Anticoagulation in Atrial Fibrillation Associated With Cardiac Amyloidosis: A Narrative Review.

Cardiac amyloidosis (CA) involves the abnormal deposition and accumulation of amyloid proteins in the heart muscle. A hallmark of disease progression is declining heart function, which can lead to structural irregularities, arrhythmias, and ultimately heart failure. Atrial fibrillation (AF) is the most common arrhythmia that presents in CA patients, and this arrhythmia is significant because it can moderately increase the risk of patients developing intracardiac thrombi, thereby putting them at risk for thromboembolic events. The management of this complication entails the use of anticoagulants like vitamin K antagonists and direct oral anticoagulants to reduce the risk of thrombus formation. This article seeks to review AF in CA and the use of anticoagulation therapy for the management and reduction of thromboembolic risk. The major conclusions of this review are centered around the need for safe administration of anticoagulant therapy to CA patients, regardless of their CHA2DS2-VASc risk score. This review highlights the importance of taking a multidisciplinary or collaborative approach to CA treatment to ensure that all aspects of this multifaceted disease can be properly managed while minimizing adverse events like bleeding risk and drug-drug interactions.

A Systematic Review of the Efficacy and Safety of Mulberry Formulations for Chemotherapy- and/or Radiotherapy-Induced Oral Mucositis.

Oral mucositis (OM) is one of the common side effects of radiotherapy and chemotherapy. It is an extremely painful condition characterized by erythema, edema, and ulceration of the oral mucosa. Many plant-based and chemical formulations are used to prevent OM. The aim of the study is to evaluate the efficacy and safety of different black mulberry formulations in chemotherapy and/or radiotherapy-induced OM. A systematic search was performed using PubMed, Excerpta Medica database (Embase), the Cochrane Library, and Web of Science databases for articles published until March 2023. We have included studies conducted on people undergoing chemotherapy and/or radiotherapy and compared the effect of any mulberry formulation with other interventions. Out of 30 articles retrieved, four articles with a cumulative sample size of (N = 297) were included in the review. Mulberry formulations were compared with no intervention, grape molasses, chlorhexidine, and sodium bicarbonate. Out of the four articles, in three articles, mulberry formulations showed a significant decrease in grade 2 and grade 3 OM and also showed better prevention of OM as compared to the other intervention and control groups, and in one article, the grape molasses was more preventive for the occurrence of OM. Mulberry showed a significant decrease in dry mouth. Mulberry showed more improvement in the pain score and quality of life. The incidence and severity were lower in the mulberry group than in other interventions. One article showed less weight loss, and another article showed gradual weight gain from the use of mulberries. From this, we conclude that mulberry is effective for the treatment of OM. Mulberry also shows improvement in the pain score and quality of life.

Evolutionary gravitational neocognitron neural network optimized with marine predators optimization algorithm for MRI brain tumor classification.

Magnetic resonance imaging (MRI) is a powerful tool for tumor diagnosis in human brain. Here, the MRI images are considered to detect the brain tumor and classify the regions as meningioma, glioma, pituitary and normal types. Numerous existing methods regarding brain tumor detection were suggested previously, but none of the methods accurately categorizes the brain tumor and consumes more computation period. To address these problems, an Evolutionary Gravitational Neocognitron Neural Network optimized with Marine Predators Algorithm is proposed in this article for MRI Brain Tumor Classification (EGNNN-VGG16-MPA-MRI-BTC). Initially, the brain MRI pictures are collected under Brats MRI image dataset. By using Savitzky-Golay Denoising approach, these images are pre-processed. The features are extracted utilizing visual geometry group network (VGG16). By utilizing VGG16, the features, like Grey level features, Haralick Texture features are extracted. These extracted features are given to EGNNN classifier, which categorizes the brain tumor as glioma, meningioma, pituitary gland and normal. Batch Normalization (BN) layer of EGNNN is eliminated and included with VGG16 layer. Marine Predators Optimization Algorithm (MPA) optimizes the weight parameters of EGNNN. The simulation is activated in MATLAB. Finally, the EGNNN-VGG16-MPA-MRI-BTC method attains 38.98%, 46.74%, 23.27% higher accuracy, 24.24%, 37.82%, 13.92% higher precision, 26.94%, 47.04%, 38.94% higher sensitivity compared with the existing AlexNet-SVM-MRI-BTC, RESNET-SGD-MRI-BTC and MobileNet-V2-MRI-BTC models respectively.

Evolutionary Gravitational Neocognitron Neural Network optimized with Marine Predators Algorithm is proposed in this article for MRI Brain Tumor Classification (EGNNN-VGG16-MPA-MRI-BTC). Initially, the brain MRI pictures are collected under Brats MRI image dataset. By using Savitzky-Golay Denoising approach, these images are pre-processed. The features are extracted utilizing visual geometry group network (VGG16). By utilizing VGG16, the features, like Grey level features, Haralick Texture features are extracted. These extracted features are given to EGNNN classifier, which categorizes the brain tumor as glioma, meningioma, pituitary gland and normal. Batch Normalization (BN) layer of EGNNN is eliminated and included with VGG16 layer. Marine Predators Optimization Algorithm (MPA) optimizes the weight parameters of EGNNN.

Multiomics Analyses Identify Proline Endopeptidase-Like Protein As a Key Regulator of Protein Trafficking, a Pathway Underlying Alzheimer's Disease Pathogenesis.

Current treatments for Alzheimer's disease (AD) help reduce symptoms for a limited time but do not treat the underlying pathology. To identify potential therapeutic targets for AD, an integrative network analysis was previously carried out using 364 human postmortem control, mild cognitive impairment, and AD brains. This analysis identified proline endopeptidase-like protein (PREPL), an understudied protein, as a downregulated protein in late-onset AD patients. In this study we investigate the role of PREPL. Analyses of data from human postmortem samples and PREPL knockdown (KD) cells suggest that PREPL expression modulates pathways associated with protein trafficking, synaptic activities, and lipid metabolism. Furthermore, PREPL KD impairs cell proliferation and modulates the structure of vesicles, levels of neuropeptide-processing enzymes, and secretion of neuropeptides. In addition, decrease in PREPL levels leads to changes in the levels of a number of synaptic proteins as well as changes in the levels of secreted amyloid beta (Aß) 42 peptide and Tau phosphorylation. Finally, we report that local decrease in PREPL levels in mouse hippocampus attenuates long-term potentiation, suggesting a role in synaptic plasticity. Together, our results indicate that PREPL affects neuronal function by modulating protein trafficking and synaptic function, an important mechanism of AD pathogenesis. SIGNIFICANCE STATEMENT: Integrative network analysis reveals proline endopeptidase-like protein (PREPL) to be downregulated in human sporadic late-onset Alzheimer's disease brains. Down regulation of PREPL leads to increases in amyloid beta secretion, Tau phosphorylation, and decreases in protein trafficking and long-term potentiation.

The role of holistic nutritional properties of diets in the assessment of food system and dietary sustainability.

Advancing sustainable diets for nutrition security and sustainable development necessitates clear nutrition metrics for measuring nutritional quality of diets. Food composition, nutrient requirements, and dietary intake are among the most common nutrition metrics used in the current assessment of sustainable diets. Broadly, most studies in the area classify animal-source foods (ASF) as having a substantially higher environmental footprint in comparison to plant-source foods (PSF). As a result, much of the current dietary advice promulgates diets containing higher proportions of PSF. However, this generalization is misleading since most of these studies do not distinguish between the gross and bioavailable nutrient fractions in mixed human diets. The bioavailability of essential nutrients including ß-carotene, vitamin B-12, iron, zinc, calcium, and indispensable amino acids varies greatly across different diets. The failure to consider bioavailability in sustainability measurements undermines the complementary role that ASF play in achieving nutrition security in vulnerable populations. This article critically reviews the scientific evidence on the holistic nutritional quality of diets and identifies methodological problems that exist in the way the nutritional quality of diets is measured. Finally, we discuss the importance of developing nutrient bioavailability as a requisite nutrition metric to contextualize the environmental impacts of different diets.

A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward.

Opioid analgesics exert their therapeutic and adverse effects by activating µ opioid receptors (MOPR); however, functional responses to MOPR activation are modulated by distinct signal transduction complexes within the brain. The ventrolateral periaqueductal gray (vlPAG) plays a critical role in modulation of nociception and analgesia, but the exact intracellular pathways associated with opioid responses in this region are not fully understood. We previously showed that knockout of the signal transduction modulator Regulator of G protein Signaling z1 (RGSz1) enhanced analgesic responses to opioids, whereas it decreased the rewarding efficacy of morphine. Here, we applied viral mediated gene transfer methodology and delivered adeno-associated virus (AAV) expressing Cre recombinase to the vlPAG of RGSz1fl\fl mice to demonstrate that downregulation of RGSz1 in this region decreases sensitivity to morphine in the place preference paradigm, under pain-free as well as neuropathic pain states. We also used retrograde viral vectors along with flippase-dependent Cre vectors to conditionally downregulate RGSz1 in vlPAG projections to the ventral tegmental area (VTA) and show that downregulation of RGSz1 prevents the development of place conditioning to low morphine doses. Consistent with the role for RGSz1 as a negative modulator of MOPR activity, RGSz1KO enhances opioid-induced cAMP inhibition in periaqueductal gray (PAG) membranes. Furthermore, using a new generation of bioluminescence resonance energy transfer (BRET) sensors, we demonstrate that RGSz1 modulates Gαz but not other Gαi family subunits and selectively impedes MOPR-mediated Gαz signaling events invoked by morphine and other opioids. Our work highlights a regional and circuit-specific role of the G protein-signaling modulator RGSz1 in morphine reward, providing insights on midbrain intracellular pathways that control addiction-related behaviors. SIGNIFICANCE STATEMENT: This study used advanced genetic mouse models to highlight the role of the signal transduction modulator named RGSz1 in responses to clinically used opioid analgesics. We show that RGSz1 controls the rewarding efficacy of opioids by actions in ventrolateral periaqueductal gray projections to the ventral tegmental area, a key component of the midbrain dopamine pathway. These studies highlight novel mechanisms by which pain-modulating structures control the rewarding efficacy of opioids.

Effect of milk protein hydrolysate supplementation on protein energy malnutrition-induced gut dysbiosis.

Dairy proteins in the diet are beneficial for the growth of probiotics; however, what is unknown is the gut-mediated immune responses under protein energy malnutrition (PEM) and if dairy protein hydrolysates can be effective as dietary interventions. This study compares the composition of the gut microbiota of rats with moderate protein deficiency (M.PEM) and severe protein deficiency (S.PEM) induced by feeding 5% and 1% hypoprotein diets, followed by replenishment with buffalo and whey protein hydrolysates. Fecal samples were collected, and the composition of the gut bacteria was analyzed by whole genome sequencing using long-read sequencing. Gene expression studies of the immunomodulatory cytokines involved and quantification of sIgA were carried out. IL-6 and IFN-γ were downregulated by about 0.17 ± 0.06 and 0.12 ± 0.10 fold when supplemented with whey protein hydrolysate in SP-RWC rats and by about 0.02 ± 0.06 and 0.35 ± 0.12 fold when using buffalo milk hydrolysate. The percentage of Firmicutes decreased in M.PEM and S.PEM rats (33.57%, 28.83 versus 47.73% of control at 3 weeks) but increased upon protein replenishment for all three protein sources at the end of nine weeks. The percentage of Bacteroidetes increased to 31.03% in S.PEM-induced rats as against 28.17% in control rats. The relative abundance of Lactobacillus sp. decreased in M.PEM and S.PEM rats while it showed the opposite effect upon protein replenishment. Gut microbiota modulated the pathogenesis of PEM differentially based on protein intervention along with a significant increase in the relative abundance of the keystone Lactobacillus genus.

GPR83 engages endogenous peptides from two distinct precursors to elicit differential signaling.

PEN is an abundant neuropeptide that activates GPR83, a G protein-coupled receptor that is considered a novel therapeutic target due to its roles in regulation of feeding, reward, and anxiety-related behaviors. The major form of PEN in the brain is 22 residues in length. Previous studies have identified shorter forms of PEN in mouse brain and neuroendocrine cells; these shorter forms were named PEN18, PEN19 and PEN20, with the number reflecting the length of the peptide. The C-terminal five residues of PEN20 are identical to the C-terminus of a procholecystokinin (proCCK)-derived peptide, named proCCK56-62, that is present in mouse brain. ProCCK56-62 is highly conserved across species although it has no homology to the bioactive cholecystokinin domain. ProCCK56-62 and a longer form, proCCK56-63 were tested for their ability to engage GPR83. Both peptides bind GPR83 with high affinity, activate second messenger pathways, and induce ligand-mediated receptor endocytosis. Interestingly, the shorter PEN peptides, ProCC56-62, and ProCCK56-63 differentially activate signal transduction pathways. Whereas PEN22 and PEN20 facilitate receptor coupling to Gai, PEN18, PEN19 and ProCCK peptides facilitate coupling to Gas. Furthermore, the ProCCK peptides exhibit dose dependent Ga subtype selectivity in that they faciliate coupling to Gas at low concentrations and Gai at high concentrations. These data demonstrate that peptides derived from two distinct peptide precursors can differentially activate GPR83, and that GPR83 exhibits Ga subtype preference depending on the nature and concentration of the peptide. These results are consistent with the emerging idea that endogenous neuropeptides function as biased ligands. Significance Statement We found that peptides derived from proCCK bind and activate GPR83, a G protein-coupled receptor that is known to bind peptides derived from proSAAS. Different forms of the proCCK- and proSAAS-derived peptides show biased agonism, activating Gas or Gai depending on the length of the peptide and/or its concentration.

Mice heterozygous for a null mutation of CPE show reduced expression of carboxypeptidase e mRNA and enzyme activity but normal physiology, behavior, and levels of neuropeptides.

Carboxypeptidase E (CPE) is an essential enzyme that contributes to the biosynthesis of the vast majority of neuropeptides and peptide hormones. There are several reports claiming that small decreases in CPE activity cause physiological changes in animals and/or cultured cells, but these studies did not provide evidence that neuropeptide levels were affected by decreased CPE activity. In the present study, we tested if CPE is a rate-limiting enzyme in neuropeptide production using CpeNeo mice, which contain a neomycin cassette within the Cpe gene that eliminates enzyme expression. Homozygous CpeNeo/Neo mice show defects found in Cpefat/fat and/or Cpe global knockout (KO) mice, including greatly decreased levels of most neuropeptides, severely impaired fertility, depressive-like behavior, adult-onset obesity, and anxiety-like behavior. Removal of the neomycin cassette with Flp recombinase under a germline promoter restored expression of CPE activity and resulted in normal behavioral and physiological properties, including levels of neuropeptides. Mice heterozygous for the CpeNeo allele have greatly reduced levels of Cpe mRNA and CPE-like enzymatic activity. Despite the decreased levels of Cpe expression, heterozygous CpeNeo mice are behaviorally and physiologically identical to wild-type mice, with normal levels of most neuropeptides. These results indicate that CPE is not a rate-limiting enzyme in the production of most neuropeptides, casting doubt upon studies claiming small decreases in CPE activity contribute to obesity or other physiological effects.

Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target.

Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the NTRK1 gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). NTRK1 encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception. Molecular modeling and biochemical analysis identified mutations that decreased the interaction between TrkA and one of its substrates and signaling effectors, phospholipase Cγ (PLCγ). We developed a cell-permeable phosphopeptide derived from TrkA (TAT-pQYP) that bound the Src homology domain 2 (SH2) of PLCγ. In HEK-293T cells, TAT-pQYP inhibited the binding of heterologously expressed TrkA to PLCγ and decreased NGF-induced, TrkA-mediated PLCγ activation and signaling. In mice, intraplantar administration of TAT-pQYP decreased mechanical sensitivity in an inflammatory pain model, suggesting that targeting this interaction may be analgesic. The findings demonstrate a strategy to identify new targets for pain relief by analyzing the signaling pathways that are perturbed in CIPA.

Markers of Oxidative Stress, Inflammation, and Endothelial Dysfunction in Diabetic and Nondiabetic Patients with Chronic Kidney Disease on Peritoneal Dialysis.

Chronic kidney disease (CKD) is a low-grade inflammatory state which is accom-panied by elevated markers of oxidative stress, inflammatory, and endothelial dysfunction in patients on peritoneal dialysis (PD). These represent a key triad for the development and progression of atherosclerosis. The present study assessed the markers of oxidative stress, inflammatory and endothelial dysfunction in diabetic and non-diabetic CKD patients on PD. A cross-sectional study was undertaken on 100 CKD patients on PD, of whom 52 patients were nondiabetic and 48 were diabetic patients. Blood samples were estimated for malondialdehyde (MDA) and ferric reducing ability of plasma (FRAP) as markers of oxidative stress; interleukin (IL)-6, high-sensitivity C-reactive protein (hs-CRP), and fibrinogen as inflammatory markers; and markers of endothelial dysfunction such as nitric oxide (NO), carotid wall intimal medial thickness (CIMT), and number of plaques, among others. The MDA levels increased and FRAP levels decreased in both diabetic and nondiabetic CKD patients on PD. The levels of IL-6, hs-CRP, fibrinogen, NO, CIMT, and the number of plaques were significantly higher in diabetic patients than in nondiabetic CKD patients on PD. The lipid profile was significantly atherogenic in diabetic patients compared with nondiabetics CKD patients. The results showed increased oxidative stress, inflammation, and endothelial dysfunction in diabetic patients compared with nondiabetics CKD patients on PD.

Ameliorative effect of enhanced Fischer ratio flaxseed protein hydrolysate in combination with antioxidant micronutrients on ethanol-induced hepatic damage in a rat model.

Alcohol abuse causes severe metabolic abnormalities inducing hepatic damage and malnutrition. Since higher Fischer ratio proteins have therapeutic value in liver diseases, an investigation was undertaken to study the ameliorative effect of the enhanced Fischer ratio flaxseed protein hydrolysate (EFR-FPH) alone and in combination with antioxidant micronutrients on ethanol-induced hepatotoxicity in a rat model. The EFR-FPH was prepared by dual enzymatic hydrolysis and charcoal treatment of flaxseed protein. The ratio of the branched-chain:aromatic amino acids (Fischer ratio) was found to be 7·08. The EFR-FPH, characterised using LC-MS/MS, showed the abundance of free leucine and isoleucine compared with phenylalanine and tyrosine. The matrix-assisted laser desorption/ionisation-time of flight MS analysis revealed the larger peptides present in EFR-FPH with mass 2·3 kDa. The EFR-FPH improved the nutritional status, liver function and antioxidant defense in the ethanol hepatotoxicity-induced rat model. The hepatoprotective effect of EFR-FPH was significantly enhanced when combined with selenium or vitamin E. Ethanol-induced changes in the liver tissue were effectively suppressed in the groups receiving EFR-FPH. Flaxseed-based hepatoprotective dietary supplement was formulated incorporating an optimum level of EFR-FPH (10 %) based on sensory acceptability and was fortified with selenium and vitamin E. The hepatoprotective formulation significantly lowered aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin by 47, 61, 55 and 78 %, respectively, and improved the antioxidant defense in the ethanol hepatotoxicity-induced rat model. The current investigation suggests that EFR-FPH in synergy with antioxidant micronutrients is potent in ameliorating ethanol-induced hepatotoxicity and has a potential to form a hepatoprotective dietary supplement.

Oxytocin and vasopressin: Signalling, behavioural modulation and potential therapeutic effects.

Oxytocin (OT) and vasopressin (AVP) are endogenous ligands for OT and AVP receptors in the brain and in the peripheral system. Several studies demonstrate that OT and AVP have opposite roles in modulating stress, anxiety and social behaviours. Interestingly, both peptides and their receptors exhibit high sequence homology which could account for the biased signalling interaction of the peptides with OT and AVP receptors. However, how and under which conditions this crosstalk occurs in vivo remains unclear. In this review we shed light on the complexity of the roles of OT and AVP, by focusing on their signalling and behavioural differences and exploring the crosstalk between the receptor systems. Moreover, we discuss the potential of OT and AVP receptors as therapeutic targets to treat human disorders, such as autism, schizophrenia and drug abuse. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.

Molecular docking and dynamic simulations of Ocimum basilicum compounds against HCC and structural, vibrational, quantum, and chemical investigation of campesterol.

Hepatocellular carcinoma (HCC) is a pervasive type of liver malignant growth and the third-driving reason for disease-related overall mortality with an expanding pervasiveness worldwide. Besides, no successful treatment can be utilized on patients with the cutting-edge or metastatic illness. Some of the natural therapeutics are paved the way for developing potential inhibitors for many types of cancer. Ocimum basilicum is one of the most well-known herbs, which contains numerous therapeutic properties and is widely used for various health issues. This study focused on its valuable medicinal property against HCC via in silico approach. Bioactive constituents from O. basilicum is subjected to molecular docking and dynamics study for 100 ns against the HCC targets (FGFR1, FGFR2, FGFR3, and FGFR4), and the selected lead compounds showed better interactions, docking score, obeys Lipinski's rule of five, highest occupied molecular orbital, lowest unoccupied molecular orbital hypothesis, protein-complex stability throughout the simulation period and the pharmacophoric features were analysed. Out of selected seven compounds, Campesterol revealed its potential therapeutic activity (Docking score - FGFR1 - 8.59 Kcal/Mol, FGFR2 - 7.11 Kcal/Mol, FGFR3 - 10.53 Kcal/Mol and FGFR4 - 9.17 Kcal/Mol, respectively. And also, it maintains good stability with the targets without any fluctuations. So, we concluded our findings that Campesterol is considered as, such a promising and potential inhibitor for HCC.Communicated by Ramaswamy H. Sarma.

A Mechanistic Review on Plant-derived Natural Inhibitors of Human Coronaviruses with Emphasis on SARS-COV-1 and SARS-COV-2.

Coronaviruses have been receiving continuous attention worldwide as they have caused a serious threat to global public health. This group of viruses is named so as they exhibit characteristic crown-like spikes on their protein coat. SARS-CoV-2, a type of coronavirus that emerged in 2019, causes severe infection in the lower respiratory tract of humans and is often fatal in immunocompromised individuals. No medications have been approved so far for the direct treatment of SARS-CoV-2 infection, and the currently available treatment options rely on relieving the symptoms. The medicinal plants occurring in nature serve as a rich source of active ingredients that could be utilized for developing pharmacopeial and non-pharmacopeial/synthetic drugs with antiviral properties. Compounds obtained from certain plants have been used for directly and selectively inhibiting different coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2. The present review discusses the potential natural inhibitors against the highly pathogenic human coronaviruses, with a systematic elaboration on the possible mechanisms of action of these natural compounds while acting in the different stages of the life cycle of coronaviruses. Moreover, through a comprehensive exploration of the existing literature in this regard, the importance of such compounds in the research and development of effective and safe antiviral agents is discussed. We focused on the mechanism of action of several natural compounds along with their target of action. In addition, the immunomodulatory effects of these active components in the context of human health are elucidated. Finally, it is suggested that the use of traditional medicinal plants is a novel and feasible remedial strategy against human coronaviruses.

Interactions between cannabinoid and opioid receptors in a mouse model of diabetic neuropathy.

ABSTRACT: Diabetic neuropathy, often associated with diabetes mellitus, is a painful condition with no known effective treatment except glycemic control. Studies with neuropathic pain models report alterations in cannabinoid and opioid receptor expression levels; receptors whose activation induces analgesia. We examined whether interactions between CB1R and opioid receptors could be targeted for the treatment of diabetic neuropathy. For this, we generated antibodies that selectively recognize native CB1R-MOR and CB1R-DOR heteromers using a subtractive immunization strategy. We assessed the levels of CB1R, MOR, DOR, and interacting complexes using a model of streptozotocin-induced diabetic neuropathy and detected increased levels of CB1R, MOR, DOR, and CB1R-MOR complexes compared with those in controls. An examination of G-protein signaling revealed that activity induced by the MOR, but not the DOR agonist, was potentiated by low nanomolar doses of CB1R ligands, including antagonists, suggesting an allosteric modulation of MOR signaling by CB1R ligands within CB1R-MOR complexes. Because the peptide endocannabinoid, hemopressin, caused a significant potentiation of MOR activity, we examined its effect on mechanical allodynia and found that it blocked allodynia in wild-type mice and mice with diabetic neuropathy lacking DOR (but have CB1R-MOR complexes). However, hemopressin does not alter the levels of CB1R-MOR complexes in diabetic mice lacking DOR but increases the levels of CB1R-DOR complexes in diabetic mice lacking MOR. Together, these results suggest the involvement of CB1R-MOR and CB1R-DOR complexes in diabetic neuropathy and that hemopressin could be developed as a potential therapeutic for the treatment of this painful condition.

CHA2DS2-VASc and has-BLED scores do not accurately stratify risk for stroke or bleed in fall victims with atrial fibrillation.

BACKGROUND: Falls are the leading cause of morbidity and mortality in the elderly. Non-valvular Atrial fibrillation (AF) is present in up to 9% of this group and often requires oral anticoagulation (OAC). The CHA2DS2-VASc and HAS-BLED scores are validated tools assessing risk of ischemic stroke from AF and major bleeding (MB) from OAC. It is unclear if these predictions remain accurate in post-fall patients. This study seeks to determine the stroke and major bleeding rate in atrial fibrillation patients after a ground level fall and identify if validated risk scoring systems accurately stratify risk in this cohort. METHODS: Retrospective review of patients with AF presented to the emergency department after a fall. CHA2DS2-VASc and HAS-BLED scores were calculated. Follow up information was reviewed to 1 year. Patients were grouped according to discharge thromboprophylaxis plan (DTP): no treatment, Anti-platelet (AP), OAC, and AP + OAC. Outcomes were ischemic stroke, MB, or death at 1 year. Ischemic stroke and MB rates were calculated. Kruskal-Wallis, Χ2, Fisher's exact, and multivariable logistic regression were used to evaluate for clinical associations. RESULTS: 192 patients were included. MB rate was 14.5 bleeds/100 person-years, and ischemic stroke rate was 10.9/100 person-years. There were no observed differences between DTPs. Overall, one-year mortality was 22.1%. On unadjusted analysis, CHA2DS2-VASc did associate with ischemic stroke (p = 0.03); HAS-BLED did not associate with MB (p = 0.17). After logistic regression accounting for known risk factors, neither system associated with ischemic stroke or MB. CONCLUSIONS: Fall patients are at higher risk for both ischemic stroke and MB compared to previously published reports. Current risk assessment tools should be used with caution. Further study of risk factors is warranted to guide medication decisions in these patients.

Maximising the bioaccessibility of iron and zinc of a complementary food mix through multiple strategies.

The investigation was undertaken to maximise the bioaccessibility of iron and zinc of a complementary food mix by multiple approaches of dephytinisation and addition of organic acids. A wheat, pulse and oilseed protein flour mix was dephytinized by phytase activation and different thermal treatments. As the mineral content of the mix was low, the spray dried mix was fortified with different iron and zinc salts to identify the salt with the highest bioaccessibility in this matrix. Based on the percent bioaccessibility, the mix with sodium iron EDTA and zinc oxide was chosen for fortification. Bioaccessibility was enhanced by the addition of fruit powders and pure organic acids. Fruit powders showed a significant increase, but citric acid at a higher dose was beneficial in enhancing bioaccessible iron. The strategy of dephytinisation followed by fortification and the addition of fruit powders or organic acids is promising in alleviating iron and zinc deficiencies.

PEN Receptor GPR83 in Anxiety-Like Behaviors: Differential Regulation in Global vs Amygdalar Knockdown.

Anxiety disorders are prevalent across the United States and result in a large personal and societal burden. Currently, numerous therapeutic and pharmaceutical treatment options exist. However, drugs to classical receptor targets have shown limited efficacy and often come with unpleasant side effects, highlighting the need to identify novel targets involved in the etiology and treatment of anxiety disorders. GPR83, a recently deorphanized receptor activated by the abundant neuropeptide PEN, has also been identified as a glucocorticoid regulated receptor (and named GIR) suggesting that this receptor may be involved in stress-responses that underlie anxiety. Consistent with this, GPR83 null mice have been found to be resistant to stress-induced anxiety. However, studies examining the role of GPR83 within specific brain regions or potential sex differences have been lacking. In this study, we investigate anxiety-related behaviors in male and female mice with global knockout and following local GPR83 knockdown in female mice. We find that a global knockdown of GPR83 has minimal impact on anxiety-like behaviors in female mice and a decrease in anxiety-related behaviors in male mice. In contrast, a local GPR83 knockdown in the basolateral amygdala leads to more anxiety-related behaviors in female mice. Local GPR83 knockdown in the central amygdala or nucleus accumbens (NAc) showed no significant effect on anxiety-related behaviors. Finally, dexamethasone administration leads to a significant decrease in receptor expression in the amygdala and NAc of female mice. Together, our studies uncover a significant, but divergent role for GPR83 in different brain regions in the regulation of anxiety-related behaviors, which is furthermore dependent on sex.

Use of the DELTA Model to Understand the Food System and Global Nutrition.

BACKGROUND: Increasing attention is being directed at the environmental, social, and economic sustainability of the global food system. However, a key aspect of a sustainable food system should be its ability to deliver nutrition to the global population. Quantifying nutrient adequacy with current tools is challenging. OBJECTIVE: To produce a computational model illustrating the nutrient adequacy of current and proposed global food systems. METHODS: The DELTA Model was constructed using global food commodity balance sheet data, alongside demographic and nutrient requirement data from UN and European Food Safety Authority sources. It also includes nutrient bioavailability considerations for protein, the indispensable amino acids, iron, and zinc, sourced from scientific literature. RESULTS: The DELTA Model calculates global per capita nutrient availability under conditions of equal distribution and identifies areas of nutrient deficiency for various food system scenarios. Modeling the 2018 global food system showed that it supplied insufficient calcium (64% of demographically weighted target intake) and vitamin E (69%), despite supplying sufficient macronutrients. Several future scenarios were modeled, including variations in waste; scaling up current food production for the 2030 global population; plant-based food production systems; and removing sugar crops from the global food system. Each of these scenarios fell short of meeting requirements for multiple nutrients. These results emphasize the need for a balanced approach in the design of future food systems. CONCLUSIONS: Nutrient adequacy must be at the forefront of the sustainable food system debate. The DELTA Model was designed for both experts and nonexperts to inform this debate as to what may be possible, practical, and optimal for our food system. The model results strongly suggest that both plant and animal foods are necessary to achieve global nutrition. The model is freely available for public use so that anyone can explore current and simulated global food systems.