Candesartan upregulates angiotensin-converting enzyme 2 in kidneys of male animals by decreased ubiquitination.

Candesartan is a common angiotensin-II receptor-1 blocker used for patients with cardiovascular and renal diseases. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of blood pressure (BP), and also a major receptor for coronaviruses. To determine whether and how candesartan upregulates ACE2, we examined BP and ACE2 in multi-organs from male and female C57BL/6J mice treated with candesartan (1 mg/kg, i.p.) for 7 days. Relative to the vehicle, candesartan lowered BP more in males than females; ACE2 protein abundances were increased in kidneys, not lungs, hearts, aorta, liver, spleen, brain, or serum, only from males. Ace2-mRNA was similar in kidneys. Candesartan also decreased BP in normal, hypertensive, and nephrotic male rats. The renal ACE2 was increased by the drug in normal and nephrotic male rats but not spontaneously hypertensive ones. In male mouse kidneys, ACE2 was distributed at sodium-hydrogen-exchanger-3 positive proximal-convoluted-tubules; ACE2-ubiquitination was decreased by candesartan, accompanied with increased ubiquitin-specific-protease-48 (USP48). In candesartan-treated mouse renal proximal-convoluted-tubule cells, ACE2 abundances and activities were increased while ACE2-ubiquitination and colocalization with lysosomal and proteosomal markers were decreased. The silence of USP48 by siRNA caused a reduction of ACE2 in the cells. Thus, the sex-differential ACE2 upregulation by candesartan in kidney from males may be due to the decreased ACE2-ubiquitination, associated with USP48, and consequent degradation in lysosomes and proteosomes. This is a novel mechanism and may shed light on candesartan-like-drug choice in men and women prone to coronavirus infections.

Detection methods and dynamic characteristics of specific antibodies in patients with COVID-19: A review of the early literature.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic. Early and accurate diagnosis and quarantine remain the most effective mitigation strategy. Although reverse transcriptase polymerase chain reaction (RT-qPCR) is the gold standard for COVID-19 diagnosis, recent studies suggest that nucleic acids were undetectable in a significant number of cases with clinical features of COVID-19.Serological assays for SARS-CoV-2 play a role in diagnosis of COVID-19, in understanding viral epidemiology and screening convalescent sera for therapeutic and prophylactic purposes, to better understand the immune response to the virus, and to assess the degree and duration of the response of specific antibodies. In this article, we retrieved PubMed, Embase, China National Knowledge Infrastructure (CNKI) and WEB OF SCI databases for articles and reviews published before December 1, 2022. Using "IgM, IgG,IgA, neutralizing antibody, specific antibody,COVID-19, dynamic characteristics" as keywords, and comprehensively reviewed on their basis.According to the authors' criteria, only articles deemed relevant were included, covering original articles, case series, experimental studies, reviews, and case reports. Articles on performance evaluation, opinion pieces, and technical issues were excluded. From the onset of COVID-19 symptoms, the median time of seroconversion was 11 days for immunoglobulin A (IgA), the median time of peak antibody titer was 23 (16-30 days) for IgA.Immunoglobulin M (IgM) is detected prior to immunoglobulin G (IgG), peaking 2-5 weeks post symptom onset and detectable for a minimum of 8 weeks in the immunocompetent.Neutralizing antibodies were earliest detectable within 6-7 days following disease onset, with levels increasing until days 14-22 before levelling and then decreasing, but titres were lower in clinically mild disease. Different clinical types of patients showed different antibody responses to SARS-CoV-2, with severe COVID-19 patients > non-severe COVID-19 patients > asymptomatic infected persons, but no difference in the early stage of the disease. Usually, IgM and IgA antibodies are detectable earlier than IgG antibodies.IgA antibodys plays an important role in local mucosal immunity.Detection of IgM antibodies tends to indicate recent exposure to SARS-CoV-2, whereas the detection of COVID-19 IgG antibodies indicates virus exposure some time ago. The detection of potent neutralizing antibodies in convalescent plasma is important in the context of development of therapeutics and vaccines.With the emergence of immune escape variants of SARS-CoV-2, humoral immunity is being challenged, and a detailed understanding of Specific antibodies is critical to guide vaccine design strategies and antibody-mediated therapies.

Chickpea protein hydrolysate as a novel plant-based cryoprotectant in frozen surimi: Insights into protein structure integrity and gelling behaviors.

Chickpea protein (CP) and its enzymatic hydrolysates are one of the most widely consumed pulse ingredients manifesting versatile applications in food industry, such as binders, emulsifiers, and meat protein substitutes. Other than those well-known functionalities, however, the use of CP as a cryoprotectant remained unexplored. In this study, we prepared the chickpea protein hydrolysate (CPH) and investigated its cryoprotective effects to frozen surimi in terms of the protein structure integrity and gelling behaviors. Results indicated that CPH could inhibit myofibrillar protein (MP) denaturation and oxidation during the freeze-thaw cycling, as evidenced by their increased solubility, Ca2+-ATPase activity, sulfhydryl concentration, and declined content of disulfide bonds, carbonyl concentration and surface hydrophobicity. Freezing-induced changes on MP secondary structures were also retarded. Moreover, gels prepared from CPH-protected frozen surimi demonstrated more stabilized microstructure, uniform water distribution, enhanced elasticity, gel strength and water holding capacity. The CPH alone, at a reducing addition content of 4% (w/w), exhibited comparable cryoprotective performance to that of the commercial formulation (4% sucrose and 4% sorbitol). Therefore, this study provides scientific insights for development of pulse proteins as novel and high-performance food cryoprotectants.

Inducing the structural interplay of binary pulse protein complex to stimulate the solubilization of chickpea (Cicer arietinum L.) protein isolate.

Chickpea protein (CP) is an exceptional nutrient-dense pulse protein prevailing in the development of plant-based foods. However, its relatively low solubility, compared to other legume proteins, hinders the practical uses of CP in food matrix. To resolve this problem, pea protein (PP), another popular pulse protein, was co-assembled with CP to form a binary complex during the alkaline pH-shifting process. Results indicated that the complexed CP exhibited significantly increased solubility to that of the pristine protein (more than 50%), whose aqueous stability was also enhanced against different environmental stresses (pH, salt, heat/frozen treatment, and centrifugation). Structural and morphology analysis confirmed the interplay between unfolded CP and PP during pH shifting, which enabled their resistance to acid-induced structural over-folding. Our experiments that induce the co-assembling of two pulse proteins provide a novel routine and scientific basis for tailoring CP functionalities, as well as the formulation of pulse protein-based products.

Octenyl Succinic Anhydride-Modified Starch Attenuates Body Weight Gain and Changes Intestinal Environment of High-Fat Diet-Fed Mice.

Effects of octenylsuccinate (OS) starch on body composition and intestinal environment in high-fat diet-fed mice were investigated. C57BL/6J mice were treated with a regular-fat (RF) diet, a high-fat (HF) diet, or a high-fat diet supplemented with OS starch (HFOSS). Fecal short-chain fatty acids (SCFAs) were quantified using gas chromatography, and the fecal microbiota profile was analyzed by 16S rDNA sequencing. One-way ANOVA and metastats analysis were performed for statistical analysis. After 22 weeks of feeding, mice in the HFOSS group had significantly lower body weight, body fat, liver weight, and cumulative food intake than those in the HF group but higher than that of the RF group. Fecal total SCFA, acetic, propionic, and butyric acid concentrations were significantly higher in the HFOSS group than that in the HF and RF groups. OS starch intervention increased the relative abundance of Parabacteroides, Alistipes, and Ruminiclostridium_5 and decreased that of Tyzzerella, Oscillibacter, Desulfovibrio, and Anaerotruncus compared with the RF and HF groups. The relative abundance of Lachnospiraceae_UCG-006 in the HFOSS group was lower than that in the HF group but higher than that in the RF group. In conclusion, OS starch prevents fat accumulation in high-fat diet-fed mice and might provide potential health benefits due to its fermentability in the gut and its ability to regulate gut microbial community structure.

Cryoprotective Roles of Carboxymethyl Chitosan during the Frozen Storage of Surimi: Protein Structures, Gel Behaviors and Edible Qualities.

Carboxymethyl chitosan (CMCh) is an ampholytic chitosan derivative that manifests versatile applications in food industry, such as antibacterial ingredients and nutritional additives. However, its use as a cryoprotectant remains under-researched. In this study, the cryoprotective effect of CMCh oligosaccharide (CMCO) on frozen surimi (silver carp) was systematically investigated in terms of protein structures, gelling behaviors, and sensory qualities. CMCO (0.6%) was incorporated in the surimi before frozen storage (-18 °C for 60 days) while the commercial cryoprotectant (4% sucrose, 4% sorbitol) was used as a positive control. Results indicated that CMCO could inhibit the freezing-induced denaturation of myofibrillar protein, whose values of solubility, Ca2+-ATPase and sulfhydryl content were 24.8%, 64.7%, and 17.1% higher than the nonprotected sample, respectively, while the surface hydrophobicity was 21.6% lower. Accordingly, CMCO stabilized microstructure of the surimi gels associated with improved gel strength, viscoelasticity, water-holding capacities, and whiteness. Moreover, the cryoprotective effect of CMCO with higher degree of carboxymethyl substitution (DS: 1.2) was more pronounced than that of low-DS-CMCO (DS: 0.8). Frozen surimi treated with high-DS-CMCO achieved competitive gelling properties and sensory acceptability to those with the commercial counterpart. This study provided scientific insights into the development of ampholytic oligosaccharides as food cryoprotectants.

Effect of carboxymethyl chitosan on the storage stability of frozen dough: State of water, protein structures and quality attributes.

Carboxymethyl chitosan (CMCh), an ampholetic chitosan derivative, has found broad applications in the food industry. However, its cryo-protective properties remained less explored compared to other viscous polysaccharides, such as carboxymethyl cellulose, carrageenan etc., which have been widely utilized as frozen food additives. In this study, we investigated the effect of CMCh addition to frozen dough in terms of water state, protein structure, and the textural properties of prepared frozen dumpling wrappers. Results indicated that CMCh restricted the water migration in dough and delayed protein deterioration during frozen storage. Specifically, the content of freezable water in dough was reduced and the water distribution became more uniform as reflected by DCS and LF-NMR analysis. CMCh also stabilized disulfide bond and secondary structures of the protein, leading to inhibition of dough rheology changes. Accordingly, the obtained frozen dumplings wrappers demonstrated decreased cracking rate and water loss, and improved textural properties. Moreover, CMCh with higher degree of carboxymethyl substitution (DS: 1.2, CMCh-B) exhibited better cryo-protective effects compared to CMCh of lower DS (DS: 0.8, CMCh-A). Our study provides novel insights and scientific basis for the development of ampholetic polysaccharides as high-performance food additives.

Hydroxychloroquine Inhibits Cardiac Conduction in Aged Patients with Nonmalaria Diseases.

BACKGROUND: The COVID-19 pandemic has brought increased focus on hydroxychloroquine (HCQ), as doctors, the medical community, and policymakers around the world attempt to understand how the risks of HCQ weigh against unknown benefits. We aim to evaluate the effects of HCQ on cardiac conduction, thus contributing to the global understanding of implications of HCQ use. METHODS: We reviewed 717 cases of nonmalaria patients treated with HCQ (302) or without HCQ (415) in our hospital from 2008 to 2019, analyzed the cardiac conduction recorded by electrocardiogram (122 vs. 180) including heart rate (HR), PR, and corrected-QT (QTc) intervals, and explored the relationship of cardiac conduction with age, HCQ dosage, HCQ duration, sex, and primary diseases in HCQ users. RESULTS: The all-cause mortality is similar between HCQ and non-HCQ groups (4.0 vs. 4.3%, p = 0.85). Patients aged 45 years or older, not younger ones, have lower HR (80.1 ± 1.7 vs. 85.7 ± 1.8 bpm, p = 0.03) but longer PR (163 ± 3.4 vs. 146.6 ± 4.2 ms, p = 0.003) and QTc (417.8 ± 3.8 vs. 407.7 ± 2.7 ms, p = 0.03) in HCQ than those in non-HCQ. The age in the HCQ group is positively correlated with PR (R = 0.31, p < 0.01) and QTc (R = 0.34, p < 0.01) but not HR. HR, PR, and QTc are not related to HCQ dosage (0.1-0.6 g/day), HCQ duration (0.2-126 months), sex, primary diseases, and repeated exams. CONCLUSION: Age is the most important risk factor of HCQ on cardiac conduction in nonmalaria patients. Electrocardiogram monitoring is suggested in aged patients due to the effects of HCQ on HR, PR, and QTc.

Position of acetyl groups on anhydroglucose unit in acetylated starches with intermediate degrees of substitution.

Waxy, normal, and high-amylose maize starches were acetylated to various degrees of substitution (DS) in aqueous medium. A stepwise addition of acetic anhydride enhanced reaction efficiency and DS was in the order of high-amylose maize starch (DS 1.72) > waxy maize starch (DS 1.60) > normal maize starch (DS 1.03) when 240% (w/w) acetic anhydride was added. Starch acetates were further fully esterified to DS 3.0 using acetic anhydride-d6 or propionic anhydride to analyze position of acetyl groups on anhydroglucose unit (AGU) by 1H NMR. Regioselective 2-O-acetyl starches were produced when the DS was lower than 0.14. At DS 1, the distribution of acetyl groups was ca. 44%, 32%, and 24% at C-2, C-3, and C-6 positions, respectively, regardless of amylose content. Deuterated acetyl group was a preferred secondary substituent over propionyl group in subsequent 1H NMR analysis because it resulted a clean spectrum without interference from propionyl methyl protons.

A Dual-Channel Supply Chain Coordination under Carbon Cap-and-Trade Regulation.

We consider a dual-channel supply chain coordination under a carbon cap-and-trade regulation. The dual-channel refers to the traditional retail channel and the network direct channel, and both two channels' selling prices can affect the market demand. We formulate the problem as a supplier-Stackelberg game model and obtain the optimal pricing decisions and corresponding profits in centralized and decentralized systems. We explore the effects of cap-and-trade regulation on optimal decisions and profits. To improve the performance of the decentralized system, we propose online channel price discount and offline channel price discount contracts to coordinate dual-channel supply chain and provide a transfer payment mechanism to make win-win of both sides. Moreover, we investigate how carbon regulation affects the coordination performance. Numerical examples illustrate the process to find the appropriate price discount coefficient and show the coordination effects of two contracts.

Identification and quantification of anthocyanins in transgenic purple tomato.

Anthocyanins are natural pigments derived from the phenylpropanoid pathway. Most tomatoes produce little anthocyanins, but the transgenic purple tomato biosynthesizes a high level of anthocyanins due to expression of two transcription factors (Del and Ros1). This study was to identify and quantify anthocyanins in this transgenic tomato line. Seven anthocyanins, including two new anthocyanins [malvidin-3-(p-coumaroyl)-rutinoside-5-glucoside and malvidin-3-(feruloyl)-rutinoside-5-glucoside], were identified by LC-MS/MS. Petunidin-3-(trans-coumaroyl)-rutinoside-5-glucoside and delphinidin-3-(trans-coumaroyl)-rutinoside-5-glucoside were the most abundant anthocyanins, making up 86% of the total anthocyanins. Compared to undetectable anthocyanins in the wild type, the contents of anthocyanins in the whole fruit, peel, and flesh of the Del/Ros1-transgenic tomato were 5.2±0.5, 5.1±0.5, and 5.8±0.3g/kg dry matter, respectively. Anthocyanins were undetectable in the seeds of both wide-type and transgenic tomato lines. Such novel and high levels of anthocyanins obtained in this transgenic tomato may provide unique functional products with potential health benefits.

Characterisation and stability of anthocyanins in purple-fleshed sweet potato P40.

Purple-fleshed sweet potato P40 has been shown to prevent colorectal cancer in a murine model. This study is to identify anthocyanins by using HPLC/MS-MS and assess the stability during various cooking conditions. P40 possesses a high content of anthocyanins up to 14 mg/g dry matter. Total 12 acylated anthocyanins are identified. Top three anthocyanins, e.g., cyanidin 3-caffeoyl-p-hydroxybenzoyl sophoroside-5-glucoside, peonidin 3-caffeoyl sophoroside-5-glucoside, and cyanidin 3-(6"-caffeoyl-6"-feruloylsophoroside)-5-glucoside, account for half of the anthocyanin contents. Over 80% of anthocyanins measured by acid hydrolysis were cyanidin derivatives, indicating P40 is unique when compared with other purple-fleshed sweet potatoes that usually contain more peonidin than cyanidin. Steaming, pressure cooking, microwaving, and frying but not baking significantly reduced 8-16% of total anthocyanin contents. Mono-acylated anthocyanins showed a higher resistance against heat than di- and non-acylated. Among of which, cyanidin 3-p-hydroxybenzoylsophoroside-5-glucoside exhibited the best thermal stability. The stable acylated and cyanidin-predominated anthocyanins in P40 may provide extra benefits for cancer prevention.

Reduced signaling of PI3K-Akt and RAS-MAPK pathways is the key target for weight-loss-induced cancer prevention by dietary calorie restriction and/or physical activity.

Weight control through either dietary calorie restriction (DCR) or exercise has been associated with cancer prevention in animal models. However, the underlying mechanisms are not fully defined. Bioinformatics using genomics, proteomics and lipidomics was employed to elucidate the molecular targets of weight control in a mouse skin cancer model. SENCAR mice were randomly assigned into four groups for 10 weeks: ad-libitum-fed sedentary control, ad-libitum-fed exercise (AE), exercise but pair-fed isocaloric amount of control (PE) and 20% DCR. Two hours after topical TPA treatment, skin epidermis was analyzed by Affymetrix for gene expression, DIGE for proteomics and lipidomics for phospholipids. Body weights were significantly reduced in both DCR and PE but not AE mice versus the control. Among 39,000 transcripts, 411, 67 and 110 genes were significantly changed in DCR, PE and AE, respectively. The expression of genes relevant to PI3K-Akt and Ras-MAPK signaling was effectively reduced by DCR and PE but not AE as measured through GenMAPP software. Proteomics analysis identified ~120 proteins, with 27 proteins significantly changed by DCR, including up-regulated apolipoprotein A-1, a key antioxidant protein that decreases Ras-MAPK activity. Of the total 338 phospholipids analyzed by lipidomics, 57 decreased by PE including 5 phophatidylinositol species that serve as PI3K substrates. Although a full impact has not been determined yet, it appears that the reduction of both Ras-MAPK and PI3K-Akt signaling pathways is a cancer preventive target that has been consistently demonstrated by three bioinformatics approaches.

Weight control, endocrine hormones and cancer prevention.

The prevalence of obesity is increasing which becomes worrisome due to its association with several diseases and certain types of cancers. While weight control through dietary caloric restriction and/or physical activity protects against cancer in animal models, the underlying mechanisms are not fully defined. Weight loss due to negative energy balance is associated with alterations of multiple growth factors and endocrine hormones. The altered hormones and hormone-related functions appear to be responsible for anti-cancer mechanisms. In this review, we summarize the recent studies related to weight loss and the altered endocrine hormones, focusing on the reduced levels of the mitogenic insulin-like growth factor 1 (IGF-1) and adipokine leptin as well as the raised levels of adiponectin and glucocorticoids. The potential molecular targets of these hormone-dependent signalling pathways are also discussed. Considering the increasing trends of obesity throughout the world, a better understanding of the underlying mechanisms between body weight, endocrine hormones and cancer risk may lead to novel approaches to cancer prevention and treatment.

Role of anthocyanin-enriched purple-fleshed sweet potato p40 in colorectal cancer prevention.

SCOPE: Anthocyanins, the natural pigments in plant foods, have been associated with cancer prevention. However, the content of anthocyanins in staple foods is typically low and the mechanisms by which they exert anticancer activity is not yet fully defined. METHODS AND RESULTS: We selected an anthocyanin-enriched purple-fleshed sweet potato clone, P40, and investigated its potential anticancer effect in both in vitro cell culture and in vivo animal model. In addition to a high level of total phenolics and antioxidant capacity, P40 possesses a high content of anthocyanins at 7.5 mg/g dry matter. Treatment of human colonic SW480 cancer cells with P40 anthocyanin extracts at 0-40 µM of peonidin-3-glucoside equivalent resulted in a dose-dependent decrease in cell number due to cytostatic arrest of cell cycle at G1 phase but not cytotoxicity. Furthermore, dietary P40 at 10-30% significantly suppressed azoxymethane-induced formation of aberrant crypt foci in the colons of CF-1 mice in conjunction with, at least in part, a lesser proliferative PCNA and a greater apoptotic caspase-3 expression in the colon mucosal epithelial cells. CONCLUSION: These observations, coupled with both in vitro and in vivo studies reported here, suggest anthocyanin-enriched sweet potato P40 may protect against colorectal cancer by inducing cell-cycle arrest, antiproliferative, and apoptotic mechanisms.