bims-supasi 2022-10-16 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2022–10–16
fourteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Glycosaminoglycan Analysis of FFPE Tissues from Prostate Cancer and Benign Prostate Hyperplasia Patients Reveals Altered Regulatory Functions and Independent Markers for Survival.
Mass spectrometric analysis of chondroitin sulfate-linked peptides.
Dual antibacterial and anti-inflammatory efficacy of a chitosan-chondroitin sulfate-based in-situ forming wound dressing.
Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses.
Investigation of the pharmacokinetic properties of synthetic heparan sulfate oligosaccharides.
Automated Solid Phase Assisted Synthesis of a Heparan Sulfate Disaccharide Library.
Characterization of Synovial Fluid Components: Albumin-Chondroitin Sulfate Interactions Seen through Molecular Dynamics.
Comparation of the structural characteristics and biological activities of chondroitin sulfates extracted from notochord and backbone of Chinese sturgeon (Acipenser sinensis).
Fucosylated Chondroitin Sulfate against Parkinson's Disease through Inhibiting Inflammation Induced by Gut Dysbiosis.
Value Ranges and Clinical Comparisons of Serum DHEA-S, IL-6, and TNF-α in Western Lowland Gorillas.
Human Dendritic Cells Transmit Enterovirus A71 via Heparan Sulfates to Target Cells Independent of Viral Replication.
Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study.
Unique features of regulation of sulfate assimilation in monocots.
Trimethylamine N-Oxide (TMAO) and Indoxyl Sulfate Concentrations in Patients with Alcohol Use Disorder.

Cancers (Basel). 2022 Oct 05. pii: 4867. [Epub ahead of print]14(19):

Glycosaminoglycan Analysis of FFPE Tissues from Prostate Cancer and Benign Prostate Hyperplasia Patients Reveals Altered Regulatory Functions and Independent Markers for Survival.

Gábor Tóth, Simon Sugár, Domonkos Pál, Kata Dorina Fügedi, László Drahos, Gitta Schlosser, Csilla Oláh, Henning Reis, Ilona Kovalszky, Tibor Szarvas, Lilla Turiák.

  Prostate cancer is one of the most frequent cancer types among men. Several biomarkers and risk assessment methods are already available; however, enhancing their selectivity and sensitivity is still necessary. For improving therapeutic decisions, both basic and clinical research studies are still ongoing for a better understanding of the underlying molecular mechanisms. The enzymatic digests of heparan sulfate (HS) and chondroitin sulfate (CS) chains were investigated in tissue samples taken from patients with prostate cancer (PCa) and benign prostate hyperplasia (BPH) with the HPLC-MS methodology. None of the HS species analyzed showed correlating alterations with currently used markers such as clinical stage, Gleason score, or prostate-specific antigen (PSA) level. The total quantity and sulfation motifs of CS were both significantly different among BPH and different risk groups of PCa. Furthermore, the cancer-specific survival of patients can be predicted based on the levels of non-sulfated and doubly sulfated CS disaccharides as well as the total HS content and the doubly and triply sulfated HS disaccharide ratios. These disaccharide ratios proved to be independent markers from clinical parameters. Further investigations of glycosaminoglycan motifs were proposed for the validation of the results on independent patient cohorts as well.

Keywords:  HPLC; benign prostate hyperplasia; chondroitin sulfate; glycomics; glycosaminoglycan; heparan sulfate; mass spectrometry; prostate cancer; proteoglycan

DOI:  https://doi.org/10.3390/cancers14194867
J Proteins Proteom. 2022 Oct 02. 1-17

Mass spectrometric analysis of chondroitin sulfate-linked peptides.

Madan Gopal Ramarajan, Mayank Saraswat, Rohit Budhraja, Kishore Garapati, Kimiyo Raymond, Akhilesh Pandey.

  Chondroitin sulfate proteoglycans (CSPGs) are extracellular matrix components composed of linear glycosaminoglycan (GAG) side chains attached to a core protein. CSPGs play a vital role in neurodevelopment, signal transduction, cellular proliferation and differentiation and tumor metastasis through interaction with growth factors and signaling proteins. These pleiotropic functions of proteoglycans are regulated spatiotemporally by the GAG chains attached to the core protein. There are over 70 chondroitin sulfate-linked proteoglycans reported in cells, cerebrospinal fluid and urine. A core glycan linker of 3-6 monosaccharides attached to specific serine residues can be extended by 20-200 disaccharide repeating units making intact CSPGs very large and impractical to analyze. The current paradigm of CSPG analysis involves digesting the GAG chains by chondroitinase enzymes and analyzing either the protein part, the disaccharide repeats, or both by mass spectrometry. This method, however, provides no information about the site of attachment or the composition of linker oligosaccharides and the degree of sulfation and/or phosphorylation. Further, the analysis by mass spectrometry and subsequent identification of novel CSPGs is hampered by technical challenges in their isolation, less optimal ionization and data analysis. Unknown identity of the linker oligosaccharide also makes it more difficult to identify the glycan composition using database searching approaches. Following chondroitinase digestion of long GAG chains linked to tryptic peptides, we identified intact GAG-linked peptides in clinically relevant samples including plasma, urine and dermal fibroblasts. These intact glycopeptides including their core linker glycans were identified by mass spectrometry using optimized stepped higher energy collision dissociation and electron-transfer/higher energy collision dissociation combined with hybrid database search/de novo glycan composition search. We identified 25 CSPGs including three novel CSPGs that have not been described earlier. Our findings demonstrate the utility of combining enrichment strategies and optimized high-resolution mass spectrometry analysis including alternative fragmentation methods for the characterization of CSPGs.
Supplementary Information: The online version contains supplementary material available at 10.1007/s42485-022-00092-3.

Keywords:  EtHCD; Glycopeptide; Glycoproteomics; Glycosaminoglycans; HCD; Proteoglycans

DOI:  https://doi.org/10.1007/s42485-022-00092-3
Carbohydr Polym. 2022 Dec 15. pii: S0144-8617(22)01031-1. [Epub ahead of print]298 120126

Dual antibacterial and anti-inflammatory efficacy of a chitosan-chondroitin sulfate-based in-situ forming wound dressing.

Swati Sharma, Harishkumar Madhyastha, Shrikant Sitaram Kirwale, Kentaro Sakai, Yash T Katakia, Syamantak Majumder, Aniruddha Roy.

  None of the currently available wound dressings exhibit combined antibacterial and anti-inflammatory activity. Using polyelectrolyte complexation (PEC) between a cationic polysaccharide chitosan (CH) and an anionic glycosaminoglycan chondroitin sulfate (CS), we have developed a unique in-situ forming scaffold (CH-CS PEC), which develops at the wound site itself to influence the function of the wound bed cells. The current study demonstrated that CH-CS PEC could induce bacterial cell death through membrane pore formation and increased ROS production. Moreover, possibly due to its unique material properties including medium-soft viscoelasticity, porosity, and surface composition, CH-CS PEC could modulate macrophage function, increasing their phagocytic ability with low TNF-α and high IL-10 production. Faster wound closure and decreased CFU count was observed in an in-vivo infected wound model, with reduced NF-κB and increased VE-cadherin expression, indicating reduced inflammation and enhanced angiogenesis. In summary, this study exhibited that CH-CS PEC has substantial antibacterial and immunomodulatory properties.

Keywords:  Anti-inflammatory; Antibacterial; Chitosan; Chondroitin sulfate; In-situ scaffold; Wound healing

DOI:  https://doi.org/10.1016/j.carbpol.2022.120126
Int J Mol Sci. 2022 Oct 03. pii: 11724. [Epub ahead of print]23(19):

Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses.

Kohtaro Minami, Hideto Morimoto, Hiroki Morioka, Atsushi Imakiire, Masafumi Kinoshita, Ryuji Yamamoto, Tohru Hirato, Hiroyuki Sonoda.

  Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.

Keywords:  biomarker; blood-brain barrier; cerebrospinal fluid; heparan sulfate; lysosomal storage disorders; mucopolysaccharidoses

DOI:  https://doi.org/10.3390/ijms231911724
Glycobiology. 2022 Oct 14. pii: cwac068. [Epub ahead of print]

Investigation of the pharmacokinetic properties of synthetic heparan sulfate oligosaccharides.

Katelyn Arnold, Zhangjie Wang, Andrew Lucas, William Zamboni, Yongmei Xu, Jian Liu.

  Heparan sulfate (HS) is a sulfated polysaccharide with a wide range of biological activities. There is increasing interest in the development of structurally homogeneous HS oligosaccharides as therapeutics. However, the factors influencing the pharmacokinetic properties of HS-based therapeutics remain unknown. Here we report the pharmacokinetic properties of a panel of dodecasaccharides (12-mers) with varying sulfation patterns in healthy mice and uncover the pharmacokinetic properties of an octadecasaccharide (18-mer) in acutely injured mice. In the 12-mer panel, one 12-mer, known as dekaparin, is anticoagulant, and three 12-mers are non-anticoagulant. The concentrations of 12-mers in plasma and urine were determined by the disaccharide analysis using a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We observed a striking difference between anticoagulant and non-anticoagulant oligosaccharides in the 12-mer panel, showing that anticoagulant dekaparin had a 4.6-to-8.6-fold slower clearance and 4.4-to-8-fold higher plasma exposure, compared to non-anticoagulant 12-mers. We also observed that the clearance of HS oligosaccharides is impacted by disease conditions. Using an anti-inflammatory 18-mer, we discovered that the clearance of 18-mer is reduced 2.8-fold in a liver failure mouse model compared to healthy mice. Our results suggest that oligosaccharides are rapidly cleared renally if they have low interaction with circulating proteins. We observed that the clearance rate of oligosaccharides is inversely associated with the degree of binding to target proteins, which can vary in response to pathophysiological conditions. Our findings uncover a contributing factor for the plasma and renal clearance of oligosaccharides which will aid the development of HS-based therapeutics.

Keywords:  heparan sulfate/ pharmacokinetics/ synthetic oligosaccharide/ therapeutics

DOI:  https://doi.org/10.1093/glycob/cwac068
Org Chem Front. 2022 Jun 07. 9(11): 2910-2920

Automated Solid Phase Assisted Synthesis of a Heparan Sulfate Disaccharide Library.

Sherif Ramadan, Guowei Su, Kedar Baryal, Linda C Hsieh-Wilson, Jian Liu, Xuefei Huang.

  Heparan sulfate (HS) regulates a wide range of biological events, including blood coagulation, cancer development, cell differentiation, and viral infections. It is generally recognized that structures of HS can critically impact its biological functions. However, with complex structures of naturally existing HS, systematic investigations into the structure-activity relationship (SAR) of HS and efforts to unlock their "sulfation code" have been largely limited due to the challenges in preparing diverse HS oligosaccharide sequences. Herein, we report an automated machine-aided solid-phase strategy that significantly expedited the assembly of HS disaccharides. The key strategically protected advanced disaccharide intermediates were immobilized onto Synphase lanterns. Divergent deprotections and sulfations of the disaccharides were achieved on the lanterns in high yields. In addition, the full synthetic process was automated, enabling the reproducible production of HS disaccharides. A library of 16 HS disaccharides with diverse sulfation patterns was prepared via this method. Compared to the traditional HS synthesis, this new strategy led to a reduction of 50% of the number of synthetic steps and over 80% of the number of column purification steps needed from the disaccharide intermediates, significantly improving the overall synthetic efficiency. The potential utility of the method was highlighted in a microarray study using the synthetic HS disaccharide library with fibroblast growth factor-2 (FGF-2), which yielded insights into the SAR of HS/FGF-2 interactions.

Keywords:  Automated synthesis; Synphase lanterns; fibroblast growth factor 2; heparan sulfate; library preparation

DOI:  https://doi.org/10.1039/d2qo00439a
Materials (Basel). 2022 Oct 06. pii: 6935. [Epub ahead of print]15(19):

Characterization of Synovial Fluid Components: Albumin-Chondroitin Sulfate Interactions Seen through Molecular Dynamics.

Natalia Kruszewska, Adam Mazurkiewicz, Grzegorz Szala, Małgorzata Słomion.

  The friction coefficient of articular cartilage (AC) is very low. A method of producing tailor-made materials with even similar lubrication properties is still a challenge. The physicochemical reasons for such excellent lubrication properties of AC are still not fully explained; however, a crucial factor seems to be synergy between synovial fluid (SF) components. As a stepping stone to being able to produce innovative materials characterized by a very low friction coefficient, we studied the interactions between two important components of SF: human serum albumin (HSA) and chondroitin sulfate (CS). The molecular dynamics method, preceded by docking, is used in the study. Interactions of HSA with two types of CS (IV and VI), with the addition of three types of ions often found in physiological solutions: Ca2+, Na+, and Mg2+, are compared. It was found that there were differences in the energy of binding values and interaction maps between CS-4 and CS-6 complexes. HSA:CS-4 complexes were bound stronger than in the case of HSA:CS-6 because more interactions were formed across all types of interactions except one-the only difference was for ionic bridges, which were more often found in HSA:CS-6 complexes. RMSD and RMSF indicated that complexes HSA:CS-4 behave much more stably than HSA:CS-6. The type of ions added to the solution was also very important and changed the interaction map. However, the biggest difference was caused by the addition of Ca2+ ions which were prone to form ionic bridges.

Keywords:  chondroitin sulfate; energy of binding; human serum albumin; hydrogen bonds; hydrophobic interactions; ionic interactions; molecular dynamics simulations; synovial fluid

DOI:  https://doi.org/10.3390/ma15196935
Carbohydr Res. 2022 Oct 03. pii: S0008-6215(22)00186-0. [Epub ahead of print]522 108685

Comparation of the structural characteristics and biological activities of chondroitin sulfates extracted from notochord and backbone of Chinese sturgeon (Acipenser sinensis).

Dawei Meng, Xiaoqian Leng, Yan Zhang, Jiang Luo, Hao Du, Yasuaki Takagi, Zhiyuan Dai, Qiwei Wei.

  To compare the structural properties and biological activities of chondroitin sulfate (CS) in two different tissues of Chinese sturgeon (Acipenser sinensis) and Russian sturgeon (Acipenser gueldenstaedti), we extracted their backbone cartilage CS (Cart-CS) and notochord CS (Noto-CS), and analyzed the CS structural properties using chromatographic and spectroscopic methods. The molecular weights of Chinese sturgeon Cart-CS and Noto-CS were 54.7 and 25.4 kDa, respectively, and the molecular weights of Russian sturgeon were 50.0 and 38.4 kDa, respectively. The disaccharide composition results showed that Cart-CS was mainly composed of CS-C, while Noto-CS was almost composed of pure CS-A. The antioxidant activity of sturgeon CS and its effect on collagen fibril formation were discussed. Sturgeon CS exhibited higher antioxidant activity than shark and bovine CSs. Sturgeon CS inhibited the self-assemble of type I collagen into fibrils. The inhibition effect of Cart-CS was higher than that of Noto-CS. The high value-added utilization of Cart-CS and Noto-CS will increase the value of sturgeon by-products. Furthermore, the disaccharide composition of CS in sturgeon depends on tissues of origin, but not on species. It means that the CS of Chinese sturgeon can be substituted by the CS of other commercial sturgeon. That will contribute to the protection of endangered species of Chinese sturgeon from illegal fishing and increase the value of commercial sturgeon by-products.

Keywords:  Antioxidant activity; Chinese sturgeon; Chondroitin sulfate; Collagen fibril; Russian sturgeon; Structure properties

DOI:  https://doi.org/10.1016/j.carres.2022.108685
J Agric Food Chem. 2022 Oct 13.

Fucosylated Chondroitin Sulfate against Parkinson's Disease through Inhibiting Inflammation Induced by Gut Dysbiosis.

Yimeng Liu, Xuyu Liu, Qiantao Ye, Yida Wang, Jiafu Zhang, Song Lin, Guang Wang, Xuesong Yang, Jichun Zhang, Shiguo Chen, Nian Wu.

  Growing evidence for the importance of the gut-brain axis in Parkinson's disease (PD) has attracted researchers' interest in the possible application of microbiota-based treatment approaches. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model, we looked into the prospect of treating PD with fucosylated chondroitin sulfate obtained from sea cucumbers Isostichopus badionotus (fCS-Ib). We showed that giving fCS-Ib polysaccharide orally greatly reduced the motor deficits, dopamine depletion, and alpha-synuclein increase caused by MPTP in the substantia nigra (SN). It appears that the anti-PD action of fCS-Ib polysaccharide could be attained by squelching inflammation. Glial cell hyperactivation in SN and overproduction of proinflammatory substances in serum could both be suppressed by fCS-Ib polysaccharide injection. The bacterial DNA in fresh colonic feces was submitted to 16S rRNA and untargeted metabolic analyses to confirm the participation of the microbiota-gut-brain axis in the aforementioned interpretation. The findings showed that the MPTP treatment-induced decrease in norank_f_Muribaculaceae and the increase in Staphylococcus were reversed by the administration of fCS-Ib polysaccharide. The NF-κB signaling pathway was shown to be involved in the fCS-Ib polysaccharide-induced anti-inflammation. In conclusion, our research demonstrated for the first time how fCS-Ib polysaccharide combats PD by reducing inflammation caused by gut microbial dysbiosis.

Keywords:  Parkinson’s disease; gut microbiota; inflammation; sea cucumber fucosylated chondroitin sulfate

DOI:  https://doi.org/10.1021/acs.jafc.2c06429
Animals (Basel). 2022 Oct 08. pii: 2705. [Epub ahead of print]12(19):

Value Ranges and Clinical Comparisons of Serum DHEA-S, IL-6, and TNF-α in Western Lowland Gorillas.

Ashley N Edes, Dawn Zimmerman, Balbine Jourdan, Janine L Brown, Katie L Edwards.

  Physiological data can provide valuable information about the health and welfare of animals. Unfortunately, few validated assays and a lack of information on species-typical levels of circulating biomarkers for wildlife make the measurement, interpretation, and practical application of such data difficult. We validated commercially available kits and calculated reference intervals (herein called "value ranges") for dehydroepiandrosterone-sulfate (DHEA-S), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) in a sample of zoo-housed western lowland gorillas due to the roles these biomarkers play in stress and immune responses. For each biomarker, we present species-specific value ranges for a sample of gorillas in human care (n = 57). DHEA-S did not vary significantly by sex or age, while IL-6 was higher in males and older gorillas and TNF-α was higher in females but not associated with age. We also compared non-clinical with clinical samples (n = 21) to explore whether these biomarkers reflect changes in health status. There was no significant difference between clinical and non-clinical samples for DHEA-S, but both IL-6 and TNF-α were significantly higher in gorillas showing clinical symptoms or prior to death. Additional work is needed to improve our understanding of normal versus clinical variation in these biomarkers, and we encourage continued efforts to identify and validate additional biomarkers that can be used to inform assessments of health and welfare in wildlife.

Keywords:  HPA axis; cytokines; health; immune response; reference intervals; stress response; zoo

DOI:  https://doi.org/10.3390/ani12192705
Microbiol Spectr. 2022 Oct 12. e0282222

Human Dendritic Cells Transmit Enterovirus A71 via Heparan Sulfates to Target Cells Independent of Viral Replication.

Leanne C Helgers, Michel S Bhoekhan, Dasja Pajkrt, Katja C Wolthers, Teunis B H Geijtenbeek, Adithya Sridhar.

  Enterovirus A71 (EV-A71) is a causative agent of life-threatening neurological diseases in young children. EV-A71 is highly infectious but it remains unclear how the virus disseminates from primary entry sites-the mucosa of the respiratory tract or the intestine-to secondary replication sites-skin or brain. Here, we investigated the role of dendritic cells (DCs) in EV-A71 dissemination. DCs reside in the mucosa of the airway and gut, and migrate to lymphoid tissues upon activation and, therefore, could facilitate EV-A71 dissemination to secondary replication sites. Monocyte-derived DCs were not permissive to different genotypes of EV-A71 but, notably, coculture with EV-A71-susceptiblle RD99 cells led to very efficient infection of RD99 cells. Notably, EV-A71 transmission of DCs to RD99 was independent of viral replication as a replication inhibitor did not affect transmission. Soluble heparin blocked EV-A71 transmission by DCs to RD99 cells, in contrast to antibodies against known attachment receptor DC-SIGN. These results strongly suggest that DCs might be a first target for EV-A71 and involved in viral dissemination via heparan sulfates and heparin derivatives might be an effective treatment to attenuate dissemination. IMPORTANCE EV-A71 is an emerging neurotropic virus that is of emerging concern and can result in polio-like illness. The exact mechanism of how EV-A71 results in neurological symptoms are unknown. In particular, the early dissemination of the virus from primary replication sites (airway and intestine) to secondary sites (central nervous system and skin) needs to be elucidated. There is evidence pointing toward a role for dendritic cells (DC) in EV-A71 transmission. Moreover, heparan sulfate (HS) binding mutations are observed in patients with severe diseases. Therefore, we evaluated the potential role of HS on DC in transmission. We find that HS are critical for transmitting EV-A71 by DC to target cells. Our data are consistent with other clinical and in vitro observations highlighting the importance of HS in EV-A71-induced disease.

Keywords:  dendritic cells; enterovirus; picornavirus; receptors

DOI:  https://doi.org/10.1128/spectrum.02822-22
Breast Cancer Res. 2022 Oct 08. 24(1): 66

Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study.

Aayah Nounu, Siddhartha P Kar, Caroline L Relton, Rebecca C Richmond.

   BACKGROUND: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.
METHODS: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.
RESULTS: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.
CONCLUSIONS: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.

Keywords:  Breast cancer; Mendelian randomization; Sex steroid hormones

DOI:  https://doi.org/10.1186/s13058-022-01553-9
J Exp Bot. 2022 Oct 12. pii: erac402. [Epub ahead of print]

Unique features of regulation of sulfate assimilation in monocots.

Parisa Rahimzadeh Karvansara, Ciaran Kelly, Raissa Krone, Ivan Zenzen, Daniela Ristova, Emely Silz, Timothy O Jobe, Stanislav Kopriva.

  Sulfate assimilation is an essential pathway of plant primary metabolism, regulated by the demand for reduced sulfur. The sulfur-containing tripeptide glutathione (GSH) is the key signal for such regulation in Arabidopsis, but little is known about the conservation of these regulatory mechanisms beyond the model species. Using two model monocot species, C3 rice (Oryza sativa) and C4Setaria viridis, and feeding of cysteine or GSH, we aimed to find out how conserved are the regulatory mechanisms described for Arabidopsis in these species. We showed that while in principle the regulation is similar, there are many species specific differences. For example, thiols supplied by the roots are translocated to the shoots in rice but remain in the roots of Setaria. Cysteine and GSH concentrations are highly correlated in Setaria, but not in rice. In both, rice and Setaria, GSH seems to be the signal for demand-driven regulation of sulfate assimilation. Unexpectedly, we observed cysteine oxidation to sulfate in both species, a reaction that does not occur in Arabidopsis. This reaction is dependent on sulfite oxidase, but the enzyme(s) releasing sulfite from cysteine still need to be identified. Altogether our data reveal a number of unique features in the regulation of sulfur metabolism in the monocot species and indicate the need of using multiple taxonomically distinct models to better understand the control of nutrient homeostasis, which is important for generating low input crop varieties.

Keywords:   Setaria viridis ; C4 photosynthesis; cysteine; glutathione; monocots; plant nutrition; regulation; rice; sulfate assimilation

DOI:  https://doi.org/10.1093/jxb/erac402
Nutrients. 2022 Sep 24. pii: 3964. [Epub ahead of print]14(19):

Trimethylamine N-Oxide (TMAO) and Indoxyl Sulfate Concentrations in Patients with Alcohol Use Disorder.

Laurent Coulbault, Alice Laniepce, Shailendra Segobin, Céline Boudehent, Nicolas Cabé, Anne Lise Pitel.

   BACKGROUND: Trimethylamine N-oxide (TMAO) and indoxyl sulfate (IS) are produced by the microbiota and the liver, and can contribute to brain aging and impaired cognitive function. This study aims to examine serum TMAO and IS concentrations in patients with alcohol-use disorder (AUD) at the entry for alcohol withdrawal, and the relationships with several biological, neuropsychological, and clinical parameters.
METHODS: TMAO and IS were quantified in thirty AUD inpatients and fifteen healthy controls (HC). The severities of AUD and alcohol withdrawal syndrome (AWS), and general cognitive abilities were assessed in AUD patients.
RESULTS: TMAO concentrations did not differ between HC and AUD patients. Several biomarkers assessing nutritional status and liver function were significantly different in AUD patients with the lowest TMAO concentrations compared to other AUD patients. IS concentration was significantly lower in AUD patients and a significant positive predictor of serum prealbumin variation during the acute phase of alcohol withdrawal. No relationship was observed between the concentrations of these metabolites and the severities of alcohol dependence, AWS, or cognitive deficits.
CONCLUSIONS: Our data suggest that AUD patients with low concentrations of TMAO or IS should probably benefit from a personalized refeeding program during the acute phase of alcohol withdrawal.

Keywords:  alcohol; alcohol used disorder; cognition; indoxyl sulfate; liver; trimethylamine N-oxide

DOI:  https://doi.org/10.3390/nu14193964