Development and Validation of USM-Insulin Adherence Module for Patients with Type 2 Diabetes Mellitus.

Background: Many patients with type 2 diabetes mellitus (T2DM) do not achieve the desired glycaemic control despite being treated with insulin. Studies found this due to an improper understanding of insulin function, its intensification process and patients' negative perspective on insulin. We developed an education module to enhance adherence to insulin therapy. Methods: This study applied a mixed design. It was conducted in three phases: i) Phase I: literature search and focus group discussions (FGDs), ii) Phase II: module development and iii) Phase III: content and face validation of Universiti Sains Malaysia-Insulin Adherence Module (USM-IAM). FGDs were used to gather patients' opinions. All researchers repeatedly discussed about the module content and arrangement, the words and images used, and the grammar in producing the final draft. Specialists and target audience performed content and face validation of the module. Results: Thirty-six participants were involved in the FGDs. Data saturation was achieved at the 4th FGD. Three themes emerged from qualitative data analysis and were incorporated into the module. USM-IAM was finalised with five units. The content validity index (CVI) was 0.92, while face validity agreements were between 86% and 97%. Conclusion: The CVI and face agreement for USM-IAM exceed the cut-off point for a sound module. It has good potential to be used as a resource for educating patients in enhancing insulin adherence.

Vitamin D deficiency enhances vascular oxidative stress, inflammation, and angiotensin II levels in the microcirculation of diabetic patients.

Low vitamin D (vitD) levels have been reported to be a risk factor for diabetes-related cardiovascular complications. This study examined the effects of vitD deficiency on oxidative stress (OS), inflammation, and levels of the vasoconstrictor angiotensin II (Ang II) in the microvascular tissue of type 2 diabetic patients. Patients were categorized into (i) vitD non-deficient diabetics (DNP, n = 10) and (ii) vitD-deficient diabetics (DDP, n = 10), based on their serum 25(OH)D levels. Subcutaneous fat tissues with intact blood vessels were collected during lower limb surgical procedures. The blood vessel were isolated; measurements of the antioxidant enzyme superoxide dismutase (SOD) activity, OS marker malondialdehyde (MDA), Ang II, and the inflammatory marker, TNF-α of the microvascular tissues were determined. Elevated MDA levels and reduced SOD activity, with higher levels of TNF-α and Ang II were observed in the microvascular tissues of DDP compared to DNP. VitD deficiency did not associate with glycemic parameters (fasting blood glucose and glycated hemoglobin) levels. In conclusion, vitD deficiency was correlated with higher microvascular tissue OS, inflammation, and Ang II levels in type 2 diabetic patients. This may contribute to early vasculopathy that occurs in diabetic patients, thus, may contribute to the planning of therapeutic strategies to delay or prevent cardiovascular complications.

Impaired peripheral microvascular reactivity in patients with nonobstructive coronary artery disease.

OBJECTIVE: This study aimed to determine whether peripheral microvascular reactivity is impaired in patients with nonobstructive coronary artery disease (NOCAD). METHODS: Stable patients presenting with angina were recruited and, based on results from coronary angiography, were categorized into OCAD (coronary stenosis of ≥50%) and NOCAD (stenosis <50%) groups. A control group with no history of angina was also recruited. Forearm skin microvascular reactivity was measured using the laser Doppler blood perfusion monitor and the process of postocclusive skin reactive hyperemia (PORH). RESULTS: Patients were categorized into OCAD (n = 42), NOCAD (n = 40), and control (n = 39) groups. Compared with the control group, the PORH perfusion percent change (PORH% change) was significantly lower in the OCAD and NOCAD groups. No significant differences were noted between the OCAD and NOCAD groups. Additionally, the NOCAD group without any coronary obstruction takes a longer time to reach peak perfusion and had lower PORH% change compared with the nonangina control group. CONCLUSION: Angina patients with NOCAD have microvascular dysfunction as demonstrated by reduced magnitude of reperfusion with an ischemic stimulus. NOCAD patients without coronary obstruction also displayed a slower response to reperfusion.

Gut Microbiota Modulation as a Novel Therapeutic Strategy in Cardiometabolic Diseases.

The human gut harbors microbial ecology that is in a symbiotic relationship with its host and has a vital function in keeping host homeostasis. Inimical alterations in the composition of gut microbiota, known as gut dysbiosis, have been associated with cardiometabolic diseases. Studies have revealed the variation in gut microbiota composition in healthy individuals as compared to the composition of those with cardiometabolic diseases. Perturbation of host-microbial interaction attenuates physiological processes and may incite several cardiometabolic disease pathways. This imbalance contributes to cardiometabolic diseases via metabolism-independent and metabolite-dependent pathways. The aim of this review was to elucidate studies that have demonstrated the complex relationship between the intestinal microbiota as well as their metabolites and the development/progression of cardiometabolic diseases. Furthermore, we systematically itemized the potential therapeutic approaches for cardiometabolic diseases that target gut microbiota and/or their metabolites by following the pathophysiological pathways of disease development. These approaches include the use of diet, prebiotics, and probiotics. With the exposition of the link between gut microbiota and cardiometabolic diseases, the human gut microbiota therefore becomes a potential therapeutic target in the development of novel cardiometabolic agents.

Systemic microvascular endothelial function with arteriovenous fistula creation in chronic kidney disease.

Background: This study aimed to determine changes in microvascular endothelial function with upper arm arteriovenous fistula (AVF) creation and maturation in patients with chronic kidney disease (CKD). Materials and Methods: This prospective cross-sectional study was performed at Hospital Universiti Sains Malaysia, a tertiary hospital in Malaysia. Forty CKD patients (stage 4-5) who were scheduled for elective AVF creation over the upper extremity for maintenance hemodialysis were recruited using convenience sampling method. Microvascular endothelial-dependent vasodilation was measured using laser Doppler flowmetry and the process of iontophoresis preoperatively and postoperatively at weeks 2 and 6. Fistula maturation was assessed at week 6. Results: Thirty-two patients had successful AVF maturation. Endothelial-dependent vasodilation (acetylcholine (Ach)% was higher (246.48 [standard deviation (SD) 209.38] vs. 104.95 [SD 43.29], P = 0.001) while systolic blood pressure was lower (142.25 [SD 21.50] vs. 162.25 [SD 13.26], P = 0.017) in this group as compared to unsuccessful AVF group. No significant changes were seen in overall microvascular endothelial-dependent vasodilation during the 6-week study period (day 0, 246.48 [SD 209.38]; week 2, 201.14 [SD 198.19]; and week 6, 203.53 [SD 145.89]). Conclusion: Upper arm AVF creation does not affect microvascular endothelial function up to 6 weeks post operation and may not contribute to the success of AVF maturation. However, the lower microvascular endothelial-dependent vasodilation and higher systolic blood pressure in unsuccessful AVF subjects need to be further studied.

Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats.

Endoplasmic reticulum (ER) stress contributes to insulin resistance and macro- and microvascular complications associated with diabetes. This study aimed to evaluate the effect of ER stress inhibition on endothelial function in the aorta of type-2 diabetic rats. Type-2 diabetes was developed in male Sprague-Dawley rats using a high-fat diet and low-dose streptozotocin. Rat aortic tissues were harvested to study endothelial-dependent relaxation. The mechanisms for acetylcholine-mediated relaxation were investigated using pharmacological blockers, Western blotting, oxidative stress, and inflammatory markers. Acetylcholine-mediated relaxation was diminished in the aorta of diabetic rats compared to control rats; supplementation with TUDCA improved relaxation. In the aortas of control and diabetic rats receiving TUDCA, the relaxation was mediated via eNOS/PI3K/Akt, NAD(P)H, and the KATP channel. In diabetic rats, acetylcholine-mediated relaxation involved eNOS/PI3K/Akt and NAD(P)H, but not the KATP channel. The expression of ER stress markers was upregulated in the aorta of diabetic rats and reduced with TUDCA supplementation. The expression of eNOS and Akt were lower in diabetic rats but were upregulated after supplementation with TUDCA. The levels of MDA, IL-6, and SOD activity were higher in the aorta of the diabetic rats compared to control rats. This study demonstrated that endothelial function was impaired in diabetes, however, supplementation with TUDCA improved the function via eNOS/Akt/PI3K, NAD(P)H, and the KATP channel. The improvement of endothelial function was associated with increased expressions of eNOS and Akt. Thus, ER stress plays a crucial role in the impairment of endothelial-dependent relaxation. Mitigating ER stress could be a potential strategy for improving endothelial dysfunction in type-2 diabetes.

Endothelial Microparticles as Potential Biomarkers in the Assessment of Endothelial Dysfunction in Hypercholesterolemia.

Background and Objectives: Endothelial microparticles (EMP) particularly CD31+/42−/AV+, CD144+/AV+ and CD62e+/AV+ have been reported as having increased in cardiovascular-related diseases, making them potential biomarkers for endothelial dysfunction. This study aimed to compare these EMPs in patients with hypercholesterolemia and healthy controls and to correlate their levels with endothelium-dependent vasodilation (EDV) assessed via pulse wave analysis (PWA); an established method of assessing endothelial function. Materials and Methods: EMPs from 88 subjects (44 hypercholesterolemia patients and 44 controls) were quantified from whole blood using flow cytometry analysis. Endothelial function was determined using PWA combined with pharmacological challenge. Results: CD31+/42−/AV+ (3.45 ± 4.74 count/µL vs. 1.33 ± 4.40 count/µL; p = 0.03), CD144+/AV+ (7.37 ± 12.66 count/µL vs. 1.42 ± 1.71 count/µL; p = 0.003) and CD62e+/AV+ (57.16 ± 56.22 count/µL vs. 20.78 ± 11.04 count/µL; p < 0.001) were significantly elevated in the hypercholesterolemic group compared with the controls, respectively. There was a significant inverse moderate correlation between all circulating EMPs and EDV: CD31+/42−/AV+ (r = −0.36, p = 0.001), CD144+/AV+ (r = −0.37, p = 0.001) and CD62e+/AV+ (r = −0.35, p = 0.002). Conclusions: All EMPs were raised in the patients with hypercholesterolemia, and these values correlated with the established method of assessing endothelial function.

Time-Restricted Feeding Improved Vascular Endothelial Function in a High-Fat Diet-Induced Obesity Rat Model.

Obesity, where there is enhancement of stored body fat in adipose tissues, is associated with cardiovascular complications that are mainly related to atherosclerosis. Time-restricted feeding (TRF) is a form of restricted eating aimed at reducing weight in obese subjects. The present study aims to investigate changes in vascular endothelial function, endothelial nitric oxide synthase (eNOS), and protein kinase B (Akt) protein expressions with TRF in obese and normal rats. Male Sprague Dawley rats were divided into two normal and three obese groups; obesity was induced in the obese groups by feeding with a high-fat diet (HFD) for six weeks. After six weeks, rats were equally divided into five groups (n = 7 per group): Normal group (NR) which continued on a standard diet for six more weeks, normal group switched to TRF with a standard diet for six weeks (NR + TRFSD), obese group (OR) which continued on HFD for six more weeks, obese group switched to TRF of HFD (OR + TRFHFD), and obese group switched to TRF of a standard diet (OR + TRFSD). TRF was practiced for six weeks, after which the rats were sacrificed. Aortic endothelium-dependent and endothelium-independent relaxations and contractions were assessed using the organ bath. Aortic eNOS and Akt protein expressions were determined using immunoblotting. Fasting blood glucose, body weight, body mass index (BMI), serum lipid profile, Lee's index, serum insulin levels, and sensitivity (HOMA-IR) were also measured. Endothelium-dependent relaxation was significantly impaired, while endothelium-dependent contraction increased in obese rats compared to that in normal rats. Both obese groups which underwent TRF with a HFD and standard diet improved their impairments in endothelium-dependent relaxation and reduced endothelium-dependent contraction; these were associated with increased expressions of aortic eNOS and Akt protein. Both obese groups with TRF reduced body weight, BMI, Lee's index, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and improved insulin sensitivity. TRF improved endothelium-dependent relaxation and reduced endothelium-dependent contraction, thus attenuating endothelial dysfunction in obese rats. These were associated with increased aortic eNOS and Akt protein expressions.

Phytochemical Contents and Pharmacological Potential of Parkia speciosa Hassk. for Diabetic Vasculopathy: A Review.

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia and is considered a major health problem in the world. It is associated with endothelial dysfunction which causes progressive vascular damage. DM is a known risk factor for atherosclerosis and cardiovascular complications such as peripheral artery disease, coronary artery disease, and stroke. Medicinal plants may act as an alternative resource or adjunctive treatment option in the treatment of diabetes and its cardiovascular complications. Parkia speciosa (Fabaceae) is a plant found abundantly in the Southeast Asian region. Its seeds, with or without pods, and roots have long been used as a traditional medicine in this region to treat hypertension and diabetes. Studies have shown its numerous beneficial pharmacological properties. Extracts of P. speciosa, particularly from its seeds and empty pods, show the presence of polyphenols. They also exhibit potent antioxidant, hypoglycemic, anti-inflammatory, and antihypertensive properties. Its hypoglycemic properties are reported to be associated with the presence of ß-sitosterol, stigmasterol, and stigmat-4-en-3-one. The current review aimed to provide an overview of the current status of P. speciosa, its pharmacological potential, and its phytochemical content in attenuating diabetic vasculopathy. Glycemic status, oxidative stress, inflammation, and hyperlipidemia are known to play pivotal roles in the initiation and severity of diabetic cardiovascular diseases; thus, targeting these factors might be beneficial for preventing and/or treating diabetic vasculopathy.

An Evaluation of the Role of Oxidative Stress in Non-Obstructive Coronary Artery Disease.

Approximately half of all women presenting to the emergency department with angina chest pain do not have obstructive coronary artery disease (CAD) on coronary angiography. This condition is termed non-obstructive coronary artery disease (NOCAD), and includes ischemia with no obstructive coronary artery disease (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA). Oxidative stress has been reported to be involved in the development and progression of CAD. However, a scarcity of studies has assessed a correlation between oxidative stress and NOCAD. Thus, a literature review was performed of available reports on the role of oxidative stress in NOCAD. Possible mechanisms involved in oxidative stress that may contribute to NOCAD were identified and evaluated. A key finding of this literature review was that oxidative stress caused vasoconstriction and endothelial damage, and this results in coronary microvascular dysfunction and vasospasm, which, in turn, lead to the pathogenesis of NOCAD.

Global endothelial function assessment using pulse wave analysis in hypercholesterolemia

To compare global endothelial function assessed by pulse wave analysis (PWA) using the ratio of endothelium dependent vasodilatation (EDV) to endothelium independent vasodilatation (EIV) in patients with hypercholesterolemia and controls. 92 subjects [46 hypercholesterolemics, 46 controls] were studied at standardized conditions. Baseline augmentation index (AIx) was assessed followed by the administration of 0.5 mg sublingual nitroglycerine, an endothelium independent vasodilator. AIx was assessed and the maximum change in AIx after nitroglycerine was recorded as EIV. After a washout period of 30 minutes, 400 µg of inhaled salbutamol, an endothelium dependent vasodilator was administered. AIx was assessed again and the maximum change in AIx after salbutamol was recorded as EDV. Global endothelial function was calculated as EDV:EIV ratio. EDV and EIV in patients with hypercholesterolemia compared to controls were 2.97 ± 3.95 and 6.65 ± 3.80 (p<0.001); and 13.41 ± 4.57 and 15.88 ± 4.78 (p=0.01) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls; 0.21 ± 0.38 and 0.44 ± 0.24 (p<0.001) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls. PWA is a potential clinical tool to assess global endothelial function in patients with hypercholesterole

Clinacanthus nutans attenuates atherosclerosis progression in rats with type 2 diabetes by reducing vascular oxidative stress and inflammation.

CONTEXT: Atherosclerosis predisposes individuals to adverse cardiovascular events. Clinacanthus nutans L. (Acanthaceae) is a traditional remedy used for diabetes and inflammatory conditions. OBJECTIVES: To investigate the anti-atherosclerotic activity of a C. nutans leaf methanol extract (CNME) in a type 2 diabetic (T2D) rat model induced by a high-fat diet (HFD) and low-dose streptozotocin. MATERIALS AND METHODS: Sixty male Sprague-Dawley rats were divided into five groups: non-diabetic fed a standard diet (C), C + CNME (500 mg/kg, orally), diabetic fed an HFD (DM), DM + CNME (500 mg/kg), and DM + Metformin (DM + Met; 300 mg/kg). Treatment with oral CNME and metformin was administered for 4 weeks. Fasting blood glucose (FBG), serum lipid profile, atherogenic index (AI), aortic tissue superoxide dismutase levels (SOD), malondialdehyde (MDA), and tumour necrosis factor-alpha (TNF-α) were measured. The rats' aortas were stained for histological analysis and intima-media thickness (IMT), a marker of subclinical atherosclerosis. RESULTS: The CNME-treated diabetic rats had reduced serum total cholesterol (43.74%; p = 0.0031), triglycerides (80.91%; p = 0.0003), low-density lipoprotein cholesterol (56.64%; p = 0.0008), AI (51.32%; p < 0.0001), MDA (60.74%; p = 0.0026), TNF-α (61.78%; p = 0.0002), and IMT (39.35%; p < 0.0001) compared to untreated diabetic rats. SOD level, however, increased (53.36%; p = 0.0326). These CNME effects were comparable to those in the metformin-treated diabetic rats. CONCLUSIONS: C. nutans possesses anti-atherosclerotic properties, which may be due to reductions in vascular tissue oxidative stress, inflammation, and serum AI. Continued studies on atherosclerotic animal models are suggested.

Vitamin D deficiency attenuates endothelial function by reducing antioxidant activity and vascular eNOS expression in the rat microcirculation.

This study examined the effects of vitamin D deficiency on vascular function and tissue oxidative status in the microcirculation; and whether or not these effects can be ameliorated with calcitriol, the active vitamin D metabolite. Three groups (n = 10 each) of male Sprague Dawley rats were fed for 10 weeks with control diet (CR), vitamin D-deficient diet without (DR), or with oral calcitriol supplementation (0.15 µg/kg) for the last four weeks (DSR). After 10 weeks, rats were sacrificed; mesenteric arterial rings were studied using wire myograph. Oxidative stress biomarkers malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured in the mesenteric arterial tissue. Vascular protein expression of endothelial nitric oxide synthase (eNOS) was determined by Western blotting. Acetylcholine-induced endothelium-dependent relaxation of DR was lower than CR. eNOS expression and SOD activity were lower in mesenteric arterial tissue of DR compared to CR. Calcitriol supplementation to DSR did not ameliorate the above parameters; in fact, augmented endothelium-dependent contraction was observed. Serum calcium was higher in DSR compared to CR and DR. In conclusion, vitamin D deficiency impaired microvascular vasodilation, associated with eNOS downregulation and reduced antioxidant activity. Calcitriol supplementation to vitamin D-deficient rats at the dosage used augmented endothelium-dependent contraction, possibly due to hypercalcaemia.

Current Status of Endoplasmic Reticulum Stress in Type II Diabetes.

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.

Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity.

The role of the endoplasmic reticulum (ER) has evolved from protein synthesis, processing, and other secretory pathways to forming a foundation for lipid biosynthesis and other metabolic functions. Maintaining ER homeostasis is essential for normal cellular function and survival. An imbalance in the ER implied stressful conditions such as metabolic distress, which activates a protective process called unfolded protein response (UPR). This response is activated through some canonical branches of ER stress, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). Therefore, chronic hyperglycemia, hyperinsulinemia, increased proinflammatory cytokines, and free fatty acids (FFAs) found in diabesity (a pathophysiological link between obesity and diabetes) could lead to ER stress. However, limited data exist regarding ER stress and its association with diabesity, particularly the implicated proteins and molecular mechanisms. Thus, this review highlights the role of ER stress in relation to some proteins involved in diabesity pathogenesis and provides insight into possible pathways that could serve as novel targets for therapeutic intervention.

Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress.

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 µg/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.

Model for type 2 diabetes exhibits changes in vascular function and structure due to vascular oxidative stress and inflammation.

We used a type 2 diabetes rat model produced by a high fat diet (HFD) followed by low dose streptozotocin (STZ) to study diabetic vasculopathy. Animals were evaluated for early vascular structural changes, endothelial function, inflammation, lipid profile and oxidative stress. We used 20 male Sprague-Dawley rats divided equally into control and diabetic groups. Diabetic rats were fed an HFD for 4 weeks, injected intraperitoneally with STZ, then sacrificed at week 15. Aortic endothelial nitric oxide synthase (eNOS), aortic superoxide dismutase (SOD), endothelial-dependent and independent relaxation and contraction, intima-media thickness (IMT), malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) were measured. Histopathological characteristics also were assessed. Diabetic rats exhibited higher fasting blood glucose (FBG), low density lipoprotein, total cholesterol and triglycerides compared to the control group. Aortic endothelium-dependent relaxation due to acetylcholine (ACh) was lower, while aortic endothelium-dependent contraction due to calcium ionophore and endothelium-independent contraction due to phenylephrine (PE) were higher for the diabetic group. eNOS expression was lower in the diabetic group compared to controls. IMT and MDA levels were increased, while SOD activity was decreased in the diabetic group compared to controls. TNF-α was higher in the diabetic group than for controls. Our type 2 diabetes model exhibited endothelial dysfunction associated with early vascular structural changes, dyslipidemia, increased vascular oxidative stress, and inflammation. Therefore, the model is suitable for studying diabetic atherosclerosis.

Clinacanthus nutans Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS.

Diabetes mellitus is associated with endothelial dysfunction; it causes progressive vascular damage resulting from an impaired endothelium-dependent vasorelaxation. In the diabetes state, presence of hyperglycemia and insulin resistance predisposes to endothelial dysfunction. Clinacanthus nutans, widely used as a traditional medicine for diabetes is reported to have hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory properties. However, the possibility of C. nutans affecting the vascular endothelial function in diabetes remains unclear. This study was aimed at evaluating the effects of C. nutans methanolic leaves extract (CNME) on endothelial function in a type 2 diabetes (T2DM) rat model. Sixty male Sprague-Dawley rats were divided into five groups (n = 12 per group): nondiabetic control, nondiabetic treated with four weeks of CNME (500 mg/kg/daily), untreated diabetic rats, diabetic treated with metformin (300 mg/kg/daily), and diabetic treated with CNME (500 mg/kg/daily). T2DM was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) to rats fed with high-fat diet (HFD). Endothelial-dependent and endothelial-independent relaxations and contractions of the thoracic aorta were determined using the organ bath. Aortic endothelial nitric oxide synthase (eNOS) expression was determined using Western blotting. Endothelial-dependent relaxation was reduced in diabetic rats. Both diabetic groups treated with CNME or metformin significantly improved the impairment in endothelium-dependent vasorelaxation; this was associated with increased expression of aortic eNOS protein. CNME- and metformin-treated groups also reduced aortic endothelium-dependent and aortic endothelium-independent contractions in diabetics. Both of these diabetic-treated groups also reduced blood glucose levels and increased body weight compared to the untreated diabetic group. In conclusion, C. nutans improves endothelial-dependent vasodilatation and reduces endothelial-dependent contraction, thus ameliorating endothelial dysfunction in diabetic rats. This may occur due to its effect on increasing eNOS protein expression.

Clinacanthus nutans: Its potential against diabetic vascular diseases

Diabetes is an independent risk factor for the development of cardiovascular disease, with approximately 80% of cardiovascular mortality and morbidity linked to vascular complications such as atherosclerosis. It has been estimated that up to one-third of patients with diabetes mellitus use some form of complementary and/or alternative medicine. One plant that has received attention from diabetic patients for its perceived antidiabetic properties is Clinacanthus nutans, a member of the Acanthaceae family that is known as snake grass. Ethnomedical applications of this herb have been identified for the treatment of certain conditions, including fever, diabetes, skin rashes, and insect bites. This review aims to assess the potential of C. nutans to be used in the prevention and/or treatment of diabetic vasculopathy. Evidence for antidiabetic, anti-inflammatory, and dyslipidemic properties of C. nutans, as shown from experimental studies, is presented and discussed. Diabetes, inflammation, and hyperlipidemia are known to play significant roles in the initiation and severity of diabetic cardiovascular disease; thus, targeting these factors might be beneficial for preventing and/or treating diabetic vasculopathy.

Microvascular endothelial function and primary open angle glaucoma.

PURPOSE: To determine the role of microvascular endothelial dysfunction as risk factor for primary open angle glaucoma. METHODS: A cross-sectional study was conducted involving 114 Malay patients with POAG seen at the eye clinic of Hospital Universiti Sains Malaysia. Patients aged between 40 and 80 years who were diagnosed with other types of glaucoma, previous glaucoma filtering surgery or other surgeries except uncomplicated cataract surgery and pterygium surgery were excluded. A total of 101 patients who were followed up for dry eyes, age-related cataracts or post cataracts extraction surgery were recruited as control subjects. Those with family history of glaucoma or glaucoma suspect were excluded. Microvascular endothelial function was assessed using laser Doppler fluximetry and the process of iontophoresis. Iontophoresis with acetylcholine (ACh) and sodium nitroprusside (SNP) was used to measure microvascular endothelium-dependent and endothelium-independent vasodilatations, respectively. RESULTS: In general, POAG patients demonstrated lower ACh% and AChmax values compared with controls. There was significant difference in microvascular endothelial function [ACh%: mean, 95% confidence interval = 503.1 (378.0, 628.3), and AChmax: mean, 95% confidence interval = 36.8 (30.2, 43.5)] between primary open angle glaucoma cases (p < 0.001) and controls [ACh%: mean, 95% confidence interval = 1378.4 (1245.4, 1511.3), and AChmax: mean, 95% confidence interval = 79.2 (72.1, 86.2)]; this difference remained significant even after controlling for potential confounders. Similar difference was also found in SNP% and SNPmax between POAG and controls (p < 0.001). Age and diastolic blood pressure were inversely correlated with microvascular endothelial function. CONCLUSION: There was an impairment of microvascular endothelial function and endothelial-independent vasodilatation in POAG patients. Microvascular endothelial function is a potential risk factor for POAG.