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Perforation of Meckel's diverticulum by a foreign body is rare, but when it occurs, it can mimic acute appendicitis, leading to diagnostic challenges. We present a case of a 45-year-old male initially diagnosed with acute appendicitis, but intra-operative exploration revealed a perforated Meckel's diverticulum with a fish bone. Meckel's diverticulum perforation remains diagnostically elusive, highlighting the need for intra-operative vigilance in cases of inconsistent findings like the presence of bilious fluid in the abdominal cavity. This case report underscores the importance of considering perforated Meckel's diverticulum in the differential diagnosis of right iliac fossa pain and the necessity of surgical exploration for atypical presentations to ensure timely diagnosis and appropriate management. [ABSTRACT FROM AUTHOR]

The article discusses a study in which researchers tell that iron-overload cardiomyopathy occurs due to genetic and acquired iron-overload conditions. Researchers also state that iron-overload cardiomyopathy is characterized by diastolic and systolic dysfunction and arrhythmias. The authors state that a study by researcher S. Kumfu and colleagues found that use of efonidine in an iron-overloaded thalassemic murine model lowers mortality, prevent myocardial iron deposition and oxidative stress.

Appropriate screening tools are required to accurately detect complex post traumatic stress disorder (CPTSD). This systematic review aimed to assess and compare measurement tools. A literature search using key words 'complex post traumatic stress disorder', 'PTSD', and 'assessment' was undertaken on Embase and PsychINFO during February 2022 by two reviewers. Inclusion criteria included full text papers between 2002–2022 which evaluated CPTSD using assessment tools. Exclusion criteria included reviews, editorials, meta-analyses, or conference abstracts. Twenty-two papers met selection criteria. Thirteen studies used the International Trauma Questionnaire (ITQ). Two studies each evaluated CPTSD with the International Trauma Interview (ITI) or Symptoms of Trauma Scale (SOTS). The Developmental Trauma Inventory (DTI), Cameron Complex Trauma Interview (CCTI), Complex PTSD Item Set additional to the Clinician Administered PTSD Scale (COPISAC), Complex Trauma Questionnaire (ComplexTQ), and Scale 8 of the Minnesota Multiphasic Personality Inventory Scale (MMPI) were used by a single study each. The ITQ was the most thoroughly investigated, validated across different populations, and is a convenient questionnaire for screening within the clinical setting. Where self-report measures are inappropriate, the ITI, SOTS, and COPISAC are interview tools which detect CPTSD. However, they require further validation and should be used alongside clinical history and examination. Validated and reliable screening tools are required to accurately detect and manage complex post traumatic stress disorder (CPTSD) The International Trauma Questionnaire (ITQ) is the most thoroughly investigated, validated across different populations, and is a freely available and convenient tool for screening within clinical settings In circumstances where self-report measures are inappropriate, the ITI, SOTS, and COPISAC are interview tools which detect CPTSD, but require further validation and should be used alongside clinical history and examination Further research is needed to ensure appropriate assessment tools for the detection and diagnosis of CPTSD are available [ABSTRACT FROM AUTHOR]

Background: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics.Methods: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations.Results: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain (MYH7) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations.Conclusions: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex. [ABSTRACT FROM AUTHOR]

Activation of the angiotensin 1-7/Mas receptor (MasR) axis counteracts angiotensin II (Ang II)-mediated cardiovascular disease. Recombinant human angiotensin-converting enzyme 2 (rhACE2) generates Ang 1-7 from Ang II. We hypothesized that the therapeutic effects of rhACE2 are dependent on Ang 1-7 action. Wild type male C57BL/6 mice (10-12 weeks old) were infused with Ang II (1.5 mg/kg/d) and treated with rhACE2 (2 mg/kg/d). The Ang 1-7 antagonist, A779 (200 ng/kg/min), was administered to a parallel group of mice. rhACE2 prevented Ang II-induced hypertrophy and diastolic dysfunction while A779 prevented these beneficial effects and precipitated systolic dysfunction. rhACE2 effectively antagonized Ang II-mediated myocardial fibrosis which was dependent on the action of Ang 1-7. Myocardial oxidative stress and matrix metalloproteinase 2 activity was further increased by Ang 1-7 inhibition even in the presence of rhACE2. Activation of Akt and endothelial nitric oxide synthase (eNOS) by rhACE2 were suppressed by the antagonism of Ang 1-7 while the activation of pathological signaling pathways was maintained. Blocking Ang 1-7 action prevents the therapeutic effects of rhACE2 in the setting of elevated Ang II culminating in systolic dysfunction. These results highlight a key cardioprotective role of Ang 1-7, and increased Ang 1-7 action represents a potential therapeutic strategy for cardiovascular diseases. Key messages: [ABSTRACT FROM AUTHOR]

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2, whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts, and solute carriers. Renal injury in TIMP3−/−, but not in TIMP2−/−, mice increased the expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β, and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3−/− mice, which was completely blocked in the kidneys of TIMP2−/− mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3−/− and its reduction in TIMP2−/− mice. The activities of tumor necrosis factor-α-converting enzyme, caspase-3, and mitogen-activated kinases were elevated in the kidneys of TIMP3−/− mice but not TIMP2−/− mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3−/− mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury: TIMP3 protects from damage, whereas TIMP2 promotes injury through MMP2 activation. [ABSTRACT FROM AUTHOR]

Aortic aneurysm is dilation of the aorta primarily due to degradation of the aortic wall extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs), the proteases that degrade the ECM. Timp3 is the only ECM-bound Timp, and its levels are altered in the aorta from patients with abdominal aortic aneurysm (AAA). We investigated the causal role of Timp3 in AAA formation. Infusion of angiotensin II (Ang II) using micro-osmotic (Alzet) pumps in Timp3-/- male mice, but not in wild type control mice, led to adverse remodeling of the abdominal aorta, reduced collagen and elastin proteins but not mRNA, and elevated proteolytic activities, suggesting excess protein degradation within 2 weeks that led to formation of AAA by 4 weeks. Intriguingly, despite early up-regulation of MMP2 in Timp3-/-Ang II aortas, additional deletion of Mmp2 in these mice (Timp3-/-/Mmp2-/-) resulted in exacerbated AAA, compromised survival due to aortic rupture, and inflammation in the abdominal aorta. Reconstitution of WT bone marrow in Timp3-/-/Mmp2-/- mice reduced inflammation and prevented AAA in these animals following Ang II infusion. Treatment with a broad spectrum MMP inhibitor (PD166793) prevented the Ang II-induced AAA in Timp3-/- and Timp3-/-/Mmp2-/- mice. Our study demonstrates that the regulatory function of TIMP3 is critical in preventing adverse vascular remodeling and AAA. Hence, replenishing TIMP3, a physiological inhibitor of a number of metalloproteinases, could serve as a therapeutic approach in limiting AAA development or expansion. [ABSTRACT FROM AUTHOR]

It is commonly known that a number of variables, including price, supply levels, time, and green level, affect how quickly certain things are in demand. Furthermore, the inventory carrying cost is considered to be a nonlinear representation of time and is subject to variation throughout time. More precisely, it rises with time since longer storage times necessitate more costly warehouse space. This study presents a fully backlogged situation inventory system for a single commodity where the product's selling price, green level, and time are used to simultaneously compute the demand rate in accordance with a power pattern. Purchase price is determined by the product's nonlinear green level. Complete backorders are available for shortages. The impact of the product's selling price, green level and time power function are combined to determine the product's demand. Moreover, the holding cost also rises as the product is stored for a longer period of time. The primary goal is to determine the best inventory policy to maximise total profit per unit of time. Though the problem is highly nonlinear in nature. Hence, we cannot solve it analytically. To overcome these difficulties, we have applied several well-known popular metaheuristic algorithms (Water Cycle Algorithm (WCA), Artificial Electric Field Algorithm (AEFA), Teaching Learning Based Optimization Algorithm (TLBOA), Grey Wolf Optimizer Algorithm (GWOA), Sparrow Search Algorithm (SSA), Whale Optimizer Algorithm (WOA), Prairie Dog Optimization Algorithm (PDOA), Gazelle Optimization Algorithm (GOA), A Sinh Cosh Optimizer Algorithm (SCHOA) and White Sherk Optimizer Algorithm (WSOA), Archimedes Optimization Paradigm Algorithm (AOPA), Marine Predator Optimization Algorithm (MPOA), Geyser Inspired Algorithm (GIA), Runge Kutta Optimization Algorithm (RKOA), Lungs Performance-based Optimization Algorithm (LPOA) and Dwarf Mongoose Optimization Algorithm (DMOA)). It is observed that WCA perform better than other algorithms with respect to the convergence rate. A numerical example is taken in order to validate the proposed model. Finally, a post optimality analysis is performed in order to make a fruitful conclusion., (© 2024. The Author(s).)

Background: Management of dementia involves a multidisciplinary approach which also requires active participation from family members and caregivers. Thus, having easy access to information about dementia care is pertinent. Internet-based information is an emerging method for the same., Aim: To perform a comparative assessment of patient-oriented online information available on treatment of dementia over web pages in English and Hindi language., Methods: Observational study was conducted online through a general internet search engine (www.google.com). Web pages containing patient-oriented online information on treatment of dementia in English and Hindi were reviewed to assess their content and quality, esthetics, and interactivity. Appropriate descriptive and inferential statistics were conducted using the Statistical Package for the Social Sciences., Results: A total of 70 web pages met the eligibility criteria. Content quality assessed using the DISCERN score was significantly higher for English web pages compared to Hindi web pages ( P < 0.01). About 72.4% (21/29) of English and only 9.8% (4/41) of Hindi web pages had a total DISCERN score of 40 or above, indicating good quality. For esthetics, the median score for English pages was significantly higher than for Hindi web pages ( P < 0.01). The web pages with Health On Net (HON) certification had significantly better content quality., Conclusion: Our study revealed a scarcity of good quality online information about dementia and its treatment, especially in the Hindi language. English language websites showed better content quality than Hindi websites. HON Code label might be used as an indicator of better content quality for online resources informing on dementia treatment by lay people., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Journal of Psychiatry.)

There has been a lot of research on pricing and lot-sizing practices for different payment methods; however, the majority has focused on the buyer's perspective. While accepting buyers' credit conditions positively impacts sales, requesting advance payments from purchasers tends to have a negative effect. Additionally, requiring a down payment has been found to generate interest revenue for the supplier without introducing default risk. However, extending the credit period, along with offering delayed payment options, has the potential to increase sales volume, albeit with an elevated risk of defaults. Taking these payment schemes into account, this study investigates and compares the per-unit profit for sellers across three distinct payment methods: advance payment, cash payment, and credit payment. The consumption rate of the product varies non-linearly not only with the time duration of different payment options but also with the price and the level of greenness of the product. The utmost objective of this work is to determine the optimal duration associated with payment schemes, selling price, green level, and replenishment period to maximize the seller's profit. The Teaching Learning Based Optimization Algorithm (TLBOA) is applied to address and solve three numerical examples, each corresponding to a distinct scenario of the considered payment schemes. Sensitivity analyses confirm that the seller's profit is markedly influenced by the environmental sustainability level of the product. Furthermore, the seller's profitability is more significantly affected by the selling price index compared to the indices of the payment scheme duration and the green level in the demand structure., (© 2024. The Author(s).)

Background and Aims: There is no data on the treatment gap and health care utilization for mental disorders from Punjab. The present study reports on the same by using the data collected during the National Mental Health Survey., Settings and Design: Multisite, multistage, stratified, random cluster sampling study conducted in four districts, namely Faridkot, Moga, Patiala, and Ludhiana (for urban metro areas). Data were collected from October 2015 to March 2016., Materials and Methods: Mini International Neuropsychiatric Interview 6.0.0 and Adapted Fagerstrom Nicotine Dependence Scale were used to diagnose mental and behavioral disorders and tobacco use disorder, respectively. Pathways Interview Schedule of the World Health Organization was applied to persons having any disorder to assess treatment gap and health care utilization. Exploratory focused group discussions (FGDs) were conducted to understand the community perceptions regarding mental and behavioral disorders., Results: The treatment gap for mental and behavioral disorders was 79.59%, and it was higher for common mental disorders than severe mental disorders and higher for alcohol and tobacco use disorders as compared to opioid use disorders. The median treatment lag was 6 months. Only seven patients out of 79 were taking treatment from a psychiatrist, and the average distance traveled by the patient for treatment was 37.61 ± 45.5 km. Many attitudinal, structural, and other barriers leading to high treatment gaps were identified during FGDs in the community, such as stigma, poor knowledge about mental health, deficiency of psychiatrists, and distance from the hospital., Conclusions: Vertical as well as horizontal multisectoral integration is required to reduce the treatment gap and improve healthcare utilization. Increasing mental health literacy, providing high-quality mental health services at the primary-healthcare level and human resources development are the need of the hour., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Psychiatry.)

Background: Although some cancer therapies have overt and/or subclinical cardiotoxic effects that increase subsequent cardiovascular risk in breast cancer patients, we have recently shown that the breast tumor itself can also induce cardiac hypertrophy through the activation of the endothelin system to contribute to cardiovascular risk. However, the extent to which the suppression of the activation of the endothelin system could improve cardiac remodeling in breast cancer patients has yet to be investigated., Objectives: We aimed to retrospectively assess the cardiac morphology/function in patients with breast cancer before receiving cancer chemotherapy and to investigate if the suppression of the activation of the endothelin system improves cardiac remodeling in a mouse model of breast cancer., Methods: Our study involved 28 previously studied women with breast cancer (including 24 after tumor resection) before receiving adjuvant therapy and 17 control healthy women. In addition, we explored how the endothelin system contributed to breast cancer-induced cardiac remodeling using a mouse model of breast cancer., Results: Our results indicate that before chemotherapy, breast cancer patients already exhibit relative cardiac remodeling and subclinical cardiac dysfunction, which was associated with the activation of the endothelin system. Importantly, our mouse data also show that the endothelin receptor blocker atrasentan significantly lessened cardiac remodeling and improved cardiac function in a preclinical model of breast cancer., Conclusions: Although our findings should be further examined in other preclinical/clinical models, our data suggest that endothelin receptor blockers may play a role in cardiac health in individuals with breast cancer. (Understanding and Treating Heart Failure With Preserved Ejection Fraction: Novel Mechanisms, Diagnostics and Potential Therapeutics [Alberta HEART]; NCT02052804 and Multidisciplinary Team Intervention in Cardio-Oncology [TITAN]; NCT01621659)., Competing Interests: This work was supported by a grant from the Canadian Institutes of Health Research and a grant from the generous supporters of the Lois Hole Hospital for Women through the Women and Children's Health Research Institute, University of Alberta to Dr Dyck. Dr Dyck is a Canada Research Chair in Molecular Medicine. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that translocates to the nucleus to regulate transcription factors in different tissues or pathologic states. Although studied extensively in cancer, its biological role in the heart remains unresolved. PKM1 is more abundant than the PKM2 isoform in cardiomyocytes, and thus, we speculated that PKM2 is not genetically redundant to PKM1 and may be critical in regulating cardiomyocyte-specific transcription factors important for cardiac survival. Here, we showed that nuclear PKM2 ( S37 P-PKM2) in cardiomyocytes interacts with prosurvival and proapoptotic transcription factors, including GATA4, GATA6, and P53. Cardiomyocyte-specific PKM2-deficient mice ( Pkm2 Mut Cre + ) developed age-dependent dilated cardiac dysfunction and had decreased amounts of GATA4 and GATA6 (GATA4/6) but increased amounts of P53 compared to Control Cre +  hearts. Nuclear PKM2 prevented caspase-1-dependent cleavage and degradation of GATA4/6 while also providing a molecular platform for MDM2-mediated reduction of P53. In a preclinical heart failure mouse model, nuclear PKM2 and GATA4/6 were decreased, whereas P53 was increased in cardiomyocytes. Loss of nuclear PKM2 was ubiquitination dependent and associated with the induction of the E3 ubiquitin ligase TRIM35. In mice, cardiomyocyte-specific TRIM35 overexpression resulted in decreased S37 P-PKM2 and GATA4/6 along with increased P53 in cardiomyocytes compared to littermate controls and similar cardiac dysfunction to Pkm2 Mut Cre +  mice. In patients with dilated left ventricles, increase in TRIM35 was associated with decreased S37 P-PKM2 and GATA4/6 and increased P53. This study supports a previously unrecognized role for PKM2 as a molecular platform that mediates cell signaling events essential for cardiac survival.

An epithelial-to-mesenchymal transition (EMT) phenotype with cancer stem cell-like properties is a critical feature of aggressive/metastatic tumors, but the mechanism(s) that promote it and its relation to metabolic stress remain unknown. Here we show that Collapsin Response Mediator Protein 2A (CRMP2A) is unexpectedly and reversibly induced in cancer cells in response to multiple metabolic stresses, including low glucose and hypoxia, and inhibits EMT/stemness. Loss of CRMP2A, when metabolic stress decreases (e.g., around blood vessels in vivo) or by gene deletion, induces extensive microtubule remodeling, increased glutamine utilization toward pyrimidine synthesis, and an EMT/stemness phenotype with increased migration, chemoresistance, tumor initiation capacity/growth, and metastatic potential. In a cohort of 27 prostate cancer patients with biopsies from primary tumors and distant metastases, CRMP2A expression decreases in the metastatic versus primary tumors. CRMP2A is an endogenous molecular brake on cancer EMT/stemness and its loss increases the aggressiveness and metastatic potential of tumors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess stress, coping, and resilience among home-quarantined individuals via a community survey during the coronavirus disease 2019 (COVID-19) pandemic., Methods: In this cross-sectional study, a combined list was generated of all contacts of positive COVID-19 cases, traced by a contact tracing team, and international travelers who had entered the country after March 8, 2020 (2 weeks before the air travel shutdown on March 22, 2020 in India). This community-based study was conducted among people who were quarantined in their homes and international travelers who arrived in the country after declaration of lockdown. Stress and coping were assessed via the 12-item General Health Questionnaire, 10-item Perceived Stress Scale, and Brief Resilient Coping Scale. The participants with higher perceived stress scores (≥ 14) were asked to seek help from telemedicine services. Study data were collected from April 8, 2020, to May 20, 2020., Results: The mean age of the 153 study participants was 40.10 years, and 41.8% were women. Poor coping was identified in 25.5% of the sample, and moderate/high stress was present in 49.7%. Significantly higher stress was noted in women ( P  = .007). Higher age, joint family structure, and contacts of COVID cases were significant predictors of moderate/severe perceived stress in the logistic regression., Conclusions: Adequate psychological supportive services should be provided to home-quarantined persons through provision of information, rapid communication, and timely supplies of general and medical items., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Single ventricle heart defects (SVDs) are congenital disorders that result in a variety of complications, including increased ventricular mechanical strain and mixing of oxygenated and deoxygenated blood, leading to heart failure without surgical intervention. Corrective surgery for SVDs are traditionally handled by the Fontan procedure, requiring a vascular conduit for completion. Although effective, current conduits are limited by their inability to aid in pumping blood into the pulmonary circulation. In this report, we propose an innovative and versatile design strategy for a tissue engineered pulsatile conduit (TEPC) to aid circulation through the pulmonary system by producing contractile force. Several design strategies were tested for production of a functional TEPC. Ultimately, we found that porcine extracellular matrix (ECM)-based engineered heart tissue (EHT) composed of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary cardiac fibroblasts (HCF) wrapped around decellularized human umbilical artery (HUA) made an efficacious basal TEPC. Importantly, the TEPCs showed effective electrical and mechanical function. Initial pressure readings from our TEPC in vitro (0.68 mmHg) displayed efficient electrical conductivity enabling them to follow electrical pacing up to a 2 Hz frequency. This work represents a proof of principle study for our current TEPC design strategy. Refinement and optimization of this promising TEPC design will lay the groundwork for testing the construct's therapeutic potential in the future. Together this work represents a progressive step toward developing an improved treatment for SVD patients. STATEMENT OF SIGNIFICANCE: Single Ventricle Cardiac defects (SVD) are a form of congenital disorder with a morbid prognosis without surgical intervention. These patients are treated through the Fontan procedure which requires vascular conduits to complete. Fontan conduits have been traditionally made from stable or biodegradable materials with no pumping activity. Here, we propose a tissue engineered pulsatile conduit (TEPC) for use in Fontan circulation to alleviate excess strain in SVD patients. In contrast to previous strategies for making a pulsatile Fontan conduit, we employ a modular design strategy that allows for the optimization of each component individually to make a standalone tissue. This work sets the foundation for an in vitro, trainable human induced pluripotent stem cell based TEPC., (Copyright © 2019. Published by Elsevier Ltd.)

Background & Aims: Abnormal iron metabolism and hepatic iron-overload is a major cause of liver injury and in the development of chronic liver diseases. Iron-overload-mediated liver disease leads to end-stage cirrhosis and/or hepatocellular carcinoma., Methods: Using a genetic hemochromatosis (hemojuvelin knockout mice) and non-genetic (secondary iron-overload) murine models of hepatic iron-overload, we elucidated the mechanism of hepatic iron injury and the therapeutic effects of resveratrol., Results: Hepatic iron-overload was associated with hepatosplenomegaly, increased oxidative stress, hepatic fibrosis, and inflammation, and a pro-apoptotic state which was markedly corrected by resveratrol therapy. Importantly our aging studies with the hemojuvelin knockout mice showed advanced liver disease in association with steatosis in the absence of a diabetic state which recapitulates the essential pathological features seen in clinical iron-overload. Chronic hepatic iron-overload showed increased nuclear localization of acetylated Forkhead fox-O-1 (FoxO1) transcription factor whereas resveratrol dietary intervention reversed the acetylation of FoxO1 in association with increased SIRT1 levels which together with its pleotropic antioxidant properties are likely key mechanisms of its therapeutic action. Importantly, resveratrol treatment did not affect the degree of hepatic iron-overload but rather direct protects the liver from iron-mediated injury., Conclusions: Our findings illustrate a novel and definitive therapeutic action of resveratrol and represent an economically feasible therapeutic intervention to treat hepatic iron-overload and liver disease., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Rationale: The classic phagocyte nicotinamide adenine dinucleotide phosphate oxidase (gp91(phox) or Nox2) is expressed in the heart. Nox2 activation requires membrane translocation of the p47(phox) subunit and is linked to heart failure. We hypothesized that loss of p47(phox) subunit will result in decreased reactive oxygen species production and resistance to heart failure., Objective: To define the role of p47(phox) in pressure overload-induced biomechanical stress., Methods and Results: Eight-week-old male p47(phox) null (p47(phox) knockout [KO]), Nox2 null (Nox2KO), and wild-type mice were subjected to transverse aortic constriction-induced pressure overload. Contrary to our hypothesis, p47(phox)KO mice showed markedly worsened systolic dysfunction in response to pressure overload at 5 and 9 weeks after transverse aortic constriction compared with wild-type-transverse aortic constriction mice. We found that biomechanical stress upregulated N-cadherin and β-catenin in p47(phox)KO hearts but disrupted the actin filament cytoskeleton and reduced phosphorylation of focal adhesion kinase. p47(phox) interacts with cytosolic cortactin by coimmunoprecipitation and double immunofluorescence staining in murine and human hearts and translocated to the membrane on biomechanical stress where cortactin interacted with N-cadherin, resulting in adaptive cytoskeletal remodeling. However, p47(phox)KO hearts showed impaired interaction of cortactin with N-cadherin, resulting in loss of biomechanical stress-induced actin polymerization and cytoskeletal remodeling. In contrast, Nox2 does not interact with cortactin, and Nox2-deficient hearts were protected from pressure overload-induced adverse myocardial and intracellular cytoskeletal remodeling., Conclusions: We showed a novel role of p47(phox) subunit beyond and independent of nicotinamide adenine dinucleotide phosphate oxidase activity as a regulator of cortactin and adaptive cytoskeletal remodeling, leading to a paradoxically enhanced susceptibility to biomechanical stress and heart failure.