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Targeting glucose metabolism with dichloroacetate (DCA) reduces zika virus replication in brain cortical progenitors at different stages of maturation.
The underlying threat of new Zika virus (ZIKV) outbreaks remains, as no vaccines or therapies have yet been developed. In vitro research has shown that glycolysis is a key factor to enable sustained ZIKV replication in neuroprogenitors. However, neither in vivo nor clinical investigation of glycolytic modulators as potential therapeutics for ZIKV-related fetal abnormalities has been conducted. Accordingly, we tested the therapeutic potential of metabolic modulators in relevant in vitro systems comprising two pools of neuroprogenitors (NPCs), which resemble early and late stages of pregnancy. Effective doses of metabolic modulators [3.0 μM] dimethyl fumarate (DMF), [3.2 mM] dichloroacetate (DCA), and [6.3 μM] VER-246608 were determined for these cells by their effect on lactate release, pyruvate dehydrogenase (PDH) activity and cell survival. The drugs were used in a 24h pre-treatment and kept throughout ZIKV infection of NPCs. Drug effects and ZIKV replication were assessed at 24- and 56-h post-infection. In early NPCs treated with DMF, DCA and VER-246608, there was a significant reduction in the extracellular release of ZIKV potentially by PDH-mediated increased mitochondrial oxidation of glucose. Out of the three drugs, only DCA was observed to reduce viral replication in late NPCs treated with DCA. Altogether, our findings suggest that reduction of anaerobic glycolysis could be of therapeutic potential against ZIKV-related fetal abnormalities and that clinical translation should consider the use of specific glycolytic modulators over different trimesters.
Lung development genes, adult lung function and cardiovascular comorbidities.
BACKGROUND: The association between lower adult lung function and increased cardiovascular comorbidity has not been adequately explained. We investigated whether shared developmental signalling pathways, critical to lung development and repair, could partly explain it. METHODS: In UK Biobank (UKB), we performed pairwise colocalisation analysis of variants in 55 lung development genes associated with adult forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1)/FVC, to see if these are also associated with coronary heart disease (CHD), blood pressure (systolic, diastolic, hypertension), pulse pressure, Arterial Stiffness index and carotid intima-media thickness. For CHD, we meta-analysed data from UKB and the CARDIoGRAM consortium. RESULTS: We found that 12 of the 55 genes shared the same variant between one (or more) lung function trait and one (or more) cardiovascular trait (H4colocalisation). The direction of effects was always in keeping with our hypothesis (lower lung function-higher cardiovascular risk) for FVC, but not always for FEV1/FVC. The seven signals for hypertension and CHD all replicated nominally in the FinnGen study, while replication was poor in the China Kadoorie Biobank (CKB) study. In addition, we found a further 10 genes where genetic associations with lung function and cardiovascular traits were within the same gene but involved different variants (H3 colocalisation). Interestingly, six of all 22 genes (H4 and H3 colocalisation) were novel for cardiovascular traits; four replicated in FinnGen, three in CKB. CONCLUSION: Lung function and cardiovascular traits have shared developmental pathways that may partly explain why lower lung function, especially FVC, is associated with increased cardiovascular risk.
AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats.
Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.
SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides.
SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides (ASOs) targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons.
Dissecting metabolic dysfunction- and alcohol-associated liver disease (MetALD) using proteomic and metabolomic profiles.
BACKGROUND: & Aim, Metabolic dysfunction associated and alcohol associated liver disease (MetALD) is a poorly understood condition that bridges cardiometabolic and alcohol-related pathological characteristics. We aim to distinguish MetALD patients who share similar molecular signatures with alcohol-related liver disease (ALD) and those share signatures with metabolic dysfunction-associated steatotic liver disease (MASLD), and assess their prognostic risk for complications and mortality. METHODS: Our analysis involved 443,453 European participants from UK Biobank, including 34,147 with MetALD, 11,220 with ALD, and 124,034 with MASLD. We employed Elastic Net Regression to classify ALD and MASLD involving 249 plasma metabolites and/or 2,941 plasma proteins with various sensitivity analyses. We then used the selected concise model in MetALD patients to identify alcohol-predominant group (classified to ALD) and cardiometabolic-predominant group (classified to MASLD). Finally, we explored their 15-year risk of major outcomes (i.e., heart failure, myocardial infarction, stroke, cirrhosis, hepatocellular carcinoma and mortality) using Cox regression. RESULTS: The metabolome alone discriminated ALD from MASLD with an Area under the Curve (AUC) of 0.86, while the proteome alone achieved an AUC of 0.96. Adding age, sex, BMI, liver enzymes, or metabolome information did not enhance the AUC of the proteome model. A ten-protein model differentiated ALD and MASLD with an AUC of 0.93. This model identified that alcohol-predominant MetALD patients had significantly higher risks of mortality, and cirrhosis, along with elevated fibrosis scores and higher fibrosis stages, compared to cardiometabolic-predominant patients. CONCLUSIONS: This study emphasizes the importance of subtyping differentiation using proteome data for personalized treatment and improved prognostic outcomes in MetALD patients.
Immunotherapy for atherosclerosis.
Cardiovascular disease is the global #1 cause of mortality and morbidity. The majority of cardiovascular diseases is caused by atherosclerosis, a lipid-driven, inflammatory disease of the middle- and large-sized arteries. The disease is characterized by the formation of atherosclerotic plaques throughout the arterial tree. Over the years, insights into the pathogenesis of atherosclerosis have shifted from a 'lipid-driven' model to a 'response-to-injury' perspective, and more recently to a 'lipid-driven inflammatory disease' viewpoint. We are now aware that a network of multiple immune cell-types and -subsets of the innate and adaptive immune system inhabit our arteries. Intricate interactions between these immune cellsubsets, non-immune cells, and local environmental substances such as lipids, cell debris and calcium cause a fluidic balance of pro-inflammatory and regulatory responses. A dysregulation of this balance towards a pro-inflammatory milieu drives atherosclerotic disease progression. Although we have acknowledged that atherosclerosis is an inflammatory disease, state-of-theart treatments are still based on lipid lowering, anti-hypertensive and lifestyle-changing strategies. In the past decade, clinical phase I, II and III trials targeting the immune system revealed that patients tolerate immunotherapy, show decreased inflammation and/or had a reduction in cardiovascular endpoints. However, the search for novel immunotherapeutic targets and treatment regimens as well as stratification of patients who would benefit from such treatments to combat atherosclerotic cardiovascular disease is only just beginning. In this review article, we will highlight the newest insights on the different cell subsets and components of the immune system in atherosclerosis and elaborate on current and future immunotherapeutics to treat atherosclerotic cardiovascular disease.
Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression
BackgroundSlope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs).MethodsWe estimated treatment effects on the acute and chronic GFR slopes and on the established CE of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes.ResultsTreatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R2 (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m2 greater acute GFR decline for the treatment versus control increased the hazard ratio for the established CE by 11.4% (7.9%-15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the 3-year total slope defined as the average slope extending from baseline to 3 years.ConclusionsTreatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.
Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches.
Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
The effects of fasting on acute ischemic infarcts in the rat.
Inflammation is largely detrimental early in the acute phase of stroke but beneficial at more chronic stages. Fasting has been shown to reduce inflammation acutely. This preliminary study aimed to determine whether post-ischemic fasting improves stroke outcomes through attenuated inflammation. After an endothelin-1 lesion was created in the striatum, Wistar rats were subjected to either regular feeding or water-only fasting for 24 hours. Brain damage and central inflammation were measured histologically, while systemic inflammation was assessed through blood analysis. After 24 hours, fasting was found to reduce infarct volume and BBB breakdown, and lower both circulating and brain neutrophils. These findings suggest that fasting may be a beneficial non-pharmacological additive therapeutic option for cerebral ischemia, potentially by reducing inflammation in the acute stage of the disease.
Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke.
The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the reopening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 h in vitro contracted after less than 1 h, which was about 7 h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia; however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a mechanism that is independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, we showed that rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 min following recanalisation. Our findings suggest that rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.
Effect of supplementation with vitamin D on biochemical markers of iron status and erythropoiesis in older people: BEST-D trial.
Previous observational studies suggested that vitamin D may control absorption of iron by inhibition of hepcidin, but the causal relevance of these associations is uncertain. Using placebo-controlled randomization, we assessed the effects of supplementation with vitamin D on biochemical markers of iron status and erythropoiesis in community-dwelling older people living in the United Kingdom (UK). The BEST-D trial, designed to establish the optimum dose of vitamin D3 for future trials, had 305 participants, aged 65 years or older, randomly allocated to 4000 IU vitamin D3 (n=102), 2000 IU vitamin D3 (n=102), or matching placebo (n=101). We estimated the effect of vitamin D allocation on plasma levels of hepcidin, soluble transferrin receptor (sTfR), ferritin, iron, transferrin, saturated transferrin (TSAT%), and the sTfR-ferritin index. Despite increases in 25-hydroxy-vitamin D, neither dose had significant effects on biochemical markers of iron status or erythropoiesis. Geometric mean concentrations were similar in vitamin D3 arms vs placebo for hepcidin (20.7 [SE 0.90] vs 20.5 [1.21] ng/mL), sTfR (0.69 [0.010] vs 0.70 [0.015] µg/mL), ferritin (97.1 [2.81] vs 97.8 [4.10] µg/L) and sTfR-ferritin ratio (0.36 [0.006] vs 0.36 [0.009]), respectively, while arithmetic mean levels were similar for iron (16.7 [0.38] vs 17.3 [0.54] µmol/L), transferrin (2.56 [0.014] vs 2.60 [0.021] g/dL), and TSAT% (26.5 [0.60] vs 27.5 [0.85]). The proportions of participants with ferritin <15 µg/L and TSAT<16% were unaltered by vitamin D3 suggesting that 12 months of daily supplementation with moderately high doses of vitamin D3 are unlikely to alter the iron status of older adults.