Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma.

BACKGROUND: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients. METHODS: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models. RESULTS: CLPP expression was detected in primary and mUM patient samples. ONC201 and 212 decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis in human UM cell lines in vitro. ONC212 inhibited OXPHOS, increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. CONCLUSIONS: Imipridones are a promising strategy for further testing and development in mUM.

How can process safety and a risk management approach guide pandemic risk management?

The coronavirus disease (COVID-19) brought the world to a halt in March 2020. Various prediction and risk management approaches are being explored worldwide for decision making. This work adopts an advanced mechanistic model and utilizes tools for process safety to propose a framework for risk management for the current pandemic. A parameter tweaking and an artificial neural network-based parameter learning model have been developed for effective forecasting of the dynamic risk. Monte Carlo simulation was used to capture the randomness of the model parameters. A comparative analysis of the proposed methodologies has been carried out by using the susceptible, exposed, infected, quarantined, recovered, deceased (SEIQRD) model. A SEIQRD model was developed for four distinct locations: Italy, Germany, Ontario, and British Columbia. The learning-based approach resulted in better outcomes among the models tested in the present study. The layer of protection analysis is a useful framework to analyze the effect of different safety measures. This framework is used in this work to study the effect of non-pharmaceutical interventions on pandemic risk. The risk profiles suggest that a stage-wise releasing scenario is the most suitable approach with negligible resurgence. The case study provides valuable insights to practitioners in both the health sector and the process industries to implement advanced strategies for risk assessment and management. Both sectors can benefit from each other by using the mathematical models and the management tools used in each, and, more importantly, the lessons learned from crises.

High resolution melting curve analysis targeting the HBB gene mutational hot-spot offers a reliable screening approach for all common as well as most of the rare beta-globin gene mutations in Bangladesh.

BACKGROUND: Bangladesh lies in the global thalassemia belt, which has a defined mutational hot-spot in the beta-globin gene. The high carrier frequencies of beta-thalassemia trait and hemoglobin E-trait in Bangladesh necessitate a reliable DNA-based carrier screening approach that could supplement the use of hematological and electrophoretic indices to overcome the barriers of carrier screening. With this view in mind, the study aimed to establish a high resolution melting (HRM) curve-based rapid and reliable mutation screening method targeting the mutational hot-spot of South Asian and Southeast Asian countries that encompasses exon-1 (c.1 - c.92), intron-1 (c.92 + 1 - c.92 + 130) and a portion of exon-2 (c.93 - c.217) of the HBB gene which harbors more than 95% of mutant alleles responsible for beta-thalassemia in Bangladesh. RESULTS: Our HRM approach could successfully differentiate ten beta-globin gene mutations, namely c.79G > A, c.92 + 5G > C, c.126_129delCTTT, c.27_28insG, c.46delT, c.47G > A, c.92G > C, c.92 + 130G > C, c.126delC and c.135delC in heterozygous states from the wild type alleles, implying the significance of the approach for carrier screening as the first three of these mutations account for ~85% of total mutant alleles in Bangladesh. Moreover, different combinations of compound heterozygous mutations were found to generate melt curves that were distinct from the wild type alleles and from one another. Based on the findings, sixteen reference samples were run in parallel to 41 unknown specimens to perform direct genotyping of the beta-thalassemia specimens using HRM. The HRM-based genotyping of the unknown specimens showed 100% consistency with the sequencing result. CONCLUSIONS: Targeting the mutational hot-spot, the HRM approach could be successfully applied for screening of beta-thalassemia carriers in Bangladesh as well as in other countries of South Asia and Southeast Asia. The approach could be a useful supplement of hematological and electrophortic indices in order to avoid false positive and false negative results.

Fermented rice bran supplementation mitigates metabolic syndrome in stroke-prone spontaneously hypertensive rats.

BACKGROUND: Previous study shown that enzyme treated-rice bran effectively improved hypertension and glucose intolerance in stroke-prone spontaneously hypertensive rat (SHRSP). However, dual fermentation of rice bran's efficacy against metabolic syndrome in SHRSP is still unknown. METHODS: Fermented rice bran (FRB) was prepared by dual fermentation of rice bran using fungi and lactic acid bacteria. The effect of FRB on metabolic syndrome in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated by single and chronic supplementation. RESULTS: Dual fermentation of rice bran enriches the functional value of rice bran. Single-dose oral administration of FRB (2 g/kg body weight) reduced systolic blood pressure; however, chronic supplementation with 5 % FRB (4 weeks) significantly reduced both systolic and diastolic blood pressure. FRB supplementation improved leptin impairment and increased serum adiponectin levels and angiotensin-converting enzyme inhibitory activity. Furthermore, FRB supplementation improved glucose tolerance and insulin sensitivity as well as serum insulin levels. Lipid profiles were also improved by the regulation of 5' adenosine monophosphate-activated protein kinase activation. Moreover, supplementation with FRB reduced the expressions of hepatic transcription factors such as liver X receptor alpha, sterol regulatory element-binding protein 1c, and carbohydrate-responsive element-binding protein alpha, as well as their target genes. In conclusion, dietary supplementation with FRB may lower hypertension and alleviate metabolic syndrome. CONCLUSION: Metabolic syndrome was better alleviated with FRB supplementation. We therefore suggest FRB as an alternative medicine to reduce the risks of lifestyle-related diseases.

Functional Evaluation of Fermented Rice Bran and Extracted Rice Bran Oil Addressing for Human Health Benefit.

Rice bran (RB) and rice bran oil (RBO) are exploring as prominent food component worldwide and their compositional variation is being varied among the world due to regional and production process. In this study, Fermented Rice Bran (FRB) was produced by employing edible gram-positive bacteria (Lactobacillus acidophilus, Lactobacillus bulgaricus and Bifidobacterium bifidum) at 125×10 5 spore g -1 of rice bran, and investigated to evaluate nutritional quality. The Crude Rice Bran Oil (CRBO) was extracted from RB and its quality was also investigated compared to market available rice bran oil (MRBO) in Bangladesh. We found that fermentation of rice bran with lactic acid bacteria increased total proteins (29.52%), fat (5.38%), ash (48.47%), crude fiber (38.96%), and moisture (61.04%) and reduced the carbohydrate content (36.61%). We also found that essential amino acids (Threonine, valine, leucine, lysine, histidine and phenylalanine) and non-essential amino acids (alanine, aspartate, glycine, glutamine, serine and tyrosine) were increased in FRB except methionine and proline. Moreover, total phenolic content, tannin content, flavonoid content and antioxidant activity were increased in FRB. The RBO analysis showed that γ-oryzanol content (10.00 mg/g) were found in CRBO compared to MRBO (ranging 7.40 to 12.70 mg/g) and Vitamin-E content 0.20% were found higher in CRBO compared to MRBO (ranging 0.097 to 0.12%). The total saturated (25.16%) and total unsaturated fatty acids (74.44%) were found in CRBO whereas MRBO contained total saturated (22.08 to 24.13%) and total unsaturated fatty acids (71.91 to 83.29%) respectively. The physiochemical parameters (density, refractive index, iodine value) were found satisfactory in all sample except acid value and peroxide value higher in CRBO. Heavy metal concentration was found within an acceptable range in both CRBO and MRBO. Thus FRB and RBO could be value added food supplement for human health.

In silico and in vivo experiment of soymilk peptide (tetrapeptide - FFYY) for the treatment of hypertension.

Enzyme-Treated Soymilk (ETS) was produced from Commercial Soymilk (CSM) with the treatment of proteinase PROTIN SD-NY10 (Bacillus amyloliquefaciens). Previously, we have isolated novel peptides from ETS but data related to isolated-peptides are scant. In this study, bio-informatics and in vivo analysis of isolated-peptides showed strong binding affinity to the active site of the Angiotensin Converting Enzyme (ACE). Among four peptides, tetrapeptide Phe-Phe-Tyr-Tyr (FFYY) showed strong binding affinity and inhibitory activity to the ACE-enzyme (binding affinity -9.5 Kcal/mol and inhibitory concentration of 1.9 µM respectively) as well as showed less toxicity compared to other peptides. The animal experiment revealed that single oral dose of FFYY (80 µg/kg body weight/day) effectively ameliorates the systolic, diastolic and mean blood pressure in the spontaneously hypertensive rat (SHR) model. Chronic oral administration of FFYY (80 µg/kg body weight/day for 3 weeks) reduced the systolic blood pressure elevation and ACE activity without any adverse side effects on the physiological and biological parameters of SHR. In conclusion, both in silico and in vivo experiments of soymilk-isolated FFYY peptide showed a promising option as a potential alternative for hypertension treatment without adverse side effects on SHR.

Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma.

Purpose: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, CLPP activators which reduce OXPHOS indirectly and have demonstrated safety in patients. Experimental Design: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201, ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic effects in vivo in UM liver metastasis models. Results: CLPP expression was confirmed in primary and mUM patient samples. ONC201/212 treatment of UM cell lines in vitro decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis. ONC212 increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. Conclusion: Imipridones are a promising strategy for further testing and development in mUM.

Early Initiation of Breastfeeding (EIBF) and Its Associated Factors Among Mothers With Infants Aged 0 to 6 Months in Jashore District, Bangladesh: A Cross-Sectional Study.

OBJECTIVE: Early initiation of breastfeeding (EIBF) is one of the most successful interventions for minimizing newborn morbidity and death. According to the database (Bangladesh Demographic Health Survey 2014), only around half of babies begin breastfeeding during the first hour of life in Bangladesh. The goal of this study was to determine the prevalence of EIBF in the Jashore area while also investigating its associated factors among mothers of infants aged 0 to 6 months in order to better understand the variables that impacted breastfeeding initiation. METHOD: A cross-sectional study was conducted in the maternity wards of the 3 busiest hospitals in the Jashore district of Bangladesh from May to July 2019. Using random sampling, a total of 423 mother-infant pairs were chosen. Pearson chi-square test and bivariable and multivariable logistic regression statistical analysis were used to identify factors linked to EIBF. RESULTS: The prevalence of EIBF was 46.3% (196/423). Mothers who had skin-to-skin contact after delivery (adjusted odds ratio [AOR], 2.25; 95% confidential interval [CI], 1.40-3.59), who did not deliver prelacteal food (AOR, 3.68; 95% CI, 1.65-8.21), and who provided colostrum (AOR, 5.89; 95% CI, 1.62-21.49) were more likely to begin breastfeeding within 1 hour than were their counterparts. CONCLUSIONS: EIBF was found to be strongly linked with skin-to-skin contact after delivery, avoidance of prelacteal feeding, and colostrum feeding practice. As a result, we strongly urge public health officials and health care practitioners to encourage these feeding behaviors in order to increase EIBF.

Infrared predissociation of ternary cluster cations: the solvent effects on the branching ratio.

Infrared (IR) predissociation of hydrogen-bonded ternary cluster ions such as aniline-water-ethanol (AWE(+)), aniline-water-isopropanol (AWP(+)), aniline-methanol-ethanol (AME(+)), aniline-water-pyrrole (AWPy(+)), and aniline-water-benzene (AWB(+)) was examined in the region of 2700-4000 cm(-1) to explore the key factors which determine the branching ratios in the concurrent unimolecular dissociation. The smaller solvent molecule was predominantly ejected when the binding energies of the two were not too different. On the other hand, when they were far off, the binding energy also acted significantly on the branching ratio. Besides, mode-selective IR predissociation was observed, while the selectivity was not quite distinct. The IR predissociation of ternary cluster ions bound via hydrogen bonding is considered to occur on a time scale much faster than intramolecular vibrational energy redistribution, which was proved by a statistical transition state theory.

Polymer Composites with Quantum Dots as Potential Electrode Materials for Supercapacitors Application: A Review.

Owing to the nanometer size range, Quantum Dots (QDs) have exhibited unique physical and chemical properties which are favourable for different applications. Especially, due to their quantum confinement effect, excellent optoelectronic characteristics is been observed. This considerable progress has not only uplifted the singular usage of QDs, but also encouraged to prepare various hybrid materials to achieve superior efficiency by eliminating certain shortcomings. Such issues can be overcome by compositing QDs with polymers. Via employing polymer composite with QDs (PQDs) for supercapacitor applications, adequate conductivity, stability, excellent energy density, and better specific capacitance is been achieved which we have elaborately discussed in this review. Researchers have already explored various types of polymer nanocomposite with different QDs such as carbonaceous QDs, transition metal oxide/sulphide QDs etc. as electrode material for supercapacitor application. Synthesis, application outcome, benefits, and drawbacks of these are explained to portray a better understanding. From the existing studies it is clearly confirmed that with using PQDs electrical conductivity, electrochemical reactivity, and the charge accumulation on the surface have prominently been improved which effected the fabricated supercapacitor device performance. More comprehensive fundamentals and observations are explained in the current review which indicates their promising scopes in upcoming times.

Pandemic risk management using engineering safety principles.

The containment of infectious diseases is challenging due to complex transmutation in the biological system, intricate global interactions, intense mobility, and multiple transmission modes. An emergent disease has the potential to turn into a pandemic impacting millions of people with loss of life, mental health, and severe economic impairment. Multifarious approaches to risk management have been explored for combating an epidemic spread. This work presents the implementation of engineering safety principles to pandemic risk management. We have assessed the pandemic risk using Paté-Cornell's six levels of uncertainty. The susceptible, exposed, infected, quarantined, recovered, deceased (SEIQRD), an advanced mechanistic model, along with the Monte Carlo simulation, has been used to estimate the fatality risk. The risk minimization strategies have been categorized into hierarchical safety measures. We have developed an event tree model of pandemic risk management for distinct risk-reducing strategies realized due to natural evolution, government interventions, societal responses, and individual practices. The roles of distinct interventions have also been investigated for an infected individual's survivability with the existing healthcare facilities. We have studied the Corona Virus Disease of 2019 (COVID-19) for pandemic risk management using the proposed framework. The results highlight effectiveness of the proposed strategies in containing a pandemic.

Functional Profiling and Future Research Direction of Rice Bran Oil in Bangladesh.

Rice bran oil (RBO) has been demonstrated to affect complex malfunctioned conditions such as oxidative stress, hyperlipidemia, hyperglycemia, hypertension, inflammation, abnormal cell growth (cancer), ulceration, immune and cognitive modulation. This unique effect of RBO is due to the presence of well-balanced fatty acid composition and several bioactive compounds, γ- oryzanol (cycloartenyl ferulate, 24-methylenecycloartanyl ferulate, campesterol ferulate, and ß-sitosteryl ferulate), vitamin E (tocopherol and tocotrienol), phytosterols (ß-sitosterol, campesterol and stigmasterol) and other nutrients. The RBO composition of bioactive compounds varied geographically, thus the clear-cut mechanisms of action on complex disease cascades are still required. This review article summarized the RBO compositional profiling and compared it with other edible oils. This article also summarized Bangladesh RBO profiling and their proposed mechanism of action as well as the first line of defense in the prevention, management, and control of complex disease conditions. This review indicates how Bangladesh RBO increase their opportunity to be functional food for 21st century's ailment.

Role of pre-operative red cell distribution width estimation in the prediction of in-hospital mortality after off-pump coronary artery bypass grafting.

BACKGROUND: Red cell distribution width (RDW) level is routinely provided in a simple and inexpensive complete blood count report. However, RDW is sometimes overlooked. Recently a higher RDW level is found associated with postoperative mortality after off-pump coronary artery bypass. Many risk-prediction tools are available, like the European System for Cardiac Operative Risk Evaluation, Society of Thoracic Surgeons score, etc. but all need improvement for better prediction. So, a new risk-factor should be discovered which is simple enough for clinical use and cost-effective, and improves the risk assessment tools that help to predict and avoid preventable mortality following cardiac surgery. METHODS: The prospective study was conducted, taking a total of 150 patients of coronary artery disease who underwent elective isolated off-pump coronary artery bypass. The study population was grouped according to their preoperative RDW level as Group A (RDW ≤ 14%), Group B (RDW 14-16%), and Group C (RDW ≥ 16%). The receiver operating characteristic (ROC) curve was constructed and multivariate regression analysis was done to see the predictive value of RDW for in-hospital mortality. RESULTS: The mortality rate was 2.7%, N = 150. ROC curve revealed Area Under the Curve 0.841 and p = 0.020 that indicates the RDW as the reliable predictor for in-hospital mortality. Multivariate regression analysis showed the RDW to be the only variable independently predicting in-hospital mortality after off-pump coronary artery bypass among possible haematological predictors. (OR 1.838, 95% CI 1.061-3.186, p = 0.030). CONCLUSION: Preoperative raised RDW level is a novel predictor of in-hospital mortality after off-pump coronary artery bypass. Further studies should be done to determine the associated mechanism.

Annexin A7 Regulates Endometrial Receptivity.

A limited window of receptivity is a prerequisite of reproductive success. Indispensable receptivity genes include cyclooxygenase 2 (COX2), an enzyme accomplishing formation of prostaglandin E2 (PGE2). A powerful regulator of PGE2 formation is Annexin A7 (ANXA7). The present study thus explored whether ANXA7 impacts on implantation and fertility. Here we show that ANXA7 is expressed in endometrial tissue and increases upon decidual transformation of human endometrial stromal cells (HESCs) in a time-dependent manner. Silencing ANXA7 significantly decreased the expression of PRL and IGFBP1, canonical decidual marker genes, but enhances COX2 and PGE2 levels. Genetic knockout of AnxA7 in mice significantly increases the number of implantation sites and litter sizes. Further, analysis of human endometrial biopsies showed that ANXA7 transcript and protein levels are decreased during the midluteal window of implantation in women suffering from recurrent pregnancy loss (RPL) when compared to subfertile patients. Taken together, the data indicate that ANXA7 has a conserved role in regulating endometrial receptivity and implantation.

Resveratrol and its Related Polyphenols Contribute to the Maintenance of Genome Stability.

Genomic destabilisation is associated with the induction of mutations, including those in cancer-driver genes, and subsequent clonal evolution of cells with abrogated defence systems. Such mutations are not induced when genome stability is maintained; however, the mechanisms involved in genome stability maintenance remain elusive. Here, resveratrol (and related polyphenols) is shown to enhance genome stability in mouse embryonic fibroblasts, ultimately protecting the cells against the induction of mutations in the ARF/p53 pathway. Replication stress-associated DNA double-strand breaks (DSBs) that accumulated with genomic destabilisation were effectively reduced by resveratrol treatment. In addition, resveratrol transiently stabilised the expression of histone H2AX, which is involved in DSB repair. Similar effects on the maintenance of genome stability were observed for related polyphenols. Accordingly, we propose that polyphenol consumption can contribute to the suppression of cancers that develop with genomic instability, as well as lifespan extension.

Gut Bacterial Metabolite Urolithin A Decreases Actin Polymerization and Migration in Cancer Cells.

SCOPE: Urolithin A (UA) is a gut-derived bacterial metabolite from ellagic acid found in pomegranates, berries, and nuts can downregulate cell proliferation and migration. Cell proliferation and cell motility require actin reorganization, which is under control of ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1). The present study explores whether UA can modify actin cytoskeleton in cancer cells. METHODS: The effect of UA on globular over filamentous actin ratio is determined utilizing Western blotting, immunofluorescence, and flow cytometry. Rac1 and PAK1 levels are measured by quantitative RT-PCR and immunoblotting. As a result, a 24 h treatment with UA (20 µm) significantly decreased Rac1 and PAK1 transcript levels and activity, depolymerized actin and wound healing. The effect of UA on actin polymerization is mimicked by pharmacological inhibition of Rac1 and PAK1. The effect is also mirrored by knock down using siRNA. CONCLUSION: UA leads to disruption of Rac1 and Pak1 activity with subsequent actin depolymerization and migration. Thus, use of dietary UA in cancer prevention or as adjuvant therapy is promising.

LEFTY2/endometrial bleeding-associated factor up-regulates Na+ Coupled Glucose Transporter SGLT1 expression and Glycogen Accumulation in Endometrial Cancer Cells.

LEFTY2 (endometrial bleeding associated factor; EBAF or LEFTYA), a cytokine released shortly before menstrual bleeding, is a negative regulator of cell proliferation and tumour growth. LEFTY2 down-regulates Na+/H+ exchanger activity with subsequent inhibition of glycolytic flux and lactate production in endometrial cancer cells. Glucose can be utilized not only for glycolysis but also for glycogen formation. Both glycolysis and glycogen formation require cellular glucose uptake which could be accomplished by the Na+ coupled glucose transporter-1 (SGLT1; SLC5A1). The present study therefore explored whether LEFTY2 modifies endometrial SGLT1 expression and activity as well as glycogen formation. Ishikawa and HEC1a cells were exposed to LEFTY2, SGLT1 and glycogen synthase (GYS1) transcript levels determined by qRT-PCR. SGLT1, GYS1 and phospho-GYS1 protein abundance was quantified by western blotting, cellular glucose uptake from 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) uptake, and cellular glycogen content utilizing an enzymatic assay and subsequent colorimetry. As a result, a 48-hour treatment with LEFTY2 significantly increased SGLT1 and GYS1 transcript levels as well as SGLT1 and GYS1 protein abundance in both Ishikawa and HEC1a cells. 2-NBDG uptake and cellular glycogen content were upregulated significantly in Ishikawa (type 1) but not in type 2 endometrial HEC1a cells, although there was a tendency of increased 2-NBDG uptake. Further, none of the effects were seen in human benign endometrial cells (HESCs). Interestingly, in both Ishikawa and HEC1a cells, a co-treatment with TGF-ß reduced SGLT1, GYS and phospho-GYS protein levels, and thus reduced glycogen levels and again HEC1a cells had no significant change. In conclusion, LEFTY2 up-regulates expression and activity of the Na+ coupled glucose transporter SGLT1 and glycogen synthase GYS1 in a cell line specific manner. We further show the treatment with LEFTY2 fosters cellular glucose uptake and glycogen formation and TGF-ß can negate this effect in endometrial cancer cells.

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs).

The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson's disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1-/-) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1-/- mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1-/- mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.

LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca2+ entry.

Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-ß family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes. KEY MESSAGES: •Endometrial receptivity is negatively regulated by LEFTY2. •LEFTY2 inhibits the expression of key murine receptivity genes, including Cox2, Bmp2 and Wnt4, and blocks embryo implantation. •LEFTY2 downregulates the expression of Orai1 and inhibits SOCE. •LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, and YM-58483 inhibit COX2, BMP2, and WNT4 expression in endometrial cells. •Targeting LEFTY2 and Orai1 may represent a novel approach for treating unexplained infertility.

Dietary Supplementation of Fermented Rice Bran Effectively Alleviates Dextran Sodium Sulfate-Induced Colitis in Mice.

Rice bran (RB) is a major by-product of rice polishing and a rich source of bioactive compounds. Here, we investigated the anti-colitis effect of diet supplementation with fermented rice bran (FRB) in a murine model of ulcerative colitis. FRB was prepared by dual fermentation of RB using fungi and lactic acid bacteria. Colitis was induced in C57Bl/6N male mice (n = 8/group) by dextran sodium sulfate (DSS). Body weight change, disease activity index (DAI), histopathology score, tissue myeloperoxidase (MPO) activity, cytokine and chemokine transcript levels, and the production of short-chain fatty acids (SCFAs) and mucin in the colonic tissue were monitored. Based on histopathology scores, DSS induced severe mucosal inflammation, with an increased loss of crypts, and inflammatory cell infiltration in the control and RB groups, but not in the FRB group. MPO activity, thiobarbituric acid-reactive substance levels, and pro-inflammatory cytokine transcript (Tnf-α, Il-1ß, Il-6, and Il-17) levels were significantly higher in the control and RB groups than in the FRB group. Thus, dietary FRB attenuated intestinal inflammation owing to elevated SCFAs and tryptamine production, which might regulate tight junction barrier integrity and intestinal homeostasis. These results suggest that FRB could comprise an effective potential preventive agent for ulcerative colitis.