BACKGROUND AND PURPOSE:Cannabidiol (CBD) and cannabigerol (CBG) are non-psychoactive phytocannabinoids with emerging therapeutic potential in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the molecular mechanisms underlying their beneficial effects remain incompletely understood. In this study, we assessed the metabolomic and lipidomic impact of CBD and CBG in a mouse model of diet-induced obesity and MASLD. EXPERIMENTAL APPROACH:Male C57Bl/6 mice fed on a high-fat diet for 14 weeks were treated for 4 weeks with daily intraperitoneal CBD, CBG or vehicle. Assessments included body composition, indirect calorimetry, glucose tolerance, serum biochemistry and VLDL-triglyceride profiling. Hepatic mechanisms were examined by metabolomics, lipidomics, creatine kinase activity, cathepsin activity-based probes and gene/protein expression, with a choline-deficient diet cohort to test phospholipid-dependence of CBG. KEY RESULTS:CBD or CBG treatment improved glycaemic control, reduced hepatic triglycerides and normalised serum lipids, without affecting energy expenditure. Metabolomics revealed increased hepatic phosphocreatine and creatine with enhanced creatine kinase activity, indicating phosphocreatine-based energy buffering independent of fatty acid oxidation changes. Lipidomics showed reduced triglycerides and ceramides, with increased phospholipids and lysobisphosphatidic acids, correlating with restored hepatic cathepsin activity and improved lysosomal lipid degradation. CBG was ineffective in choline-deficient MASLD, indicating phospholipid pathway dependence. CONCLUSIONS AND IMPLICATIONS:These findings identify a novel, endocannabinoid system-independent mechanism by which CBD and CBG enhance hepatic energy buffering and lysosomal function, contributing to improved liver lipid handling and supporting phytocannabinoids as promising MASLD therapeutics.

OBJECTIVE:Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequent cognitive and psychiatric comorbidities. Although current antiseizure medications provide symptomatic relief, they fail to prevent or modify epileptogenesis. Heat shock protein 90 (Hsp90) is increasingly recognized as a regulator of neuroinflammatory and oxidative stress pathways implicated in seizure generation and disease progression. Here, we investigated the therapeutic potential of cemdomespib, a novel and selective Hsp90 inhibitor, across complementary preclinical models of epilepsy. METHODS:In vitro, cemdomespib was evaluated in the low-magnesium model of epileptiform activity for its effects on neuronal calcium dynamics, mitochondrial membrane stability, and reactive oxygen species (ROS) generation. In vivo, acute seizure protection was assessed in the pentylenetetrazol (PTZ) model, and antiepileptogenic efficacy was tested in the kainic acid-induced status epilepticus (KA-SE) model using chronic video-electrocorticographic recordings. Behavioral outcomes relevant to epilepsy-associated comorbidities, including anxiety-like behavior and exploratory activity, were also examined. RESULTS:Cemdomespib reduced epileptiform calcium oscillations, stabilized mitochondrial membrane potential, and suppressed ROS generation in vitro. In the PTZ model, 45% of pretreated animals were protected from seizures, and those that seized exhibited reduced severity, shorter duration, and delayed onset. In the KA-SE model, cemdomespib significantly mitigated the severity of SE and reduced the emergence of spontaneous recurrent seizures during the chronic phase, as evidenced by lower seizure frequency, decreased cumulative seizure burden, and prolonged latency to seizure onset. Furthermore, treated animals demonstrated improved anxiety-like behavior and enhanced exploratory activity. SIGNIFICANCE:Cemdomespib confers both acute seizure protection and long-term suppression of epileptogenesis, likely through Hsp90-dependent regulation of mitochondrial integrity and redox signaling. These findings highlight Hsp90 inhibition as a promising therapeutic strategy for seizure control while also mitigating the progression of epileptogenesis and its associated neurobehavioral impairments.

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, inflammation, and metabolic dysregulation. The endocannabinoid system (ECS), particularly the cannabinoid-1 receptor (CB1R), regulates renal metabolism and inflammatory signaling, yet its role in ADPKD remains largely unexplored. Methods We analyzed publicly available human kidney transcriptomic datasets (bulk microarray GSE7869; single-nucleus RNA-sequencing from ADPKD GSE185948, and diabetic kidney disease cohorts GSE195460) and validated findings in ADPKD patient kidney tissue versus non-cystic controls using quantitative PCR, liquid chromatography-tandem mass spectrometry, and Western blotting. Longitudinal disease progression was evaluated in Pkd1 RC/RC mice at 3, 6, 9, and 12 months, with comprehensive assessment of ECS components, endocannabinoid (eCB) levels, and kidney function parameters. Correlation examined associations between ECS markers and disease severity. Results Human ADPKD kidneys demonstrated consistent upregulation of CNR1 transcripts across platforms, with single-nucleus analysis revealing enrichment in proximal tubule-derived populations including failed-repair proximal tubule cells. ADPKD tissue exhibited significant reductions in key ECS-metabolizing enzymes (FAAH, NAPEPLD, MGLL) and marked depletion of eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG). In contrast, diabetic kidney disease showed minimal ECS alterations, indicating ADPKD-specific dysregulation. Pkd1 RC/RC mice recapitulated human findings, with Cnr1 upregulation beginning at 6 months and significant AEA/N-oleoylethanolamine (OEA) depletion at 9–12 months. CB1R protein elevation preceded ligand depletion, suggesting progressive receptor sensitization. Correlation analyses revealed robust associations between CB1R/enzyme expression, eCB depletion, and declining kidney function (kidney weight-to-body weight ratio, blood urea nitrogen, and creatinine clearance). Conclusions ADPKD kidneys exhibit disease-specific dysregulation of the ECS, characterized by increased CB1R expression accompanied by paradoxical depletion of eCB ligands. These alterations correlate with cyst burden and functional decline across human and murine disease stages, identifying the ECS as a prominently affected pathway during ADPKD progression. While our findings establish a strong association between ECS dysregulation and disease severity, whether altered CB1R signaling represents a causal driver of cystogenesis or a secondary, yet therapeutically targetable component of the cystic and injury response will require direct genetic or pharmacologic modulation of CB1R/ECS signaling.

Background: The endocannabinoid system (ECS) regulates homeostasis, inflammation, and organ-specific function. In the kidney, ECS activity modulates renal hemodynamics, and its overactivation is linked to chronic injury. However, the importance of the ECS involvement in acute kidney injury (AKI) remains unclear. This study aimed to characterize changes in circulating endocannabinoid (eCB) levels before and after relief of upper urinary tract obstruction (UUTO), to better understand ECS dynamics during acute renal dysfunction. These findings may inform the development of novel biomarkers and therapeutic targets for renal injury. Objectives: To characterize changes in circulating eCB levels before and after relief of UUTO, and to compare responses between patients with and without AKI. Design: Prospective observational cohort with paired, within-person sampling. Methods: Patients presenting to the emergency department with acute renal colic due to obstructive urolithiasis who underwent kidney decompression within 24 h were prospectively enrolled. Clinical, laboratory, and imaging data plus paired blood samples for eCB analysis were collected pre and post-drainage. Patients were divided into two groups: those who had AKI at presentation, and non-AKI controls. Serum eCBs were quantified, and fold changes compared using nonparametric analysis. Results: Twenty-two patients enrolled (10 had AKI and 12 served as non-AKI controls). Serum N -acylethanolamines (NAEs) showed divergent responses between the two groups. In AKI, N -arachidonoylethanolamine (AEA), N -palmitoylethanolamine, and N -oleoylethanolamine increased following drainage ( p = 0.06, 0.008, 0.08). In contrast, patients without AKI demonstrated a reduction in NAE levels, with a significant AEA drop ( p = 0.03) after obstruction relief. Notably, the fold-change in NAE levels post-drainage was significantly higher in patients with AKI compared to those without AKI. Conclusion: Circulating NAEs increase following relief of obstruction in patients with acute renal dysfunction, suggesting a potential role for ECS activation in the pathophysiology of UUTO-induced kidney injury. These findings highlight the ECS as a promising target for further investigation as a possible therapeutic avenue in AKI. Trial registration: Not applicable.

This study investigated the interactions between phenolic compounds from Israeli and Chilean white wines and human serum carrier proteins, including human serum albumin (HALB), gamma-globulin (HGLO), and fibrinogen (HFB), to characterize their antioxidant capacity and serum protein-binding behavior under controlled experimental conditions. The analyzed wines included Israeli Chardonnay (ICR), Chilean Chardonnay (CCR), Israeli Sauvignon Blanc (ISB), and Chilean Sauvignon Blanc (CSB). HPLC and FTIR fingerprinting revealed cultivar- and region-dependent differences in phenolic composition, with Chardonnay wines showing stronger protein-binding behavior and Sauvignon Blanc samples displaying high antioxidant efficiency relative to their phenolic content. ICR exhibited the highest total binding capacity, 46.44%, and the strongest albumin interaction, with a binding constant (Kb) of 8.44 × 104 M-1 and a Gibbs free energy (ΔG) value of -35.03 kJ/mol. Empirical fluorescence quenching kinetics demonstrated that white wine phenolics establish stable physical complexes with human serum proteins, displaying a distinct preferential affinity for HALB as the protein showing the strongest apparent interaction among the proteins tested. Two- and three-dimensional fluorescence spectroscopy confirmed substantial quenching of the intrinsic tryptophan and tyrosine residues, indicating meaningful microenvironmental alterations within the protein's active transport sites. These empirical interactions were closely mirrored by complementary molecular docking simulations, which provided a structural visualization of the physical binding interactions. ICR also showed the highest antioxidant capacity, with DPPH and CUPRAC values of 1.66 and 2.91 mmol TE/L, respectively. Ethanol control showed negligible effects, indicating that the observed bioactivity was mainly associated with the polyphenolic matrix. Among the investigated samples, Chardonnay showed higher apparent protein-binding capacity, whereas Sauvignon Blanc showed relatively high antioxidant efficiency in relation to its phenolic content.

OBJECTIVE:We have previously shown that valproic acid (VPA) alters the expression of placental carriers of essential nutrients, including folates. Here, we exposed a placental cell line to VPA, its central nervous system-active amide derivative sec-butylpropylacetamide (SPD), and its individual stereoisomers to address the question of whether folate carrier expression can predict the teratogenicity of VPA-related compounds. We additionally conducted a pilot analysis of folate transfer across placental cell monolayers to estimate the translation of altered carrier expression to carrier activity. METHODS:BeWo cells were incubated for 2 or 5 days with racemic SPD, its stereoisomers (2S,3S)-SPD, (2R,3S)-SPD, and (2R,3R)-SPD (previously found to be teratogenic at high doses in mice; .5 or 1 mmol·L-1), VPA (1 mmol·L-1 = 144 mg/L), or their vehicle. Expression of FOLR1 (folate receptor alpha), SLC19A1 (reduced folate carrier), and ABCG2 (breast cancer resistance protein) was measured by real-time polymerase chain reaction. Folate transfer across monolayers of BeWo b30 cells exposed to .5 mmol·L-1 (2R,3R)-SPD or 1 mmol·L-1 VPA was quantified by liquid chromatography-mass spectrometry analysis. RESULTS:At 1 mmol·L-1, racemic SPD, (2S,3S)-SPD, and (2R,3S)-SPD reduced by twofold SLC19A1 expression, similar to VPA (p < .001). SPD and its enantiomers induced FOLR1 expression by up to twofold (p < .05) or did not significantly affect it, and racemic SPD increased ABCG2 expression (p < .01). After 5 days, VPA, but not (2R,3R)-SPD, enhanced both maternal-to-fetal and fetal-to-maternal folate transfer (p < .01), resulting in a 15% increase in net transfer in the fetal direction. SIGNIFICANCE:Altered expression of the studied carriers could not explain the folate transfer kinetics across placental cell monolayers. Future studies should assess the effects of VPA and other antiseizure medications on transplacental transfer of essential compounds in vivo and the ability to predict it by functional in vitro assays.

The development of peripherally selective cannabinoid-1 receptor (CB1R) antagonists offers a promising strategy for obesity treatment. Here, we evaluated the efficacy of novel tricyclic CB1R antagonists, focusing on BNS808. Our findings demonstrate that BNS808 exhibits robust CB1R antagonism with notable CB2R selectivity, minimal brain penetration, and potent in vitro and in vivo efficacy. The compound's high plasma protein binding reduces free drug availability for CNS entry, enhancing safety and minimizing drug-drug interactions. In diet-induced obese mice, BNS808 effectively reduced body weight, adiposity, liver triglycerides, and liver enzymes, supporting its peripherally mediated action. These results highlight BNS808 as a promising candidate for obesity treatment. Additionally, our novel library of peripherally selective CB1R antagonists provides a strong foundation for future drug development. With further refinement, BNS808 holds significant clinical potential to address the global obesity epidemic.

OBJECTIVE:Kidney glucose reabsorption, primarily mediated by glucose transporter 2 (GLUT2), is essential for systemic glucose homeostasis. While GLUT2's role has been studied in diabetic conditions, its function in kidney proximal tubule cells (KPTCs) under normo-physiological conditions remains unclear. This study aimed to delineate the metabolic consequences of KPTC-specific GLUT2 deletion on renal and whole-body energy homeostasis. METHODS:We utilized a conditional mouse model with KPTC-specific deletion of GLUT2 to assess the impact of impaired renal glucose reabsorption on systemic metabolism. Comprehensive metabolic and behavioral phenotyping, tissue-specific glucose uptake assays, and multi-omics analyses were performed to evaluate changes in energy balance, organ-specific metabolism, and signaling pathways. RESULTS:Loss of KPTC-GLUT2 led to increased food intake, enhanced systemic carbohydrate oxidation, and elevated fat and muscle mass. These changes were accompanied by altered glucose utilization across metabolic organs and improvements in whole-body lipid profile. Mechanistically, the phenotype was linked to metabolic reprogramming in the kidney, characterized by increased reabsorption and bioavailability of taurine and creatine, overactivation of mTORC1 signaling, and elevated endocannabinoid tone. CONCLUSIONS:KPTC-GLUT2 plays a previously unrecognized role in regulating renal and systemic energy metabolism. Its deletion induces a systemic energy-conserving phenotype driven by kidney-intrinsic changes, highlighting the kidney's contribution to whole-body metabolic homeostasis beyond glucose filtration.

The growing trend in fruit wine production reflects consumers’ interest in novel, diverse drinking experiences and the increasing demand for healthier beverage options. Fruit wines made from kiwi, pomegranates, and persimmons fermented using S. bayanus Lalvin strain EC1118 demonstrate the versatility of winemaking techniques. Kiwifruit, persimmon, and pomegranate wines were analyzed using HPLC and GC-TOFMS analyses to determine their concentrations of phenolic acids and volatile compounds. These results were supported by Fourier transform infrared (FTIR) spectroscopy to characterize and compare chemical shifts in the polyphenol regions of these wines. The wines’ characterization included an anti-inflammatory assay based on NO, TNF-alpha, and IL-6 production in the RAW 264.7 macrophage model. FTIR spectroscopy predicted the antioxidant and phenolic contents in the wines. In terms of polyphenols, predominantly represented by chlorogenic, caffeic, and gallic acids, pomegranate and kiwifruit wines showed greater benefits. However, kiwifruit wines exhibited a highly diverse profile of volatile compounds. Further analysis is necessary, particularly regarding the use of other microorganisms in the fermentation process and non-Saccharomyces strains methods. These wines exhibit high biological antioxidant potential and health properties, providing valuable insights for future endeavors focused on designing healthy functional food products.

The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain and has an important role in the neurobiological processes underlying drug addiction. We have previously shown that an elevated ECS response to psychostimulant (cocaine) is involved in regulating the development and expression of cocaine-conditioned reward and sensitization. We therefore hypothesized that drug-induced elevation in endocannabinoids (eCBs) and/or eCB-like molecules (eCB-Ls) may represent a protective mechanism against drug insult, and boosting their levels exogenously may strengthen their neuroprotective effects. Here, we determine the involvement of ECS in alcohol addiction. We first measured the eCBs and eCB-Ls levels in different brain reward system regions following chronic alcohol self-administration using LC–MS. We have found that following chronic intermittent alcohol consumption, N -oleoyl glycine (OlGly) levels were significantly elevated in the prefrontal cortex (PFC), and N -oleoyl alanine (OlAla) was significantly elevated in the PFC, nucleus accumbens (NAc) and ventral tegmental area (VTA) in a region-specific manner. We next tested whether exogenous administration of OlGly or OlAla would attenuate alcohol consumption and preference. We found that systemic administration of OlGly or OlAla (60 mg/kg, intraperitoneal) during intermittent alcohol consumption significantly reduced alcohol intake and preference without affecting the hedonic state. These findings suggest that the ECS negatively regulates alcohol consumption and boosting selective eCBs exogenously has beneficial effects against alcohol consumption and potentially in preventing relapse.

Recently we reported about the consumption of red wines from grapes, having several health properties. There are different types of wines that originated from grapes and other fruits. In the present study fruit wines from persimmon, kiwifruit and pomegranate were investigated and compared for their antioxidant ability, using cupric ion reducing antioxidant capacity (CUPRAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. To the fruit wines were applied the same methods of investigation as to the traditional ones made from grapes. The results showed the highest antioxidant activity of pomegranate, followed by kiwifruit and persimmon wines. Fourier transform infrared (FTIR) spectroscopy was used in order to correlate these results. The interaction of wine bioactive compounds with the main serum proteins in the human metabolism, such as human serum albumin (HSA), globulin (GL), and fibrinogen (FB), showed that pomegranate wine possesses higher quenching properties than kiwifruit and persimmon wines. All determined fluorescence indices have a direct correlation with the bioactivity of polyphenols and not with the content of alcohol. We hypothesize that the results of the interaction of main human serum proteins with bioactive compounds of wines can be additional predictors of their health properties. The used analytical methods for quality of fruit wines can be applied to a wide range of fruits and vegetables.

The endocannabinoid system (ECS) regulates various physiological processes, including energy homeostasis and kidney function. ECS upregulation in obese animals and humans suggests a potential link to obesity-induced chronic kidney disease (CKD). However, obesity-induced ECS changes in the kidney are mainly studied in rodents, leaving the impact on obese humans unknown. In this study, a total of 21 lean and obese males (38–71 years) underwent a kidney biopsy. Biochemical analysis, histology, and endocannabinoid (eCB) assessment were performed on kidney tissue and blood samples. Correlations between different parameters were evaluated using a comprehensive matrix. The obese group exhibited kidney damage, reflected in morphological changes, and elevated kidney injury and fibrotic markers. While serum eCB levels were similar between the lean and obese groups, kidney eCB analysis revealed higher anandamide in obese patients. Obese individuals also exhibited reduced expression of cannabinoid-1 receptor (CB1R) in the kidney, along with increased activity of eCB synthesizing and degrading enzymes. Correlation analysis highlighted connections between renal eCBs, kidney injury markers, obesity, and related pathologies. In summary, this study investigates obesity’s impact on renal eCB “tone” in humans, providing insights into the ECS’s role in obesity-induced CKD. Our findings enhance the understanding of the intricate interplay among obesity, the ECS, and kidney function.

Renal ischemia–reperfusion (IR), a routine feature of partial nephrectomy (PN), can contribute to the development of acute kidney injury (AKI). Rodent studies show that the endocannabinoid system (ECS) is a major regulator of renal hemodynamics and IR injury; however, its clinical relevance remains to be established. Here, we assessed the clinical changes in systemic endocannabinoid (eCB) levels induced by surgical renal IR. Sixteen patients undergoing on-clamp PN were included, with blood samples taken before renal ischemia, after 10 min of ischemia time, and 10 min following blood reperfusion. Kidney function parameters (serum creatinine (sCr), blood urea nitrogen (BUN), and serum glucose) and eCB levels were measured. Baseline levels and individual changes in response to IR were analyzed and correlation analyses were performed. The baseline levels of eCB 2-arachidonoylglycerol (2-AG) were positively correlated with kidney dysfunction biomarkers. Unilateral renal ischemia increased BUN, sCr, and glucose, which remained elevated following renal reperfusion. Renal ischemia did not induce changes in eCB levels for all patients pooled together. Nevertheless, stratifying patients according to their body mass index (BMI) revealed a significant increase in N-acylethanolamines (anandamide, AEA; N-oleoylethanolamine, OEA; and N-palmitoylethanolamine, PEA) in the non-obese patients. No significant changes were found in obese patients who had higher N-acylethanolamines baseline levels, positively correlated with BMI, and more cases of post-surgery AKI. With the inefficiency of ‘traditional’ IR-injury ‘preventive drugs’, our data support future research on the role of the ECS and its manipulation in renal IR.

Over-activation of the endocannabinoid/CB1R system is a hallmark feature of obesity and its related comorbidities, most notably type 2 diabetes (T2D), and non-alcoholic fatty liver disease (NAFLD). Although the use of drugs that widely block the CB1R was found to be highly effective in treating all metabolic abnormalities associated with obesity, they are no longer considered a valid therapeutic option due to their adverse neuropsychiatric side effects. Here, we describe a novel nanotechnology-based drug delivery system for repurposing the abandoned first-in-class global CB1R antagonist, rimonabant, by encapsulating it in polymeric nanoparticles (NPs) for effective hepatic targeting of CB1Rs, enabling effective treatment of NAFLD and T2D. Rimonabant-encapsulated NPs (Rimo-NPs) were mainly distributed in the liver, spleen, and kidney, and only negligible marginal levels of rimonabant were found in the brain of mice treated by iv/ip administration. In contrast to freely administered rimonabant treatment, no CNS-mediated behavioral activities were detected in animals treated with Rimo-NPs. Chronic treatment of diet-induced obese mice with Rimo-NPs resulted in reduced hepatic steatosis and liver injury as well as enhanced insulin sensitivity, which were associated with enhanced cellular uptake of the formulation into hepatocytes. Collectively, we successfully developed a method of encapsulating the centrally acting CB1R blocker in NPs with desired physicochemical properties. This novel drug delivery system allows hepatic targeting of rimonabant to restore the metabolic advantages of blocking CB1R in peripheral tissues, especially in the liver, without the negative CB1R-mediated neuropsychiatric side effects.

Metabolic disorders are often linked to alterations in insulin signaling. Omega-3 (n-3) fatty acids modulate immunometabolic responses; thus, we examined the effects of peripartum n-3 on systemic and adipose tissue (AT)-specific insulin sensitivity, immune function, and the endocannabinoid system (ECS) in dairy cows. Cows were supplemented peripartum with saturated fat (CTL) or flaxseed supplement rich in alpha-linolenic acid (ALA). Blood immunometabolic biomarkers were examined, and at 5–8 d postpartum (PP), an intravenous glucose-tolerance-test (GTT) and AT biopsies were performed. Insulin sensitivity in AT was assessed by phosphoproteomics and proteomics. Peripartum n-3 reduced the plasma concentrations of Interleukin-6 (IL-6) and IL-17α, lowered the percentage of white blood cells PP, and reduced inflammatory proteins in AT. Systemic insulin sensitivity was higher in ALA than in CTL. In AT, the top canonical pathways, according to the differential phosphoproteome in ALA, were protein-kinase-A signaling and insulin-receptor signaling; network analysis and immunoblots validated the lower phosphorylation of protein kinase B (Akt), and lower abundance of insulin receptor, together suggesting reduced insulin sensitivity in ALA AT. The n-3 reduced the plasma concentrations of ECS-associated ligands, and lowered the abundances of cannabinoid-1-receptor and monoglycerol-lipase in peripheral blood mononuclear cells PP. Peripartum ALA supplementation in dairy cows improved systemic insulin sensitivity and immune function, reduced ECS components, and had tissue-specific effects on insulin-sensitivity in AT, possibly counter-balancing the systemic responses.

Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion of KPTC-GLUT2 has been recently found to ameliorate DKD, raising the plausible idea of considering it as a therapeutic target against DKD. However, the underlying molecular mechanisms by which GLUT2 exerts its deleterious effects in KPTCs remain vague. Herein, we review the current findings on the proximal tubule GLUT2 biology and function under physiologic conditions, and its involvement in the pathophysiology of DKD. Furthermore, we shed new light on its cellular regulation during diabetic conditions.

Environmental heat load (HL) adversely affects the performance of dairy cows. The endocannabinoid system (ECS) regulates metabolism and the stress response, thus we hypothesized that HL may affect the ECS of dairy cows. Our objective was to determine the levels of endocannabinoids (eCBs) and gene and protein expressions of the ECS components in adipose tissue (AT) and plasma of early postpartum (PP) and late-lactation cows. In addition, we examined eCBs in milk, and studied the interaction of eCBs with bovine cannabinoids receptors CB1 and CB2. In the first experiment, plasma and AT were sampled from cows calving during summer (S, n = 9) or winter (W, n = 9). Dry matter intake (DMI) and energy balance (EB) were lower in S vs. W, and relative gene expressions of transient-receptor-potential-cation-channel-subfamily-V-member-1 (TRPV1), the cannabinoid receptors CNR1 (CB1) and CNR2 (CB2), and monoglyceride lipase (MGLL) were decreased in AT of S compared to W. Protein abundance of peroxisome proliferator-activated-receptor-alpha (PPAR-α) was decreased, while tumor-necrosis factor-α (TNF-α) was increased in AT of S vs. W. Other components of the ECS were not different between S and W calving cows. To study whether the degree of HL may affect the ECS, we performed a second experiment with 24 late-lactation cows that were either cooled (CL) or not cooled (heat-stressed; HS) during summer. DMI was lower in HS vs. CL, AT protein abundance of PPAR-α was lower, and TRPV1 tended to be lower in HS vs. CL, but other components of the ECS were not different between groups. Milk levels of 2-arachidonoylglycerol (2-AG) tended to increase in HS vs. CL. Additionally, modeling of the bovine cannabinoid receptors demonstrated their binding to anandamide and 2-AG. Environmental HL, possibly via lower intake, is associated with limited alterations in ECS components in AT of dairy cows.

Background: The endocannabinoid system (ECS) plays a key physiological role in bladder function and it has been suggested as a potential target for relieving lower urinary tract symptoms (LUTSs). Whereas most studies indicate that activating the ECS has some beneficial effects on the bladder, some studies imply the opposite. In this study, we investigated the therapeutic potential of peripheral cannabinoid-1 receptor (CB1R) blockade in a mouse model for LUTSs. Materials and Methods: To this end, we used the cyclophosphamide (CYP; 300 mg/kg, intraperitoneal)-induced cystitis model of bladder dysfunction, in which 12-week-old, female C57BL/6 mice were treated with the peripherally restricted CB1R antagonist, JD5037 (3 mg/kg), or vehicle for three consecutive days. Bladder dysfunction was assessed using the noninvasive voiding spot assay (VSA) as well as the bladder-to-body weight (BW) ratio and gene and protein expression levels; ECS tone was assessed at the end of the study. Results: Peripheral CB1R blockade significantly ameliorated the severity of CYP-induced cystitis, manifested by reduced urination events measured in the VSA and an increased bladder-to-BW ratio. Moreover, JD5037 normalized CYP-mediated bladder ECS tone imbalance by affecting both the expression of CB1R and the endocannabinoid levels. These effects were associated with the ability of JD5037 to reduce CYP-induced inflammatory response, manifested by a reduction in levels of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα), in the bladder and serum. Conclusions: Collectively, our results highlight the therapeutic relevance of peripheral CB1R blockade in ameliorating CYP-induced cystitis; they may further support the preclinical development and clinical use of peripherally restricted CB1R antagonism for treatment of LUTSs.

Background Dietary supplementation of omega-3 fatty acids can reduce the activation of the endocannabinoid system (ECS) by decreasing the availability of arachidonic acid, thus lowering endocannabinoids (eCBs) levels. The ECS is a modulator of energy metabolism, stress response and inflammation in mammals, yet there is little information on the roles of the ECS in transition dairy cows. During the periparturient period, the adipose tissue and liver are the main metabolic organs that participate in the adaptations of dairy cows to onset of lactation; however, exceeded adipose tissue lipolysis and accumulation of lipids in the liver have adverse effects on cows’ physiology. Here we aimed to examine whether omega-3 supplementation during the transition period will modulate ECS activation and affect metabolic and inflammatory indices in postpartum dairy cows, by supplementing twenty-eight transition Holstein dairy cows with either saturated fat (CTL) or encapsulated flaxseed oil (FLX). Components of the ECS, metabolic and inflammatory markers were measured in blood, liver, and subcutaneous adipose tissue. Results FLX supplementation reduced feed intake by 8.1% ( P < 0.01) and reduced plasma levels of arachidonic acid (by 44.2%; P = 0.02) and anandamide (by 49.7%; P = 0.03) postpartum compared to CTL. The mRNA transcription levels of the cannabinoid receptor 1 ( CNR1 /CB1) tended to be lower (2.5 folds) in white blood cells of FLX than in CTL ( P = 0.10), and protein abundance of ECS enzyme monoacylglycerol lipase was higher in peripheral blood mononuclear cells of FLX than in CTL ( P = 0.04). In adipose tissue, palmitoylethanolamide levels were lower in FLX than in CTL (by 61.5%; P = 0.02), relative mRNA transcription of lipogenic genes were higher, and the protein abundance of cannabinoid receptor 2 ( P = 0.08) and monoacylglycerol lipase ( P = 0.10) tended to be higher in FLX compared to CTL. Hepatic 2-arachidonoylglycerol tended to be higher (by 73.1%; P = 0.07), and interlukin-6 mRNA transcription level was 1.5 folds lower in liver of FLX than in CTL ( P = 0.03). Conclusions Nutritional supplementation of omega-3 fatty acids seems to partly modulate ECS activation, which could be related to lower feed intake. The altered ECS components in blood, adipose tissue and liver are associated with moderate modulations in lipid metabolism in the adipose and inflammation in liver of peripartum dairy cows.