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.

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.

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.

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.

Dimethyl fumarate-mediated Nrf2/ARE pathway activation and glibenclamide-mediated NLRP3 inflammasome cascade inhibition alleviate type II diabetes-associated fatty liver in rats by mitigating oxidative stress and inflammation.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is much higher in patients with type II diabetes (T2D). Inflammasomes are multimolecular complexes reported to involve inflammatory conditions. The nuclear factor (erythroid-derived 2)-like factor 2/antioxidant responsive element (Nrf2/ARE) pathway is an important regulator of antioxidant status in cells. Antidiabetic drug glibenclamide (GLB) is reported as  NACHT, leucine-rich repeat, and pyrin domain domains-containing protein 3 (NLRP3) inflammasome inhibitor, whereas anti-multiple sclerosis drug dimethyl fumarate (DMF) is reported as an Nrf2/ARE pathway activator. Both GLB and DMF possess anti-inflammatory and antioxidant properties, therefore, the hypothesis was made to look into the alone as well as the combination potential of GLB, DMF, and GLB + DMF, against NAFLD in diabetic rats. This study was aimed to investigate (1) the involvement of NLRP3 inflammasome and Nrf2/ARE signaling in diabetes-associated NAFLD (2) the effect of GLB, DMF, GLB + DMF, and metformin (MET) interventions on NLRP3 inflammasome and Nrf2/ARE signaling in diabetes-associated NAFLD. The rats were injected with streptozotocin (STZ) 35 mg/kg and fed a high-fat diet (HFD) for 17 consecutive weeks to induce diabetic NAFLD. The oral treatment of GLB 0.5 mg/kg/day, DMF 25 mg/kg/day, their combination and MET 200 mg/kg/day, were provided from the 6th to the 17th week. Treatment with GLB, DMF, GLB + DMF, and MET significantly alleviated HFD + STZ-induced plasma glucose, triglycerides, cholesterol, %HbA1c, hepatic steatosis, NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain, CARD, caspase-1, interleukin-1ß (IL-1ß), nuclear factor-κB (NF-κB), Nrf2, superoxide dismutase 1, catalase, IGF 1, heme oxygenase 1, receptor for the advanced glycation end product (RAGE), and collagen-1 in diabetic rats. Further, a mechanistic molecular study employing other specific NLRP3 inhibitors and Nrf2 activators will significantly contribute to the development of novel therapy for fatty liver diseases.

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.

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.

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 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.

Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform.

PURPOSE: Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional ex vivo tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives. EXPERIMENTAL DESIGN: We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatially colocalized regions of the tumor. Independently, we evaluated clinical applicability of our findings in 19 patients with metastatic RCC (39 metastases) treated with first-line antiangiogenic drugs or checkpoint inhibitors. RESULTS: DCE-MRI identified tumor features associated with angiogenesis and inflammation, which differed within and across tumors, and likely contribute to the efficacy of antiangiogenic drugs and immunotherapies. Our vertically integrated analyses show that angiogenesis and inflammation frequently coexist and spatially anti-correlate in the same tumor. Furthermore, MRI contrast enhancement identifies phenotypes with better response to antiangiogenic therapy among patients with metastatic RCC. CONCLUSIONS: These findings have important implications for decision models based on biopsy samples and highlight the potential of more comprehensive imaging-based approaches.

Magnetic Resonance Imaging Radiomics Analyses for Prediction of High-Grade Histology and Necrosis in Clear Cell Renal Cell Carcinoma: Preliminary Experience.

INTRODUCTION: Percutaneous renal mass biopsy results can accurately diagnose clear cell renal cell carcinoma (ccRCC); however, their reliability to determine nuclear grade in larger, heterogeneous tumors is limited. We assessed the ability of radiomics analyses of magnetic resonance imaging (MRI) to predict high-grade (HG) histology in ccRCC. PATIENTS AND METHODS: Seventy patients with a renal mass underwent 3 T MRI before surgery between August 2012 and August 2017. Tumor length, first-order statistics, and Haralick texture features were calculated on T2-weighted and dynamic contrast-enhanced (DCE) MRI after manual tumor segmentation. After a variable clustering algorithm was applied, tumor length, washout, and all cluster features were evaluated univariably by receiver operating characteristic curves. Three logistic regression models were constructed to assess the predictability of HG ccRCC and then cross-validated. RESULTS: At univariate analysis, area under the curve values of length, and DCE texture cluster 1 and cluster 3 for diagnosis of HG ccRCC were 0.7 (95% confidence interval [CI], 0.58-0.82, false discovery rate P = .008), 0.72 (95% CI, 0.59-0.84, false discovery rate P = .004), and 0.75 (95% CI, 0.63-0.87, false discovery rate P = .0009), respectively. At multivariable analysis, area under the curve for model 1 (tumor length only), model 2 (length + DCE clusters 3 and 4), and model 3 (DCE cluster 1 and 3) for diagnosis of HG ccRCC were 0.67 (95% CI, 0.54-0.79), 0.82 (95% CI, 0.71-0.92), and 0.81 (95% CI, 0.70-0.91), respectively. CONCLUSION: Radiomics analysis of MRI images was superior to tumor size for the prediction of HG histology in ccRCC in our cohort.

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.

Zinc deficient diet increases the toxicity of bisphenol A in rat testis.

Zinc (Zn) plays an important role in maintaining the process of spermatogenesis and reproductive health. Bisphenol A (BPA), an endocrine disrupting chemical is known to be a reproductive toxicant in different animal models. The present study was designed to study the effect of two of the utmost determinative factors (Zn deficient condition and influence of toxicant BPA) on germ cell growth and overall male reproductive health in the testis, epididymis, and sperm using (a) biochemical, (b) antioxidant, (c) cellular damage, (d) apoptosis, and (e) protein expression measurements. Rats were divided into Control (normal feed and water), BPA (100 mg/kg/d), zinc deficient diet (ZDD; fed with ZDD), and BPA + ZDD for 8 weeks. Body and organ weights, sperm motility and counts, and sperm head morphology were evaluated. The histology of testes, epididymides, and prostate was investigated. Testicular deoxyribonucleic acid (DNA) damage was evaluated by Halo and Comet assay, apoptosis of sperm and testes were quantified by TUNEL assay. Serum protein electrophoretic patterns and testicular protein expressions such as Nrf-2, catalase, PCNA, and Keap1 were analyzed by Western blot analysis. The results showed that BPA significantly increased the testicular, epididymal, and prostrate toxicity in dietary Zn deficient condition due to testicular hypozincemia, hypogonadism, increased cellular and DNA damage, apoptosis, as well as perturbations in protein expression.

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.

Dimethyl fumarate protects thioacetamide-induced liver damage in rats: Studies on Nrf2, NLRP3, and NF-κB.

The present study was designed to investigate the hepatoprotective potential of dimethyl fumarate (DMF) against thioacetamide (TAA)-induced liver damage. Wistar rats were treated with DMF (12.5, 25, and 50 mg/kg/day, orally) and TAA (200 mg/kg intraperitoneally, every third day) for 6 consecutive weeks. TAA exposure significantly reduced body weight, increased liver weight and index, and intervention with DMF did not ameliorate these parameters. DMF treatment significantly restored TAA-induced increase in the levels of aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, total bilirubin, uric acid, malondialdehyde, reduced glutathione, and histopathological findings such as inflammatory cell infiltration, deposition of collagen, necrosis, and bridging fibrosis. DMF treatment significantly ameliorated TAA-induced hepatic stellate cell activation, increase in inflammatory cascade markers (NACHT, LRR, and PYD domains-containing protein 3; NLRP3, apoptosis-associated speck like protein containing a caspase recruitment domain; ASC, caspase-1, nuclear factor-kappa B; NF-κB, interleukin-6), fibrogenic makers (α-smooth muscle actin; ɑ-SMA, transforming growth factor; TGF-ß1, fibronectin, collagen 1) and antioxidant markers (nuclear factor (erythroid-derived 2)-like factor 2; Nrf2, superoxide dismutase-1; SOD-1, catalase). The present findings concluded that DMF protects against TAA-induced hepatic damage mediated through the downregulation of inflammatory cascades and upregulation of antioxidant status.

Effect of Echo Times on Prostate Cancer Detection on T2-Weighted Images.

PURPOSE: To compare the effect of different echo times (TE) on the detection of prostate cancer (PCa) on T2-weighted MR images. MATERIALS AND METHODS: This study recruited patients (n = 38) with histologically confirmed PCa who underwent preoperative 3T MRI. Three radiologists independently marked region on interests (ROIs) on suspected PCa lesions on T2-weighted images at different TEs: 90, 150, and 180 ms obtained with Turbo Spin Echo imaging protocol with multiple echoes. The ROIs were assigned a value 1-5 indicating the reviewer's confidence in accurately detecting PCa. These ROIs were compared to histologically confirmed PCa (n = 95) on whole mount prostatectomy sections to calculate sensitivity, positive predictive value (PPV), and confidence score. RESULTS: Two radiologists (R1, R2) showed significantly increased sensitivity for PCa detection at 180 ms TE compared to 90 ms (R1: 43.2, 50.5, 50.5%, R2: 45.3, 44.2, 53.7% at TE of 90, 150, 180 ms, respectively) (p = 0.048, 0.033 for R1 and R2). Sensitivity was similar for radiologist 3 (45.3%-46.3%) at different TE values (p = 0.953). No significant difference in the PPV (R1: 64.1%-70.6%, R2: 46.7%-56.0%, R3: 70.5%-81.5%) and the confidence score assigned (R1: 4.6-4.8, R2: 4.6-4.8 R3: 4.3-4.4) was found for either of the radiologists. CONCLUSION: Our results suggest improved detection of PCa with similar PPV and confidence scores when higher TE values are utilized for T2-weighted image acquisition.

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.

Impact of Bedside Combined Cardiopulmonary Ultrasound on Etiological Diagnosis and Treatment of Acute Respiratory Failure in Critically Ill Patients.

AIMS AND OBJECTIVES: To prospectively evaluate the impact of cardiopulmonary ultrasound (CPUS) on etiological diagnosis and treatment of critically ill acute respiratory failure (ARF) patients. DESIGN: This is a prospective observational study conducted in a general intensive care unit (ICU) of a tertiary care center in India. Patients over 18 years old with presence of one of the objective criteria of ARF. Patients either consecutively admitted for ARF to ICU or already admitted to ICU for a different reason but later developed ARF during their hospital stay. Written informed consent in local language was obtained from next of kin. INTERVENTIONS: All included patients underwent bedside CPUS including lung ultrasound (US) and transthoracic echocardiography plus targeted venous US by single investigator, blinded to clinical data. The US diagnosis of ARF etiology was shared with treating intensivist. Initial clinical diagnosis (ICD) and treatment plan (made before US) of each patient were compared with post-US clinical diagnosis and treatment plan. The changes in diagnosis and treatment up to 24 hours post-US were considered as impact of US. RESULTS: Mean age of 108 included patients was 45.7 ± 20.4 years (standard deviation). The ICD was correct in 67.5% (73/108) cases, whereas the combined CPUS yielded correct etiological diagnosis in 88% (95/108) cases. Among the 108 included patients, etiological diagnosis of ARF was altered after CPUS in 40 (37%) patients, which included "diagnosis changed" in 18 (17%) and "diagnosis added" in 22 (20%). Treatment plan was changed in 39 (36%) patients after CPUS, which included surgical interventions in 17 (16%), changes in medical therapy in 12 (11%), and changes in ventilation strategy in 4 (3.5%) patients. CONCLUSION: This study demonstrates that use of combined US approach as an initial test in ARF, improves diagnostic accuracy for identification of underlying etiology, and frequently changes clinical diagnosis and/or treatment. HOW TO CITE THIS ARTICLE: Barman B, Parihar A, Kohli N, Agarwal A, Dwivedi DK, Kumari G. Impact of Bedside Combined Cardiopulmonary Ultrasound on Etiological Diagnosis and Treatment of Acute Respiratory Failure in Critically Ill Patients. Indian J Crit Care Med 2020;24(11):1062-1070.

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.