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Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. Registration: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.

BMP10 plays an essential role in regulating cardiac growth, chamber maturation, and maintaining normal expressions of several key cardiogenic factors; however, other functional roles of BMP10 in muscle remain unexplored. This study therefore undertook to investigate the roles of BMP10 in muscle physiology, using mouse-derived C2C12 myoblasts. Bmp10 silencing prevented a number of biological processes such as myogenic differentiation, glucose uptake, and lipid catabolism, whereas exogenous induction of BMP10 in C2C12 cells significantly stimulated the expression of proteins and genes involved in these processes, as well as mitochondrial biogenesis and thermogenesis, resulting in reduced lipid accumulation. A mechanistic study revealed that BMP10 stimulates myogenesis mainly via the Smad 1/5/8 signaling pathway. In conclusion, our data unveiled a previously unknown mechanism in the regulation of lipid metabolisms by BMP10 in muscle cells and identified its significant roles in systemic metabolic homeostasis, shedding light on BMP10 as a pharmacotherapeutic target to treat metabolic disorders.

Background: Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population.Methods: AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921.Findings: Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [Interpretation: Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke.Funding: National Health and Medical Research Council of Australia.

Salvianolic acid B (Sal B), a natural compound extracted from Salvia miltiorrhiza (Danshen), is well known for its anti-oxidative activity and treatment of cardiovascular diseases. However, little is known about the functional roles of Sal B in white adipocytes. Therefore, this study aimed to investigate the functions of Sal B in 3T3-L1 white adipocytes, with a focus on white fat browning effect. Exposure to Sal B significantly increased the expressions of beige-specific genes and thermogenic marker proteins. Sal B also suppressed lipogenesis and enhanced lipolysis in white adipocytes. A mechanistic study revealed that Sal B stimulates white fat browning via β3-AR and ERK signaling pathways in an independent manner. In conclusion, our findings indicate that Sal B is beneficial in the prevention and treatment of obesity, at least in part by promoting thermogenesis.

Aims Browning induction (beiging) of white adipocytes is an emerging prospective strategy to defeat obesity and its related metabolic disorders. Cytochrome P450 2E1 (CYP2E1), a membrane protein which belongs to the cytochrome P450 superfamily, reportedly functions in the xenobiotic metabolism in the body, especially ethanol metabolism. Although previous studies have reported the effect of CYP2E1 on obesity in animal models, the data remains controversial. In the current study, we investigate for the first time, the role of CYP2E1 in lipid metabolism in 3T3-L1 white adipocytes, with a focus on fat browning. Methods 3T3-L1 white adipocytes and Cyp2e1 siRNA were applied to investigate the role of CYP2E1 in white adipocytes. After that, cells were seperately exposed to β3-AR agonist, β3-AR antagonist and p38 inhibitor to identify the pathway which CYP2E1 was involved in to regulate browning event in white adipocytes. Key findings We found that CYP2E1 deficiency results in reduced adipogenesis and lipogenesis as well as brown adipocyte-like phenotype induction. A mechanistic study to identify the molecular signals for CYP2E1 regulation in the browning of white adipocytes revealed that CYP2E1 inhibition deters the β3-adrenergic receptor activation and its downstream targets. Significance Our data unveilved a previously unknown mechanism in the regulation of browning by CYP2E1 in 3T3-L1 white adipocytes, suggesting that CYP2E1 is a promising molecular target for the treatment of obesity and its related diseases.

With an average annual rainfall of 800-1150 mm/year, the Binh Thuan province is one of the driest places in Vietnam. The quantity and quality of groundwater play a significant role in the agriculture, aquaculture development, and daily life of the local communities. Recently, prolonged droughts combined with sea level rise and over-extraction of groundwater increased dramatically the seawater intrusion process. In 2012, the national center for water resources delineated the seawater intrusion extent in Binh Thuan based on water samples taken from shallow boreholes. The salinity thresholds of 3g/L and 1.5g/L were exceeded in the estuaries of the Luy, Long Song, and Ca Ty rivers. The geochemistry of groundwater in the Luy River catchment was studied to investigate the contamination of the aquifers. From 1991 to 2015, 98 water samples had been taken mostly from the shallow (< 10 m) wells in the area in both dry and rainy seasons. 71% of the water samples were fresh while 21% and 5% were lightly saline and moderately saline respectively. In summer 2020, 110 new water samples from both shallow and deep wells were collected in the Luy river catchment in wells from 3m to 40m. The TDS values are ranging from 105 to 23080 mg/L among which 48% are fresh (mostly at depth < 10 m), 40% slightly saline, 8% moderately saline, and 4% very saline. The samples show that the seawater intrusion expands not only horizontally at shallow depth along the river but also deeper down the aquifer in most of the study area, with some strong variations at short distance, which is confirmed by geophysical data. The chemical composition of water samples was analyzed showing evidence of seawater intrusion, but also the occurrence of freshening processes within the study area. The sediments in the Luy’s river catchment consist of sand, clay, marine fossils, gravel, and pebble and are quite heterogeneously distributed. They also underwent cyclic transgressive and regressive events from the Pleistocene to the Holocene. Therefore, the presence of fossil seawater trapped in the heterogeneous sediments in the Luy’s river delta is a possible hypothesis. Together with the presence of saltwater at larger depths, this points towards a situation more complex than previously thought. Saltwater intrusions are likely not only related to interaction with the river estuary, but also to the presence of fossil saltwater in the aquifer, and groundwater pumping and irrigation practices.

Cytochromes P450 (CYPs) are a multigene superfamily of constitutively expressed and inducible enzymes responsible for the detoxification of many endogenous and exogenous compounds and for the metabolism of numerous medications. The cytochrome P450 2F2 (CYP2F2) subfamily is preferentially expressed in the respiratory tract, but its functional role in adipocytes has never been explored. We found that CYP2F2 was highly expressed during the differentiation of the C3H10T1/2 murine mesenchymal stem cells to adipocytes and here we have explored its functional role in adipocytes. The expression of thermogenic marker proteins such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PR domain containing 16 (PRDM16), and uncoupling protein 1 (UCP1) and beige-fat specific genes were significantly increased in Cyp2f2-deficient 3T3-L1 adipocytes. Moreover, Cyp2f2 silencing led to reduced adipogenesis and lipogenesis, and enhanced lipid catabolism through the increased expression of lipolytic and fatty acid oxidative enzymes. A mechanistic study to identify molecular signals for CYP2F2-mediated negative regulation in the browning of white adipocytes revealed that CYP2F2 impairs the beta-3 adrenergic receptor (β3-AR) activation as well as its downstream regulators including protein kinase A (PKA), p38 mitogen-activated protein kinase (p38 MAPK), and activating transcription factor 2 (ATF2). This data provides evidence that CYP2F2 is a negative regulator of lipid catabolism and browning in white adipocytes, suggesting that inhibitors of CYP2F2 could be potential drugs for the treatment of obesity with a focus on enhancing energy expenditure.