MRI-based virtual pathology of the prostate.

Prostate cancer poses significant diagnostic challenges, with conventional methods like prostate-specific antigen (PSA) screening and transrectal ultrasound (TRUS)-guided biopsies often leading to overdiagnosis or miss clinically significant cancers. Multiparametric MRI (mpMRI) has emerged as a more reliable tool. However, it is limited by high inter-observer variability and radiologists missing up to 30% of clinically significant cancers. This article summarizes a few of these recent advancements in quantitative MRI techniques that look at the "Virtual Pathology" of the prostate with an aim to enhance prostate cancer detection and characterization. These techniques include T2 relaxation-based techniques such as luminal water imaging, diffusion based such as vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT) and restriction spectrum imaging or combined relaxation-diffusion techniques such as hybrid multi-dimensional MRI (HM-MRI), time-dependent diffusion imaging, and diffusion-relaxation correlation spectrum imaging. These methods provide detailed insights into underlying prostate microstructure and tissue composition and have shown improved diagnostic accuracy over conventional MRI. These innovative MRI methods hold potential for augmenting mpMRI, reducing variability in diagnosis, and paving the way for MRI as a 'virtual histology' tool in prostate cancer diagnosis. However, they require further validation in larger multi-center clinical settings and rigorous in-depth radiological-pathology correlation are needed for broader implementation.

Design, synthesis, and biological evaluation of a small molecule oral agonist of the glucagon-like-peptide-1 receptor.

An absolute or relative deficiency of pancreatic ß-cells mass and functionality is a crucial pathological feature common to type 1 diabetes mellitus and type 2 diabetes mellitus. Glucagon-like-peptide-1 receptor (GLP1R) agonists have been the focus of considerable research attention for their ability to protect ß-cell mass and augment insulin secretion with no risk of hypoglycemia. Presently commercially available GLP1R agonists are peptides that limit their use due to cost, stability, and mode of administration. To address this drawback, strategically designed distinct sets of small molecules were docked on GLP1R ectodomain and compared with previously known small molecule GLP1R agonists. One of the small molecule PK2 (6-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-6H-indolo[2,3-b]quinoxaline) displays stable binding with GLP1R ectodomain and induces GLP1R internalization and increasing cAMP levels. PK2 also increases insulin secretion in the INS-1 cells. The oral administration of PK2 protects against diabetes induced by multiple low-dose streptozotocin administration by lowering high blood glucose levels. Similar to GLP1R peptidic agonists, treatment of PK2 induces ß-cell replication and attenuate ß-cell apoptosis in STZ-treated mice. Mechanistically, this protection was associated with decreased thioredoxin-interacting protein expression, a potent inducer of diabetic ß-cell apoptosis and dysfunction. Together, this report describes a small molecule, PK2, as an orally active nonpeptidic GLP1R agonist that has efficacy to preserve or restore functional ß-cell mass.

Simultaneous intervention against oxidative stress and inflammation by targeting Nrf2/ARE and NLRP3 inflammasome pathway mitigates thioacetamide-induced liver fibrosis in rat.

Liver fibrosis is a typical pathological state/stage involved in most chronic liver diseases and its persistence results in cirrhosis. Inflammasomes are cytoplasmic sensors that induce inflammation in response to stress. Glibenclamide (GLB) is an USFDA-approved drug for type 2 diabetes and is reported to possess anti-inflammatory activity by inhibiting inflammatory cytokines. Dimethyl fumarate (DMF) is an USFDA-approved drug for multiple sclerosis and has been reported to activate the Nrf2/ARE pathway to maintain the cellular antioxidant balance. A total of 36 rats were randomized into six groups (n = 6 each). The rats were injected with thioacetamide (TAA) 200 mg/kg, intraperitoneally every third day for eight consecutive weeks to induce liver fibrosis and oral treatment of GLB 0.5 mg/kg/day and DMF 25 mg/kg/day, and their combinations were provided for the last four consecutive weeks. Treatment with GLB, DMF, and GLB+DMF significantly protected against TAA-mediated oxidative stress and inflammatory conditions by improving hepatic function test, triglycerides, hydroxyproline, and histopathological alterations, by inhibiting the NLRP3 inflammasome signaling and fibrogenic markers, and by activating Nrf2/ARE pathway in Wistar rats. The present results suggest that simultaneous Nrf2/ARE activation and NLRP3 inflammasome inhibition could significantly contribute to developing a novel therapy for patients with liver fibrosis.

Emerging MR methods for improved diagnosis of prostate cancer by multiparametric MRI.

Current challenges of using serum prostate-specific antigen (PSA) level-based screening, such as the increased false positive rate, inability to detect clinically significant prostate cancer (PCa) with random biopsy, multifocality in PCa, and the molecular heterogeneity of PCa, can be addressed by integrating advanced multiparametric MR imaging (mpMRI) approaches into the diagnostic workup of PCa. The standard method for diagnosing PCa is a transrectal ultrasonography (TRUS)-guided systematic prostate biopsy, but it suffers from sampling errors and frequently fails to detect clinically significant PCa. mpMRI not only increases the detection of clinically significant PCa, but it also helps to reduce unnecessary biopsies because of its high negative predictive value. Furthermore, non-Cartesian image acquisition and compressed sensing have resulted in faster MR acquisition with improved signal-to-noise ratio, which can be used in quantitative MRI methods such as dynamic contrast-enhanced (DCE)-MRI. With the growing emphasis on the role of pre-biopsy mpMRI in the evaluation of PCa, there is an increased demand for innovative MRI methods that can improve PCa grading, detect clinically significant PCa, and biopsy guidance. To meet these demands, in addition to routine T1-weighted, T2-weighted, DCE-MRI, diffusion MRI, and MR spectroscopy, several new MR methods such as restriction spectrum imaging, vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT) method, hybrid multi-dimensional MRI, luminal water imaging, and MR fingerprinting have been developed for a better characterization of the disease. Further, with the increasing interest in combining MR data with clinical and genomic data, there is a growing interest in utilizing radiomics and radiogenomics approaches. These big data can also be utilized in the development of computer-aided diagnostic tools, including automatic segmentation and the detection of clinically significant PCa using machine learning methods.

The intervention of tert-butylhydroquinone protects ethanol-induced gastric ulcer in type II diabetic rats: the role of Nrf2 pathway.

Ethanol consumption increases the prevalence of gastric ulcer (GU) in rats with type II diabetes (T2D). Induction of GU by absolute ethanol (5 mL/kg or 3.94 g/kg) in the animal model resembles human ulcer characteristics. The aim was to investigate the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the treatment of GU in diabetic condition. The rats were exposed to absolute ethanol 1 h before sacrifice and T2D was induced by combined exposure of high-fat diet and low dose streptozotocin. Pretreatment of tert-butylhydroquinone (tBHQ) (25 and 50 mg/kg), metformin (500 mg/kg), and omeprazole (20 mg/kg) were given once daily for last three consecutive weeks. In ethanol-exposed diabetic rats, pretreatment with tBHQ, omeprazole, and metformin reduced gastric mucosal lesion, ulcer index, histological alterations, malondialdehyde level, and apoptosis. Furthermore, the intervention of tBHQ, omeprazole, and metformin improved the integrity of the stomach mucosa, glutathione, gastric pH, collagen, and goblet cells. tBHQ treatment improved ethanol-induced alterations of Nrf2, catalase, heat shock protein 70 (HSP70), NF-κB, and endothelin-1 expressions in diabetic rats. In diabetic conditions, the incidence of GU is increased due to elevated levels of reactive oxygen species, inflammatory mediators, depleted levels of cellular antioxidants, and altered gastric parameters. The tBHQ intervention could be a rational strategy to protect these changes.

Diethylnitrosamine and thioacetamide-induced hepatic damage and early carcinogenesis in rats: Role of Nrf2 activator dimethyl fumarate and NLRP3 inhibitor glibenclamide.

Two-stage rat hepatocarcinogenesis model was used to induce early carcinogenesis in which thioacetamide (TAA) promotes diethylnitrosamine (DEN) initiated carcinogenesis. Dimethyl fumarate (DMF) used to treat multiple sclerosis, activates the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway during oxidative stress, and maintains antioxidant levels. Glibenclamide (GLB), a sulphonylurea drug used to treat type II diabetes, possesses anti-inflammatory properties and inhibits NLRP3 inflammasomes. The present study was designed to investigate the concurrent intervention of DMF and GLB on DEN + TAA-induced early hepatic carcinogenesis. DMF and GLB treatment improved DEN + TAA-induced decrease in body weight, increase in liver weight and plasma transaminases, histopathological alterations, DNA damage, and apoptosis. DMF and GLB intervention significantly ameliorated the DEN + TAA-induced alterations in the antioxidant (Nrf2, HO-1, SOD-1, catalase), inflammatory (NF-κB, NLRP3, ASC, caspase-1), fibrogenic (TGF-ß1, collagen) and regenerative proliferative stress (GST-p, HGF, c-MET, TGFα, EGF, AFP) markers. The present results indicate that Nrf2/ARE activation and NLRP3 inhibition might be a rational approach to attenuate oxidative stress and chronic inflammation associated progression of hepatocarcinogenesis.

Amelioration of Repeated Restraint Stress-Induced Behavioral Deficits and Hippocampal Anomalies with Taurine Treatment in Mice.

Taurine, an essential neutraceutical, has been reported to exhibit antioxidant and anti-inflammatory properties. Substantial evidence indicates that prolonged stress is one of the leading causes of psychological and physiological anomalies. Restraint stress (RS) rat model is the most widely used experimental model for the induction of chronic psycho-emotional stress. In the present study, Swiss albino male mice were restrained for 6 h/day for 28 consecutive days. Animals were divided into four groups: control, RS, RS + taurine, and taurine control group. Taurine, a potent antioxidant, was administered (200 mg/kg) orally along with RS for 28 days. The taurine intervention significantly restored the RS-induced neurobehavioral alterations evident by the elevated plus-maze, Morris water maze test, forced swim test, tail suspension test, and a sucrose preference test. Moreover, taurine significantly prevented hippocampal oxidative stress (lipid peroxidation, reduced glutathione, and nitrite) and other neurochemical (acetylcholinesterase, and IL-1ß) anomalies. Using western blotting analyses, we demonstrate that taurine treatment significantly ameliorated the alterations in Brain-derived neurotrophic factor, caspase-3, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) level in the hippocampus. Thus, Taurine effectively inhibited RS-induced oxidative stress, neuroinflammation, and apoptosis via a mechanism involving the inhibition of the NF-κB signaling pathway. In summary, our study is the first to demonstrate that NF-κB and caspase-3 inhibition, as well as BDNF augmentation, was involved in neuroprotective potential of taurine against RS-induced behavioural anomalies.

Prebiopsy multiparametric MRI-based risk score for predicting prostate cancer in biopsy-naive men with prostate-specific antigen between 4-10 ng/mL.

BACKGROUND: Risk calculators have traditionally utilized serum prostate-specific antigen (PSA) values in addition to clinical variables to predict the likelihood of prostate cancer (PCa). PURPOSE: To develop a prebiopsy multiparametric MRI (mpMRI)-based risk score (RS) and a statistical equation for predicting the risk of PCa in biopsy-naive men with serum PSA between 4-10 ng/mL that may help reduce unnecessary biopsies. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: In all, 137 consecutive men with PSA between 4-10 ng/mL underwent prebiopsy mpMRI (diffusion-weighted [DW]-MRI and MR spectroscopic imaging [MRSI]) during 2009-2015 were recruited for this study. FIELD STRENGTH/SEQUENCE: 1.5T (Avanto, Siemens Health Care, Erlangen, Germany); T1 -weighted, T2 -weighted, DW-MRI, and MRSI sequences were used. ASSESSMENT: All eligible patients underwent mpMRI-directed, cognitive-fusion transrectal ultrasound (TRUS)-guided biopsies. STATISTICAL TESTS: An equation model and an RS were developed using receiver operating characteristic (ROC) curve analysis and a multivariable logistic regression approach. A 10-fold crossvalidation and simulation analyses were performed to assess diagnostic performance of various combinations of mpMRI parameters. RESULTS: Of 137 patients, 32 were diagnosed with PCa on biopsy. Multivariable analysis, adjusted with positive pathology, showed apparent diffusion coefficient (ADC), metabolite ratio, and PSA as significant predictors of PCa (P < 0.05). A statistical equation was derived using these predictors. A simple 6-point mpMRI-based RS was derived for calculating the risk of PCa and it showed that it is highly predictive for PCa (odds ratio = 3.74, 95% confidence interval [CI]: 2.24-6.27, area under the curve [AUC] = 0.87). Both models (equation and RS) yielded high predictive performance (AUC ≥0.85) on validation analysis. DATA CONCLUSION: A statistical equation and a simple 6-point mpMRI-based RS can be used as a point-of-care tool to potentially help limit the number of negative biopsies in men with PSA between 4 and 10 ng/mL. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1227-1236.

Stratification of the aggressiveness of prostate cancer using pre-biopsy multiparametric MRI (mpMRI).

Risk stratification, based on the Gleason score (GS) of a prostate biopsy, is an important decision-making tool in prostate cancer management. As low-grade disease may not need active intervention, the ability to identify aggressive cancers on imaging could limit the need for prostate biopsies. We assessed the ability of multiparametric MRI (mpMRI) in pre-biopsy risk stratification of men with prostate cancer. One hundred and twenty men suspected to have prostate cancer underwent mpMRI (diffusion MRI and MR spectroscopic imaging) prior to biopsy. Twenty-six had cancer and were stratified into three groups based on GS: low grade (GS ≤ 6), intermediate grade (GS = 7) and high grade (GS ≥ 8). A total of 910 regions of interest (ROIs) from the peripheral zone (PZ, range 25-45) were analyzed from these 26 patients. The metabolite ratio [citrate/(choline + creatine)] and apparent diffusion coefficient (ADC) of voxels were calculated for the PZ regions corresponding to the biopsy cores and compared with histology. The median metabolite ratios for low-grade, intermediate-grade and high-grade cancer were 0.29 (range: 0.16, 0.61), 0.17 (range: 0.13, 0.32) and 0.13 (range: 0.05, 0.23), respectively (p = 0.004). The corresponding mean ADCs (×10(-3) mm(2) /s) for low-grade, intermediate-grade and high-grade cancer were 0.99 ± 0.08, 0.86 ± 0.11 and 0.69 ± 0.12, respectively (p < 0.0001). The combined ADC and metabolite ratio model showed strong discriminatory ability to differentiate subjects with GS ≤ 6 from subjects with GS ≥ 7 with an area under the curve of 94%. These data indicate that pre-biopsy mpMRI may stratify PCa aggressiveness noninvasively. As the recent literature data suggest that men with GS ≤ 6 cancer may not need radical therapy, our data may help limit the need for biopsy and allow informed decision making for clinical intervention. Copyright © 2015 John Wiley & Sons, Ltd.

Magnetic resonance spectroscopy imaging-directed transrectal ultrasound biopsy increases prostate cancer detection in men with prostate-specific antigen between 4-10 ng/mL and normal digital rectal examination.

OBJECTIVES: To evaluate the ability of magnetic resonance spectroscopic imaging to improve prostate cancer detection rate. METHODS: A retrospective analysis was carried out of 278 men with prostate-specific antigen in the range of 4-10 ng/mL and normal digital rectal examination who underwent transrectal ultrasound-guided prostate biopsy. Outcomes were compared between men who had a standard biopsy versus those who also underwent a prebiopsy magnetic resonance spectroscopic imaging. Men with an abnormal voxel on magnetic resonance spectroscopic imaging had standard transrectal ultrasound biopsies plus biopsies directed to the abnormal voxels. RESULTS: The study group (n = 140) and control group (n = 138) were similar in baseline parameters, such as mean age, prostate size and mean prostate-specific antigen. The overall cancer detection in the magnetic resonance spectroscopic imaging positive group (24.4%) was more than double that of the control group (10.1%). On comparing the magnetic resonance spectroscopic imaging results with the transrectal ultrasound biopsy findings, magnetic resonance spectroscopic imaging had 95.6% sensitivity, 41.9% specificity, a positive predictive value of 24.4%, a negative predictive value of 98% and an accuracy of 51.4%. CONCLUSIONS: Magnetic resonance spectroscopic imaging-directed transrectal ultrasound biopsy increases the cancer detection rate compared with standard transrectal ultrasound biopsy in patients with normal digital rectal examination and elevated prostate-specific antigen in the range of 4-10 ng/mL.

Boldine: a narrative review of the bioactive compound with versatile biological and pharmacological potential.

OBJECTIVE: Boldine is a plant-derived bioactive compound that has a beneficial impact on human health. Boldine is an aporphine alkaloid mainly obtained from the leaves and bark of the Chilean Boldo tree (Peumus boldus, Family: Monimiaceae). There are plenty of preclinical evidence supports that boldine exerts its beneficial effects against various diseases. Lumiskin™, a patented and marketed formulation by Revitol Skincare for skin brightening, contains Dicetyl boldine, a boldine derivative. CONTENT: All the available information on the Chilean boldo tree (P. boldus Molina) species was actualized by systematically searching the scientific databases (PubMed, SciFinder, Web of Science, Google Scholar, Scopus and others) and scientific literature. This article covers the recent advances in pharmacokinetic, toxicological, pharmacological/biological activities, and molecular mechanisms of the bioactive compound to understand health benefits of boldine better. SUMMARY: Boldine exerts antioxidant, hepatoprotective, anti-atherosclerotic, anti-diabetic, analgesic, antipyretic, anti-inflammatory, anti-epileptic, neuroprotective, nephroprotective, anti-arthritis, anticancer and nootropic effects. Moreover, boldine exhibits its various pharmacological activities by altering antioxidant parameters (MDA, superoxide dismutase, glutathione), peroxynitrite, inflammatory markers apoptotic index, caspase-3, acetyl-cholinesterase, myeloperoxidase, TNF-α (Tumor necrosis factor-α), iNOS, Bcl-2-associated X protein (BAX), ACE-1(Angiotensin-converting enzyme-1), dopamine D2 receptors and nicotinic acetylcholine receptor. Boldine has the potential to modulate a variety of biological networks. OUTLOOK: Due to its versatile pharmacological effects reported in various experimental animals as well as in randomized clinical trials for the treatment of facial melasma and for treatment of urinary stone lithotripsy in children as a complementary phytotherapy; in the future, this compound might be developed as a novel drug for a different indication.

Efficacy of ultrasonography and color-Doppler for early prediction of hemodialysis arteriovenous fistula unassisted maturation.

BACKGROUND: Arteriovenous fistula (AVF) failure is a prevalent concern for patients with end-stage kidney disease on hemodialysis. Recognizing the efficacy of ultrasound Doppler in post-operative AVF evaluation, this study sought to discern the predictive capabilities of various ultrasonographic and color-Doppler metrics for early AVF outcomes. METHODS: This single-center, prospective cohort study spanned 1 year and, post ethical clearance, included all patients who underwent native AVF creation surgery and were subsequently referred for standard post-operative ultrasound Doppler assessment. Parameters such as fistula size, cephalic vein area and diameter, and AVF flow velocity and rates were assessed on post-operative day 2, week 2, and week 6. These initial findings were juxtaposed with later outcomes to determine unassisted AVF results. RESULTS: Of the initial cohort of 40 patients, 75% encountered AVF failure, whereas 25% realized successful unassisted AVF maturation. A notable observation was the significant variance in AVF flow rates as early as post-operative day 2. A threshold of >246 ml/min was indicative of successful unassisted AVF maturation, leading to a sensitivity of 80% and a specificity of 70%. Although the cephalic vein diameter on post-operative day 2 lacked a robust association with AVF outcomes, a cut-off of >3.4 mm, when combined with flow rate testing, augmented the cumulative sensitivity to 92%. CONCLUSION: Ultrasound Doppler stands out as a valuable quantitative imaging modality, adept at prognosticating AVF outcomes from as early as post-operative day 2. In particular, a flow rate exceeding 246 ml/min and a cephalic vein diameter surpassing 3.4 mm are salient indicators for the early prediction of successful AVF outcomes.

Mechanisms of NLRP3 inflammasome-mediated hepatic stellate cell activation: Therapeutic potential for liver fibrosis.

The liver injury leads to an inflammatory response, which causes the activation of hepatic stellate cells (HSCs) that further secrete ECM proteins and play an important role in liver fibrosis. Moreover, the inflammatory response is a driving force for fibrogenesis, which is triggered by many types of injuries. Exaggerated inflammatory immune responses are mediated by cytoplasmic protein complexes known as inflammasomes, which are involved in many chronic liver diseases. Inflammasomes are pattern recognition receptors (PRRs) that can sense any microbial motifs known as pathogen-associated molecular patterns (PAMPs), and host- or environmental-derived stress signals known as damage-associated molecular patterns (DAMPs). The inflammasomes cause caspase-mediated proteolytic cleavage of pro-IL-1ß and pro-IL-18 into active IL-1ß and IL-18. In this review, we provide a comprehensive summary of the important roles of NLRP3 inflammasome in the pathogenesis of liver fibrosis with an emphasis on several direct and indirect pathways responsible for the NLRP3 inflammasome-mediated HSCs activation and fibrogenesis. In addition, we discuss the general pharmacological and genetics strategies for the inhibition of NLRP3 inflammasome activation and its downstream signaling with examples of emerging pharmacotherapeutics, targeting the NLRP3 inflammasome signaling as well as a possible way to develop effective and safer NLRP3 inflammasome inhibitors.

Mucocutaneous manifestations of COVID-19-associated mucormycosis: A retrospective cross-sectional study.

Background Cutaneous mucormycosis has shown a significant upsurge during the COVID-19 pandemic. Due to the rapid progression and high mortality of cutaneous mucormycosis in this context, it is important to identify it early. However, very few studies report detailed clinical descriptions of cutaneous mucormycosis in COVID-19 patients. Objectives To describe mucocutaneous lesions of COVID-19-associated mucormycosis based on clinical morphology and attempt to correlate them with radiological changes. Methods A retrospective cross-sectional study was conducted at a tertiary care centre from 1st April to 31st July 2021. Eligibility criteria included hospitalised adult patients of COVID-19-associated mucormycosis with mucocutaneous lesions. Results All subjects were recently recovering COVID-19 patients diagnosed with cutaneous mucormycosis. One of fifty-three (2%) patients had primary cutaneous mucormycosis, and all of the rest had secondary cutaneous mucormycosis. Secondary cutaneous mucormycosis lesions presented as cutaneous-abscess in 25/52 (48%), nodulo-pustular lesions in 1/52 (2%), necrotic eschar in 1/52 (2%) and ulcero-necrotic in 1/52 (2%). Mucosal lesions were of three broad sub-types: ulcero-necrotic in 1/52 (2%), pustular in 2/52 (4%) and plaques in 1/52 (2%). Twenty out of fifty-two patients (38%) presented with simultaneous mucosal and cutaneous lesions belonging to the above categories. Magnetic resonance imaging of the face showed variable features of cutaneous and subcutaneous tissue involvement, viz. peripherally enhancing collection in the abscess group, "dot in circle sign" and heterogeneous contrast enhancement in the nodulo-pustular group; and fat stranding with infiltration of subcutaneous tissue in cases with necrotic eschar and ulcero-necrotic lesions. Limitations The morphological variety of cutaneous mucormycosis patients in a single-centre study like ours might not be very precise. Thus, there is a need to conduct multi-centric prospective studies with larger sample sizes in the future to substantiate our morphological and radiological findings. Conclusions COVID-19-associated mucormycosis patients in our study presented with a few specific types of mucocutaneous manifestations, with distinct magnetic resonance imaging findings. If corroborated by larger studies, these observations would be helpful in the early diagnosis of this serious illness.

Simultaneous Modulation of NLRP3 Inflammasome and Nrf2/ARE Pathway Rescues Thioacetamide-Induced Hepatic Damage in Mice: Role of Oxidative Stress and Inflammation.

Chronic tissue injury resulting in fibrosis of multiple organs, responsible for one-third of the death globally. Liver fibrosis is a common pathway/condition involved in all chronic liver diseases. Thioacetamide (TAA), a hepatotoxicant, was used to induce hepatic fibrosis. Anti-diabetic drug glibenclamide (GLB) possesses anti-inflammatory properties and inhibits NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation. Dimethyl fumarate (DMF), a multiple sclerosis drug, activates the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and maintains the antioxidant status in the cell. The present study was designed to investigate (i) role of NLRP3 inflammasome and Nrf2/ARE pathway in TAA-induced hepatotoxicity and liver fibrosis, (ii) mechanism involved in GLB and DMF mediated hepatoprotection against TAA-induced hepatotoxicity, and (iii) additional/synergistic hepatoprotective effect of combination treatment with NLRP3 inhibition + Nrf2 activation or GLB + DMF or MCC950 + 4OI to reverse/ameliorate the experimental liver fibrosis completely. TAA was administered intraperitoneally to mice for seven consecutive weeks, and treatments of GLB, DMF, GLB + DMF, MCC950, 4OI, and MCC950 + 4OI were provided for the last three consecutive weeks. The intervention with GLB, DMF, GLB + DMF, MCC950, 4OI, and MCC950 + 4OI significantly protected TAA-induced oxidative stress and inflammatory conditions by improving biochemical, histological, and immunoexpression changes in mice. The GLB, DMF, and GLB + DMF intervention exhibited a better protective effect compared with MCC950, 4OI, and MCC950 + 4OI, which revealed that this specific inhibitor/activator possesses only NLRP3 inflammasome inhibitory/Nrf2 activatory properties. In contrast, the clinical drug GLB and DMF have several other beneficial effects, which are independent of NLRP3 inhibition and Nrf2 activation.

NLRP3 inhibitor glibenclamide attenuates high-fat diet and streptozotocin-induced non-alcoholic fatty liver disease in rat: studies on oxidative stress, inflammation, DNA damage and insulin signalling pathway.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is much higher in diabetic and obese individuals. Combined exposure of high-fat diet (HFD) and single low-dose streptozotocin (STZ) was used to induce type II diabetes-associated NAFLD, as it better replicates the human pathology of fatty liver. Glibenclamide (GLB) is a potent NLRP3 inflammasome inhibitor and possesses anti-inflammatory and anti-oxidant properties. So it was pertinent to investigate its hepatoprotective potential against NAFLD in rat. HFD was provided to rat for 17 consecutive weeks and glibenclamide (GLB; 0.5 and 2.5 mg/kg/day, orally) was administered for the last 12 consecutive weeks. Establishment of NAFLD was clearly indicated by significant increase in liver weight, glucose, triglyceride, cholesterol, % glycosylated haemoglobin and insulin levels, and GLB intervention reduced the same. GLB restored HFD-induced significant increase in ROS, MDA and decrease in GSH. Histopathological studies revealed the macro- and micro-vascular steatosis and mild degree of inflammation in HFD-fed rat compared with control, and GLB intervention reduced the same. HFD exposure significantly increased the DNA damage and apoptosis compared with control, and GLB intervention reduced the same. Immunohistochemical and immunoblotting findings showed that GLB improved the hepatic expressions of inflammatory markers (NLRP3, ASC, caspase-1, IL-1ß, NF-κB), anti-oxidant markers (SOD, catalase) and insulin signalling markers (p-AKT, p-GSK-3ß, p-IRS). Hepatoprotective effects of GLB was mediated by decreasing the levels of glucose, triglycerides, cholesterol, DNA damage, apoptosis and inflammatory markers, and by improving the anti-oxidant status and insulin signalling pathway in HFD fed rat.

7,8-Dihydroxyflavone alleviated the high-fat diet and alcohol-induced memory impairment: behavioral, biochemical and molecular evidence.

RATIONALE: Alcoholism and obesity impart a deleterious impact on human health and affects the quality of life. Chronic consumption of alcohol and western diet has been reported to cause memory deficits. 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, comprises antioxidant and anti-inflammatory properties in treating various neurological disorders. OBJECTIVES: The current study was aimed to determine the protective effect and molecular mechanism of 7,8-DHF against alcohol and high-fat diet (HFD)-induced memory deficits in rats. METHODS: The adult male Wistar rats were given alcohol (3-15%) and HFD ad libitum for 12 weeks in different experimental groups. 7,8-DHF (5 mg/kg) was intraperitoneally injected daily for the last 4 weeks (9th-12th week). RESULTS: The alcohol and HFD administration caused cognitive impairment as evaluated through the Morris water maze (MWM) test in alcohol, HFD, and alcohol + HFD-fed animals. The last 4-week treatment of 7,8-DHF (5 mg/kg; i.p.) attenuated alcohol and HFD-induced memory loss. 7,8-DHF treatment also restored the glutathione (GSH) level along with attenuation of nitrite, malondialdehyde content (markers of oxidative and nitrosative stress), and reduction of the acetylcholinesterase activity in the hippocampus of alcohol and HFD-fed animals. Furthermore, the administration of 7,8-DHF caused downregulation of NF-κB, iNOS, and caspase-3 and upregulation of Nrf2, HO-1, and BDNF mRNA level in rat hippocampus. CONCLUSION: 7,8-DHF administration conferred beneficial effects against alcohol and HFD-induced memory deficit via its unique antioxidant, anti-inflammatory, anti-apoptotic potential, along with the activation of TrkB/BDNF signaling pathway in the hippocampus.

Hepatoprotective potential of 7,8-Dihydroxyflavone against alcohol and high-fat diet induced liver toxicity via attenuation of oxido-nitrosative stress and NF-κB activation.

BACKGROUND: Fatty liver diseases are the most common and major health concern arises from the modern lifestyle and alcohol (ethanol) abuse. The prevalence of non-alcoholic fatty liver diseases (NAFLD) has been observed prominently in obese and diabetic individuals, while alcoholic liver disease is common in alcoholic persons. Fatty liver disease, such as steatohepatitis, leads to fibrosis, cirrhosis and eventually hepatocellular carcinoma. The present study was designed to investigate the effect of 7,8-Dihydroxyflavone (7,8-DHF) against high-fat diet (HFD) and ethanol (EtOH)-induced hepatotoxicity in rats. METHODS: Male Wistar rats (150-200 g) were fed HFD (58% calories from fat) and EtOH (3-15% in drinking water) for 12 weeks. 7,8-DHF was administered intraperitoneally at the dose of 5 mg/kg/day for the last four weeks. After 12 weeks, biochemical, ELISA, RT-PCR, and histological studies have been carried out. RESULTS: Biochemical analyses revealed the involvement of oxidative stress and inflammation in the liver of HFD and EtOH-fed rats. 7,8-DHF treatment significantly reduced HFD and EtOH-induced oxidative stress as evidenced by the reduction of lipid peroxidation and augmentation of reduced glutathione level. Moreover, IL-1ß level was found significantly reduced in 7,8-DHF treated EtOH, HFD and EtOH+HFD groups. The semi-quantitative RT-PCR results indicated down-regulation of Nrf-2 and HO-1 and up-regulation of NF-κB and iNOS mRNA expression level in the liver of HFD and EtOH-fed rats, which was ameliorated by 7,8-DHF treatment. CONCLUSION: The present study suggested that 7,8-DHF could be an effective pharmacological intervention in combating HFD and EtOH-induced hepatotoxicity.

Ameliorative effect of fisetin against lipopolysaccharide and restraint stress-induced behavioral deficits via modulation of NF-κB and IDO-1.

BACKGROUND: Fisetin, a plant active polyphenol, is well known for its antioxidant and free radical scavenging activities. The present study was designed to explore the detailed molecular mechanism underlying its neuroprotective effects. METHODS: The young male mice were either administered a single dose of lipopolysaccharide (0.83 mg/kg) or subjected to restraint stress (6 h per day for 28 days) to induce behavioral deficits in different groups. Fisetin (15 mg/kg) was orally administered for the last 14 days of the study. RESULTS: Lipopolysaccharide (LPS) as well as restraint stress (RS) exposure caused behavioral alterations (anxiety and depressive-like behavior). Gene expression analysis showed upregulation of nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and indoleamine 2,3-dioxygenase (IDO)-1 gene expression along with downregulation of Nrf-2 (nuclear factor erythroid 2-related factor 2), HO-1 (heme oxygenase-1), and ChAT (choline acetyltransferase) gene expression level in RS and RS+LPS groups. Fisetin administration significantly ameliorated behavioral and neurochemical deficits in LPS, RS, and RS+LPS groups. CONCLUSION: These findings clearly indicated that fisetin administration improved behavioral functions and suppressed the NF-κB and IDO-1 (indoleamine 2,3-dioxygenase) activation along with their antioxidant effect, suggesting fisetin as an intriguing nutraceutical for the management of inflammation-associated neurological disorders.