Microcystin Exposure and Liver Injury Outcomes in NAFLD

Non-alcoholic fatty liver disease (NAFLD) is an emerging worldwide pandemic which is highly prevalent among obese individuals including children and adults. In a NAFLD condition, exposure to environmental contaminants or toxins can act as a second/ multiple hit, which leads to the progression of simple steatosis to NASH and ultimately may result in liver cirrhosis. With climate change today, elevated levels of microcystins are an emerging problem in fresh water bodies, which are a source of drinking water. Individuals are therefore at risk of exposure to microcystin through consuming contaminated water. In the progression of NAFLD from one clinical stage to another, microcystin can play an important role. Research has proved that the main mechanism of the Microcystin-LR is to work as an exogenous Protein phosphatase 2A (PP2A) inhibitor. In this thesis we test the hypothesis that microcystin activates Kupffer cells as well as the hepatic stellate cells, which are the crucial mediators in hepatic inflammation and fibrogenesis via NOX2 dependent pathway in NAFLD condition. Results showed that microcystin exposure via intraperitoneal routes in mice that have mild steatosis will lead to advanced histopathological characteristics of NAFLD. Further, we looked at the effect of early microcystin exposure in young mice, which were then fed a high fat diet to induce obesity/NAFLD. Early exposure to microcystin resulted in exacerbation of NAFLD clinical pathology with increased expression of proinflammatory cytokines, compared to vehicle control treated mice. This process has been shown to be reduced in mice that lacked miR21, p47 phox , or NLRP3 genes. In addition, inhibition of AKT pathway reduced microcystin -induced NOX2 activation as well as upregulation of miR21. All things considered, it was observed that microcystin exposure exacerbated NAFLD pathology via activating NOX2-dpendent peroxynitare generation by increasing miR21 levels. Moreover, early childhood exposure to microcystin will exacerbate adult hepatic injury following HFD via NLRP3 inflammasomes

Lipocalin 2 Induces Neuroinflammation and Blood-Brain Barrier Dysfunction Through Liver-Brain Axis in Murine Model of Nonalcoholic Steatohepatitis

BACKGROUND: Recent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology. METHODS: Using murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis. RESULTS: Results showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1β from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1β. CONCLUSION: In conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation

Environmental Microcystin Targets the Microbiome and Increases the Risk of Intestinal Inflammatory Pathology via NOX2 in Underlying Murine Model of Nonalcoholic Fatty Liver Disease

With increased climate change pressures likely to influence harmful algal blooms, exposure to microcystin, a known hepatotoxin and a byproduct of cyanobacterial blooms can be a risk factor for NAFLD associated comorbidities. Using both in vivo and in vitro experiments we show that microcystin exposure in NAFLD mice cause rapid alteration of gut microbiome, rise in bacterial genus known for mediating gut inflammation and lactate production. Changes in the microbiome were strongly associated with inflammatory pathology in the intestine, gut leaching, tight junction protein alterations and increased oxidative tyrosyl radicals. Increased lactate producing bacteria from the altered microbiome was associated with increased NOX-2, an NADPH oxidase isoform. Activationof NOX2 caused inflammasome activation as shown by NLRP3/ASCII and NLRP3/Casp-1 colocalizations in these cells while use of mice lacking a crucial NOX2 component attenuated inflammatory pathology and redox changes. Mechanistically, NOX2 mediated peroxynitrite species were primary to inflammasome activation and release of inflammatory mediators. Thus, in conclusion, microcystin exposure in NAFLD could significantly alter intestinal pathology especially by the effects on microbiome and resultant redox status thus advancing our understanding of the co-existence of NAFLD-linked inflammatory bowel disease phenotypes in the clinic

Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology

About 14% of veterans who suffer from Gulf war illness (GWI) complain of some form of gastrointestinal disorder but with no significant markers of clinical pathology. Our previous studies have shown that exposure to GW chemicals resulted in altered microbiome which was associated with damage associated molecular pattern (DAMP) release followed by neuro and gastrointestinal inflammation with loss of gut barrier integrity. Enteric glial cells (EGC) are emerging as important regulators of the gastrointestinal tract and have been observed to change to a reactive phenotype in several functional gastrointestinal disorders such as IBS and IBD. This study is aimed at investigating the role of dysbiosis associated EGC immune-activation and redox instability in contributing to observed gastrointestinal barrier integrity loss in GWI via altered tight junction protein expression. Using a mouse model of GWI and studies with cultured EGC and use of antibiotics to ensure gut decontamination we show that exposure to GW chemicals caused dysbiosis associated change in EGCs. EGCs changed to a reactive phenotype characterized by activation of TLR4-S100β/RAGE-iNOS pathway causing release of nitric oxide and activation of NOX2 since gut sterility with antibiotics prevented this change. The resulting peroxynitrite generation led to increased oxidative stress that triggered inflammation as shown by increased NLRP-3 inflammasome activation and increased cell death. Activated EGCs and were associated with decrease in tight junction protein occludin and selective water channel aquaporin-3 with a concomitant increase in Claudin-2. The tight junction protein levels were restored following a parallel treatment of GWI mice with a TLR4 inhibitor SsnB and butyric acid that are known to decrease the immunoactivation of EGCs. Our study demonstrates that immune-redox mechanisms in EGC are important players in the pathology in GWI and may be possible therapeutic targets for improving outcomes in GWI symptom persistence

An evaluation of the efficacy and the safety of home blood pressure monitoring in the control of hypertensive disorders of pregnancy in both pre and postpartum periods: a systematic review and meta-analysis

Abstract Background Hypertensive disorders of pregnancy (HDP) can significantly impact maternal, neonatal, and fetal health. For controlling these disorders, frequent blood pressure measurements are required. Home blood pressure monitoring (HBPM) is a suggested alternative to conventional office monitoring that requires frequent visits. This systematic review was conducted to evaluate the efficacy and safety of HBPM in the control of HDP. Methods We systematically conducted databases search for relevant studies in June 2022. The relevant studies were identified, and qualitative synthesis was performed. An inverse variance quantitative synthesis was conducted using RevMan software. Continuous outcome data were pooled as means differences, whereas dichotomous ones were summarized as risk ratios. The 95% confidence interval was the measure of variance. Results Fifteen studies were included in our review (n = 5335). Our analysis revealed a superiority of HBPM in reducing the risk of induction of labor, and postpartum readmission (P = 0.02, and 0.01 respectively). Moreover, the comparison of birth weights showed a significant variation in favor of HBPM (P = 0.02). In the analysis of other outcomes, HBPM was equally effective as office monitoring. Furthermore, HBPM did not result in an elevated risk of maternal, neonatal, and fetal adverse outcomes. Conclusion Home monitoring of blood pressure showed superiority over office monitoring in some outcomes and equal efficacy in other outcomes

Application of Virtual Reality-Assisted Exergaming on the Rehabilitation of Children with Cerebral Palsy: A Systematic Review and Meta-Analysis

Background: Rehabilitation programs for children with cerebral palsy (CP) aim to improve their motor and cognitive skills through repeated and progressively challenging exercises. However, these exercises can be tedious and demotivating, which can affect the effectiveness and feasibility of the programs. To overcome this problem, virtual reality VR-assisted exergaming has emerged as a novel modality of physiotherapy that combines fun and motivation with physical activity. VR exergaming allows children with CP to perform complex movements in a secure and immersive environment, where they can interact with virtual objects and scenarios. This enhances their active engagement and learning, as well as their self-confidence and enjoyment. We aim to provide a comprehensive overview of the current state of research on VR exergaming for CP rehabilitation. The specific objectives are: To identify and describe the existing studies that have investigated the effects of VR exergaming on motor function and participation outcomes in children with CP. In addition, we aim to identify and discuss the main gaps, challenges, and limitations in the current research on VR exergaming for CP rehabilitation. Finally, we aim to provide recommendations and suggestions for future research and practice in this field. Methods: In June 2023, we conducted a systematic search on Scopus, Web of Science, PubMed, Cochrane, and Embase for randomized trials and cohort studies that applied VR-assisted exergaming to rehabilitating patients with CP. The inclusion criteria encompassed the following: (1) Randomized controlled trials (RCTs) and cohort studies involving the rehabilitation of children with CP; (2) the application of VR-based exergaming on the rehabilitation; (3) in comparison with conventional rehabilitation/usual care. The quality of the selected RCTs was evaluated using Cochrane’s tool for risk of bias assessment bias includes. Whereas the quality of cohort studies was assessed using the National Institutes of Health (NIH) tool. Results: The systematic search of databases retrieved a total of 2576 studies. After removing 863 duplicates, 1713 studies underwent title and abstract screening, and 68 studies were then selected as eligible for full-text screening. Finally, 45 studies were involved in this review (n = 1580), and 24 of those were included in the quantitative analysis. The majority of the included RCTs had a low risk of bias regarding study reporting, participants’ attrition, and generating a random sequence. Nearly half of the RCTs ensured good blinding of outcomes assessors. However, almost all the RCTs were unclear regarding the blinding of the participants and the study personnel. The 2020 retrospective cohort study conducted at Samsung Changwon Hospital, investigating the effects of virtual reality-based rehabilitation on upper extremity function in children with cerebral palsy, demonstrated fair quality in its methodology and findings. VR-assisted exergaming was more effective than conventional physiotherapy in improving the Gross Motor Function Measurement (GMFM)-88 score (MD = 0.81; 95% CI [0.15, 1.47], p-value = 0.02) and the GMFM walking and standing dimensions (MD = 1.45; 95% CI [0.48, 2.24], p-value = 0.003 and MD = 3.15; 95% CI [0.87, 5.42], p-value = 0.007), respectively. The mobility and cognitive domains of the Pediatric Evaluation of Disability Inventory score (MD = 1.32; 95% CI [1.11, 1.52], p-value p-value p-value p-value p-value < 0.001) improved as well. This new intervention is similarly beneficial as conventional therapy in improving other efficacy measures. Conclusions: Our findings suggest that VR-assisted exergaming may have some advantages over conventional rehabilitation in improving CP children’s functioning and performance in daily life activities, upper and lower limb mobility, and cognition. VR-assisted exergaming seems to be as effective as conventional physiotherapy in the other studied function measures. With its potential efficacy, better feasibility, no reported side effects, and entertaining experience, VR-assisted exergaming may be a viable complementary approach to conventional physiotherapy in rehabilitating children with CP

Comparing the effectiveness of corticosteroid and surgery in managing chronic subdural hematoma: A systematic review and meta-analysis

Background: The optimal treatment for Chronic Subdural Hematoma (CSDH), corticosteroids or surgery, remains controversial. This meta-analysis compares the efficacy and safety of these interventions. Methods: We searched four databases until July 2023 for relevant studies. Data extraction was independently performed by two authors. Risk ratios (RR) with a 95% confidence interval (CI) were calculated for dichotomous outcomes and mean difference (MD) with a 95% CI for continuous outcomes. Results: Six studies involving 804 patients were included. Dexamethasone showed non-inferiority to surgery for good neurological outcomes (pooled RR = 1.02, 95% CI [0.95, 1.09], P = 0.60). No significant differences were found in mortality, recurrence rate, and hospital stay length between the two groups. Conclusion: Our analysis indicated that there was no statistically significant difference in terms of good neurological outcomes, length of hospital stay, mortality, and recurrence rate between the surgical interventions and dexamethasone. However, we noticed only clinical and numerical differences between the surgical interventions and dexamethasone regarding length of hospital stay, mortality, and recurrence rate. On the other hand, dexamethasone was associated with statistically higher complications compared to surgery. However, we should treat these results with caution as the only included RCT reported a high recurrence rate with dexamethasone indicating that surgery may be the first-line treatment for patients with CSDH

High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease

High circulatory insulin and leptin followed by underlying inflammation are often ascribed to the ectopic manifestations in non-alcoholic fatty liver disease (NAFLD) but the exact molecular pathways remain unclear. We have shown previously that CYP2E1-mediated oxidative stress and circulating leptin in NAFLD is associated with renal disease severity. Extending the studies, we hypothesized that high circulatory leptin in NAFLD causes renal mesangial cell activation and tubular inflammation via a NOX2 dependent pathway that upregulates proinflammatory miR21. High-fat diet (60% kcal) was used to induce fatty liver phenotype with parallel insulin and leptin resistance. The kidneys were probed for mesangial cell activation and tubular inflammation that showed accelerated NASH phenotype and oxidative stress in the liver. Results showed that NAFLD kidneys had significant increases in α-SMA, a marker of mesangial cell activation, miR21 levels, tyrosine nitration and renal inflammation while they were significantly decreased in leptin and p47 phox knockout mice. Micro RNA21 knockout mice showed decreased tubular immunotoxicity and proinflammatory mediator release. Mechanistically, use of NOX2 siRNA or apocynin,phenyl boronic acid (FBA), DMPO or miR21 antagomir inhibited leptin primed-miR21-mediated mesangial cell activation in vitro suggesting a direct role of leptin-mediated NOX-2 in miR21-mediated mesangial cell activation. Finally, JAK-STAT inhibitor completely abrogated the mesangial cell activation in leptin-primed cells suggesting that leptin signaling in the mesangial cells depended on the JAK-STAT pathway. Taken together the study reports a novel mechanistic pathway of leptin-mediated renal inflammation that is dependent on NOX-2-miR21 axis in ectopic manifestations underlying NAFLD-induced co-morbidities. Keywords: Leptin, NOX-2, NADPH, Mesangial cells, miR21, Oxidative stress, NAFLD, JAK/STAT, siRN

Anticryptosporidium Efficacy of Olea europaea and Ficus carica Leaves Extract in Immunocompromised Mice Associated with Biochemical Characters and Antioxidative System

Cryptosporidiosis is caused by an opportunistic protozoan parasite (Cryptosporidium parvum and C. hominis) known as a parasite of humans, especially children and immunocompromised patients. The current study was designed to evaluate the therapeutic efficacy of a mixture of fig and olive leaf extracts as an alternative medicinal plant. Parasitological examination for oocysts in the stool and histopathological alterations in the small intestines were examined. Additionally, biochemical analyses of liver and kidney functions in addition to antioxidant parameters such as superoxide dismutase (SOD), glutathione peroxidase (GSH) and catalase (CAT) in the plasma were evaluated. Our results showed that marked reduction in oocysts shedding and amelioration in intestinal histopathological changes and hepatic or renal functions were detected in all treated groups compared to the control infected group. Additionally, the treated groups with tested extracts at ratios 1:3 and 1:5 showed a significant decrease in the number of oocysts compared to the other treated groups. Results exhibited a significant increase in the plasma SOD, CAT and GSH levels in treated groups compared to the infected control one. This study suggested that a mixture of fig and olive leaf extracts is a convenient promising therapeutic agent for Cryptosporidiosis

How to Differentiate between Resistant and Susceptible Wheat Cultivars for Leaf Rust Fungi Using Antioxidant Enzymes and Histological and Molecular Studies?

Eight wheat cultivars, Sakha-94, Giza-171, Sids-1, Sids-12, Sids-13, Shandweel-1, Misr-1, and Misr-2, were evaluated for leaf rust at the seedling and adult stages in the 2021 and 2022 seasons. Biochemical, histological, and genetic analyses were performed to determine the link between cultivars that were either sensitive or resistant to the disease. Misr-2 and Giza-171 cultivars had the highest levels of resistance to leaf rust races in 2021 (LTCGT, STSJT, and TTTST) and 2022 (MBGJT, TTTKS, and TTTTT) at the seedling stage. However, at the adult stage, Sakha-94, Giza-171, Misr-1, and Misr-2 cultivars had the highest levels of resistance; consequently, they had the lowest final disease severity and the lowest values of AUDPC. The correlation between the seedling reaction and adult reaction was non-significant, with values of 0.4401 and 0.4793 in the 2021 and 2022 seasons, respectively. Throughout the biochemical, histological, and genetic analyses, it was observed that catalase, peroxidase, and polyphenol oxidase activities significantly increased in the resistant cultivars. The discoloration of superoxide (O2-) and hydrogen peroxide (H2O2) significantly decreased in resistant and moderately resistant wheat cultivars (Sakha-94, Giza-171, Misr-1, and Misr-2); higher hydrogen peroxide (H2O2) and superoxide (O2-) levels were recorded for the susceptible cultivars compared to the resistant cultivars. Molecular markers proved that the Lr50 gene was detected in the resistant cultivars. Puccinia triticina infections negatively affected most histological characteristics of flag leaves, especially in susceptible cultivars. The thickness of the blade (µ), the thickness of the upper and lower epidermis (UE and LE), the thickness of mesophyll tissue (MT), and bundle length and width in the midrib were decreased in susceptible cultivars such as Sids-1, Sids-13, and Shandwel-1 compared with resistant cultivars