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Karel David, Vanessa Dubois, Anja Verhulst, Vera Sommers, Dieter Schollaert, Ludo Deboel, Karen Moermans, Geert Carmeliet, Patrick D'Haese, Dirk Vanderschueren, Frank Claessens, Pieter Evenepoel, and Brigitte Decallonne

Patients suffering from chronic kidney disease (CKD) often experience bone loss and arterial calcifications. It is unclear if hypogonadism contributes to the development of these complications, and whether androgen therapy might prevent them. Male adult rats were randomized into 4 groups. The first group received standard chow (Control), while three other groups were fed a 0.25% adenine/low vitamin K diet (CKD). Two CKD groups were treated with testosterone (T) or dihydrotestosterone (DHT), whereas the control group and one CKD group received vehicle (VEH). CKD animals had 10-fold higher serum creatinine and more than 15-fold higher PTH-levels compared to controls. Serum T levels were more than 2-fold lower in the CKD-VEH group compared to Control-VEH and CKD-T groups. Seminal vesicle weight was reduced by 50% in CKD-VEH animals, and restored by T and DHT. CKD animals showed a low bone mass phenotype with decreased trabecular bone volume fraction and increased cortical porosity, which was not rescued by androgen treatment. Aortic calcification was much more prominent in CKD animals and not unequivocally prevented by androgens. Messenger RNA expression of the androgen receptor-responsive genes Acta1 and Col1a1 was reduced by CKD and stimulated by androgen treatment in levator ani muscle, but not in bone or aortic tissue. We conclude that adenine-induced CKD results in the development of hypogonadism in male rats. Androgen therapy is effective in restoring serum T levels and androgen-sensitive organ weights, but does not prevent bone loss or arterial calcifications, at least not in the presence of severe hyperparathyroidism.

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J N Zamarbide Losada, E Sulpice, S Combe, G S Almeida, D A Leach, J Choo, L Protopapa, M P Hamilton, S McGuire, X Gidrol, C L Bevan, and C E Fletcher

Breast cancer (BC) is the most diagnosed cancer in women worldwide. In estrogen receptor (ER)-positive disease, anti-estrogens and aromatase inhibitors (AI) improve patient survival; however, many patients develop resistance. Dysregulation of apoptosis is a common resistance mechanism; thus, agents that can reinstate the activity of apoptotic pathways represent promising therapeutics for advanced drug-resistant disease. Emerging targets in this scenario include microRNAs (miRs). To identify miRs modulating apoptosis in drug-responsive and -resistant BC, a high-throughput miR inhibitor screen was performed, followed by high-content screening microscopy for apoptotic markers. Validation demonstrated that miR-361-3p inhibitor significantly increases early apoptosis and reduces proliferation of drug-responsive (MCF7), plus AI-/antiestrogen-resistant derivatives (LTED, TamR, FulvR), and ER- cells (MDA-MB-231). Importantly, proliferation-inhibitory effects were observed in vivo in a xenograft model, indicating the potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as a direct miR-361-3p target, and validation suggested miR-361-3p inhibitor effects might be mediated in part through FANCA modulation. Moreover, miR-361-3p inhibition resulted in p53-mediated G1 cell cycle arrest through activation of p21 and reduced BC invasion. Analysis of publicly available datasets showed miR-361-3p expression is significantly higher in primary breast tumours vspaired normal tissue and is associated with decreased overall survival. In addition, miR-361-3p inhibitor treatment of BC patient explants decreased levels of miR-361-3p and proliferation marker, Ki67. Finally, miR-361-3p inhibitor showed synergistic effects on BC growth when combined with PARP inhibitor, Olaparib. Together, these studies identify miR-361-3p inhibitor as a potential new treatment for drug-responsive and -resistant advanced BC.

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Emma Hamilton and Stephen Twigg

Diabetes-related foot disease (DFD), defined as ulceration, infection, or destruction of tissues of the foot in a person with current or previously diagnosed diabetes mellitus, is associated with a heavy burden for both patients and the healthcare system with high morbidity, mortality and costs. Improved outcomes for people with DFD are achieved with an interdisciplinary approach and adherence to best practice clinical guidelines, however in the Australian context, the vastness of the country presents unique challenges in achieving optimal outcomes for all people with DFD, with variation in service delivery, availability and accessibility between metropolitan, rural and remote areas. Aboriginal and Torres Strait Islander Australians and people with diabetes living in rural and remote areas experience higher rates of lower extremity amputation and further efforts and resources are required to improve outcomes for these high risk groups. In recent years, there have been advances in knowledge, including the understanding of the pathogenesis of diabetes-related peripheral neuropathy, genetic polymorphisms and mechanisms of disease associated with acute Charcot neuroarthropathy, biomarkers and potential mediators of diabetes-related foot ulcer (DFU) healing, the microbiology and microbiome profile of DFUs, pressure assessment and management as well as an expanded understanding of DFU sequelae and comorbidities. In this review, we describe new insights into pathophysiology, sequelae and comorbidities of DFD with a focus on basic and translational aspects and contributions to the field from Australian and New Zealand DFD researchers.

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Shiho Fujisaka, Yoshiyuki Watanabe, and Kazuyuki Tobe

The human body is inhabited by numerous bacteria, fungi, and viruses, and each part has a unique microbial community structure. The gastrointestinal tract harbors approximately 100 trillion strains comprising more than 1000 bacterial species that maintain symbiotic relationships with the host. The gut microbiota consists mainly of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Of these, Firmicutes and Bacteroidetes constitute 70–90% of the total abundance. Gut microbiota utilize nutrients ingested by the host, interact with other bacterial species, and help maintain healthy homeostasis in the host. In recent years, it has become increasingly clear that a breakdown of the microbial structure and its functions, known as dysbiosis, is associated with the development of allergies, autoimmune diseases, cancers, and arteriosclerosis, among others. Metabolic diseases, such as obesity and diabetes, also have a causal relationship with dysbiosis. The present review provides a brief overview of the general roles of the gut microbiota and their relationship with metabolic disorders.

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Yingning Ji, Wei Liu, Yemin Zhu, Yakui Li, Ying Lu, Qi Liu, Lingfeng Tong, Lei Hu, Nannan Xu, Zhangbing Chen, Na Tian, Lifang Wu, Lian Zhu, Shuang Tang, Ping Zhang, and Xuemei Tong

Transketolase (TKT), an enzyme in the non-oxidative branch of the pentose phosphate pathway (PPP), bi-directionally regulates the carbon flux between the PPP and glycolysis. Loss of TKT in adipose tissues decreased glycolysis and increased lipolysis and uncoupling protein-1 (UCP1) expression, protecting mice from high-fat diet-induced obesity. However, the role of TKT in brown adipose tissue (BAT)-dependent glucose homeostasis under normal chow diet remains to be elucidated. We found that TKT ablation increased levels of glucose transporter 4 (GLUT4), promoting glucose uptake and glycogen accumulation in BAT. Using the streptozotocin (STZ)-induced diabetic mouse model, we discovered that enhanced glucose uptake due to TKT deficiency in BAT contributed to decreasing blood glucose and weight loss, protecting mice from STZ-induced diabetes. Mechanistically, TKT deficiency decreased the level of thioredoxin-interacting protein, a known inhibitor for GLUT4, by decreasing NADPH and glutathione levels and inducing oxidative stress in BAT. Therefore, our data reveal a new role of TKT in regulating the anti-diabetic function of BAT as well as glucose homeostasis.

Open access

Vicki Chen, Gia V. Shelp, Jacob L. Schwartz, Niklas D.j. Aardema, Madison L. Bunnell, and Clara E. Cho

Micronutrients consumed in excess or imbalanced amounts during pregnancy may increase the risk of metabolic diseases in offspring but the mechanisms underlying these effects are unknown. Serotonin (5-hydroxytryptamine, 5-HT), a multifunctional indoleamine in the brain and the gut, may have key roles regulating metabolism. We investigated the effects of gestational micronutrient intakes on the central and peripheral serotonergic systems as modulators of the offspring metabolic phenotypes. Pregnant Wistar rats were fed an AIN-93G diet with 1-fold recommended vitamins (RV), high 10-fold multivitamins (HV), high 10-fold folic acid with recommended choline (HFolRC) or high 10-fold folic acid with no choline (HFolNC). Male and female offspring were weaned to a high-fat RV diet for 12 weeks. We assessed the central function using the 5-HT2C receptor agonist, 1-(3-chlorophenyl)piperazine (mCPP), and found that male offspring from the HV- or HFolRC-fed dams were less responsive (P<0.05) whereas female HFolRC offspring were more responsive to mCPP (P<0.01) at 6 weeks post-weaning. Male and female offspring from the HV and HFolNC groups, and male HFolRC offspring had greater food intake (males P<0.001; females P<0.001) and weight gain (males P<0.0001; females P<0.0001), elevated colon 5-HT (males P<0.01; females P<0.001) and fasting glucose concentrations (males P<0.01; females P<0.01) as well as body composition toward obesity (males P<0.01; females P<0.01) at 12 weeks post-weaning. Colon 5-HT was correlated with fasting glucose concentrations (males R2=0.78, P<0.0001; females R2=0.71, P<0.0001). Overall, the serotonergic systems are sensitive to the composition of gestational micronutrients, with alterations consistent with metabolic disturbances in offspring.

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Chau Thien Tay, Rhonda Garad, Aya Mousa, Mahnaz Bahri Khomami, Anju Joham, and Helena Teede

Polycystic ovary syndrome (PCOS) affects 8-13% of reproductive-aged women, impacts biopsychosocial factors, and creates a significant health-related economic burden across the reproductive, metabolic and psychological spectrum of complications. Despite being a heterogenous condition, recent genomic studies indicate that PCOS, regardless of diagnostic criteria and clinical features shares similar underlying biologic mechanisms. However, recent advances have shown that clinical reproductive and diagnostic features are poorly correlated to genotype and do not represent true phenotypes. Until we have better understanding of genetic and epigenetic influences on PCOS and long-term outcomes, targeted treatment is limited. In the interim a unified approach to integrate evidence, optimise management and guide future research is needed in PCOS is necessary. This has motivated an international collaboration to develop an International Evidence-Based PCOS Guideline to improve health outcomes in women with PCOS. Dissemination and translation of the guideline into health policy and clinical practice are crucial steps to close knowledge-practice gap, guide future research and enhance positive impact on the health of women with PCOS. Here we review the (i) understanding of aetiology and genetics of PCOS (ii) development and translation efforts of the 2018 International Evidence-based PCOS Guideline; (iii) current progress and plans for the guideline update, including the involvement of an early career researcher network to assist with evidence synthesis; and (iv the opportunity to target and guide future research for PCOS.

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Sunita M. C. De Sousa, Nele F Lenders, Lydia Lamb, Warrick J Inder, and Ann I McCormack

‘Pituitary tumours’ is an umbrella term for various tumours originating from different regions of the hypothalamic-pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours (PitNET). The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare. This review addresses the molecular and genetic aspects of pituitary adenomas. We first discuss the germline genetic variants underlying familial pituitary tumours, which account for approximately 5% of all pituitary adenoma cases. This includes variants in established pituitary adenoma/hyperplasia predisposition genes (MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHA, SDHB, SDHC, SDHD, SDHAF2) as well as emerging genetic associations. In addition, we discuss McCune-Albright syndrome which lies between the germline and somatic pituitary tumour genes as the causative GNAS mutations are postzygotic rather than being inherited, and the condition is associated with multiglandular features due to involvement of different cell lines rather than being limited to the pituitary. By contrast, somatic GNAS mutations contribute to sporadic acromegaly. USP8 is the only other gene where somatic driver mutations have been established in sporadic pituitary tumorigenesis. However, there are now known to be a variety of other somatic genetic and molecular changes underpinning sporadic pituitary adenomas which we will review, namely: copy number variation, molecular changes in signalling and hypoxia pathways, epithelial-mesenchymal transition, DNA repair, senescence, the immune microenvironment and epigenetics.

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Virginia Pszczolkowski, Meghan K Connelly, Adam D Beard, Amara D Benn, Jimena Laporta, Laura L Hernandez, and Sebastian I Arriola Apelo

Energy partitioning in lactating cows affects milk production, feed efficiency, and body reserves, with the latter having health implications for the transition into the following lactation. One mole-cule likely involved in the regulation of energy partitioning is serotonin. The objective of this ex-periment was to explore how increasing circulating serotonin, by intravenous infusion of the sero-tonin precursor 5-hydroxytrypophan (5-HTP), affects metabolic responses to a glucose challenge in mid-lactation cows as means to manipulate energy partitioning. We intravenously infused Hol-stein cows with 5-HTP (1 mg/kg bodyweight dissolved in saline, n=11), or saline alone as control (n=9), over 1 h/day for 3 days. Cows were fasted overnight on day 2. On day 3, fasted cows were given an intravenous bolus of glucose (0.092 g/kg bodyweight). Blood samples were collected for the following 120 minutes for metabolic and hormonal analysis. Infusion of 5-HTP elevated circu-lating concentration of serotonin and free fatty acids, reduced concentration of insulin and amino acids, and did not affect concentration of glucose and glucagon before the glucose challenge. Sur-rogate insulin sensitivity indices indicated improved insulin sensitivity in 5-HTP cows, but due to the unique metabolism of lactating ruminants, these index changes may instead reflect effects in insulin-independent glucose disposal, like milk synthesis. Challenging 5-HTP-treated cows with a glucose bolus reduced the insulin spike and blunted the decrease in free fatty acids, compared to saline cows, without changing glucose dynamics. Overall, these results suggest that serotonin stimulates insulin-independent glucose disposal, requiring less insulin to maintain normoglycemia.

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Melanie Tran, Golam Mostofa, Michael Picard, Jianguo Wu, Li Wang, and Dong-Ju Shin

Aberrant hepatic lipid metabolism is the major cause of non-alcoholic fatty liver disease (NAFLD) and is associated with insulin resistance and type 2 diabetes. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) is highly expressed in the liver; however, its functional role in regulating NAFLD and associated metabolic disorders are not known. Male wildtype and hepatocyte Serpina3N knockout (HKO) mice were fed a control diet, methionine- and choline-deficient diet or high-fat high-sucrose diet to induce NAFLD and markers of lipid metabolism and glucose homeostasis were assessed. SerpinA3N protein was markedly induced in mice with fatty livers. Hepatic deletion of SerpinA3N attenuated steatosis which correlated with altered lipid metabolism genes, increased fatty acid oxidation activity and enhanced insulin signaling in mice with NAFLD. Additionally, SerpinA3N HKO mice had reduced epididymal white adipose tissue mass, leptin, and insulin levels, improved glucose tolerance, and enhanced insulin sensitivity which was associated with elevated insulin-like growth factor binding protein-1 (IGFBP1) and activation of the leptin receptor (LEPR)-STAT3 signaling pathway. Our findings provide a novel insight into the functional role of SerpinA3N in regulating NAFLD and glucose homeostasis.