Silica nanoparticles alleviate the immunosuppression, oxidative stress, biochemical, behavioral, and histopathological alterations induced by Aeromonas veronii infection in African catfish (Clarias gariepinus).

In the aquaculture industry, silica nanoparticles (SiNPs) have great significance, mainly for confronting diseases. Therefore, the present study aims to assess the antibacterial efficiency of SiNPs as a versatile trial against Aeromonas veronii infection in African catfish (Clarias gariepinus). Further, we investigated the influence of SiNPs in palliating the immune-antioxidant stress biochemical, ethological, and histopathological alterations induced by A. veronii. The experiment was conducted for 10 days, and about 120 fish were distributed into four groups at random, with 30 fish each. The first group is a control that was neither exposed to infection nor SiNPs. The second group (SiNPs) was vulnerable to SiNPs at a concentration of 20 mg/L in water. The third group was experimentally infected with A. veronii at a concentration of 1.5 × 107 CFU/mL. The fourth group (A. veronii + SiNPs) was exposed to SiNPs and infected with A. veronii. Results outlined that A. veronii infection induced behavioral alterations and suppression of immune-antioxidant responses that appeared as a clear decline in protein profile indices, complement 3, lysozyme activity, glutathione peroxidase, and total antioxidant capacity. The kidney and liver function biomarkers (creatinine, urea, alkaline phosphatase, and alanine aminotransferase) and lipid peroxide (malondialdehyde) were substantially increased in the A. veronii group, with marked histopathological changes and immunohistochemical alterations in these tissues. Interestingly, the exposure to SiNPs resulted in a clear improvement in all measured biomarkers and a noticeable regeneration of the histopathological changes. Overall, it will establish that SiNPs are a new, successful tool for opposing immunological, antioxidant, physiological, and histopathological alterations induced by A. veronii infection.

The Role of Intraoral Scanners in the Shade Matching Process: A Systematic Review.

PURPOSE: The variation in findings with regards to the accuracy and precision of intraoral scanners for shade selection are no doubt confusing for clinicians who may find it difficult to make evidence-based decisions. The aim of this systematic review is to provide a comprehensive and in-depth assessment of available studies to determine the viability of using intraoral scanners for the purpose of shade matching. The PICO-guided research question is as follows: when shade matching, are intraoral scanners as valid as visual or other digital shade measuring devices in determining tooth colors. METHODS: Electronic databases including PubMed/MEDLINE, SCOPUS, EBSCO, Cochrane, and ProQuest were systematically searched for articles published between January 1, 2011 and December 30, 2021 using the main search terms: "intraoral scanners," "scanners," "TRIOS," "CEREC," "Planmeca," "Medit," "digital dentistry" in concurrence with one of the following keywords: "EasyShade" OR "shade selection" OR "shade matching" OR "shade" OR "tooth color" OR "tooth shade" OR "digital shade matching." Bibliographies of included articles and the following journals were searched for relevant articles: Journal of Prosthetic Dentistry, Journal of Prosthodontics, Journal of Esthetic and Restorative Dentistry, Journal of Advanced Prosthodontics, and Journal of Dentistry. A total of 15 articles were included in the review. RESULTS: Intraoral scanners are highly repeatable for shade matching, and outperformed visual shade matching. Accuracy varied significantly between studies, with the majority recommending the use of visual shade matching to confirm/verify the intraoral scanner results. Setting intraoral scanners to the Vita 3D Master shade guide improved both accuracy and precision. Shade matching with intraoral scanners may be influenced by external factors such as ambient light sources and incorrect use or manipulation. CONCLUSION: Intraoral scanners set to the Vita 3D Master shade guide may be used for shade matching, but shade should be verified with visual shade matching. Further studies are required to address limitations of current studies.

In vitro efficacy of a non-instrumentation technique to remove intracanal multispecies biofilm.

AIM: The aim of this study was to assess the efficacy of a non-instrumentation technique to disinfect root canals infected by a human dental plaque-derived multispecies biofilm. METHODOLOGY: Twenty-two mandibular incisors were accessed, autoclaved and inoculated with dental plaque. The Center for Disease Control biofilm reactor was used to promote contamination of the root canal space. In the conventional technique (control), the specimens were instrumented until size 35/04 and irrigated with 6% NaOCl. In the non-instrumentation technique, a glide path was established using K-files size 10-20 and specimens were immediately cleaned with the GentleWave System. Samples were obtained for culture and 16S rRNA gene sequencing. Differences in abundances of genera were evaluated using Kruskal-Wallis test, and differences in alpha diversity were compared using anova. Alpha and beta diversity indices were calculated using mothur. The Shannon and Chao1 indices were used to measure alpha diversity. The Bray-Curtis dissimilarity was used to measure beta diversity. Differences in community composition were evaluated using analysis of similarity with Bonferroni correction for multiple comparisons. RESULTS: The total numbers of reads in biological samples ranged from 126 to 45 286. Significantly fewer reads were obtained from samples following cleaning by either method (p < .0001), and significantly fewer reads were obtained in post-cleaning samples following conventional versus non-instrumentation cleaning regiment (p = .002). Communities in pre-treatment samples were similar in both groups; however, significantly greater relative abundances of Streptococcus, Veillonella and Campylobacter were observed following cleaning using non-instrumentation technique (Kruskal-Wallis p = .009, .033, and .001, respectively). Whilst no significant differences were observed in Shannon alpha diversity, the Chao1 index was significantly lower in post-cleaning samples. CONCLUSIONS: Significant shifts in composition were observed following cleaning by using both regimens, but the impact of this change was greater following a conventional cleaning technique.

Mathematical Tooth Proportions: A Systematic Review.

PURPOSE: The aim of this systematic review was to evaluate and compare three commonly used proportions that include the golden proportion, golden percentage, and Recurring Esthetic Dental (RED) proportion to identify which of the mathematical formulas, if any, can be used to provide predictable and repeatable esthetic clinical outcomes. METHODS: A comprehensive search of electronic databases that included EBSCO, ProQuest, SCOPUS, Science Direct, Wiley, Google Scholar and PubMed was conducted using the terms: "golden proportion," "golden percentage," and "Recurring Esthetic Dental (RED) proportions" alone or in concurrence with one or both ensuing terms: "tooth proportions" and "esthetic tooth proportions." In addition, the following journals were hand searched for relevant articles: Journal of Prosthodontics, Journal of Prosthetic Dentistry and Journal of Esthetic and Restorative Dentistry. Related citations were also considered. RESULTS: Tooth proportions varied substantially in the natural dentition. No studies revealed findings that supported the use of one mathematical formula to predict esthetic success. The golden proportion is present between the central to lateral incisor in some cases, but rarely between the lateral incisor and the canine. When compared to the other proportions, the golden percentage provided better starting points for tooth shape and size, but only when values were adjusted to consider other factors such as ethnicity and/or facial proportions. CONCLUSION: Mathematical formulas did not provide consistent results that would allow for their use as a standardized guide for esthetically pleasing smiles. Although the golden percentage may be a good starting point if the percentages are adjusted on a case-by-case basis, generalized esthetic ideals cannot be determined by a mathematical formula and are open to interpretation by both the clinician and the patient.

Thioacetamide-induced acute hepatic encephalopathy: central vs peripheral effect of Allicin.

Hepatic encephalopathy (HE) is a debilitating and life-threatening disease. Results from acute or chronic liver failure and is characterized by abnormal cerebral and neurological alterations. This study aimed at investigating the effect of allicin, the major functional component in freshly crushed garlic extract, on thioacetamide (TAA)-induced HE in rats. Induction of HE by a single dose of TAA (300 mg/kg; I.P.) was associated with a marked elevation in the serum levels of alanine aminotransferase, aspartate aminotransferase, bilirubin, albumin, total protein, blood urea nitrogen and serum ammonia besides reduction in the serum level of albumin. Moreover, it was accompanied with an increase in the hepatic and brain levels of inflammatory mediators; TNF-α and IL-1ß as well as elevation of the hepatic and brain levels of oxidative stress biomarkers; reduced glutathione and lipid peroxidation evidenced by malondialdeyde. Oral administration of allicin (50, 100 and 200 mg/kg; P.O.) for 6 days prior to TAA injection restored the serum liver function, hepatic and brain levels of inflammatory mediators as well as oxidative stress biomarkers in a dose-dependent manner. From our results, it can be concluded that allicin has a protective effect on TAA-induced HE in rats in a dose-dependent manner due to its powerful antioxidant and anti-inflammatory properties.

Exposure to intranasal chromium triggers dose and time-dependent behavioral and neurotoxicological defects in rats.

The extensive recorded environmental and occupational dispersal of hexavalent chromium (CrVI) dust contributes to an increased interest in its toxicological consequences. A previous study of our team described a brain injury induced by acute intranasal instillation of Cr(VI) in rats, which was characterized by oxidative stress and inflammation. This proposed a high risk of brain damage among Cr(VI) exposed individuals either environmentally or occupationally especially through the nasal cavity. Accordingly, the main aim of this study was to evaluate the effects of subacute/subsubacute/subchronic exposure to intranasal potassium dichromate (inPDC) solution in three dose levels (0.125, 0.25, or 0.5 mg/kg/day for five successive days/week) for 3 different intervals/dose: two weeks, one month, and two months, on the brain of rats. The rats were sacrificed 24 h following the last inPDC dose. The locomotor activity, motor coordination, and object recognition behavior of the rats have been measured. Evaluation of oxidative stress; evidenced by lipid peroxidation and reduced glutathione, and inflammatory markers; evidenced by interleukin 1-beta in the brain tissues, as well as the brain PI3K and PKB contents were performed. Furthermore, the brain anti-glial fibrillary acidic protein (GFAP); marker of neurotoxicity was assessed immunohistochemically. Brain histopathological alterations were also studied. The findings of the current study revealed a dose- and time-dependent inPDC-induced brain toxicity in rats, as displayed by the biochemical, immunohistochemical and histopathological evaluation. Behaviorally, the major toxic effects of inPDC were observed on the locomotor and cognition functions, however, minor effects were observed on the motor coordination. The results suggest that short-term exposure to intranasal Cr(VI), in theses doses, does not trigger a major brain injury in rats; however, observation of more toxic alterations in a time-dependent manner is a threat of more sever toxicity upon longer exposure.

Rapid Maxillary Expansion and Nocturnal Enuresis in Children and Adolescents: A Systematic Review of Controlled Clinical Trials.

OBJECTIVES: To evaluate the effectiveness of rapid palatal expansion in the treatment of nocturnal enuresis among 6-18-year-old children and adolescents. METHODS: Comprehensive searches were carried out in 6 electronic databases (EBSCO, ProQuest, Clinical Key, Science Direct, SCOPUS, and OVID) and supplemented by additional manual searches in 4 orthodontic journals until June 2020. Randomized controlled clinical trials (RCTs) and controlled clinical trials (CCTs) of children and adolescents aged 6-18 years old of both genders who underwent rapid palatal expansion and were considered unresponsive to previous conventional nocturnal enuresis treatment were included in this review. Risk of bias of individual trials was assessed using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) assessment tool for CCTs and the revised Cochrane Risk-of-Bias tool for RCTs (RoB 2). RESULTS: Four studies met all inclusion criteria and were finally included in this systematic review, of which one was an RCT and three were CCTs. Reduction in nocturnal enuresis frequency was reported in all included studies with varying rates and methods of reporting, but most studies reported a statistically significant reduction in the number of wet nights per week. The average range of becoming completely dry 1 year after treatment with an RME was 0%-60%. Also, there was a statistically significant correlation between an improvement in bedwetting and an increase in nasal volume after the use of RME. CONCLUSION: A rapid palatal expansion device may be considered as an alternative treatment option of the nocturnal enuresis condition with guarded prognosis when other treatment modalities have failed.

Neuroprotective effect of Crocus sativus against cerebral ischemia in rats.

The present study aimed to investigate the role of vascular endothelial growth factor (VEGF) in the neuroprotective effect of Crocus sativus (saffron) against cerebral ischemia/reperfusion injury (I/R) in rats. Four groups of a total forty I/R rats with 60-min occlusion followed by 48 h reperfusion or sham surgery were used. The sham and left-brain I/R control groups where treated with normal saline. The rats of the other two groups received saffron extract (100 or 200 mg/kg, ip, respectively) for 3 successive weeks prior to left-brain I/R. Other four doses of saffron extract were received by the rats of the last 2 groups 60 min prior to operation, during the surgery, and on days 1 and 2 following reperfusion. I/R group showed marked neurobehavioral, neurochemical and histopathological alterations. The results revealed a significant reduction in neurological deficit scores in the saffron-treated rats at both doses. Saffron significantly attenuated lipid peroxidation, decreased NO and brain natriuretic peptide (BNP) contents in I/R-brain tissue. On the other hand, saffron reversed the depletion of GSH in the injured brain. Moreover, saffron treatment evidently reduced apoptosis as revealed by a decrease in caspase-3 and Bax protein expression with a marked decrease in the apoptotic neuronal cells compared to I/R group. In addition, saffron administration effectively upregulated the expression of VEGF in I/R-brain tissue. In conclusion, saffron treatment offers significant neuroprotection against I/R damage possibly through diminishing oxidative stress and apoptosis and enhancement of VEGF.

Oral micronised flavonoids versus tranexamic acid for treatment of heavy menstrual bleeding secondary to copper IUD use: a randomised double-blind clinical trial.

OBJECTIVE: The aim of the study was to compare the efficacy of micronised flavonoids versus tranexamic acid in reducing menstrual blood loss (MBL) associated with the use of the TCu 380A intrauterine contraceptive device (IUD) in women with heavy menstrual bleeding (HMB). METHODS: We conducted a randomised double-blind clinical trial between October 2016 and August 2017 in 100 women with HMB (defined as a pictorial blood assessment chart [PBAC] score >100) secondary to IUD use. After assessment of MBL using PBAC score in a baseline cycle, participants were randomised to receive either oral tranexamic acid 500 mg or oral micronised flavonoids 500 mg every 6 h for the first three days of menstruation. PBAC scores were collected in the three subsequent treatment cycles. The primary outcome was the difference in PBAC scores between the groups. Two-way repeated measures ANOVA was used to assess the primary outcome of the change in PBAC scores. RESULTS: Mean PBAC scores were significantly improved in the tranexamic acid group compared with the micronised flavonoids group (236 ± 48, 105 ± 26, 97 ± 16 and 93 ± 15 at the baseline, first, second and third study cycle, respectively, versus 227 ± 52, 139 ± 29, 128 ± 25 and 125 ± 24 in the micronised flavonoids group; p = .01). Moreover, the number of bleeding days and number of pads used were significantly reduced in the tranexamic acid group compared with the micronised flavonoids group (p = .009 and p = .03, respectively). Side effects were comparable between the two groups. CONCLUSION: Oral tranexamic acid compared with oral micronised flavonoids is more effective in reducing HMB associated with copper IUD use. Treating IUD-induced HMB using tranexamic acid was more effective compared with micronised flavonoids in decreasing MBL volume and the number of bleeding days.

Impact of material supply chain on the productivity optimization for the construction of roads projects.

Materials require special consideration when developing a project plan because they make up such a sizable chunk of the overall budget. Materials supply and delivery are crucial especially in road construction projects as they are required for the daily construction process. Lack of materials is a major source of jobsite productivity loss. This is due to the lack of structured communication and clearly defined tasks in the current materials management methods. The divergence between design and construction, the failure to coordinate and integrate multiple functional specializations, and poor communication lead to excessive fragmentation. All of these contribute to performance issues like late material ordering and delivery, low productivity, and budget overruns. This research develops a material supply chain (MSC) framework for best practices in road construction projects at all phases. This ensures that contractors receive the supplies they need at the optimum time, with the required quantities, and at the lowest possible cost. Contractors can enhance output, save money, and stay competitive. A questionnaire was designed to investigate current practices in MSC, identify the most common obstacles that faced contractors throughout the project phases, and identify the most important contributors to the integration of supply chain in construction. The developed framework was then evaluated by road construction experts; 90% stated that the proposed framework promotes project participants to share information and data. 80% assured that the framework promotes completing the project with desired quality and encourages problem solving before it even occurs.

Predictive modeling of wide-shallow RC beams shear strength considering stirrups effect using (FEM-ML) approach.

This paper presents an analysis and prediction of the shear strength of wide-shallow reinforced concrete beams, utilizing Finite Element Analysis (FEA) and machine learning techniques. The methodology involves validating a detailed Finite Element Model (FEM) against experimental results, conducting a parametric study, and developing three Machine Learning prediction equations. The FEM captures concrete and steel behaviors, including cracking and crushing for concrete and linear isotropic properties for steel reinforcement. Loading and boundary conditions are defined for accuracy and validated against 13 experimental specimens, exhibiting a maximum 8% and 12% difference in loads and deflections, respectively. A parametric study generates a dataset of 77 wide beam configurations, exploring variations in beam widths, concrete strengths, compression rebars, and shear reinforcement. This dataset is used to develop machine learning models, including "Genetic Programming (GP)", "Evolutionary Polynomial Regression (EPR)", and "Artificial Neural Network (ANN)". Comparative analysis reveals GP and EPR models with over 95% correlation, while the ANN model outperforms with 99% accuracy. Sensitivity analysis underscores the significant influence of concrete strength and beam aspect ratio on shear strength. In conclusion, the study demonstrates the potential of FEA and machine learning models to predict shear strength in wide-shallow reinforced concrete beams, providing valuable insights for architectural design and engineering practices and emphasizing the role of concrete strength and beam geometry in shear behavior.

Optimizing the superstructure configuration of highway bridges for cost-effective construction.

The structural progress of bridges in conjunction with efficiency has gained researchers' attention in the last few decades. Structures optimization applying mathematical analysis is utilized to achieve sustainability in the design and construction of bridges. Despite the extensive research in this area of knowledge, further structural optimization development needs to be developed. The main goal of this research is to develop a decision support system (DSS) that selects the optimum superstructure configuration for highway bridges, considering financial and technical parameters. The most common structural systems in the longitudinal and transverse directions of bridges are considered in this research. Simple and continuous spans are included in the longitudinal direction, while open and closed sections for the transverse direction. Different construction materials are considered as well, like reinforced concrete, pre-stressed concrete, steel sections, and composite sections, to achieve a wide diversity of alternatives. The developed DSS was illustrated graphically as a map for the optimum superstructure configuration for certain span and span to depth ratio combinations. These different configurations obtained from the DSS were mapped three times. The first was based on direct cost only, the second on construction time only, and the third on the total cost of each alternative. Eventually, the DSS was verified using collected case studies and proposed a convenient selection of bridge superstructure configurations within the considered range of span dimensions.

Numerical and machine learning modeling of GFRP confined concrete-steel hollow elliptical columns.

This article investigates the behavior of hybrid FRP Concrete-Steel columns with an elliptical cross section. The investigation was carried out by gathering information through literature and conducting a parametric study, which resulted in 116 data points. Moreover, multiple machine learning predictive models were developed to accurately estimate the confined ultimate strain and the ultimate load of confined concrete at the rupture of FRP tube. Decision Tree (DT), Random Forest (RF), Adaptive Boosting (ADAB), Categorical Boosting (CATB), and eXtreme Gradient Boosting (XGB) machine learning techniques were utilized for the proposed models. Finally, these models were visually and quantitatively verified and evaluated. It was concluded that the CATB and XGB are standout models, offering high accuracy and strong generalization capabilities. The CATB model is slightly superior due to its consistently lower error rates during testing, indicating it is the best model for this dataset when considering both accuracy and robustness against overfitting.

Efficacy of Quercetin and Quercetin Loaded Chitosan Nanoparticles Against Cisplatin-Induced Renal and Testicular Toxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis.

BACKGROUND/OBJECTIVES: Flavonoids, including quercetin, have attracted much attention due to their potential health-promoting effects. METHODS: The current experiment aims to see whether quercetin (QUE) in nanoparticle form could mitigate testicular and renal toxicity caused by cisplatin (CIS) more effectively than normally formulated QUE. Rats were randomly treated with CIS alone or in combination with QUE or QUE.NPs (Quercetin-loaded chitosan nanoparticles) for 4 weeks. QUE and QUE.NPs were given orally (10 mg/kg, three times a week), while CIS was given intraperitoneally (2 mg/kg, twice a week). RESULTS: Compared to QUE- and CIS + QUE.NP-treated rats, CIS exposure induced anxiety and emotional stress as well as promoted oxidative stress in both testicular and renal tissues. Moreover, CIS reduced serum testosterone levels and diminished testicular IL-10, as well as CIS-induced renal failure, as indicated by hypokalemia, and increased levels of creatinine, urea, sodium, IL-18, and KIM-1. Further, severe histological changes were observed in the testis and kidney of CIS-intoxicated rats. Regarding immunohistochemical staining, CIS significantly upregulated Bax, downregulated Bcl-2, and moderately enhanced PCNA expression. CONCLUSIONS: Our findings suggest that both QUE and QUE.NPs modulated emotional disturbance and improved testicular and renal functions via modulation of oxidation, inflammation, and apoptosis. However, QUE.NPs performed better than QUE-treated rats.

Progress is impossible without change: understanding the evolving nomenclature of steatotic liver disease and its effect on hepatology practice.

The American, European, and Latin American liver societies have proposed a change in the nomenclature we use to describe alcohol-related liver disease and non-alcoholic fatty liver disease. Additionally, a term encompassing both is now advocated: steatotic liver disease, which includes metabolic dysfunction associated steatotic liver disease (MASLD) and MASLD with greater alcohol consumption (MetALD). These classifications offer increased relevance for clinicians, researchers, and patients alike. In this Viewpoint, we discuss the basis for this nomenclature shift and how it was developed. We also explore the challenges that will be faced in the adoption of such change. The proposed change seeks to banish stigma associated with phrasing such as alcoholic and fatty. However stigma, particularly related to the term fatty, is culturally nuanced, and reflects different entities depending on location. If such a change is internationally accepted, there will be wide-reaching effects on practitioners in primary care and metabolic medicine, and on patients. We discuss those effects and the opportunities the nomenclature change could offer, particularly for patients with alcohol and metabolic risk factors who represent a group previously ignored by clinical trials.

The regulation of ATP release from the urothelium by adenosine and transepithelial potential.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Stretch of the urothelium, as occurs during bladder filling, is associated with a release of ATP that is postulated to act as a sensory neurotransmitter. The regulation of ATP release is poorly understood and in particular if there is a feedback mechanism provided by ATP itself. Adenosine, a breakdown product of ATP, is a potent inhibitor of stretch-induced ATP release, acting through and A1 receptor; endogenous levels are about 0.6µM. Data are consistent with ATP release relying on the rise of intracellular Ca2+. Transepithelial potential also controls ATP release, also acting via an A1 receptor-dependent pathway. OBJECTIVES: To test the hypothesis that distension-induced ATP release from the bladder urothelium is regulated by adenosine as well as changes to transurothelial potential (TEP). To examine the role of changes to intracellular [Ca(2+) ] in ATP release. MATERIALS AND METHODS: Rabbit urothelium/suburothelium membranes were used in an Ussing chamber system. Distension was induced by fluid removal from the chamber bathing the serosal (basolateral) membrane face. The TEP and short-circuit current were measured. ATP was measured in samples aspirated from the serosal chamber by a luciferin-luciferase assay. Intracellular [Ca(2+) ] was measured in isolated urothelial cells using the fluorochrome Fura-2. All experiments were performed at 37°C. RESULTS: Distension-induced ATP release was decreased by adenosine (1-10 µm) and enhanced by adenosine deaminase and A1- (but not A2-) receptor antagonists. Distension-induced ATP release was reduced by 2-APB, nifedipine and capsazepine; capsaicin induced ATP release in the absence of distension. ATP and capsaicin, but not adenosine, generated intracellular Ca(2+) transients; adenosine did not affect the ATP-generated Ca(2+) transient. ATP release was dependent on a finite transepithelial potential. Changes to TEP, in the absence of distension, generated ATP release that was in turn reduced by adenosine. CONCLUSION: Adenosine exerts a powerful negative feedback control of ATP release from the urothelium via A1 receptor activation. Distension-induced ATP release may be mediated by a rise of the intracellular [Ca(2+) ]. Modulation of distension-induced ATP release by adenosine and TEP may have a common pathway.

Lactiplantibacillus plantarum and Saussurea costus as Therapeutic Agents against a Diabetic Rat Model-Approaches to Investigate Pharmacophore Modeling of Human IkB Kinase and Molecular Interaction with Dehydrocostus Lactone of Saussurea costus.

Lactic acid bacteria is well-known as a vital strategy to alleviate or prevent diabetes. Similarly, the plant Saussurea costus (Falc) Lipsch is a preventive power against diabetes. Here, we aimed to determine whether lactic acid bacteria or Saussurea costus is more effective in treating a diabetic rat model in a comparative study manner. An in vivo experiment was conducted to test the therapeutic activity of Lactiplantibacillus plantarum (MW719476.1) and S. costus plants against an alloxan-induced diabetic rat model. Molecular, biochemical, and histological analyses were investigated to evaluate the therapeutic characteristics of different treatments. The high dose of S. costus revealed the best downregulated expression for the IKBKB, IKBKG, NfkB1, IL-17A, IL-6, IL-17F, IL-1ß, TNF-α, TRAF6, and MAPK genes compared to Lactiplantibacillus plantarum and the control groups. The downregulation of IKBKB by S. costus could be attributed to dehydrocostus lactone as an active compound with proposed antidiabetic activity. So, we performed another pharmacophore modeling analysis to test the possible interaction between human IkB kinase beta protein and dehydrocostus lactone as an antidiabetic drug. Molecular docking and MD simulation data confirmed the interaction between human IkB kinase beta protein and dehydrocostus lactone as a possible drug. The target genes are important in regulating type 2 diabetes mellitus signaling, lipid and atherosclerosis signaling, NF-κB signaling, and IL-17 signaling pathways. In conclusion, the S. costus plant could be a promising source of novel therapeutic agents for treating diabetes and its complications. Dehydrocostus lactone caused the ameliorative effect of S. costus by its interaction with human IkB kinase beta protein. Further, future studies could be conducted to find the clinical efficacy of dehydrocostus lactone.

Stratification Of LIver Disease (SOLID): protocol for a prospective observational cohort study to determine the optimum biomarker strategies for the detection of advanced liver disease at the primary-secondary care interface.

INTRODUCTION: Undiagnosed fatty liver disease is prevalent in the community, due to high rates of harmful alcohol consumption and/or obesity. Fatty liver disease can progress to cirrhosis and its complications. Early identification of liver disease and treatment may prevent progression to cirrhosis. Biomarkers including FIB-4, enhanced liver fibrosis (ELF), PRO-C3 and vibration controlled transient elastography (VCTE) can stage liver fibrosis, but it is not known how well they perform in a primary care population. Moreover, no assessment of long-term prognostic ability of these biomarkers has been conducted in primary care. We aim to evaluate the performance of fibrosis biomarkers in primary care to develop a pathway to detect advanced fibrosis. METHODS AND ANALYSIS: This prospective, observational cohort study will recruit 3000 individuals with fatty liver disease risk factors (obesity, type 2 diabetes or hazardous alcohol consumption) at their primary care 'annual chronic disease review'. Participants will have a 'liver health check'. Two pathways will be evaluated: (1) all have FIB-4, ELF and VCTE performed, and (2) patients have an initial assessment with FIB-4 and ELF, followed by VCTE in only those with increased FIB-4 and/or ELF. Individuals with suspected significant/advanced liver fibrosis (liver stiffness measurement>8 kPa), will be reviewed in secondary care to confirm their fibrosis stage and institute treatment. The performance of FIB-4, ELF, PRO-C3, VCTE and novel biomarkers alone or in combination for advanced fibrosis/cirrhosis will be evaluated. Participants will be followed longitudinally via their electronic health records to assess long-term clinical outcomes. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London-Chelsea Research Ethics Committee (22/PR/0535; 27 June 2022). Recruitment began on 31 October 2022. Outcomes of this study will be published in peer-reviewed journals and presented at scientific meetings. A lay summary of the results will be available for study participants and will be disseminated widely by LIVErNORTH.

Erythropoietin Suppresses the Hepatic Fibrosis Caused by Thioacetamide: Role of the PI3K/Akt and TLR4 Signaling Pathways.

Erythropoietin (EPO) is recognized for its function in erythropoiesis; however, its potential antifibrotic effect against liver fibrosis remains unknown. This study examined whether EPO affects thioacetamide (TAA)-induced liver fibrosis by concentrating on the Toll-like receptor 4 (TLR4) cascade and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway as possible pathways. Male Wistar rats were randomized into four groups, which included: the negative control group, the TAA group (intraperitoneal; TAA 100 mg/kg three times per week for 2 weeks), and EPO-treated groups (150 and 300 IU/kg, i.p.) for 2 weeks after TAA injections. EPO attenuated hepatic fibrosis in a dosage-dependent way, as manifested by the diminution in serum alanine aminotransferase and aspartate aminotransferase activities, as well as the increase in albumin level. EPO inhibited the increase in tissue levels of tumor necrosis factors-α, interleukin-1ß, transforming growth factor-ß1, and TLR4 and raised tissue levels of PI3K and p-PI3K. EPO antioxidant properties were demonstrated by restoring hepatic glutathione and superoxide dismutase by preventing the accumulation of hepatic malondialdehyde. Further, EPO increased the protein expression of PI3K and Akt and decreased TLR4 protein expression. Immunohistochemically, EPO treatment altered tissue histology and downregulated mitogen-activated protein kinase protein expression. Overall, the research suggested that EPO could prevent TAA-induced hepatic fibrosis through upregulating the PI3K/Akt signaling cascade and downregulation the TLR4 downstream axis.

British Society of Gastroenterology Best Practice Guidance: outpatient management of cirrhosis - part 3: special circumstances.

The prevalence of cirrhosis has risen significantly over recent decades and is predicted to rise further. Widespread use of non-invasive testing means cirrhosis is increasingly diagnosed at an earlier stage. Despite this, there are significant variations in outcomes in patients with cirrhosis across the UK, and patients in areas with higher levels of deprivation are more likely to die from their liver disease. This three-part best practice guidance aims to address outpatient management of cirrhosis, in order to standardise care and to reduce the risk of progression, decompensation and mortality from liver disease. Part 1 addresses outpatient management of compensated cirrhosis: screening for hepatocellular cancer, varices and osteoporosis, vaccination and lifestyle measures. Part 2 concentrates on outpatient management of decompensated disease including management of ascites, encephalopathy, varices, nutrition as well as liver transplantation and palliative care. In this, the third part of the guidance, we focus on special circumstances encountered in managing people with cirrhosis, namely surgery, pregnancy, travel, managing bleeding risk for invasive procedures and portal vein thrombosis.