Influence of °Brix/Acid, and flow rate of pineapple juice and electric field strength on the performance of continuous ohmic heating system.

A lab-scale continuous ohmic heating (COH) system was developed, and its performance was studied for pineapple juice heating as a model sample. The effect of independent parameters [°Brix/Acid (unstandardized, 18, 22, 26) and flow rate (80-120 mL/min) of juice and electric field strength (EFS: 25-45 V/cm)] were analysed for responses viz. come-up-time, heating rate (HR) and system performance coefficient (SPC). The full factorial experimental design was used for this study. The results showed that with an increase in °Brix/Acid, the % acidity and electrical conductivity decreased significantly (p < 0.05); thus, the come-up-time to reach 90 °C increased significantly. The HR was significantly (p < 0.05) influenced by °Brix/Acid and EFS but less so by flow rates at higher EFS. The SPC was more than 0.90 and reduced significantly (p < 0.05) with an increase in °Brix/Acid and flow rate. The HR was modeled using a feed-forward back-propagation artificial neural network (ANN) with the best topology of 3, 5, and 1 neurons in the input (independent), hidden, and output (response) layers, respectively. The model performed efficiently, which is evident from the high R2 (0.998) and low RMSE (1.255). Thus, the COH, with its high efficiency and HR, can effectively be used to process fruit juice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-024-05961-x.

Effect of Cold- and Hot-Break Heat Treatments on the Physicochemical Characteristics of Currant Tomato (Solanum pimpinellifolium) Pulp and Paste.

Currant tomato (Solanum pimpinellifolium), an underutilized wild species of modern tomato, was investigated to determine the physicochemical properties and understand the effect of cold- and hot-break heat treatments on physicochemical characteristics. Moreover, a new Arrhenius-type equation was used to model the temperature-dependent viscosity of currant tomato pulp and paste. The currant tomato's porosity, surface area, and lycopene content were 40.96 ± 0.84%, 663.86 ± 65.09 mm2, and 9.79 ± 1.88 mg/100 g, respectively. Cold- and hot-break heat treatments had a significant (p < 0.05) effect on tomato pulp and paste color change (0.09 to 0.26; 0.19 to 1.96), viscosity (0.06 to 0.02 Pa.s; 0.85 to 0.37 Pa.s), and lycopene content (9.70 to 9.07 mg/100 g; 9.60 to 9.37 mg/100 g), respectively. An Arrhenius-type equation described the temperature-dependent viscosity of currant tomato pulp and paste with activation energy (Ea) ranging from 7.54 to 11.72 kJ/mol and 8.62 to 8.97 kJ/mol, respectively. Principal component analysis (PCA) revealed a total of variance 99.93% in tomato pulp and paste as affected by the cold- and hot-break heat treatments. Overall, the findings may provide knowledge for design graders and process optimization to develop currant tomato-based products.

Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19).

Amino acid restriction by inhibition of neutral amino acid transporter, B0AT1 (SLC6A19) activity has been recently shown to improve glyceamic control by upregulating glucagon like peptide (GLP1) and fibroblast growth factor (FGF21) in mice. Hence, pharmacological inhibition of B0AT1 is expected to treat type-2 diabetes and related disorder. In this study, rationally designed trifluoromethyl sulfonyl derivatives were identified as novel, potent and orally bioavailable B0AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC50: 0.035 µM) B0AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model.

Sono-hydro priming process (ultrasound modulated hydration): Modelling hydration kinetic during paddy germination.

Application of ultrasound technology in modulating the hydration process during paddy germination was analyzed in this study. The effect of hydropriming (24 h) and sono-hydro priming (ultrasound priming, 12 h) on the hydration behaviour of paddies was determined at different temperatures (25-40 °C). Ultrasound pulse was applied for 10 min after every one hour for sono-hydro priming. Germination potential and microstructure analysis of treated paddies were also performed. Downward concave curve observed in hydration process of paddies indicates initial high-water absorptionthrough diffusion process. Sono-hydro priming process showed higher hydration rate compared to hydropriming. The changes in moisture content during hydration processes fitted to theoretical (Fick's model) and empirical model (Peleg model) exhibited high regression coefficient (R2 > 0.95) indicating suitability for predicting hydration behaviour in both paddies for germination. The Peleg model adequately predicted saturation moisture content and sono-hydro priming efficiently increased the water absorption rate. Effective moisture diffusivity determined from Fick's diffusion model increased for sono-hydro priming. Activation energy estimated from effective moisture diffusivity required in sono-hydro priming (Ea = 20.32 and 19.19 KJ/mol respectively) for pigmented rice and non-pigmented rice was lower than hydropriming (Ea = 27.11 and 32.15 KJ/mol respectively). Both hydration processes were endothermic and non-spontaneous inferred from thermodynamic properties. Sono-hydro priming exhibited < 95% germination potential with shorter soaking time (12 h) owing to the high mass transfer rate. SEM micrograph revealed water absorption through various micro-cavities during sono-hydro priming. Thus, sono-hydro priming potentially reduced the soaking process (approximately 50%) with higher germination rate in paddies beneficial for commercial malting of grains.

IgG4-related pancreatitis: an uncommon cause of hyperglycaemia.

Hyperglycaemia is one of the most common metabolic disturbances encountered in clinical practice, with an important differential diagnosis. We report a case of a 72-year-old woman referred to diabetes services with rapidly increasing blood glucose and weight loss despite oral hypoglycaemic therapy. She reported mild upper abdominal discomfort and liver function tests were deranged, prompting further investigation. Abdominal imaging demonstrated a diffusely enlarged pancreas and subsequent investigations noted a markedly raised serum IgG4. She was diagnosed with IgG4-related pancreatitis and swiftly responded to steroid therapy. Secondary causes of diabetes should be considered in people with atypical presentation such as weight loss or rapid progression to insulin use. While IgG4-related disease is rare, its varied clinical presentation as a result of its multiorgan involvement requires a high index of suspicion. This case highlights the importance of a detailed diagnostic work-up and describes an unusual clinical presentation of this increasingly recognised multisystem disease.

The Ussing chamber system for measuring intestinal permeability in health and disease.

BACKGROUND: The relationship between intestinal epithelial integrity and the development of intestinal disease is of increasing interest. A reduction in mucosal integrity has been associated with ulcerative colitis, Crohn's disease and potentially could have links with colorectal cancer development. The Ussing chamber system can be utilised as a valuable tool for measuring gut integrity. Here we describe step-by-step methodology required to measure intestinal permeability of both mouse and human colonic tissue samples ex vivo, using the latest equipment and software. This system can be modified to accommodate other tissues. METHODS: An Ussing chamber was constructed and adapted to support both mouse and human tissue to measure intestinal permeability, using paracellular flux and electrical measurements. Two mouse models of intestinal inflammation (dextran sodium sulphate treatment and T regulatory cell depletion using C57BL/6-FoxP3DTR mice) were used to validate the system along with human colonic biopsy samples. RESULTS: Distinct regional differences in permeability were consistently identified within mouse and healthy human colon. In particular, mice showed increased permeability in the mid colonic region. In humans the left colon is more permeable than the right. Furthermore, inflammatory conditions induced chemically or due to autoimmunity reduced intestinal integrity, validating the use of the system. CONCLUSIONS: The Ussing chamber has been used for many years to measure barrier function. However, a clear and informative methods paper describing the setup of modern equipment and step-by-step procedure to measure mouse and human intestinal permeability isn't available. The Ussing chamber system methodology we describe provides such detail to guide investigation of gut integrity.

Factors Associated With Outcomes of Patients With Primary Sclerosing Cholangitis and Development and Validation of a Risk Scoring System.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.

Identification and preclinical characterization of a novel and potent poly (ADP-ribose) polymerase (PARP) inhibitor ZYTP1.

PURPOSE: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in the detection and repair of DNA damage. Studies have shown that inhibition of PARP and Tankyrase (TNKS) has significant antitumor effect in several types of cancers including BRCA-negative breast cancers. METHODS: Identification of ZYTP1, a novel PARP inhibitor, through a battery of in vitro assays and in vivo studies. PARP and TNKS inhibitory activity of ZYTP1 was assessed in cell-free kinase assay. In vitro cell killing potency of ZYTP1 was tested in a panel of cell lines including BRCA-negative cells. ZYTP1 was also tested in xenograft models in combination with temozolomide (TMZ). The pharmacokinetic profile of ZYTP1 was determined in rodent and non-rodent preclinical species. Safety of ZYTP1 was assessed in Wistar rats and Beagle dogs upon repeated dosing. RESULTS: ZYTP1 inhibited PARP1, PARP2, Tankyrase-1 and Tankyrase-2 with IC50 of 5.4, 0.7, 133.3 and 289.8 nM, respectively, and additionally trapped PARP1 onto damaged DNA. It also potentiated MMS-mediated killing of different cancer cell lines. Compound demonstrated good Caco-2 cell permeability. The oral bioavailability of ZYTP1 in mice, rats and dogs ranged between 40 and 79% and demonstrated efficacy in colon cancer xenograft model at a dose of 1-10 mg/kg in combination with TMZ. In a 28-day repeat dosing, oral toxicity study in rats, it was found to show > 10× safety margin. CONCLUSIONS: ZYTP1 is a novel PARP inhibitor that showed potential for development as a treatment for various solid tumors.

Predicting enzymatic starch hydrolysis mechanism during paddy malting by vibrational spectroscopy and multivariate calibration analysis.

Vibrational spectroscopic techniques were employed to predict the mechanism of starch hydrolysis based on structural changes during germination of paddy. The proposed mechanism for starch hydrolysis dealt with the synthesis of amylase at the onset of germination, depicting an increased intensity of spectral bands at amide I, II and III regions. The process commenced with the enzyme actions on skeletal mode of pyranose ring structure of glucose units followed by cleavage of the glycosidic linkage by the process of multiple and multi-chain attack resulting in decrease of the bands (400-900 cm-1). The increased intensity of the bands (1200-1500 cm-1) indicated the process of starch hydrolysis and formation of d-glucose. Multivariate calibration analysis (PCA and PLS) was employed to correlate Raman spectral data with biochemical changes during germination and to develop a calibration model. The model showed a high prediction ability with low root mean square error of prediction (RMSEP) (0.043-0.568).

Association between progressive hepatic morphology changes on serial MR imaging and clinical outcome in primary sclerosing cholangitis.

INTRODUCTION: Hepatic morphology changes are well described in Primary Sclerosing Cholangitis and characterised by a combination of atrophy and hypertrophy changes. This study investigates the relationship between progression of these changes over time and clinical outcome in patients with PSC. METHODS: Fifty-three patients with PSC (mean age 44, 28 males and 25 females) who underwent serial MRI liver studies at least one year apart were identified. The first and the last MRI studies were selected for the retrospective analysis. Three radiologists reviewed and compared both studies for changes in hepatic morphology, specifically atrophy and/or hypertrophy. The imaging findings were correlated with adverse clinical outcomes defined as death or liver transplantation and with serum bilirubin. RESULTS: There was a mean interval of 60 months between MRI examinations and a mean clinical follow-up period thereafter of 22 months. Thirty-three (62.3%) patients had stable hepatic morphology, whilst 20 (37.7%) patients showed hepatic morphology changes (atrophy: 13 patients, 24%; hypertrophy: 16 patients, 30%). Eleven patients (21%) died or underwent liver transplantation. There was a significant correlation between interval hepatic atrophy and adverse clinical outcomes (P = 0.001). Significant correlations were found between increasing serum bilirubin level and interval hepatic atrophy, hepatic hypertrophy and combined changes (P = 0.025, P = 0.022, P = 0.027, respectively). CONCLUSION: Hepatic morphology changes over time in patients with PSC are heterogeneous with some patients developing atrophy and/or hypertrophy whilst other patients remain stable. In this retrospective study, progressive hepatic atrophy showed significant association with adverse clinical outcome defined by either death or liver transplantation.

Influence of germination conditions on malting potential of low and normal amylose paddy and changes in enzymatic activity and physico chemical properties.

Malting potential of two rice cultivar i.e. low (12.5%) (LR) and normal (20.2%) amylose paddy (NR) were evaluated under different germination conditions (25-40°C for 120h). Based on malting potential, 30 and 35°C germination temperatures were found suitable. Enzymes (amylolytic and α-amylase) activity increased at both temperatures for LR and NR whereas NR exhibited higher activity. NR malted rice showed higher starch degradation (64 and 74 times) when compared to LR (58 and 62 times) at 30 and 35°C respectively leading to formation of reducing sugar and lowering of viscosity. During germination of LR and NR significant morphological and structural changes were observed as evident from pin-holes and eroded surface in micrographs, decreased % crystallinity and FTIR peaks. Outcome of present study concluded that the amylose amylopectin ratio played an important role during germination and NR paddy was found more suitable for malting at 30 and 35°C.

Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice.

Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

Hepatic changes in systemic infection.

Liver is an integral part of the host-defense mechanism and facilitates clearance of pathogenic organisms in systemic infection by modulating the immunological response. It undergoes several cellular and molecular changes resulting in the release of pro-inflammatory cytokines, which regulate various metabolic and immunological signalling pathways. Some of these changes are pathogen-specific and essential in determining the host response to systemic infection. However, alterations in the immunological homeostasis can adversely affect the liver and lead to hepatic dysfunction. This article focuses on these molecular and immunological changes that occur within the liver in response to extra-hepatic systemic infection and its consequences.

Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC. METHODS: We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls. RESULTS: The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10⁻6, OR(A vs G) = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10⁻4, OR(A vs G) = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10⁻4, OR(A vs T) = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P (combined) = 3.8 × 10⁻¹²) and rs4147359 (10p15 (IL2RA), P (combined) = 1.5 × 10⁻8). CONCLUSION: We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association.

Hair growth stimulator property of thienyl substituted pyrazole carboxamide derivatives as a CB1 receptor antagonist with in vivo antiobesity effect.

A few thienyl substituted pyrazole derivatives were synthesized to aid in the characterization of the cannabinoid receptor antagonist and also to serve as potentially useful antiobesity agent. Structural requirements for selective CB1 receptor antagonistic activity of 5-thienyl pyrazole derivatives included the structural similarity with potent, specific antagonist rimonabant 1. Compound 3 has been identified as a hair growth stimulator and an antiobesity agent in animal models.

Facile synthesis, ex-vivo and in vitro screening of 3-sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716) a potent CB1 receptor antagonist.

Facile synthesis of biaryl pyrazole sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716, 1) and an investigation of the effect of replacement of the -CO group in the compound 1 by the -SO(2) group in the aminopiperidine region is reported. Primary ex-vivo pharmacological testing and in vitro screening of sulfonamide derivative 2 showed the loss of CB1 receptor antagonism.

Bioisosteric replacement of dihydropyrazole of 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) a potent CB1 receptor antagonist by imidazole and oxazole.

Design, synthesis and conformational analysis of few imidazole and oxazole as bioisosters of 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) 2 is reported. Computer assisted conformational analysis gave a direct clue for the loss of CB1 antagonistic activity of the ligands without a fine docking simulation for the homology model.