptosis. In vitro, the synthesized Myr-PN demonstrated potent anticancer properties. Furthermore, more research should be conducted in vitro and in vivo to study the more details of Myr-PN anti-cancer effects.

Novel formulation of parthenolide-loaded liposome coated with chitosan and evaluation of its potential anticancer effects in vitro.

BACKGROUND: In this study the formulation of parthenolide (PN), an anticancer agent extracted from a natural product, into a liposome (PN-liposome), was examined. The surface of the PN-liposome was modified using chitosan (PN-chitosome). By using real-time quantitative PCR and flow cytometry, we examined the release of PN-chitosomes, cytotoxicity, and ability to induce apoptosis in vitro. METHODS AND RESULTS: According to the present study, PN-chitosomes had a size of 251 nm which is acceptable for efficient enhanced permeation and retention (EPR) performance. PN-chitosomes were confirmed to be spherical in shape and size through FESEM analysis. In terms of encapsulation efficiency, 94.5% was achieved. PN-chitosome possessed a zeta potential of 34.72 mV, which was suitable for its stability. According to the FTIR spectra of PN and PN-chitosome, PN was chemically stable due to the intermolecular interaction between the liposome and the drug. After 48 h, only 10% of the PN was released from the PN-chitosome in PBS (pH 7.4), and less than 20% was released after 144 h. CONCLUSION: In a dose-dependent manner, PN-chitosome exhibited anticancer properties that were more cytotoxic against cancer cells than normal cells. Moreover, the formulation activated both the apoptosis pathway and cytotoxic genes in real-time qPCR experiments. According to the cytotoxicity and activating apoptosis of the prepared modified particle, PN-chitosome may be helpful in the treatment of cancer.

Utilization of the internal mammary perforators as the recipient vessels for microsurgical breast reconstruction: A systematic review and meta-analysis of the literature.

BACKGROUND: The selection of reliable recipient vessels is essential for successful free tissue transfer. The use of internal mammary intercostal perforators (IMAPs), instead of the internal mammary vessels as the recipient vessels, has been described in breast reconstruction. Debates exist regarding the reliability of these perforators as recipient vessels because of their variability in location and caliber. The aim of this paper was to conduct a systematic literature review and meta-analysis to determine the reliability of the IMAPs as recipient vessels. METHODS: A systematic literature review was performed on the "PubMed," "Medline," "Ovid," and "Cochrane library" databases for articles published from January 1990 to March 2021. Exclusion criteria were non-English studies, reports with case number less than 5, cadaveric or animal studies, and studies with incomplete postoperative outcomes. The reliability of using IMAPs for breast reconstruction was determined by assessing the reported rates of partial or complete flap failure and other complications (fat necrosis, skin necrosis, and requirement for revision surgery). RESULTS: Three hundred and sixteen cases in 13 studies were included for further analysis with more than 85% of the IMAPs suitable for anastomosis being located in the second and third intercostal spaces. Partial or total flap failure was reported in three of 316 patients (0.95%). The rate of other complications such as fat necrosis, skin necrosis, and requirement for revision surgery were all less than 5%. CONCLUSION: With deliberate preoperative planning, delicate perioperative manipulation, and meticulous microvascular anastomosis, the internal mammary perforators can be used as reliable recipient vessels in microvascular breast reconstruction.

CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses.

Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase-like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator of virophagy. Loss-of-function mutations in CDKL5 are associated with a severe neurodevelopmental encephalopathy. We found that deletion of CDKL5 or expression of a clinically relevant pathogenic mutant of CDKL5 reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid protein aggregates and cellular cytotoxicity. Cdkl5-knockout mice displayed increased viral antigen accumulation and neuronal cell death after SINV infection and enhanced lethality after infection with several neurotropic viruses. Mechanistic studies demonstrated that CDKL5 directly binds the canonical selective autophagy receptor p62 and phosphorylates p62 at T269/S272 to promote its interaction with viral capsid aggregates. We found that CDKL5-mediated phosphorylation of p62 facilitated the formation of large p62 inclusion bodies that captured viral capsids to initiate capsid targeting to autophagic machinery. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear intracellular toxic viral protein aggregates during infection.

A novel nanoformulation of parthenolide coated with polydopamine shows selective cytotoxicity and induces apoptosis in gastric cancer cells.

An anticancer agent derived from a natural product, parthenolide (PN), was studied to formulate PN into poly(lactic-co-glycolic acid) (PLGA). Polydopamine (PDA) was employed to modify the surface of PN-PLGA. Following characterization, the PN-PLGA-PDA was evaluated for its in vitro release, cytotoxicity, and ability to induce apoptosis using flow cytometry and real-time quantitative PCR. According to the present study, PN-PLGA-PDA had a size of 195.5 nm which is acceptable for efficient enhanced permeation and retention (EPR) performance. The SEM results confirmed the size and spherical shape of the nanoparticles. The percentage of encapsulation efficiency was 96.9%. The zeta potential of PN-PLGA-PDA was - 31.8 mV which was suitable for its stability. FTIR spectra of the PN-PLGA-PDA indicated the chemical stability of the PN due to intermolecular hydrogen bonds between polymer and drug. The release of PN from PN-PLGA-PDA in PBS (pH 7.4) was only 20% during the first 48 h and less than 40% during 144 h. PN-PLGA-PDA exhibited anticancer properties in a dose-dependent manner that was more cytotoxic against cancer cells than normal cells. Moreover, real-time qPCR results indicated that the formulation activated apoptosis genes to exert its cytotoxic effect and activate the NF-kB pathway. Based on our findings, PN-PLGA-PDA could serve as a potential treatment for cancer.

Exploring expected reward and efficacy in enhancing cognitive control in patients with depression.

BACKGROUND: Depression is associated with impairments in cognitive control. Considering the lack of mechanistic models accounting for cognitive control deficits in depression, the expected value of control (EVC) theory offers a mechanistic view for allocating cognitive control emphasizing motivational components (efficacy, value). Efficacy refers to the possibility that an effort leads to a special outcome and reward refers to the value (amount) associated with the outcome. This study aimed to examine the role of the EVC in depression. METHOD: This study used a within-between-subject design. Participants with depression (n = 36) and healthy controls (n = 31) completed a clinical diagnostic interview, the Beck Depression Inventory-II, the General Health Questionnaire-12, and a computer-based incentivized Stroop Color-Word Paradigm in which levels of efficacy (high vs. low) and the amount of rewards (high vs. low) were presented as cues before target stimuli. RESULTS: We found significant interaction effects of group × efficacy and efficacy × reward in terms of reaction time in the Stroop Paradigm. Follow-up analyses indicated the Depressed group were significantly slower than Controls on high efficacy trials, but the two groups did not differ significantly on low efficacy trials. Additionally, on high efficacy trials, reward did not influence performance, but on low efficacy trials, high reward improved performance in both groups. LIMITATION: Lack of neurological measures and eye tracking techniques. CONCLUSION: Overall, our findings suggest that reward and efficacy may jointly improve cognitive control allocation and highlight the need for further research examining EVC theory as a mechanistic account of cognitive control deficits in depression.

Wnt16 Promotes Vascular Smooth Muscle Contractile Phenotype and Function via Taz (Wwtr1) Activation in Male LDLR-/- Mice.

Wnt16 is expressed in bone and arteries, and maintains bone mass in mice and humans, but its role in cardiovascular physiology is unknown. We show that Wnt16 protein accumulates in murine and human vascular smooth muscle (VSM). WNT16 genotypes that convey risk for bone frailty also convey risk for cardiovascular events in the Dallas Heart Study. Murine Wnt16 deficiency, which causes postnatal bone loss, also reduced systolic blood pressure. Electron microscopy demonstrated abnormal VSM mitochondrial morphology in Wnt16-null mice, with reductions in mitochondrial respiration. Following angiotensin-II (AngII) infusion, thoracic ascending aorta (TAA) dilatation was greater in Wnt16-/- vs Wnt16+/+ mice (LDLR-/- background). Acta2 (vascular smooth muscle alpha actin) deficiency has been shown to impair contractile phenotype and worsen TAA aneurysm with concomitant reductions in blood pressure. Wnt16 deficiency reduced expression of Acta2, SM22 (transgelin), and other contractile genes, and reduced VSM contraction induced by TGFß. Acta2 and SM22 proteins were reduced in Wnt16-/- VSM as was Ankrd1, a prototypic contractile target of Yap1 and Taz activation via TEA domain (TEAD)-directed transcription. Wnt16-/- VSM exhibited reduced nuclear Taz and Yap1 protein accumulation. SiRNA targeting Wnt16 or Taz, but not Yap1, phenocopied Wnt16 deficiency, and Taz siRNA inhibited contractile gene upregulation by Wnt16. Wnt16 incubation stimulated mitochondrial respiration and contraction (reversed by verteporfin, a Yap/Taz inhibitor). SiRNA targeting Taz inhibitors Ccm2 and Lats1/2 mimicked Wnt16 treatment. Wnt16 stimulated Taz binding to Acta2 chromatin and H3K4me3 methylation. TEAD cognates in the Acta2 promoter conveyed transcriptional responses to Wnt16 and Taz. Wnt16 regulates cardiovascular physiology and VSM contractile phenotype, mediated via Taz signaling.

Relationship Between Human FCγRIIA rs1801274 G Allele and Risk of Death Among Different SARS-CoV-2 Variants.

Coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and spread very quickly across the world. Different responses to infections have been related to fragment crystallizable gamma-receptor II alpha (FcγRIIA) polymorphisms. The purpose of this investigation was to determine if FCγRIIA rs1801274 polymorphism was related to COVID-19 mortality among different variants of SARS-CoV-2. The FCγRIIA rs1801274 polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism technique in 1,734 recovered and 1,450 deceased patients. Deceased patients had significantly higher minor allele frequency of the FCγRIIA rs1801274 G allele than in the recovered cases. The COVID-19 mortality was associated with FCγRIIA rs1801274 GG and AG genotypes in the Delta variant and with FCγRIIA rs1801274 GG genotypes in the Alpha and Omicron BA.5 variants. The reverse transcription-quantitative polymerase chain reaction Ct values revealed statistically significant differences between individuals with a G allele and those with an A allele. In conclusion, among the several SARS-CoV-2 variants, there may be a correlation between the mortality rate of COVID-19 and the G allele of FCγRIIA rs1801274. To confirm our findings, thorough research is still required.

A Large Sublingual Dermoid Cyst Causing Dysphagia and Dysphonia: A Case Review Study.

A seventeen-year-old girl was referred to the emergency department with dysphagia and dyspnea due to large swelling in the floor of the mouth after 20 days of evaluation. Magnetic resonance imaging shows a well-defined sublingual mass measuring 70 mm × 74 mm × 46 mm, causing severe oral and oropharyngeal space narrowing. The surgical excision of the lesion was performed through an intraoral approach under general anesthesia. Moreover, the pathologist reported a dermoid cyst. A dermoid cyst rapidly enlarging can lead to a life-threatening condition, particularly if they grow near main upper airway structures, so their resection in golden time has an especially clinical importance.

Global protein-protein interaction networks in yeast saccharomyces cerevisiae and helicobacter pylori.

Understanding many biological processes relies heavily on accurately predicting protein-protein interactions (PPIs). In this study, we propose a novel method for predicting PPIs that is based on LogitBoost with a binary bat feature selection algorithm. Our approach involves the extraction of an initial feature vector by combining pseudo amino acid composition (PseAAC), pseudo-position-specific scoring matrix (PsePSSM), reduced sequence and index-vectors (RSIV), and autocorrelation descriptor (AD). Subsequently, a binary bat algorithm is applied to eliminate redundant features, and the resulting optimal features are fed into the LogitBoost classifier for the identification of PPIs. To evaluate the proposed method, we test it on two databases, Saccharomyces cerevisiae and Helicobacter pylori, using 10-fold cross-validation, and achieve accuracies of 94.39% and 97.89%, respectively. Our results showcase the significant potential of our pipeline in accurately predicting protein-protein interactions (PPIs), thereby offering a valuable resource to the scientific research community.

Assessing land use changes' effect on river water quality in the Dez Basin using land change modeler.

Changes in land use due to urbanization, industrialization, and agriculture will adversely affect water quality at all scales. This study examined the possible effects of future land use on the water quality of the Dez River located in Iran. The QUAL2Kw dynamic model was used to simulate the water quality of the Dez River. Data and information available in July 2019 and 2013 were used for calibration and validation. According to the comparison of the RMSE, RMSE%, and percent bias error indices for the model during the calibration and validation period, the QUAL2Kw model of Dez River had high accuracy with acceptable values of errors. The land use changes in the Dez river basin were modeled and predicted by the LCM model after simulating water quality. The images from Landsat 8/OLI were used for 2013, 2016, and 2019, respectively. Based on the accurate evaluation of classified images, Kappa coefficients for 2013, 2016, and 2019 were 88.19, 87.46, and 89.91, respectively. Modeling land use and land cover changes was conducted to predict 2030. As a result of the study, agricultural and built-up areas and water bodies will increase in 2030. The possible effects of land use changes in 2030 on river water quality were examined as a final step. Based on the results of the water quality simulation in 2030, biochemical oxygen demand, chemical oxygen demand, and NO3 parameters exceeded the maximum permissible level of drinking standard. This study recommends frequent water quality monitoring and LULC planning and management to reduce pollution in river basins.

Does the Mutation Type Affect the Response to Cranial Vault Expansion in Children With Apert Syndrome?

LEVEL OF EVIDENCE: III.

A Novel Anticoagulation Method Based on Electrochemical Characteristics of Blood: An in vitro Study.

This in vitro experimental investigation aimed to provide a novel method for preventing blood clotting based on the electrochemical characteristics of blood. Using this method in cases such as dialysis can minimize the risk of blood clots and also avoid hemorrhagic risk for patients. Blood samples were collected from 13 sheep (45 kg) (25 mL), and the clotting time (CT) was measured using a 20-min cutoff after they were separated into control and experimental samples. The test blood sample was put in a cell designed with two aluminum electrodes (positive pole/anode) located in a container containing 0.9% sodium chloride (as a salt bridge) and a platinum (negative pole/cathode) linked to a power supply (-3.5 V, 1 mA/cm2). Biochemical and hematological tests to check blood damage and clotting were performed. The control sample coagulated after 8 min, while the electrified blood did not, even at the end of the cutoff time. Among hematologic and biochemical tests, the average time of prothrombin time (PT) and partial thromboplastin time (PTT) was significantly different between the control and test samples (p = 0.001). Our findings on electrified blood with expanding CT, PT, and PTT times revealed that the electric current passing through the blood enhanced the CT. Furthermore, no change in biochemical or hematological factors demonstrated that this current had no detrimental effect on the blood.

Effects of curcumin and metformin on oxidative stress and apoptosis in heart tissue of type 1 diabetic rats.

Introduction: Hyperglycemia enhances oxidative stress and apoptosis and induces damages in heart tissue. Based on antioxidant properties of curcumin and metformin, we hypothesized that these agents may exhibit cardioprotective effects by attenuating oxidative stress and modulating expression of the genes involved in apoptosis in type-1 diabetes. Methods: Thirty-six male rats were randomly divided into six groups; (N): control; (D): streptozotocin-induced diabetic rats; (D+Cur50) and (D+Cur150): diabetic rats treated with 50 and 150 milligram of curcumin per kilogram of body weight (mg/kg.bw), respectively; (D+Met300) and (D+Met500): diabetic rats received 300 and 500 mg/kg.bw of metformin, respectively. Heart tissues were dissected and gene expression levels of Bax, Bcl-2, and caspase-3 were analyzed. Total anti-oxidant capacity (TAC), total oxidant status (TOS), and malondialdehyde (MDA) level, and activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured. Results: Enhancement in TOS, OSI, and MDA levels as well as increased in the activity of CAT and reduction in SOD and GPx activities were observed in diabetic group (D) compared with control rats. Treatment of diabetic animals with either curcumin or metformin normalized TOS, OSI, and MDA levels and restored CAT, SOD, and GPx activities. Diabetes caused extensive damages in heart tissue of rats (group D) and increased expression of caspase-3 and Bax genes and enhanced ratio of Bax/Bcl-2 expression compared with controls. Treatment with curcumin or metformin mitigated histopathological changes and dampened apoptosis by normalizing Bax and caspase-3 expression. Conclusion: Curcumin and metformin modulated diabetes-induced cardiac damage probably by reducing oxidative stress.

Mindfulness-based cognitive therapy combined with repetitive transracial magnetic stimulation (rTMS) on information processing and working memory of patients with multiple sclerosis.

Background: MS is a demyelinating disease that can result in significant disability. Along with physical complications, this disease is associated with significant psychological complications, including cognitive decline. Therefore, this study aimed to determine the efficacy of mindfulness-based cognitive therapy in combination with rTMS on information processing and working memory in patients with MS. Methods: The current study used a single-case experimental design and included a follow-up (A-B-A). The statistical population of the present study was all MS patients in Tehran who referred to Imam Khomeini Hospital in Tehran in 2020. The present study sample consisted of 5 MS patients selected by the sampling methods available. Subjects were assessed three times before, during, and after the intervention using the Zahlen-Verbindongs and n-back tests in the two-back position. Subjects received cognitive therapy based on mindfulness and rTMS at a frequency of 10 Hz. Visual and graphical recovery percentage and effect size methods were used to analyze the data. Results: The current study's findings indicate that combining mindfulness with rTMS has a beneficial effect on the information processing and working memory of MS patients. Overall, 67.24% recovered following the intervention stage, 53.64% recovered following the follow-up for information processing, 104.04% recovered following the intervention stage, and 76.98% recovered following the follow-up for working memory. Conclusion: The study shows the effect of mindfulness combined with rTMS on cognitive problems in MS patients. Significant improvements in MS patients' information processing, working memory, and therapeutic outcomes were observed throughout the follow-up period.

Age-Independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association With Energy Metabolic Reprograming in Myocardium-A Targeted Metabolomics Study.

Background We showed that Beclin-1-dependent autophagy protects the heart in young and adult mice that underwent endotoxemia. Herein, we compared the potential therapeutic effects of Beclin-1 activating peptide, TB-peptide, on endotoxemia-induced cardiac outcomes in young adult and aged mice. We further evaluated lipopolysaccharide (lipopolysaccharide)-induced and TB-peptide treatment-mediated alterations in myocardial metabolism. Methods and Results C57BL/6J mice that were 10 weeks and 24 months old were challenged by lipopolysaccharide using doses at which cardiac dysfunction occurred. Following the treatment of TB-peptide or control vehicle, heart contractility, circulating cytokines, and myocardial autophagy were evaluated. We detected that TB-peptide boosted autophagy, attenuated cytokines, and improved cardiac performance in both young and aged mice during endotoxemia. A targeted metabolomics assay was designed to detect a pool of 361 known metabolites, of which 156 were detected in at least 1 of the heart tissue samples. Lipopolysaccharide-induced impairments were found in glucose and amino acid metabolisms in mice of all ages, and TB-peptide ameliorated these alterations. However, lipid metabolites were upregulated in the young group but moderately downregulated in the aged by lipopolysaccharide, suggesting an age-dependent response. TB-peptide mitigated lipopolysaccharide-mediated trend of lipids in the young mice but had little effect on the aged. (Study registration: Project DOI: https://doi.org/10.21228/M8K11W). Conclusions Pharmacological activation of Beclin-1 by TB-peptide is cardiac protective in both young and aged population during endotoxemia, suggest a therapeutic potential for sepsis-induced cardiomyopathy. Metabolomics analysis suggests that an age-independent protection by TB-peptide is associated with reprograming of energy production via glucose and amino acid metabolisms.

The effects of metformin monotherapy and combination of metformin and glibenclamide therapy on the expression of RAGE, Sirt1, and Nrf2 genes in peripheral blood mononuclear cells of type 2 diabetic patients.

Purpose: Although metformin is the first-line treatment of type 2 diabetes mellitus (T2DM), a few studies have evaluated the benefits of monotherapies (metformin) versus combination therapy (metformin and glibenclamide) for treatment of T2DM patients. The present study aimed to evaluate the effect of monotherapy with metformin compared to combination therapy with metformin and glibenclamide on the expression of RAGE, Nrf 2, and Sirt1genes. Methods: EightyT2DM patients and 40 healthy individuals participated in this case-control study. The patients in the treatment group were divided into two groups who received either metformin alone (n = 40) or metformin in combination with glibenclamide (n = 40). FBS, HbA1c, and fructosamine were measured. The expression of RAGE, Nrf 2, and Sirt 1 genes in PBMC of all subjects were assessed using real-time PCR. Results: RAGE gene expression in both treatment groups was significantly lower than the control (P < 0.05). RAGE gene expression was significantly reduced in the combination of metformin and glibenclamide treated group compared to metformin group (P < 0.05). Additionally, the expression of Sirt 1 and Nrf 2 genes in both treatment groups was higher than that of the control group (P < 0.05). The expression of Sirt 1 and Nrf 2 genes in metformin and glibenclamide treated group were higher than the metformin group (P < 0.05). Conclusion: Combination therapy (metformin and glibenclamide) showed stronger effect on repression of the RAGE gene and activation of Nrf 2 and Sirt 1 genes compared to monotherapy (metformin); therefore, it can be concluded that combination therapy may have more protective effects on the T2DM patients. No significant correlation was observed between HbA1c and RAGE, Sirt 1, and Nrf 2 genes expression.