P2Y13 receptor deficiency favors adipose tissue lipolysis and worsens insulin resistance and fatty liver disease.

Excessive lipolysis in white adipose tissue (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of Gi-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the Gi-coupled P2Y13 receptor (P2Y13-R) is a purinergic receptor expressed in WAT, we investigated its role in adipocyte lipolysis and its effect on IR and metabolic dysfunction-associated steatotic liver disease (MASLD). In humans, mRNA expression of P2Y13-R in WAT was negatively correlated to adipocyte lipolysis. In mice, adipocytes lacking P2Y13-R displayed higher intracellular cAMP levels, indicating impaired Gi signaling. Consistently, the absence of P2Y13-R was linked to increased lipolysis in adipocytes and WAT explants via hormone-sensitive lipase activation. Metabolic studies indicated that mice lacking P2Y13-R showed a greater susceptibility to diet-induced IR, systemic inflammation, and MASLD compared with their wild-type counterparts. Assays conducted on precision-cut liver slices exposed to WAT conditioned medium and on liver-specific P2Y13-R-knockdown mice suggested that P2Y13-R activity in WAT protects from hepatic steatosis, independently of liver P2Y13-R expression. In conclusion, our findings support the idea that targeting adipose P2Y13-R activity may represent a pharmacological strategy to prevent obesity-associated disorders, including type 2 diabetes and MASLD.

Number of medically prescribed pharmaceutical agents as predictor of mortality risk: a longitudinal, time-variable analysis in the EPIC-Heidelberg cohort.

The number of prescribed medications might be used as proxy indicator for general health status, in models to predict mortality risk. To estimate the time-varying association between active pharmaceutical ingredient (API) count and all-cause mortality, we analyzed data from a population cohort in Heidelberg (Germany), including 25,546 participants with information on medication use collected at 3-yearly intervals from baseline recruitment (1994-1998) until end of 2014. A total of 4548 deaths were recorded until May 2019. Time-dependent modeling was used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for all-cause mortality in relation to number of APIs used, within three strata of age (≤ 60, > 60 to ≤ 70 and > 70 years) and adjusting for lifestyle-related risk factors. For participants reporting commonly used APIs only (i.e., API types accounting for up to 80% of medication time in the population) total API counts showed no association with mortality risk within any age stratum. However, when at least one of the APIs was less common, the total API count showed a strong relationship with all-cause mortality especially up to age ≤ 60, with HR up to 3.70 (95% CI 2.30-5.94) with 5 or 6 medications and 8.19 (5.61-11.97) for 7 or more APIs (versus none). Between > 60 and 70 years of age this risk association was weaker, with HR up to 3.96 (3.14-4.98) for 7 or more APIs, and above 70 years it was weakened further (HR up to 1.54 (1.34-1.79)). Multiple API-use may predict mortality risk in middle-aged and women and men ≤ 70 years, but only if it includes at least one less frequently used API type. With advancing age, and multiple medication becomes increasingly prevalent, the association of API count with risk of death progressively attenuates, suggesting an increasing complexity with age of underlying mortality determinants.

Sex- and Age Group-Specific Fracture Incidence Rates Trends for Type 1 and 2 Diabetes Mellitus.

The incidence of major osteoporotic fractures has declined in men and women in Western countries over the last two decades. Although fracture risk is higher in persons with diabetes mellitus, trends of fractures remain unknown in men and women with diabetes. We investigated the trends in fracture incidence rates (IRs) in men and women with type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D) in Denmark between 1997 and 2017. We identified men and women aged 18+ years who sustained a fracture (excluding skull and facial fractures) between 1997 and 2017 using the Danish National Patient Registry. We calculated sex-specific IRs of fractures per 10,000 person-years separately in persons with T1D, T2D, or without diabetes. Furthermore, we compared median IRs of the first 5 years (1997-2002) to the median IRs of the last 5 years (2012-2017). We identified 1,235,628 persons with fractures including 4863 (43.6% women) with T1D, 65,366 (57.5% women) with T2D, and 1,165,399 (54.1% women) without diabetes. The median IRs of fractures declined 20.2%, 19.9%, and 7.8% in men with T1D, T2D, and without diabetes, respectively (p-trend <0.05). The median IRs decreased 6.4% in women with T1D (p-trend = 0.35) and 25.6% in women with T2D (p-trend <0.05) but increased 2.3% in women without diabetes (p-trend = 0.08). Fracture IRs decreased in men with both diabetes types and only in women with T2D, highlighting the need for further attention behind the stable trend observed in women with T1D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The Therapeutic Wound Healing Bioactivities of Various Medicinal Plants.

The skin serves as the body's first line of defense, guarding against mechanical, chemical, and thermal damage to the interior organs. It includes a highly developed immune response that serves as a barrier against pathogenic infections. Wound healing is a dynamic process underpinned by numerous cellular activities, including homeostasis, inflammation, proliferation, and remodeling, that require proper harmonious integration to effectively repair the damaged tissue. Following cutaneous damage, microorganisms can quickly enter the tissues beneath the skin, which can result in chronic wounds and fatal infections. Natural phytomedicines that possess considerable pharmacological properties have been widely and effectively employed forwound treatment and infection prevention. Since ancient times, phytotherapy has been able to efficiently treat cutaneous wounds, reduce the onset of infections, and minimize the usage of antibiotics that cause critical antibiotic resistance. There are a remarkable number of wound-healing botanicals that have been widely used in the Northern Hemisphere, including Achiella millefolium, Aloe vera, Althaea officinalis, Calendula officinalis, Matricaria chamomilla, Curcuma longa, Eucalyptus, Jojoba, plantain, pine, green tea, pomegranate, and Inula. This review addresses the most often used medicinal plants from the Northern Hemisphere that facilitate the treatment of wounds, and also suggests viable natural alternatives that can be used in the field of wound care.

Low Bone Turnover Associates With Lower Insulin Sensitivity in Newly Diagnosed Drug-Naïve Persons With Type 2 Diabetes.

CONTEXT: Bone turnover markers (BTMs) are lower in type 2 diabetes mellitus (T2D). The relationships between bone turnover, ß-cell function, and insulin sensitivity in T2D are uncertain. OBJECTIVE: To investigate if fasting levels of BTMs in persons with T2D are associated with ß-cell function or insulin sensitivity. METHODS: We defined three T2D phenotypes, the insulinopenic (low ß-cell function, high insulin sensitivity), the classical (low ß-cell function, low insulin sensitivity), and the hyperinsulinemic (high ß-cell function, low insulin sensitivity) phenotypes, in the Danish Centre for Strategic Research T2D cohort using the homeostatic model assessment. We selected age- and gender-matched subgroups to represent the three T2D phenotypes, yielding 326 glucose-lowering treatment-naïve persons with T2D. Median values of BTMs between the three T2D phenotypes were compared. Regression models were applied to assess the association between BTMs, ß-cell function, and insulin sensitivity adjusted for potential confounders. RESULTS: Median serum levels of procollagen type I N-terminal propeptide, C-terminal telopeptide of type I collagen, and osteocalcin were higher in the insulinopenic phenotype (52.3 µg/L, IQR 41.6, 63.3; 259.4 ng/L, IQR 163.4, 347.7; and 18.0 µg/L, IQR 14.4, 25.2, respectively) compared with the classical (41.4, IQR 31.0, 51.4; 150.4 IQR 103.5, 265.1; 13.1, IQR 10.0, 17.6, respectively) and the hyperinsulinemic (43.7, IQR 32.3, 57.3; 163.3, IQR 98.9, 273.1; 15.7 IQR 10.2, 20.8, respectively) phenotypes (all P < .01). These differences persisted after adjustment for age, sex, waist to hip ratio, or fasting plasma glucose (P < .01). CONCLUSION: BTMs are lower in newly diagnosed persons with T2D characterized by low insulin sensitivity.

Site-Specific Fracture Incidence Rates Among Patients With Type 1 Diabetes, Type 2 Diabetes, or Without Diabetes in Denmark (1997-2017).

OBJECTIVE: To investigate trends in incidence rates (IRs) at various fracture sites for patients with type 1 diabetes and type 2 diabetes compared with patients without diabetes in Denmark in 1997-2017. RESEARCH DESIGN AND METHODS: Patients aged ≥18 years with a vertebral, hip, humerus, forearm, foot, or ankle fracture between 1997 and 2017 were identified from Danish hospital discharge data. IRs per 10,000 person-years were calculated over the study period. Median IRs for the first (1997-2001) and the last (2013-2017) 5 years were compared. We used Poisson models to estimate age-adjusted IR ratios (IRRs) of fractures among patients with type 1 and type 2 diabetes versus patients without diabetes. RESULTS: Except for foot fractures, fracture IRs were higher in patients with type 1 or type 2 diabetes compared with patients without diabetes. Hip fracture IRs declined between the first and last 5 years by 35.2%, 47.0%, and 23.4% among patients with type 1, type 2, and without diabetes, respectively. By contrast, vertebral fracture IRs increased 14.8%, 18.5%, 38.9%, respectively. While age-adjusted IRRs remained elevated in patients with type 1 diabetes compared with patients without diabetes, IRRs in patients with type 2 diabetes converged with those observed in patients without diabetes. CONCLUSIONS: Unadjusted fracture rates are higher in patients with diabetes but have decreased between 1997 and 2017 except for vertebral fractures, which increased in all groups. Fracture rates change after age adjustment.

The functional outcome after tumor resection and endoprosthesis around the knee: a systematic review.

The evidence for the functional outcome of endo- prosthetic replacement (EPR) after tumour resection has been from few cohort studies. A scoping search revealed no systematic review on patient reported outcome measures after EPR around the knee. The purpose of this study was to evaluate the functional outcome of distal femoral and proximal tibial EPR after tumour resection. A systematic review was conducted using the PRISMA guidelines. The search identified 2560 articles from MEDLINE, EMBASE, CINAHL, and Web of Science. 36 studies satisfying the selection criteria were included for data synthesis. Pooled analysis was performed for homogenous studies. Narrative synthesis was performed for all the studies due to heterogeneity in methodological and statistical analysis. Amongst the overall patient population of 2930, mean ages ranged from 18-66 years and the mean follow up periods in the studies ranged from 12 - 180 months. The weighted mean functional outcome was similar for patients who had DFEPR and PTEPR. The functional outcome scores of Rotating Hinge Knee implants (RHK) were significantly greater than that for Fixed Hinge Knee implants (FHK). The weighted mean functional outcome scores were higher after cemented fixation and after primary EPR procedures. The current evidence suggests that functional out- come after EPR in the knee is good, and RHK implants are better than FHK implants. Functional outcome after primary EPR was significantly better than following revision EPR, and this underscores the importance of minimising complications at the primary surgery.

Study of Neuroprotection by a Combination of the Biological Antioxidant (Eucalyptus Extract) and the Antihypertensive Drug Candesartan against Chronic Cerebral Ischemia in Rats.

Chronic cerebral ischemia with a notable long-term cessation of blood supply to the brain tissues leads to sensorimotor defects and short- and long-term memory problems. Neuroprotective agents are used in an attempt to save ischemic neurons from necrosis and apoptosis, such as the antioxidant agent Eucalyptus. Numerous studies have demonstrated the involvement of the renin-angiotensin system in the initiation and progression of cardiovascular and neurodegenerative diseases. Candesartan is a drug that acts as an angiotensin II receptor 1 blocker. We established a rat model exhibiting sensorimotor and cognitive impairments due to chronic cerebral ischemia induced by the ligation of the right common carotid artery. Wistar male rats were randomly divided into five groups: Sham group, Untreated Ligated group, Ischemic group treated with Eucalyptus (500 mg/kg), Ischemic group treated with Candesartan (0.5 mg/kg), and Ischemic group treated with a combination of Eucalyptus and Candesartan. To evaluate the sensorimotor disorders, we performed the beam balance test, the beam walking test, and the modified sticky test. Moreover, the object recognition test and the Morris water maze test were performed to assess the memory disorders of the rats. The infarct rat brain regions were subsequently stained using the triphenyltetrazolium chloride staining technique. The rats in the Sham group had normal sensorimotor and cognitive functions without the appearance of microscopic ischemic brain lesions. In parallel, the untreated Ischemic group showed severe impaired neurological functions with the presence of considerable brain infarctions. The treatment of the Ischemic group with a combination of both Eucalyptus and Candesartan was more efficient in improving the sensorimotor and cognitive deficits (p < 0.001) than the treatment with Eucalyptus or Candesartan alone (p < 0.05), by the comparison to the non-treated Ischemic group. Our study shows that the combination of Eucalyptus and Candesartan could decrease ischemic brain injury and improve neurological outcomes.

Pomegranate Juice Extract Decreases Cisplatin Toxicity on Peripheral Blood Mononuclear Cells.

BACKGROUND: Lung cancer is one of the most prevalent cancers worldwide. Chemotherapy regimens, targeted against lung cancer, are considered an effective treatment; albeit with multiple fatal side effects. An alternative strategy, nowadays, is using natural products. Medicinal plants have been used, in combination with chemotherapy, to ameliorate side effects. AIMS: This study aims to investigate the antitumor effect of pomegranate juice (Punica granatum) on human lung adenocarcinoma basal epithelial cells (A549), to check the effect, when combined with low dose cisplatin (CDDP), at different doses. We also have evaluated the potential protective effect of pomegranate on normal peripheral blood mononuclear cells (PBMC). METHODS: Phytochemical screening of the extract was done using standard classical tests. Total phenolic and sugar contents were determined using the Folin-Ciocalteu and anthrone reagents, respectively. The antioxidant activity of pomegranate was estimated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. The viability of A549 cells and PBMC was evaluated using the neutral red assay. RESULTS: Our results demonstrated that Punica granatum or pomegranate juice (with different concentrations: 150, 300, 600 µg/mL) contained high levels of flavonoids, alkaloids, tanins, lignins, terpenoids, and phenols. The DPPH method showed that pomegranate juice had a strong antioxidant scavenging activity. Neutral red showed that combining pomegranate juice with low dose CDDP (8 µg/mL) decreased the cell viability of A549 cells, by 64%, compared to treatment with CDDP or pomegranate alone. When added to low dose CDDP, pomegranate increased the viability of normal PBMC cells by 46%. CONCLUSIONS: These results demonstrated that pomegranate could potentiate the anticancer effect of low dose CDDP on human lung adenocarcinoma cells (A549 cells) and could as well decrease its toxicity on PBMC.

Improvement of Skeletal Muscle Regeneration by Platelet-Rich Plasma in Rats with Experimental Chronic Hyperglycemia.

Herein, the structural effect of autologous platelet-rich plasma (PRP) on posttraumatic skeletal muscle regeneration in rats with chronic hyperglycemia (CH) was tested. 130 white laboratory male rats divided into four groups (I-control; II-rats with CH; III-rats with CH and PRP treatment; and IV-rats for CH confirmation) were used for the experiment. CH was simulated by streptozotocin and nicotinic acid administration. Triceps surae muscle injury was reproduced by transverse linear incision. Autologous PRP was used in order to correct the possible negative CH effect on skeletal muscle recovery. On the 28th day after the injury, the regenerating muscle fiber and blood vessel number in the CH+PRP group were higher than those in the CH rats. However, the connective tissue area in the CH group was larger than that in the CH+PRP animals. The amount of agranulocytes in the regenerating muscle of the CH rats was lower compared to that of the CH+PRP group. The histological analysis of skeletal muscle recovery in CH+PRP animals revealed more intensive neoangiogenesis compared to that in the CH group. Herewith, the massive connective tissue development and inflammation signs were observed within the skeletal muscle of CH rats. Obtained results suggest that streptozotocin-induced CH has a negative effect on posttraumatic skeletal muscle regeneration, contributing to massive connective tissue development. The autologous PRP injection promotes muscle recovery process in rats with CH, shifting it away from fibrosis toward the complete muscular organ repair.

Potency of Combining Eucalyptus camaldulensis subsp. camaldulensis with Low-Dose Cisplatin in A549 Human Lung Adenocarcinomas and MCF-7 Breast Adenocarcinoma.

Background: Lung and breast cancers are common in the world and represent major public health problems. Systemic chemotherapy is an effective way to prolong survival but it is associated with side effects. Plants are used as traditional treatments for many types of cancers, mostly in combination with chemotherapy. We investigated the antitumor effect of ethanolic (EE) and aqueous (AE) extracts of Eucalyptus camaldulensis on human alveolar adenocarcinoma basal epithelial cells (A549) and breast adenocarcinoma cell line (MCF-7) and checked the synergistic effect of the combination with low-dose cisplatin (CDDP). Methods: AE and EE were characterized for their secondary metabolites including content of phenol and antioxidant activity of both extracts. Cell viability was tested by the neutral red assay and MTT. Combinations of extract with low-dose CDDP on A549, MCF-7 cells, and normal cells peripheral blood mononuclear cells was used to study cell viability. Results: AE contains higher level of active constituents than EE. Higher antioxidant activity was observed in AE. Both extracts showed cytotoxic activity on A549 and MCF-7 cells. Moreover, combining E. camaldulensis with low-dose CDDP increases significantly the cell death of treated cells in comparison to those treated with CDDP alone. Conclusions: Our results highlight a new therapeutic concept that combines Eucalyptus camaldulensis with low-dose CDDP to treat lung and breast adenocarcinoma.

Short-term prognostic value of TAPSE, RVFAC and Tricuspid S' wave peak systolic velocity after first acute myocardial infarction.

OBJECTIVES: Right ventricular dysfunction impacts the prognosis of various heart diseases. We set-out to examine which right ventricular functional parameters after STEMI and NSTEMI have prognostic value. Of 297 eligible participants, 266 (149 STEMI and 117 NSTEMI) completed follow-up. All patients underwent Grace score and 2D-echocardiography within 24 h. Outcome was defined as occurrence of Major Adverse Cardiovascular events (MACE), such as death, recurrent ischaemia, arrhythmia, reinfarction, stroke or heart failure, within 30 days. Patients were categorized into patients with MACE and patients without MACE. RESULTS: In STEMI-patients, compared to those without MACE, patients with MACE experienced higher grace score, left ventricle (LV) end-systolic volume, LV end-systolic dimension and wall motion score index values, but lower tricuspid annular plane systolic excursion, right ventricle (RV) fractional area change, Tricuspid S' wave peak systolic velocity and LV ejection fraction. Nevertheless, in NSTEMI-patients, those with MACE exhibited higher left atrial volume index values, but lower tricuspid annular plane systolic excursion, RV fractional area change, S' wave peak systolic velocity and LVEF. Right ventricular fractional area change < 37.5%, tricuspid annular plane systolic excursion < 15.8 mm and Tricuspid S' peak systolic velocity < 9.67 cm/s are independent predictors of MACE within first 30 days after STEMI and NSTEMI.

Deroplax silphoides (Thunberg, 1783) (Hemiptera: Heteroptera: Scutelleridae) Invasive Species in Egypt with additional morphological and behavioral data.

Invasive species continue to be a noteworthy risk to a wide range of biological systems and species diversity throughout the world. At present, accessible data about invasive species in Egypt are still insufficient despite the genuine danger these species pose to the Egyptian environment, economy and human well-being. The present study adds new distribution records of the invasive scutellerid species, Deroplax silphoides (Thunberg, 1783), to the Egyptian fauna. In 2008, this bug was first observed in Egypt in South Sinai, followed by Giza in 2016. Recently, hundreds of specimens were reported from Cairo in 2018. A new host plant, Chrysanthemum morifolium L. (Asteraceae), is reported for this bug. This work also provides additional information about the male and female genitalia. New characteristic features, photos, examined material, map of its world distribution, ecological and behavioral notes are also provided. Moreover, egg sculpturing of Deroplax silphoides was examined for the first time.

Dataset on significant role of Candesartan on cognitive functions in rats having memory impairment induced by electromagnetic waves.

Rapid growing of mobile phones users has raised about the possible effects of these electromagnetic waves (EMW) on human health. Many studies have examined the role of these EMW on biological systems, but the results are still contradictory and controversial. In addition to EMW, over-activation of angiotensin type 1 receptor (AT1R) has been associated with cognitive decline, incidence and progression of neurodegenerative diseases. Candesartan, an AT1R blocker, is well recognized for treatment of hypertension. However, its role on cognitive functions such as spatial and recognition memory remains elusive. Thus, young rats were divided into 3 groups: control, exposed to radiofrequency electromagnetic waves (EMW), and exposed to EMW during Candesartan treatment (EMW+Cand). Spatial memory performance was assessed using the object recognition test and recognition memory performance using Morris water maze test. Significant differences where found between EMW exposed rats and EMW+Cand exposed rats treated with Candesartan compared to control, EMW group impaired learning, spatial and short term memory along with unaffected sensorimotor function whereas EMW+Cand group improved learning, spatial memory and short term memory deficit induced by EMW in addition to absence of its role on sensorimotor function. Although our data provides evidences of the protective role of Candesartan against EMW-induced cognitive decline, more future studies are still needed to confirm these findings which can provide new fields in treatment of EMW-induced damage by Candesartan.

Efficiency of combining pomegranate juice with low-doses of cisplatin and taxotere on A549 human lung adenocarcinoma cells

Objective: To test the coalescence effect of two chemotherapy drugs at low effective dose (cisplatin and taxotere) combined with pomegranate juice on A549 cancer cells. Methods: Infrared spectroscopy method is a qualitative test that was performed to ensure the existence of the phytochemicals providing the antioxidant activity through the presence of the hydroxyl group (-OH). The viability of A549 cell line and normal MCs was tested using the neutral red uptake, Clonogenic survival, XTT and Cell migration assays. Results: Our results showed that this combination firstly led to a greater decrease in the viability of cells comparing to those treated with chemotherapy drugs alone, and secondly led to a significant reduction in cell migration. Conclusions: These data suggest a synergistic effect between the pomegranate and cisplatin which makes probably this combination a powerful option for treating lung adenocarcinoma and in parallel minimizing the systemic side effects.

Candesartan restores pressure-induced vasodilation and prevents skin pressure ulcer formation in diabetic mice.

BACKGROUND: Angiotensin II type 1 receptor (AT1R) blockers have beneficial effects on neurovascular complications in diabetes and in organ's protection against ischemic episodes. The present study examines whether the AT1R blocker candesartan (1) has a beneficial effect on diabetes-induced alteration of pressure-induced vasodilation (PIV, a cutaneous physiological neurovascular mechanism which could delay the occurrence of tissue ischemia), and (2) could be protective against skin pressure ulcer formation. METHODS: Male Swiss mice aged 5-6 weeks were randomly assigned to four experimental groups. In two groups, diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ, 200 mg.kg(-1)). After 6 weeks, control and STZ mice received either no treatment or candesartan (1 mg/kg-daily in drinking water) during 2 weeks. At the end of treatment (8 weeks of diabetes duration), C-fiber mediated nociception threshold, endothelium-dependent vasodilation and PIV were assessed. Pressure ulcers (PUs) were then induced by pinching the dorsal skin between two magnetic plates for three hours. Skin ulcer area development was assessed during three days, and histological examination of the depth of the skin lesion was performed at day three. RESULTS: After 8 weeks of diabetes, the skin neurovascular functions (C-fiber nociception, endothelium-dependent vasodilation and PIV) were markedly altered in STZ-treated mice, but were fully restored by treatment with candesartan. Whereas in diabetes mice exposure of the skin to pressure induced wide and deep necrotic lesions, treatment with candersartan restored their ability to resist to pressure-induced ulceration as efficiently as the control mice. CONCLUSION: Candesartan decreases the vulnerability to pressure-induced ulceration and restores skin neurovascular functions in mice with STZ-induced established diabetes.

Opposite effects of angiotensins receptors type 2 and type 4 on streptozotocin induced diabetes vascular alterations in mice.

BACKGROUND: We examined the effect of chronic administration of angiotensin IV (AngIV) on the vascular alterations induced by type 1 diabetes in mice. METHODS: Diabetes was induced in adult Swiss mice with a single injection of streptozotocin (STZ). Mice were treated subcutaneously with AngIV (1.4 mg/kg/day) either immediately following diabetes induction (preventive treatment), or treated with AngIV (0.01 to 1.4 mg/kg), alone or with the AT4 receptor antagonist Divalinal or the AT2 receptor antagonist PD123319, for two weeks after 4 weeks of diabetes duration (rescue treatment). Acetylcholine-induced, endothelium-dependent relaxation (EDR) was measured in isolated aortic rings preparations. Histomorphometric measurements of the media thickness were obtained, and nitric oxide (NO) and superoxide anion production were measured by electron paramagnetic resonance in aorta and mesenteric arteries. The effect of diabetes on mesenteric vascular alterations was also examined in genetically modified mice lacking the AT2 receptor. RESULTS: Induction of diabetes with STZ was associated with a progressive decrease of EDR and an increase of the aortic and mesenteric media thickness already significant after 4 weeks and peaking at week 6. Immediate treatment with AngIV fully prevented the diabetes-induced endothelial dysfunction. Rescue treatment with AngIV implemented after 4 weeks of diabetes dose-dependently restored a normal endothelial function at week 6. AngIV blunted the thickening of the aortic and mesenteric media, and reversed the diabetes-induced changes in NO and O2•- production by the vessels. The protective effect of AngIV on endothelial function was completely blunted by cotreatment with Divalinal, but not with PD123319. In contrast, both the pharmacological blockade and genetic deletion of the AT2 receptor reversed the diabetes-induced morphologic and endothelial alteration caused by diabetes. CONCLUSIONS: The results suggest an opposite contribution of AT2 and AT4 receptors to the vascular alterations caused by streptozotocin-induced diabetes in mice, since chronic stimulation of AT4 by AngIV and inhibition of AT2 similarly reverse diabetes-induced endothelial dysfunction and hypertrophic remodeling, and increase NO bioavailability.