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We have previously demonstrated that KS-133 is a specific and potent antagonist of vasoactive intestinal peptide receptor 2 (VIPR2). We have also shown that vasoactive intestinal peptide-VIPR2 signaling affects the polarity and activation of tumor-associated macrophages, which is another strategy for cancer immunotherapy apart from the activation of effector T cells. In this study, we aimed to examine whether the selective blockade of VIPR2 by KS-133 changes the polarization of macrophages and induces anti-tumor effects. In the presence of KS-133, genetic markers indicative of tumor-aggressive M1-type macrophages were upregulated, and conversely, those of tumor-supportive M2-type macrophages were downregulated. Daily subcutaneous administration of KS-133 tended to suppress the growth of CT26 tumors (murine colorectal cancer-derived cells) implanted subcutaneously in Balb/c mice. To improve the pharmacological efficacy and reduce the number of doses, we examined a nanoformulation of KS-133 using the US Food and Drug Administration-approved pharmaceutical additive surfactant Cremophor® EL. KS-133 nanoparticles (NPs) were approximately 15 nm in size and stable at 4°C after preparation. Meanwhile, KS-133 was gradually released from the NPs as the temperature was increased. Subcutaneous administration of KS-133 NPs once every 3 days had stronger anti-tumor effects than daily subcutaneous administration of KS-133. Furthermore, KS-133 NPs significantly enhanced the pharmacological efficacy of an immune checkpoint-inhibiting anti-PD-1 antibody. A pharmacokinetic study suggested that the enhancement of anti-tumor activity was associated with improvement of the pharmacokinetic profile of KS-133 upon nanoformulation. Our data have revealed that specific blockade of VIPR2 by KS-133 has therapeutic potential for cancer both alone and in combination with immune checkpoint inhibitors.

Previous studies reported that there is an association between abnormal body fluid balance and prognosis in colitis patients. However, it remains to be clarified the effects of colitis on characteristics of body electrolytes or water content, including alternation in blood pressure. In this study, we examined the effects of colon injury on body water balance and blood pressure in the dextran sodium sulfate (DSS)-induced colitis mouse model. We evaluated body electrolytes and water content, blood pressure, and urea-associated water conservation in DSS mice. By 5 days after the treatment, DSS mice exhibited diarrhea but relatively maintained body weight and total body sodium, potassium, and water content by increases in water intake and hepatic ureagenesis. On 7 days after DSS treatment, when colitis becomes severe, DSS mice significantly decreased food and water intake, and body weight but significantly increased relative total body sodium, potassium, and water content per dry mass. Notably, DSS induced more total body dry mass loss relative to water loss. These body electrolytes and water accumulation on day 7 were associated with a reduction in urinary osmole excretion and urine volume accompanied by renal urea accumulation. DSS mice significantly increased blood pressure by day 5 and then decreased on day 7. These findings suggest that body electrolyte and fluid imbalance and alternations in blood pressure in colitis vary with the stage and severity of the condition. Assessment and correction of electrolyte and water content at the tissue level would be important to improve the prognosis of colitis., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Ulva prolifera , known as Aonori in Japan, is an edible alga species that is mass-cultivated in Japan. Supplementation with Aonori-derived biomaterials has been reported to enhance metabolic health in previous studies. This was an experimental study that evaluated the metabolic health effects of NBF2, a formula made of algal and junos Tanaka citrus -derived biomaterials, on obesity and type 2 diabetes (T2DM). We used 18 obese and hyperglycemic Otsuka Long-Evans Tokushima Fatty (OLETF) rats that were assigned randomly to three groups of six animals: a high-dose NBF2 drink (20 mg/kg) group, a low-dose (10 mg/kg) NBF2 drink group and the control group that received 2 mL of tap water daily for a total of six weeks. We also used eight LETO rats as the normal control group. In addition to the glucose tolerance test (OGTT), ELISA and real-time PCR assays were performed. High-dose and lowdose NBF2 improved insulin sensitivity, as well as glycemic and lipid profiles, as compared with control rats. The OGTT showed that both NBF2 groups and LETO rats had normalized glycemia by the 90-min time-point. NBF2 up-regulated PPARα/γ-mRNA and Sirt2-mRNA gene expressions in BAT and improved the blood pressure profile. These findings suggest that the NBF2 formula, which activates PPAR-α/γ mRNA and Sirt2-mRNA, may reverse dyslipidemia and hyperglycemia in T2DM.

The hallmark of pathological cardiac hypertrophy is the decline in myocardial contractility caused by an energy deficit resulting from metabolic abnormalities, particularly those related to glucose metabolism. Here, we aim to explore whether D-Allose, a rare sugar that utilizes the same transporters as glucose, may restore metabolic equilibrium and reverse cardiac hypertrophy. Isolated neonatal rat cardiomyocytes were stimulated with phenylephrine and treated with D-Allose simultaneously for 48 h. D-Allose treatment resulted in a pronounced reduction in cardiomyocyte size and cardiac remodelling markers accompanied with a dramatic reduction in the level of intracellular glucose in phenylephrine-stimulated cells. The metabolic flux analysis provided further insights revealing that D-Allose exerted a remarkable inhibition of glycolysis as well as glycolytic capacity. Furthermore, in mice subjected to a 14-day continuous infusion of isoproterenol (ISO) to induce cardiac hypertrophy, D-Allose treatment via drinking water notably reduced ISO-induced cardiac hypertrophy and remodelling markers, with minimal effects on ventricular wall thickness observed in echocardiographic analyses. These findings indicate that D-Allose has the ability to attenuate the progression of cardiomyocyte hypertrophy by decreasing intracellular glucose flux and inhibiting glycolysis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Beta-adrenergic receptors (β-AR) are expressed on the membranes of various cell types and their activation affects body water balance by modulating renal sodium and water excretion, cardiovascular function and metabolic processes. However, β-AR-associated body fluid imbalance has not been well characterised. In the present study, we hypothesized that chronic β-AR stimulation increases electrolyte and water content at the tissue level. We evaluated the effects of isoproterenol, a non-selective β-AR agonist, on electrolyte and water balance at the tissue level. Continuous isoproterenol administration for 14 days induced cardiac hypertrophy, associated with sodium-driven water retention in the heart, increased the total body sodium, potassium and water contents at the tissue level, and increased the water intake and blood pressure of the mice. There was greater urine output in response to the isoproterenol-induced body water retention. These isoproterenol-induced changes were reduced by propranolol, a non-selective beta-receptor inhibitor. Isoproterenol-treated mice even without excessive water intake had higher total body electrolyte and water contents, and this tissue water retention was associated with lower dry body mass, suggesting that β-AR stimulation in the absence of excess water intake induces catabolism and water retention. These findings suggest that β-AR activation induces tissue sodium and potassium retention, leading to body fluid retention, with or without excess water intake. This characterisation of β-AR-induced electrolyte and fluid abnormalities improves our understanding of the pharmacological effects of β-AR inhibitors. Significance Statement We have shown that chronic β-AR stimulation causes cardiac hypertrophy associated with sodium-driven water retention in the heart and increases the accumulation of body sodium, potassium and water at the tissue level. This characterisation of the β-AR-induced abnormalities in electrolyte and water balance at the tissue level improves our understanding of the roles of β-AR in physiology and pathophysiology and the pharmacological effects of β-AR inhibitors., (Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.)

2-Deoxy-d-glucose (2DG) induces anticancer effects through glycolytic inhibition but it may raise the risk of arrhythmia. The rare monosaccharide d-allose also has anticancer properties, but its cardiac effects are unknown. We examined the effects of d-allose on adenosine triphosphate (ATP) production in neonatal rat cardiomyocytes. We showed that 25 mM d-allose selectively reduced glycolytic ATP, but had minimal impact on mitochondrial ATP, while 1 mM 2DG strongly inhibited both. Furthermore, d-allose had less impact on cell viability and was less cytotoxic than 2DG; neither compound caused apoptosis. Thus, d-allose selectively diminished glycolytic ATP production with no apparent effects on cardiomyocytes., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Air pollution and a number of metabolic disorders have been reported to increase the risk of severe COVID-19 outcomes. This study explored the association between severe COVID-19 outcomes, metabolic disorders and environmental air pollutants, at regional level, across 38 countries., Methods: We conducted an ecological study using COVID-19 data related to countries of the Organization for Economic Cooperation and Development (OECD), with an estimated population of 1.4 billion. They were divided into 3 regions: 1. Europe & Middle east; 2. Americas (north, central & south America); 3. East-Asia & West Pacific. The outcome variables were: COVID-19 case-fatality rate (CFR) and disability-adjusted life years (DALYs) at regional level. Freely accessible datasets related to regional DALYs, demographics and other environmental pollutants were obtained from OECD, WHO and the World in Data websites. Generalized linear model (GLM) was performed to determine the regional determinants of COVID-19 CFR and DALYs using the aggregate epidemiologic data (Dec. 2019-Dec. 2021)., Results: Overall cumulative deaths were 65,000 per million, for mean CFR and DALYs of 1.31 (1.2)% and 17.35 (2.3) years, respectively. Globally, GLM analysis with adjustment for elderly population rate, showed that COVID-19 CFR was positively associated with atmospheric PM 2.5 level (beta = 0.64(0.0), 95%CI: 0.06-1.35; p < 0.05), diabetes prevalence (beta = 0.26(0.1), 95%CI: 0.12-0.41; p < 0.001). For COVID-19 DALYs, positive associations were observed with atmospheric NOx level (beta = 0.06(0.0), 95%CI: 0.02-0.82; p < 0.05) and diabetes prevalence (beta = 0.32(0.2), 95%CI: 0.04-0.69; p < 0.05). At regional level, adjusted GLM analysis showed that COVID-19 CFR was associated with atmospheric PM 2.5 level in the Americas and East-Asia & Western Pacific region; it was associated with diabetes prevalence for countries of Europe & Middle east and East-Asia & Western Pacific region. Furthermore, COVID-19 DALYs were positively associated with atmospheric PM 2.5 and diabetes prevalence for countries of the Americas only., Conclusion: These findings confirm that diabetes and air pollution increase the risk of disability and fatality due to COVID-19, with disparities in terms of their impact. They suggest that efficient preventive and management programs for diabetes and air pollution countermeasures would have curtailed severe COVID-19 outcome rates.

Inappropriate sympathetic nervous activation is the body's response to biological stress and is thought to be involved in the development of various lifestyle-related diseases through an elevation in blood pressure. Experimental studies have shown that surgical renal denervation decreases blood pressure in hypertensive animals. Recently, minimally invasive catheter-based renal denervation has been clinically developed, which results in a reduction in blood pressure in patients with resistant hypertension. Accumulating evidence in basic studies has shown that renal denervation exerts beneficial effects on cardiovascular disease and chronic kidney disease. Interestingly, recent studies have also indicated that renal denervation improves glucose tolerance and inflammatory changes. In this review article, we summarize the evidence from animal studies to provide comprehensive insight into the organ-protective effects of renal denervation beyond changes in blood pressure., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)