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Introduction The Warburg effect describes the propensity of cancer cells to favor the conversion of glucose to lactate for energy production, even in the presence of oxygen (1, 2). In [...], Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Phenolic acids are recognized as chemopreventive and chemotherapeutic agents. Altered glucose and glutamine metabolism are recognized hallmarks of cancer cells. We aimed to test the influence of phenolic acids on glucose and glutamine cellular uptake by a breast (MCF-7) and a pancreatic (AsPC-1) cancer cell line. Several phenolic acids (caffeic, ferrulic, proctocatechuic, coumaric and gallic acid) affected [sup.3]H-glutamine and/or [sup.3]H-deoxy-d-glucose ([sup.3]H-DG) uptake. Gallic acid (100 [micro]M) caused a 3-fold increase in [sup.3]H-DG uptake by AsPC-1 cells, associated with a 3.7-fold increase in lactic acid production. Gallic acid stimulated GLUT1-mediated [sup.3]H-DG uptake and increased the affinity of this transporter for [sup.3]H-DG. We further verified that gallic acid does not change GLUT1 transcription rates and cellular redox state and that its effect does not involve PI3K, mTOR and MAP kinases and is not associated with a proproliferative effect. Gallic acid also increased [sup.3]H-DG uptake by MCF-7 cells, although less potently. Further investigation is necessary to elucidate the cellular pathways involved in this effect of gallic acid. Key words: Gallic acid, pancreatic cancer, GLUT1, glucose, Introduction One of the hallmarks of cancer cells, which are distinctive and complementary traits that allow cancer cells to survive, proliferate and disseminate, consists in the reprogramming of energy metabolism [...]

Byline: Mainak. Banerjee, Ayan. Mukherjee, Avijit. Hazra, Satinath. Mukhopadhyay Dear Editor, Individuals with type 2 diabetes mellitus (T2DM) have a 3-5-fold increased risk of developing genital mycotic infections (GMI) following [...]

Two recent clinical trials, using sodium glucose cotransporter (SGLT2) or endothelin-A receptor (ET-A) blocker, reported the first efficacious treatments in 18 years to slow progression of diabetic kidney disease (DKD). We hypothesized that combined inhibition of SGLT2 and ET-A receptor may confer greater protection against renal injury than either agent alone. Uninephrectomized male db/db mice were randomized to four groups: vehicle, SGLT2 inhibitor (dapagliflozin (dapa), 1 mg/kg/day), ET-A blocker (atrasentan (atra), 5 mg/kg/day), or dual treatment from 10 weeks until 22 weeks of age. At 10 weeks of age, no differences were observed in body weight, blood glucose or urinary albumin excretion among the four groups. At 16 and 22 weeks of age, body weight was lower and blood glucose levels higher in the vehicle and atra groups compared with dapa- and dualtreated groups. No notable differences were observed among the four groups in urinary albumin excretion at weeks 16 and 22. Histological analysis showed mild glomerulosclerosis and tubular injury ( Key words: diabetic kidney disease, SGLT2, endothelin-A receptor, combined therapy A l'aide d'inhibiteurs du cotransporteur sodium-glucose (SGLT2) ou du recepteur A de l'endotheline (ET-A), deux essais cliniques recents ont rapporte les premiers traitements efficaces permettant de ralentir l'evolution de l'insuffisance renale diabetique depuis 18 ans. Nous avons formule une hypothese selon laquelle l'inhibition combinee du SGLT2 et des recepteurs ET-A pourrait apporter une meilleure protection contre les lesions renales que chacun des agents pris isolement. Nous avons reparti des souris db/db males nephrectomisees unilateralement dans 4 groupes : vehicule, dapa (dapaglifozine comme inhibiteur du SGLT2 a 1 mg/kg/jour), atra (atrasentane comme inhibiteur des recepteurs ET-A a 5 mg/kg/jour) ou traitement d'association de l'age de 10 a 22 semaines. A l'age de 10 semaines, nous n'avons observe aucune difference entre les 4 groupes en matiere de masse corporelle, de glycemie ou d'excretion urinaire d'albumine. Aux ages de 16 et de 22 semaines, la masse corporelle etait moins elevee et la glycemie etait plus elevee dans les groupes vehicule et atra que dans le groupe dapa et avec le traitement d'association. Aux semaines 16 et 22, nous n'avons pas observe de difference marquee entre les 4 groupes quant a l'excretion urinaire d'albumine. L'etude histologique a revele la presence d'une legere sclerose glomerulaire et de legeres lesions tubulaires (< 5 %) dans chacun des 4 groupes, malgre une sclerose glomerulaire moins importante avec le traitement d'association qu'avec le vehicule. Dans ce modele, les inhibiteurs du SGLT2 et/ou des recepteurs ET-A n'avaient pas d'effets nephropotecteurs isolement ou en association l'un avec l'autre. [Traduit par la Redaction] Mots-cles : insuffisance renale diabetique, SGLT2, recepteurs A de l'endotheline, traitement d'association, Introduction Diabetes mellitus is the leading cause of end-stage kidney disease worldwide (Diabetic Kidney Disease 2021). Until 2019, the only known efficacious therapies for diabetic kidney disease (DKD) were renin [...]

Glucose homeostasis can be improved after bariatric surgery, which alters bile flow and stimulates gut hormone secretion, particularly FGF15/19. FGFR1 expression in AGRP-expressing cells is required for bile acids' ability to improve glucose control. We show that the mouse Agrp gene has 3 promoter/enhancer regions that direct transcription of each of their own AGRP transcripts. One of these Agrp promoters/enhancers, Agrp-B, is regulated by bile acids. We generated an Agrp-B knockin FLP/knockout allele. AGRP-B-expressing cells are found in endocrine cells of the pars tuberalis and coexpress diacylglycerol lipase B--an endocannabinoid biosynthetic enzyme--distinct from pars tuberalis thyrotropes. AGRP-B expression is also found in the folliculostellate cells of the pituitary's anterior lobe. Mice without AGRP-B were protected from glucose intolerance induced by high-fat feeding but not from excess weight gain. Chemogenetic inhibition of AGRP-B cells improved glucose tolerance by enhancing glucose-stimulated insulin secretion. Inhibition of the AGRP-B cells also caused weight loss. The improved glucose tolerance and reduced body weight persisted up to 6 weeks after cessation of the DREADD-mediated inhibition, suggesting the presence of a biological switch for glucose homeostasis that is regulated by long-term stability of food availability., Introduction The hypothalamic AGRP/NPY neuron is well known to be orexigenic (1, 2), opposing the action of its counterpart, the hypothalamic anorexigenic POMC neuron (3, 4). However, constitutive absence of [...]

Byline: S. Parthasarathy, Sanjay. Kalra, Madhuri. Kurdi, Sukhminder. Singh Bajwa In spite of so many advancements in the medical sciences, precise control of hyperglycaemia has always been a tough challenge [...]