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BACKGROUND Digital health literacy has emerged as a critical skillset to navigate the digital age. OBJECTIVE This review sought to broadly summarise the literature on associations between digital health literacy and: (a) socio-demographic characteristics, (b) health resource use, and (c) health outcomes in the general population, patient groups, or parent/caregiver groups. METHODS A rapid review of literature published between January 2016 and May 2022 was conducted through a search of four online databases. Inclusion criteria for articles were: participants were from countries where English was primary language; research was either cross-sectional, longitudinal, prospective or retrospective, and published in English. RESULTS Thirty-six articles met the inclusion criteria. Evidence on the associations between digital health literacy and sociodemographic characteristics varied (27 of 36 included studies; 75%), with higher education (16 of 21 studies that examined the association; 76.2%) and younger age (12 of 21 studies; 57.1%%) tending to predict higher digital health literacy, however, other studies found no associations. No differences between genders were found across the majority of studies. Evidence across ethnic groups was too limited to draw conclusions; some studies showed those from minority groups had higher digital health literacy than Caucasians, while other studies showed no associations. Higher digital health literacy was associated with digital health resource use in the majority of the 20 studies (20/36; 55.6%) that examined this relationship. In addition, higher digital health literacy was also associated with health outcomes across three areas (psychosocial outcomes; chronic disease and health management behaviours; physical outcomes) across the 17 included studies (17/36; 47.2%) that explored these relationships. However, not all studies on the relationship between digital health literacy and health resource use and health outcomes were in the expected direction. CONCLUSIONS The review presents mixed results regarding the relationship between digital health literacy and sociodemographic characteristics, although studies broadly found that increased digital health literacy was positively associated with improved health outcomes and behaviours. Further investigations of digital health literacy on chronic disease outcomes are needed, particularly across diverse groups. Empowering individuals with the skills to critically access and appraise reliable health information on digital platforms and devices is critical, given emerging evidence that suggests those with low digital health literacy seek health information from unreliable sources. Identifying cost-effective strategies to rapidly assess and enhance digital health literacy capacities across community settings thus warrants continued investigation.

ObjectiveThe objective of this study was to evaluate the acceptance and uptake of COVID-19 vaccines in rural Bangladesh.DesignThis was a cross-sectional study conducted between June and November 2021.SettingThis study was conducted in rural Bangladesh.ParticipantsPeople older than 18 years of age, not pregnant and no history of surgery for the last 3 months were eligible to participate.Primary and secondary outcomesThe primary outcomes were proportions of COVID-19 vaccine acceptance and roll-out participation among the rural population. The secondary outcome was identification of correlates which contributed to COVID-19 vaccine acceptance and roll-out participation. Χ2tests and multivariable logistic regression analyses were performed to identify relevant correlates such as sociodemographic factors, clinical conditions and COVID-19-related factors.ResultsA total of 1603 participants were enrolled. The overall COVID-19 vaccine acceptance was very high (1521/1601, 95%), and half of the participants received at least one dose of the COVID-19 vaccine. Majority of participants wanted to keep others safe (89%) and agreed to the benefits of COVID-19 vaccines (88%). To fulfil the requirement of online registration for the vaccine at the time, 62% of participants had to visit an internet café and only 31% downloaded the app. Over half (54%) of participants were unaware of countries they knew and trust to produce the COVID-19 vaccine. Increased age, being housewives, underweight and undergraduate education level were associated with vaccine acceptance, while being female, increased age and being overweight/obese were associated with vaccine uptake. Trust in the health department and practical knowledge regarding COVID-19 vaccines were positively associated with both vaccine acceptance and uptake.ConclusionThis study found a very high COVID-19 vaccine acceptance in rural Bangladesh. Policymakers should support interventions aimed at increasing vaccine and general health literacy and ensure ongoing vaccine supply and improvement of infrastructure in rural areas.

Background Kidney disease is associated with impaired work productivity. However, the collective effect of missed work days, reduced output at work, and early withdrawal from the workforce is rarely considered in health-economic evaluations. Methods To determine the effect on work productivity of preventing incident cases of kidney disease, using the novel measure "productivity-adjusted life year" (PALY), we constructed a dynamic life table model for the Australian working-age population (aged 15-69 years) over 10 years (2020-2029), stratified by kidney-disease status. Input data, including productivity estimates, were sourced from the literature. We ascribed a financial value to the PALY metric in terms of gross domestic product (GDP) per equivalent full-time worker and assessed the total number of years lived, total PALYs, and broader economic costs (GDP per PALY). We repeated the model simulation, assuming a reduced kidney-disease incidence; the differences reflected the effects of preventing new kidney-disease cases. Outcomes were discounted by 5% annually. Results Our projections indicate that, from 2020 to 2029, the estimated number of new kidney-disease cases will exceed 161,000. Preventing 10% of new cases of kidney disease during this period would result in >300 premature deaths averted and approximately 550 years of life and 7600 PALYs saved-equivalent to a savings of US$1.1 billion in GDP or US$67,000 per new case avoided. Conclusions Pursuing a relatively modest target for preventing kidney disease in Australia may prolong years of life lived and increase productive life years, resulting in substantial economic benefit. Our findings highlight the need for investment in preventive measures to reduce future cases of kidney disease.

BACKGROUND In March 2020, the Australian Government expanded general practitioner (GP) telehealth services in response to the coronavirus disease 2019 pandemic. OBJECTIVE This study sought to assess utilisation patterns of GP telehealth services in response to changing circumstances (before and during the COVID-19 pandemic, with or without lockdown) in regional Victoria, Australia. METHODS We conducted a secondary analysis of monthly Medicare claims data from July 2019 to June 2021 from 140 regional GP practices in western Victoria. The longitudinal patterns of proportion of GP telehealth consultations stratified by type of consultation (videoconference vs. telephone) and by geographical, consumer and consultation characteristics were analysed. RESULTS Telehealth comprised 25.8% of GP consultations over the two-year period (n total = 2,025,615). After the introduction of the Australian telehealth expansion policy in March 2020, there was a rapid uptake in GP telehealth services (from 0% to 15% of all consultations), with a peak in August 2020 (55%). Thereafter, utilisation declined steadily to 31% in January 2021 and tapered off to 28% in June 2021. Telephone services and shorter consults were the most dominant form, and those aged 15-64 years had higher telehealth utilisation rates than younger or older age groups. The proportion of video consultations was higher during periods with government-imposed lockdown, and higher in the most socioeconomically advantaged areas compared to less socioeconomically advantaged areas. CONCLUSIONS Our findings support the continuation of telehealth use in rural and regional Australia post-pandemic. Future policy must identify mechanisms to reduce existing equity gaps in video consultations and consider patient- and system-level implications of the dominant use of short telephone consults.

Background Cardiorenal syndrome (CRS) is a major health burden worldwide in need of novel therapies, as current treatments remain suboptimal. The present study assessed the therapeutic potential of apoptosis signal-regulating kinase 1 (ASK1) inhibition in a rat model of CRS. Methods Adult male Sprague-Dawley rats underwent surgery for myocardial infarction (MI) (week 0) followed by 5/6 subtotal nephrectomy (STNx) at week 4 to induce to induce a combined model of heart and kidney dysfunction. At week 6, MI + STNx animals were randomized to receive either 0.5% carboxymethyl cellulose (Vehicle, n = 15, Sham = 10) or G226 (15 mg/kg daily, n = 11). Cardiac and renal function was assessed by echocardiography and glomerular filtration rate (GFR) respectively, prior to treatment at week 6 and endpoint (week 14). Haemodynamic measurements were determined at endpoint prior to tissue analysis. Results G226 treatment attenuated the absolute change in left ventricular (LV) fractional shortening and posterior wall thickness compared to Vehicle. G226 also attenuated the reduction in preload recruitable stroke work. Increased myocyte cross sectional area, cardiac interstitial fibrosis, immunoreactivity of cardiac collagen-I and III and cardiac TIMP-2 activation, were significantly reduced following G226 treatment. Although we did not observe improvement in GFR, G226 significantly reduced renal interstitial fibrosis, diminished renal collagen-I and -IV, kidney injury molecule-1 immunoreactivity as well as macrophage infiltration and SMAD2 phosphorylation. Conclusion Inhibition of ASK1 ameliorated LV dysfunction and diminished cardiac hypertrophy and cardiorenal fibrosis in a rat model of CRS. This suggests that ASK1 is a critical pathway with therapeutic potential in the CRS setting.

BACKGROUND There has been a rapid shift towards adoption of virtual healthcare services in Australia. It is unknown how widely virtual care has been implemented or evaluated for the care of older adults in Australia. OBJECTIVE To review literature evaluating virtual care initiatives for older adults across a wide range of health conditions and modalities and identify key challenges and opportunities for wider adoptions at both patient and system levels in Australia. METHODS A scoping review of the literature was conducted. Medline, EMBASE, PsycInfo, CINAHL, AgeLine and grey literature (1 January 2011 – 8 March 2021) were searched to identify virtual care initiatives for older Australians (≥65 years of age). Results are reported according to the World Health Organisation digital health evaluation framework. RESULTS Among the 6,201 documents in the search results, we identified 94 documents that reported 80 unique virtual care initiatives. The majority were pilot studies (89%) targeting community-dwelling older adults (81%) with chronic disease (65%). Mode of delivery included videoconference, telephone, apps, device/monitoring systems and web-based technologies. Most initiatives showed either similar or better health and behavioural outcomes compared to in-person care. Key barriers for wider adoption were physical, cognitive, or sensory impairment in older adults; and staffing issues, legislative issues, and a lack of motivation among providers. CONCLUSIONS Virtual care is a viable model of care to address a wide range of health conditions in older adults in Australia. More embedded and integrative evaluations are needed to ensure virtually enabled care can be used more widely by older Australians and providers.

Background There has been a rapid shift toward the adoption of virtual health care services in Australia. It is unknown how widely virtual care has been implemented or evaluated for the care of older adults in Australia. Objective We aimed to review the literature evaluating virtual care initiatives for older adults across a wide range of health conditions and modalities and identify key challenges and opportunities for wider adoption at both patient and system levels in Australia. Methods A scoping review of the literature was conducted. We searched MEDLINE, Embase, PsycINFO, CINAHL, AgeLine, and gray literature (January 1, 2011, to March 8, 2021) to identify virtual care initiatives for older Australians (aged ≥65 years). The results were reported according to the World Health Organization’s digital health evaluation framework. Results Among the 6296 documents in the search results, we identified 94 that reported 80 unique virtual care initiatives. Most (69/80, 89%) were at the pilot stage and targeted community-dwelling older adults (64/79, 81%) with chronic diseases (52/80, 65%). The modes of delivery included videoconference, telephone, apps, device or monitoring systems, and web-based technologies. Most initiatives showed either similar or better health and behavioral outcomes compared with in-person care. The key barriers for wider adoption were physical, cognitive, or sensory impairment in older adults and staffing issues, legislative issues, and a lack of motivation among providers. Conclusions Virtual care is a viable model of care to address a wide range of health conditions among older adults in Australia. More embedded and integrative evaluations are needed to ensure that virtually enabled care can be used more widely by older Australians and health care providers.

Graphical abstract, Highlights • Increasing sphingolipid metabolism in cardiac fibroblasts inhibited TGFβ mediated collagen synthesis. • Dihydrosphingosine inhibits collagen synthesis in cardiac fibroblasts through substrate-enzyme-receptor interaction. • Dihydrosphingosine suppresses TGFβ/Smad and Akt signalling in cardiac fibroblasts., The sphingolipid de novo synthesis pathway, encompassing the sphingolipids, the enzymes and the cell membrane receptors, are being investigated for their role in diseases and as potential therapeutic targets. The intermediate sphingolipids such as dihydrosphingosine (dhSph) and sphingosine (Sph) have not been investigated due to them being thought of as precursors to other more active lipids such as ceramide (Cer) and sphingosine 1 phosphate (S1P). Here we investigated their effects in terms of collagen synthesis in primary rat neonatal cardiac fibroblasts (NCFs). Our results in NCFs showed that both dhSph and Sph did not induce collagen synthesis, whilst dhSph reduced collagen synthesis induced by transforming growth factor β (TGFβ). The mechanisms of these inhibitory effects were associated with the increased activation of the de novo synthesis pathway that led to increased dihydrosphingosine 1 phosphate (dhS1P). Subsequently, through a negative feedback mechanism that may involve substrate-enzyme receptor interactions, S1P receptor 1 expression (S1PR1) was reduced.

Non-dialysable protein-bound uremic toxins (PBUTs) contribute to the development of cardiovascular disease (CVD) in chronic kidney disease (CKD) and vice versa. PBUTs have been shown to alter sphingolipid imbalance. Dihydroceramide desaturase 1 (Des1) is an important gatekeeper enzyme which controls the non-reversible conversion of sphingolipids, dihydroceramide, into ceramide. The present study assessed the effect of Des1 inhibition on PBUT-induced cardiac and renal effects in vitro, using a selective Des1 inhibitor (CIN038). Des1 inhibition attenuated hypertrophy in neonatal rat cardiac myocytes and collagen synthesis in neonatal rat cardiac fibroblasts and renal mesangial cells induced by the PBUTs, indoxyl sulfate and p-cresol sulfate. This is at least attributable to modulation of NF-κB signalling and reductions in β-MHC, Collagen I and TNF-α gene expression. Lipidomic analyses revealed Des1 inhibition restored C16-dihydroceramide levels reduced by indoxyl sulfate. In conclusion, PBUTs play a critical role in mediating sphingolipid imbalance and inflammatory responses in heart and kidney cells, and these effects were attenuated by Des1 inhibition. Therefore, sphingolipid modifying agents may have therapeutic potential for the treatment of CVD and CKD and warrant further investigation. Refereed/Peer-reviewed

Cardiac fibrosis and myocyte hypertrophy play contributory roles in the progression of diseases such as heart Failure (HF) through what is collectively termed cardiac remodelling. The phosphoinositide 3- kinase (PI3K), protein kinase B (Akt) and mammalian target for rapamycin (mTOR) signalling pathway (PI3K/Akt- mTOR) is an important pathway in protein synthesis, cell growth, cell proliferation, and lipid metabolism. The sphingolipid, dihydrosphingosine 1 phosphate (dhS1P) has been shown to bind to high density lipids in plasma. Unlike its analog, spingosine 1 phosphate (S1P), the role of dhS1P in cardiac fibrosis is still being deciphered. This study was conducted to investigate the effect of dhS1P on PI3K/Akt signalling in primary cardiac fibroblasts and myocytes. Our findings demonstrate that inhibiting PI3K reduced collagen synthesis in neonatal cardiac fibroblasts (NCFs), and hypertrophy in neonatal cardiac myocytes (NCMs) induced by dhS1P, in vitro. Reduced activation of the PI3K/Akt- mTOR signalling pathway led to impaired translation of fibrotic proteins such as collagen 1 (Coll1) and transforming growth factor β (TGFβ) and inhibited the transcription and translation of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). PI3K inhibition also affected the gene expression of S1P receptors and enzymes such as the dihydroceramide delta 4 desaturase (DEGS1) and sphingosine kinase 1 (SK1) in the de novo sphingolipid pathway. While in myocytes, PI3K inhibition reduced myocyte hypertrophy induced by dhS1P by reducing skeletal muscle α- actin (αSKA) mRNA expression, and protein translation due to increased glycogen synthase kinase 3β (GSK3β) mRNA expression. Our findings show a relationship between the PI3K/Akt- mTOR signalling cascade and exogenous dhS1P induced collagen synthesis and myocyte hypertrophy in primary neonatal cardiac cells.

Background Coronary heart disease (CHD) is the highest individual disease burden in Australia and associated with productivity losses through unplanned absence from work, reduced output while at work and early labour force withdrawal. Approximately eighty per cent of CHD cases in Australia are preventable, suggesting the potential benefit of employing preventive strategies addressing populations at risk of CHD. Purpose To determine the preventable productivity burden attributable to CHD over the next ten years, using the novel productivity measure: the “productivity-adjusted life year” (PALY). Methods A dynamic life table model was constructed for the total Australian population, separated by CHD status. Analysis was limited to the Australian working-age population (15–69 years) over ten years (2020–2029). Australian age- and sex-specific prevalence, incidence, migration and mortality data was employed, and productivity estimates were sourced from the literature. The PALY was ascribed a financial value in terms of gross domestic product (GDP) per equivalent full-time worker. The total number of years lived, total PALYs, and total economic burden (in terms of cost of PALYs) were estimated for each year. The model simulation was repeated assuming incidence was reduced, and the differences represented the preventable productivity burden attributable to CHD. All outcomes beyond the first year were discounted by 5% per annum. Results Over the next ten years, the total projected years lived and PALYs among the Australian working-age population (with and without CHD) were approximately 132 million and 83 million, respectively, amounting to A$17.2 trillion (€10.5 trillion) in GDP. We predicted nearly 40,000 new (incident) CHD cases over this ten-year period. If, however, we could prevent these new cases of CHD, a total of 14,000 deaths could be averted, resulting in more than 8,000 years of life saved and 100,000 PALYs gained, equivalent to A$21 billion (€12.9 billion) in GDP. Conclusion Prevention of CHD will prolong both years of life lived and productive life years, resulting in substantial economic benefit. Policy makers and employers are encouraged to engage in preventive measures addressing CHD. Funding Acknowledgement Type of funding source: None

Protein-bound uremic toxins (PBUTs) have adverse effects on vascular function, which is imperative in the progression of cardiovascular and renal diseases. The role of sphingolipids in PBUT-mediated vasculo-endothelial pathophysiology is unclear. This study assessed the therapeutic potential of dihydroceramide desaturase 1 (Des1) inhibition, the last enzyme involved in de novo ceramide synthesis, to mitigate the vascular effects of the PBUT indoxyl sulfate (IS). Rat aortic rings were isolated and vascular reactivity was assessed in organ bath experiments followed by immunohistochemical analyses. Furthermore, cultured human aortic endothelial cells were assessed for phenotypic and mechanistic changes. Inhibition of Des1 by a selective inhibitor CIN038 (0.1 to 0.3 μM) improved IS-induced impairment of vasorelaxation and modulated immunoreactivity of oxidative stress markers. Des1 inhibition also reversed IS-induced reduction in endothelial cell migration (1.0 μM) by promoting the expression of angiogenic cytokines and reducing inflammatory and oxidative stress markers. These effects were associated with a reduction of TIMP1 and the restoration of Akt phosphorylation. In conclusion, Des1 inhibition improved vascular relaxation and endothelial cell migration impaired by IS overload. Therefore, Des1 may be a suitable intracellular target to mitigate PBUT-induced adverse vascular effects. Refereed/Peer-reviewed

Aims To determine the impact of preventing new (incident) cases of coronary heart disease (CHD) on years of life and productivity, using the novel measure ‘productivity-adjusted life year’ (PALY), over the next 10 years. Methods and results A dynamic life table model was constructed for the total Australian working-age population (15–69 years) over 10 years (2020–2029), separated by CHD status. Productivity estimates were sourced from the literature. The PALY was ascribed a financial value in terms of gross domestic product (GDP) per equivalent full-time worker. The total number of years lived, PALYs, and economic burden (in terms of GDP per PALY) were estimated. The model simulation was repeated assuming incidence was reduced, and the differences represented the impact of CHD prevention. All outcomes were discounted by 5% per annum. Over 10 years, the total projected years lived and PALYs in the Australian working-age population (with and without CHD) were 133 million and 83 million, respectively, amounting to A$17.2 trillion in GDP. We predicted more than 290 000 new (incident) CHD cases over the next 10 years. If all new cases of CHD could be prevented during this period, a total of 4 000 deaths could be averted, resulting in more than 8 000 years of life saved and 104 000 PALYs gained, equivalent to a gain of nearly A$21.8 billion (US$14.8 billion) in GDP. Conclusion Prevention of CHD will prolong years of life lived and productive life years, resulting in substantial economic benefit. Policy makers and employers are encouraged to engage in preventive measures addressing CHD.

Cardiorenal syndrome (CRS) is a multi-organ disease, encompassing heart, kidney and vascular system dysfunction. CRS is a worldwide problem, with high morbidity, mortality, and inflicts a significant burden on the health care system. The pathophysiology is complex, involving interactions between neurohormones, inflammatory processes, oxidative stress and metabolic derangements. Therapies remain inadequate, mainly comprising symptomatic care with minimal prospect of full recovery. Challenges include limiting the contradictory effects of multi-organ targeted drug prescriptions and continuous monitoring of volume overload. Novel strategies such as multi-organ transplantation and innovative dialysis modalities have been considered but lack evidence in the CRS context. The adjunct use of pharmaceuticals targeting alternative pathways showing positive results in preclinical models also warrants further validation in the clinic. In recent years, studies have identified the involvement of gut dysbiosis, uraemic toxin accumulation, sphingolipid imbalance and other unconventional contributors, which has encouraged a shift in the paradigm of CRS therapy.

Background The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial demonstrated that dapagliflozin reduced heart failure hospitalisations and mortality in patients with established heart failure, regardless of diabetic status. Purpose To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure, from the perspective of the Australian public healthcare system. Methods A Markov model populated with 1000 hypothetical individuals was constructed based on the DAPA-HF trial to assess the clinical outcomes and costs of patients with established heart failure and reduced ejection fraction over a lifetime time horizon. The model consisted of three health states: “Alive and event-free”, “Alive after non-fatal hospitalisation for heart failure” or “Dead”. Costs and utilities were estimated from published sources. Outcomes of interest were the incremental cost-effectiveness ratios (ICERs) in terms of cost per quality-adjusted life year (QALY) gained and cost per year of life saved (YoLS). All outcomes were discounted at a rate of 5% annually. Results Over a lifetime analysis, addition of dapagliflozin to standard care in patients with chronic heart failure prevented 88 acute heart failure hospitalisations (including readmission), and saved 416 (discounted) years of life and 288 (discounted) QALYs, at an additional cost of A$3,692,440 or €2,263,204 (discounted). This resulted in ICERs of A$8,875 (€5,439) per YoLS and A$12,482 (€7,650) per QALY gained, well below the Australian arbitrary willingness-to-pay threshold of A$50,000 (€30,645). Conclusion From the Australian public healthcare perspective, dapagliflozin is cost-effective when used as an adjunct therapy to standard care compared to standard care alone for the treatment of chronic heart failure with reduced ejection fraction. Funding Acknowledgement Type of funding source: None

Aims Indoxyl sulfate (IS), a protein-bound uremic toxin, is implicated in endothelial dysfunction, which contributes to adverse cardiovascular events in chronic kidney disease. Apoptosis signal regulating kinase 1 (ASK1) is a reactive oxygen species-driven kinase involved in IS-mediated adverse effects. This study assessed the therapeutic potential of ASK1 inhibition in alleviating endothelial effects induced by IS. Main methods IS, in the presence and absence of a selective ASK1 inhibitor (GSK2261818A), was assessed for its effect on vascular reactivity in rat aortic rings, and cultured human aortic endothelial cells where we evaluated phenotypic and mechanistic changes. Key findings IS directly impairs endothelium-dependent vasorelaxation and endothelial cell migration. Mechanistic studies revealed increased production of reactive oxygen species-related markers, reduction of endothelial nitric oxide synthase and increased protein expression of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). IS also increases angiopoietin-2 and tumour necrosis factor α gene expression and promotes transforming growth factor β receptor abundance. Inhibition of ASK1 ameliorated the increase in oxidative stress markers, promoted autocrine interleukin 8 pro-angiogenic signalling and decreased anti-angiogenic responses at least in part via reducing TIMP1 protein expression. Significance ASK1 inhibition attenuated vasorelaxation and endothelial cell migration impaired by IS. Therefore, ASK1 is a viable intracellular target to alleviate uremic toxin-induced impairment in the vasculature.

Cardiac fibrosis and myocyte hypertrophy are hallmarks of the cardiac remodelling process in cardiomyopathies such as heart failure (HF). Dyslipidemia or dysregulation of lipids contribute to HF. The dysregulation of high density lipoproteins (HDL) could lead to altered levels of other lipid metabolites that are bound to it such as sphingosine-1- phosphate (S1P). Recently, it has been shown that S1P and its analogue dihydrosphingosine-1-phosphate (dhS1P) are bound to HDL in plasma. The effects of dhS1P on cardiac cells have been obscure. In this study, we show that extracellular dhS1P is able to increase collagen synthesis in neonatal rat cardiac fibroblasts (NCFs) and cause hypertrophy of neonatal cardiac myocytes (NCMs). The janus kinase/signal transducer and activator (JAK/STAT) signalling pathway was involved in the increased collagen synthesis by dhS1P, through sustained increase of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). Extracellular dhS1P increased phosphorylation levels of STAT1 and STAT3 proteins, also caused an early increase in gene expression of transforming growth factor-β (TGFβ), and sustained increase in TIMP1. Inhibition of JAKs led to inhibition of TIMP1 and TGFβ gene and protein expression. We also show that dhS1P is able to cause NCM hypertrophy through S1P-receptor-1 (S1PR1) signalling which is opposite to that of its analogue, S1P. Taken together, our results show that dhS1P increases collagen synthesis in cardiac fibroblasts causing fibrosis through dhS1P-JAK/STAT-TIMP1 signalling.

Dihydrosphingolipids refer to sphingolipids early in the biosynthetic pathway that do not contain a C4-trans-double bond in the sphingoid backbone: 3-ketosphinganine (3-ketoSph), dihydrosphingosine (dhSph), dihydrosphingosine-1-phosphate (dhS1P) and dihydroceramide (dhCer). Recent advances in research related to sphingolipid biochemistry have shed light on the importance of sphingolipids in terms of cellular signalling in health and disease. However, dihydrosphingolipids have received less attention and research is lacking especially in terms of their molecular mechanisms of action. This is despite studies implicating them in the pathophysiology of disease, for example dhCer in predicting type 2 diabetes in obese individuals, dhS1P in cardiovascular diseases and dhSph in hepato-renal toxicity. This review gives a comprehensive summary of research in the last 10-15 years on the dihydrosphingolipids, 3-ketoSph, dhSph, dhS1P and dhCer, and their relevant roles in different diseases. It also highlights gaps in research that could be of future interest.

Cardiorenal syndrome (CRS) remains a global health burden with a lack of definitive and effective treatment. Protein-bound uremic toxin (PBUT) overload has been identified as a non-traditional risk factor for cardiac, renal and vascular dysfunction due to significant albumin-binding properties, rendering these solutes non-dialyzable upon the state of irreversible kidney dysfunction. Although limited, experimental studies have investigated possible mechanisms in PBUT-mediated cardiac, renal and vascular effects. The ultimate aim is to identify relevant and efficacious targets that may translate beneficial outcomes in disease models and eventually in the clinic. This review will expand on detailed knowledge on mechanisms involved in detrimental effects of PBUT, specifically affecting the heart, kidney and vasculature, and explore potential effective intracellular targets to abolish their effects in CRS initiation and/or progression.

Background Cardiac remodelling is a dynamic process whereby structural and functional changes occur within the heart in response to injury or inflammation. Recent studies have demonstrated reactive oxygen species sensitive MAPK, apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in cardiac remodelling. This study aims to determine the effectiveness of small molecule ASK1 inhibitors on these processes and their therapeutic potential. Methods Neonatal rat cardiac fibroblasts (NCF) were pre-treated with ASK1 inhibitors, G2261818A (G226) and G2358939A (G235), for 2 hours before stimulated with 100 nM angiotensin II (AngII), 10 μM indoxyl sulphate (IS) or 10 ng/ml transforming growth factor β1 (TGFβ1) for 48 hours. Neonatal rat cardiac myocytes (NCM) were pre-treated with G226 and G235 for 2 hours before being stimulated with 100 nM AngII for 60 hours, 10 μM IS, 10 ng/ml interleukin 1β (IL-1β) or tumour necrosis factor α (TNFα) for 48 hours. 3H-proline and 3H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Pro-fibrotic, pro-hypertrophic and THP-1 inflammatory cytokine gene expressions were determined by RT-PCR. Results Both G226 and G235 dose-dependently attenuated AngII-, IS-, IL-1β- and TNFα-stimulated NCM hypertrophy and hypertrophic gene expression, IS-, AngII- and TGFβ1-stimulated NCF collagen synthesis and AngII- and TGFβ1-stimulated pro-fibrotic gene expression. Inhibition of ASK1 by G226 and G235 inhibited lipopolysaccharides-stimulated inflammatory cytokine gene expression in THP-1 cells. Conclusions Selective ASK1 inhibition confers anti-hypertrophic and anti-fibrotic effects in cardiac cells, and anti-inflammation in monocytic cells. ASK1 inhibitors may represent novel therapeutic agents to alleviate cardiac remodelling post cardiac injury where hypertrophy, fibrosis and inflammation play critical roles.

Stem cell therapy has been tested for cardiac disease therapy for decades. Initially, researchers only considered stem cells’ differentiative ability to repair damaged cardiac tissue. However, studies have now uncovered novel mechanisms contributing to stem cell healing properties to repair injured cardiac tissue, including via paracrine signaling and exosome secretions, leading to amelioration of cardiac remodeling and enhancement of proliferation, regeneration and survival of stem cell-derived cardiac cells. Understanding these underlying mechanisms could help researchers utilize stem cells as a therapeutic strategy for cardiac disease effectively and address the current limitations, mainly surrounding its survival and differentiative ability in the cardiac milieu. This review will discuss the known potential mechanisms underlying the role of stem cells in contributing to and for the treatment of heart diseases.