Physicochemical and Volatile Compounds Analysis of Fruit Wines Fermented with Saccharomyces cerevisiae: FTIR and Microscopy Study with Focus on Anti-Inflammatory Potential.

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.

Systemic Changes in Endocannabinoids and Endocannabinoid-like Molecules in Response to Partial Nephrectomy-Induced Ischemia in Humans.

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.

Renal Endocannabinoid Dysregulation in Obesity-Induced Chronic Kidney Disease in Humans.

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.

Salivary Endocannabinoid Profiles in Chronic Orofacial Pain and Headache Disorders: An Observational Study Using a Novel Tool for Diagnosis and Management.

The endocannabinoid system is involved in physiological and pathological processes, including pain generation, modulation, and sensation. Its role in certain types of chronic orofacial pain (OFP) has not been thoroughly examined. By exploring the profiles of specific salivary endocannabinoids (eCBs) in individuals with different types of OFP, we evaluated their use as biomarkers and the influence of clinical parameters and pain characteristics on eCB levels. The salivary levels of anandamide (AEA), 2-arachidonoyl glycerol (2-AG), and their endogenous breakdown product arachidonic acid (AA), as well as the eCB-like molecules N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), were assessed in 83 OFP patients and 43 pain-free controls using liquid chromatography/tandem mass spectrometry. Patients were grouped by diagnosis: post-traumatic neuropathy (PTN), trigeminal neuralgia (TN), temporomandibular disorder (TMD), migraine, tension-type headache (TTH), and burning mouth syndrome (BMS). Correlation analyses between a specific diagnosis, pain characteristics, and eCB levels were conducted. Significantly lower levels of 2-AG were found in the TN and TTH groups, while significantly lower PEA levels were found in the migraine group. BMS was the only group with elevated eCBs (AEA) versus the control. Significant correlations were found between levels of specific eCBs and gender, health-related quality of life (HRQoL), BMI, pain duration, and sleep awakenings. In conclusion, salivary samples exhibited signature eCBs profiles for major OFP disorders, especially migraine, TTH, TN, and BMS. This finding may pave the way for using salivary eCBs biomarkers for more accurate diagnoses and management of chronic OFP patients.

Reduced Endocannabinoid Tone in Saliva of Chronic Orofacial Pain Patients.

BACKGROUND: the endocannabinoid system (ECS) participates in many physiological and pathological processes including pain generation, modulation, and sensation. Its involvement in chronic orofacial pain (OFP) in general, and the reflection of its involvement in OFP in salivary endocannabinoid (eCBs) levels in particular, has not been examined. OBJECTIVES: to evaluate the association between salivary (eCBs) levels and chronic OFP. METHODS: salivary levels of 2 eCBs, anandamide (AEA), 2-arachidonoylglycerol (2-AG), 2 endocannabinoid-like compoundsN-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed using liquid chromatography/tandem mass spectrometry in 83 chronic OFP patients and 43 pain-free controls. The chronic OFP patients were divided according to diagnosis into musculoskeletal, neurovascular/migraine, and neuropathic pain types. RESULTS: chronic OFP patients had lower levels of OEA (p = 0.02) and 2-AG (p = 0.01). Analyzing specific pain types revealed lower levels of AEA and OEA in the neurovascular group (p = 0.04, 0.02, respectively), and 2-AG in the neuropathic group compared to controls (p = 0.05). No significant differences were found between the musculoskeletal pain group and controls. Higher pain intensity was accompanied by lower levels of AA (p = 0.028), in neuropathic group. CONCLUSIONS: lower levels of eCBs were found in the saliva of chronic OFP patients compared to controls, specifically those with neurovascular/migraine, and neuropathic pain. The detection of changes in salivary endocannabinoids levels related to OFP adds a new dimension to our understanding of OFP mechanisms, and may have diagnostic as well as therapeutic implications for pain.

Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design, Synthesis, X-ray Structure and Therapeutic Potential.

A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(-)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2',6'-dimethoxy-4'-(2″-methyloctan-2″-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (Ki = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [35S]GTPγS binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 2.59 nM, E(max) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site.

Dragon Fruits as a Reservoir of Natural Polyphenolics with Chemopreventive Properties.

Dragon fruits are a valued source of bioactive compounds with high potential to become a functional food. The aim of the study was to evaluate and compare the chemopreventive potential and chemical composition of fruits harvested in Thailand and Israel. The amount of different compounds in water and methanol extracts and antioxidant activity was investigated. Moreover, cytotoxic activity against cancer and normal cells of skin, prostate, and gastrointestinal origin was performed, accompanied by anti-inflammatory assay based on NO production in RAW 264.7 macrophage model. Additionally, the quenching properties of polyphenols from fruits were determined by the interaction of the main drug carrier in blood human serum (HSA). The chemometric analysis was used to reveal the relationships between the determined parameters. Dragon fruits harvested in Israel revealed higher antioxidant properties and total content of polyphenols and betacyanins when compared to those from Thailand. The examined fruits of both origins showed significant cytotoxic activity toward colon and prostate cancer cells, with no toxic effect on normal cells, but also no anti-inflammatory effect. Moreover, a high binding ability to HSA was observed for water extracts of dragon fruits. All these predestine dragon fruits are the candidates for the attractive and chemopreventive elements of daily diet.

Cannabinoid-1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells.

AIMS: To evaluate the specific role of the endocannabinoid/cannabinoid type-1 (CB1 R) system in modulating mitochondrial dynamics in the metabolically active renal proximal tubular cells (RPTCs). MATERIALS AND METHODS: We utilized mitochondrially-targeted GFP in live cells (wild-type and null for the CB1 R) and electron microscopy in kidney sections of RPTC-CB1 R-/- mice and their littermate controls. In both in vitro and in vivo conditions, we assessed the ability of CB1 R agonism or fatty acid flux to modulate mitochondrial architecture and function. RESULTS: Direct stimulation of CB1 R resulted in mitochondrial fragmentation in RPTCs. This process was mediated, at least in part, by modulating the phosphorylation levels of the canonical fission protein dynamin-related protein 1 on both S637 and S616 residues. CB1 R-induced mitochondrial fission was associated with mitochondrial dysfunction, as documented by reduced oxygen consumption and ATP production, increased reactive oxygen species and cellular lactate levels, as well as a decline in mitochondrial biogenesis. Likewise, we documented that exposure of RPTCs to a fatty acid flux induced CB1 R-dependent mitochondrial fission, lipotoxicity and cellular dysfunction. CONCLUSIONS: CB1 R plays a key role in inducing mitochondrial fragmentation in RPTCs, leading to a decline in the organelle's function and contributing to the renal tubular injury associated with lipotoxicity and other metabolic diseases.

Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy.

Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.

Expanding the Arsenal of PtIV Anticancer Agents: Multi-action PtIV Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group.

Most multi-action PtIV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general approach for synthesis of PtIV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the PtIV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO2 , rapidly generating the active drugs. In contrast, succinate-linked drugs did not readily release the free drugs. The carbonate-bridged ctc-[Pt(NH3 )2 (PhB)(Gem-Carb)Cl2 ] was significantly more cytotoxic than the succinate-bridged ctc-[Pt(NH3 )2 (PhB)(Gem-Suc)Cl2 ], and more potent and less toxic than gemcitabine, cisplatin, and co-administration of cisplatin and gemcitabine.

Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD.

Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid ß-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB1R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.

Oral delivery system prolongs blood circulation of docetaxel nanocapsules via lymphatic absorption.

An original oral formulation of docetaxel nanocapsules (NCs) embedded in microparticles elicited in rats a higher bioavailability compared with the i.v. administration of the commercial docetaxel solution, Taxotere. In the present study, various animal studies were designed to elucidate the absorption process of docetaxel from such a delivery system. Again, the docetaxel NC formulation elicited a marked enhanced absorption compared with oral Taxotere in minipigs, resulting in relative bioavailability and Cmax values 10- and 8.4-fold higher, respectively, confirming the previous rat study results. It was revealed that orally absorbed NCs altered the elimination and distribution of docetaxel, as shown in the organ biodistribution rat study, due to their reinforced coating, while transiting through the enterocytes by surface adsorption of apoproteins and phospholipids. These findings were demonstrated by the cryogenic-temperature transmission electron microscopy results and confirmed by the use of a chylomicron flow blocker, cycloheximide, that prevented the oral absorption of docetaxel from the NC formulation in an independent pharmacokinetic study. The lipoproteinated NCs reduced the docetaxel release in plasma and its distribution among the organs. The improved anticancer activity compared with i.v. Taxotere, observed in the metastatic lung cancer model in Severe Combined Immune Deficiency-beige (SCID-bg) mice, should be attributed to the extravasation effect, leading to the lipoproteinated NC accumulation in lung tumors, where they exert a significant therapeutic action. To the best of our knowledge, no study has reported that the absorption of NCs was mediated by a lymphatic process and reinforced during their transit.

N-Oleoyl Glycine and Its Derivatives Attenuate the Acquisition and Expression of Cocaine-Induced Behaviors.

Introduction: The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain and plays an important role in the neurobiological processes underlying drug addiction. Impaired endocannabinoid (eCB) signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, and craving that propel addiction. Therefore, we hypothesized that boosting the ECS by exogenous administration of selective eCBs will attenuate cocaine-induced behaviors. Materials and Methods: The behavioral paradigms included psychomotor sensitization (PS) and conditioned place preference (CPP). Liquid chromatography-mass spectrometry analysis was used for quantitative profiling of eCBs in mouse brain. Results: We first measured the levels of eCBs in different brain areas of the reward system following chronic cocaine treatment. We found that following daily administration of cocaine, the levels of N-oleoyl glycine (OlGly) were significantly elevated in the nucleus accumbens (NAc) in a region-specific manner. We next tested whether administration of OlGly will attenuate cocaine-induced behaviors. We found that administration of OlGly during withdrawal, but not during acquisition of PS, attenuated the expression of cocaine sensitization. In addition, the administration of OlGly during the acquisition of cocaine CPP, but not during withdrawal, attenuated the expression of cocaine-conditioned reward. To enhance the stability of OlGly and its duration of action, two methylated derivatives of OlGly were synthesized, the monomethylated OlGly (HU-595) and dimethylated OlGly (HU-596). We found that the effect of administration of HU-595 or HU-596 during cocaine conditioning did not differ from the OlGly-induced decrease in the expression of CPP. Conclusion: Our findings suggest that the ECS is involved in the common neurobiological mechanisms underlying the development and expression of cocaine reward and drug-seeking. Boosting the ECS exogenously has beneficial effects against cocaine-induced behaviors.

Peripheral Cannabinoid-1 Receptor Blockade Ameliorates Cystitis Severity.

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.

N-oleoyl glycine and N-oleoyl alanine attenuate alcohol self-administration and preference in mice.

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.

Alpha-linolenic acid modulates systemic and adipose tissue-specific insulin sensitivity, inflammation, and the endocannabinoid system in dairy cows.

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.

Hepatic targeting of the centrally active cannabinoid 1 receptor (CB1R) blocker rimonabant via PLGA nanoparticles for treating fatty liver disease and diabetes.

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.

Analytical determination of bioactive compounds as an indication of fruit quality.

The aim of this investigation was to determine the bioactive compounds in kiwifruit as an indication of quality after extraction using methanol and ethyl acetate. Using FTIR and three-dimensional fluorescence spectroscopy and electrospray ionization/MS, the contents of polyphenols, flavonoids, flavanols, and tannins, and the level of the antioxidant activity by 2, 2-azino-bis (3-ethyl-benzothiazoline-6-sulfonic acid) diammonium salt, 1, 1-diphenyl-2-picrylhydrazyl, ferric-reducing/ antioxidant power, and cupric reducing antioxidant capacity assays were determined and compared. It was found that the methanol extracts of kiwifruit showed significantly higher amounts of bioactive acetate extracts. The cultivar Bidan, in comparison compounds and antioxidant activities than the ethyl with the classic Hayward, showed significantly higher bioactivity. For the first time, Bidan organic kiwifruit was analyzed for its antioxidant activities and compared with the widely consumed Hayward organic based on its bioactive compounds and fluorescence properties. Relatively high content of bioactive compounds and positive antioxidant and antiproliferative properties of kiwifruit determined by the advanced analytical methods justify its use as a source of valuable antioxidants. The methods used are applicable for bioactivity determination, in general, for any food products.

Herbal Cannabis Use Is Not Associated with Changes in Levels of Endocannabinoids and Metabolic Profile Alterations among Older Adults.

Activation of the endocannabinoid system has various cardiovascular and metabolic expressions, including increased lipogenesis, decreased blood pressure, increased heart rate, and changes in cholesterol levels. There is a scarcity of data on the metabolic effects of exogenous cannabis in older adults; therefore, we aimed to assess the effect of exogenous cannabis on endocannabinoid levels and the association with changes in 24 h ambulatory blood pressure and lipid levels. We conducted a prospective study of patients aged 60 years or more with hypertension treated with a new prescription of herbal cannabis. We assessed changes in endocannabinoids, blood pressure, and metabolic parameters prior to and following three months of cannabis use. Fifteen patients with a mean age of 69.47 ± 5.83 years (53.3% male) underwent complete evaluations. Changes in 2-arachidonoylglycerol, an endocannabinoid, were significantly positively correlated with changes in triglycerides. Changes in arachidonic acid levels were significantly positively correlated with changes in C-reactive protein and with changes in mean diastolic blood pressure. Exogenous consumption of cannabidiol was negatively correlated with endogenous levels of palmitoylethanolamide and oleoylethanolamide. On average, cannabis treatment for 3 months does not result in a significant change in the levels of endogenous cannabinoids and thus has a safe metabolic risk profile.

Kidney Proximal Tubule GLUT2-More than Meets the Eye.

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.