Dapagliflozin Pretreatment Prevents Cardiac Electrophysiological Changes in a Diet and Streptozotocin Induction of Type 2 Diabetes in Rats: A Potential New First-Line?

Purpose: Dapagliflozin exerts cardioprotective effects in Type 2 Diabetes Mellitus (T2DM). However, whether these effects prevent electrocardiographic changes associated with T2DM altogether remain unknown. Our aim was to investigate the prophylactic effect of dapagliflozin pretreatment on the rat ECG using a high-fat, high-fructose (HFHf) diet and a low dose streptozotocin (STZ) model of T2DM. Methods: Twenty-five (25) rats were randomized into five (5) groups: normal control receiving a normal diet while the other groups received an 8-week HFHf and 40mg/kg STZ on day 42, and either: saline for the diabetic control (1 mg/kg/d), low dose (1.0 mg/kg/d) and high dose dapagliflozin (1.6 mg/kg/d), or metformin (250 mg/kg/d). Oral glucose tolerance (OGT), electrocardiograms (ECGs), paracardial adipose mass, and left ventricular fibrosis were determined. Data were analyzed using GraphPad version 9.0.0.121, with the level of significance at p < 0.05. Results: Compared to the diabetic control group, a high dose of dapagliflozin preserved the OGT (p = 0.0001), QRS-duration (p = 0.0263), QT-interval (p = 0.0399), and QTc intervals (p = 0.0463). Furthermore, the high dose dapagliflozin group had the lowest paracardial adipose mass (p = 0.0104) and fibrotic area (p = 0.0001). In contrast, while metformin showed favorable effects on OGT (p = 0.0025), paracardial adiposity (p = 0.0153) and ventricular fibrosis (p = 0.0291), it did not demonstrate significant antiarrhythmic effects. Conclusion: Pretreatment with higher doses of Dapagliflozin exhibits prophylactic cardioprotective characteristics against diabetic cardiomyopathy that include antifibrotic and antiarrhythmic qualities. This suggests that higher doses of dapagliflozin could be a more effective initial therapeutic option in T2DM.

Co-administration of rimonabant prevents glucose intolerance in Sprague-Dawley rats treated chronically with lopinavir/ritonavir and zidovudine: an experimental study design.

Introduction: treatment of HIV infection with Protease Inhibitors (PIs) and Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can lead to insulin resistance and changes in body fat distribution. Overactivity of the endogenous cannabinoid system produces similar disturbances in metabolic syndrome within the general population. However, Cannabinoid receptor type 1 antagonism, in both human and animal studies, reverses many of these biochemical and physical derangements observed in the metabolic syndrome. Methods: using an experimental study design, fifteen adult male Sprague-Dawley rats housed under standard conditions were randomized into three groups; Control, combined Anti-Retroviral Therapy (cART) only and cART + rimonabant. Drugs were administered daily by oral gavage for four weeks. After four weeks, insulin tolerance tests were conducted, the rats were euthanised and fat depots were excised and weighed. Experimental data were analysed using STATA 16.0 with the significance level set at p<0.05. The Shapiro-Wilk test determined normalcy. In cases of significance, post hoc analysis was performed by either the Dunn test or the Tukey HSD test. Results: Sprague Dawley rats treated with cART + rimonabant demonstrated better insulin sensitivity (p = 0.0239) and lower body weight (p = 0.044) than rats treated with cART alone. They had leaner body composition with 58% less adiposity than cART-only rats. Conclusion: the study results suggest a role for the endogenous cannabinoid system in cART induced metabolic derangements and physical changes. Future studies can directly assay ECS activity in cART associated metabolic syndrome.

The significant antidyslipidemic, hypoglycemic, antihyperglycemic, and antiobesity activities of the aqueous extracts of Agave Sisalana juice are partly mediated via modulation of calcium signaling pathways.

Plant species in the genus Agave, including Agave sisalana, have found extensive application in African and Asian traditional medicine. Inspired by the use of the edible sweet sap known as Aguamiel (obtained from specific mature agave species such as Agave salmiana) in Mexico by diabetic patients to improve their diabetic condition, this study investigated the effects of Agave sisalana extracts prepared by lyophilization, fermentation, and saponin extraction from sisal juice in a rodent model of metabolic syndrome. The metabolic syndrome was induced by administering a high fat and high fructose diet to freshly weaned Sprague-Dawley rats for eight weeks. The A. sisalana extracts possessed significant hypoglycemic effects [3.883 ± 0.371 mmol/L (normal group) vs. 8.183 ± 0.5845 mmol/L (negative control) vs. 3.767 ± 0.2716 mmol/L (positive control) vs. 4.167 ± 0.4602 mmol/L (FSP) vs. 4.533 ± 0.3169 mmol/L (FerSP) vs. 3.5 ± 0.2309 mmol/L (FS LD) vs. 3.867 ± 0.3353 mmol/L (FS HD) vs. 4.617 ± 0.2725 mmol/L (FerS LD) vs. 4.383 ± 0.3114 mmol/L (FerS HD): p < 0.0001]. The extracts also possessed significant antihyperlipidemic effects with significant differences in total serum cholesterol between the groups [1.398 ± 0.1232 mmol/L (normal group) vs. 4.225 ± 0.4135 mmol/L (negative control) vs. 1.582 ± 0.154 mmol/L (positive control) vs. 1.245 ± 0.0911 mmol/L (FSP) vs. 1.393 ± 0.1423 mmol/L (FerSP) vs. 1.387 ± 0.0924 mmol/L (FS LD) vs. 1.761 ± 0.1495 mmol/L (FS HD) vs. 1.698 ± 0.1294 mmol/L (FerS LD) vs. 1.6975 ± 0.0982 mmol/L (FerS HD): p < 0.0001]. Further, significant antiobesity effects of the A.sisalana extracts were observed with significant differences in weight among the groups [196.3 ± 6.49 g (normal group) vs. 298.9 ± 6.67 g (negative control) vs. 215.3 ± 6.06 g (positive control) vs. 195.4 ± 3.92 g (FSP) vs. 213.1 ± 5.21 g (FerSP) vs. 190.8 ± 6.49 g (FS LD) vs. 198.9 ± 4.31 g (FS HD) vs. 204.7 ± 4.78 g (FerS LD) vs. 208.7 ± 6.21 g (FerS HD): p < 0.0001]. Network pharmacology studies indicated that the chemical components found in sisal juice primarily exert their effects by modulating the voltage-gated calcium channels CACNA1S, CACNA1D, and CACNA1C, in the beta cells of the islets of Langerhans.

Polyoxypregnane Ester Derivatives and Lignans from Euphorbia gossypina var. coccinea Pax.

From the aerial parts of Euphorbiagossypina var. coccinea Pax., eight new pregnane glycosides (euphogossypins A-H, 1-8) of the cynanforidine and deacetylmetaplexigenin aglycons, two new lignans (gossypilignans A and B, 9 and 10), and four known compounds, namely, the pregnane 12-O-benzoyldeaxcylmetaplexigenin (11), the lignan 9α-hydroxypinoresinol (12), and the flavonoids naringenin (13) and quercitrin (14) were isolated. The structure elucidation of the new compounds was carried out by a spectroscopic analysis, including HRMS, 1D (1H, 13C JMOD), and 2D NMR (HSQC, 1H-1H COSY, HMBC, and NOESY) experiments. The obtained pregnane glycosides were substituted with acetyl and benzoyl ester moieties, and sugar chains containing thevetose, cymarose, digitoxose, and glucose monosaccharides. All of the compounds are described for the first time from E. gossypina var. coccinea. The isolated pregnanes and lignans were tested for their antiproliferative activity on HeLa cells using the MTT assay; the compounds exerted no significant effect against the tumor cells.

Bioactive Compounds from Euphorbia usambarica Pax. with HIV-1 Latency Reversal Activity.

Euphorbia usambarica is a traditional medicine used for gynecologic, endocrine, and urogenital illnesses in East Africa; however, its constituents and bioactivities have not been investigated. A variety of compounds isolated from Euphorbia species have been shown to have activity against latent HIV-1, the major source of HIV-1 persistence despite antiretroviral therapy. We performed bioactivity-guided isolation to identify 15 new diterpenoids (1-9, 14-17, 19, and 20) along with 16 known compounds from E. usambarica with HIV-1 latency reversal activity. Euphordraculoate C (1) exhibits a rare 6/6/3-fused ring system with a 2-methyl-2-cyclopentenone moiety. Usambariphanes A (2) and B (3) display an unusual lactone ring constructed between C-17 and C-2 in the jatrophane structure. 4ß-Crotignoid K (14) revealed a 250-fold improvement in latency reversal activity compared to crotignoid K (13), identifying that configuration at the C-4 of tigliane diterpenoids is critical to HIV-1 latency reversal activity. The primary mechanism of the active diterpenoids 12-14 and 21 for the HIV-1 latency reversal activity was activation of PKC, while lignans 26 and 27 that did not increase CD69 expression, suggesting a non-PKC mechanism. Accordingly, natural constituents from E. usambarica have the potential to contribute to the development of HIV-1 eradication strategies.

Application of Raman spectroscopy in type 2 diabetes screening in blood using leucine and isoleucine amino-acids as biomarkers and in comparative anti-diabetic drugs efficacy studies.

Diabetes is an irreversible condition characterized by elevated blood glucose levels. Currently, there are no predictive biomarkers for this disease and the existing ones such as hemoglobin A1c and fasting blood glucose are used only when diabetes symptoms are noticed. The objective of this work was first to explore the potential of leucine and isoleucine amino acids as diabetes type 2 biomarkers using their Raman spectroscopic signatures. Secondly, we wanted to explore whether Raman spectroscopy can be applied in comparative efficacy studies between commercially available anti-diabetic drug pioglitazone and the locally used anti-diabetic herbal extract Momordica spinosa (Gilg.)Chiov. Sprague Dawley (SD) rat's blood was used and were pipetted onto Raman substrates prepared from conductive silver paste smeared glass slides. Prominent Raman bands associated with glucose (926, 1302, 1125 cm-1), leucine (1106, 1248, 1302, 1395 cm-1) and isolecucine (1108, 1248, 1437 and 1585 cm-1) were observed. The Raman bands centered at 1125 cm-1, 1395 cm-1 and 1437 cm-1 associated respectively to glucose, leucine and isoleucine were chosen as biomarker Raman peaks for diabetes type 2. These Raman bands displayed decreased intensities in blood from diabetic SD rats administered antidiabetic drugs pioglitazone and herbal extract Momordica spinosa (Gilg.)Chiov. The intensity decrease indicated reduced concentration levels of the respective biomarker molecules: glucose (1125 cm-1), leucine (1395 cm-1) and isoleucine (1437 cm-1) in blood. The results displayed the power and potential of Raman spectroscopy in rapid (10 seconds) diabetes and pre-diabetes screening in blood (human or rat's) with not only glucose acting as a biomarker but also leucine and isoleucine amino-acids where intensities of respectively assigned bands act as references. It also showed that using Raman spectroscopic signatures of the chosen biomarkers, the method can be an alternative for performing comparative efficacy studies between known and new anti-diabetic drugs. Reports on use of Raman spectroscopy in type 2 diabetes mellitus screening with Raman bands associated with leucine and isoleucine molecules acting as reference is rare in literature. The use of Raman spectroscopy in pre-diabetes screening of blood for changes in levels of leucine and isoleucine amino acids is particularly interesting as once elevated levels are noticed, necessary interventions to prevent diabetes development can be initiated.

Freeze dried extracts of Bidens biternata (Lour.) Merr. and Sheriff. show significant antidiarrheal activity in in-vivo models of diarrhea.

ETHNOPHARMACOLOGICAL RELEVANCE OF THE STUDY: Diarrhea remains one of the main killers of children aged below five years. Traditional antidiarrheal remedies form a potentially viable source of novel low cost efficacious treatments in low resource settings. There is therefore a pressing need to scientifically evaluate these remedies. AIM OF THE STUDY: This study aimed to investigate the in vivo and in vitro antidiarrheal activity of freeze dried Bidens biternata, a herb used in traditional Ayurvedic medicine in the management of diarrhea. MATERIALS AND METHODS: In the castor oil test, twenty (20) adult Sprague-Dawley rats were randomized to a negative control (normal saline, n=5), a positive control (5mg/kg loperamide, n=5), and two test groups. The low dose test group received 200mg/kg Bidens biternata extract (n=5) while the high dose test group received 400mg/kg B. biternata extract (n=5). Castor oil (4ml/kg) was then administered to the animals one hour after administration of the respective treatments after which the total mass of fecal output excreted after four (4) hours was determined. In the charcoal meal test fifteen (15) Sprague Dawley rats were randomized to a control group (normal saline 5ml/kg orally, n=5), a positive control group (atropine sulfate 0.1mg/kg i.p., n=5) and a test group (400mg/kg B. biternata extract, n=5). Charcoal meal was then administered via oral gavage to each rat thirty (30) minutes after the administration of the various treatments. The distance covered by the charcoal meal from the pylorus was then determined after sacrifice of the animals thirty minutes after the meal. In the enteropooling test twenty (20) Sprague-Dawley rats were randomized to a control group (5% v/v ethanol in normal saline, n=5), a positive control group (5mg/kg loperamide, n=5) and a test group (400mg/kg B. biternata extract, n=5). For each group prostaglandin E2 (PGE2) (100µg/kg) was administered immediately after the treatments. The animals were then sacrificed half an hour later and the volume of the small intestine contents determined. The effects of different concentrations of B. biternata extract (0.5. 1.0, 2.0, 3.0 and 5.0mg/ml) on jejunal contraction were investigated and a dose-response curve constructed using the experimental data after which The ED50 dose was determined. The effect of tamsulosin (α1 adrenergic blocker), yohimbine (α2 adrenergic blocker), propranolol (ß adrenergic blocker) and naloxone (µ opioid blocker) on the contractile activity of the extract were also investigated. The experimental data were expressed as mean±standard error of mean (SEM) and then analyzed using one-way ANOVA followed by Tukey's post hoc test in cases of significance (set at p<0.05). RESULTS: The freeze dried extracts of B. biternata had significant antidiarrheal effects in the castor oil induced diarrhea model (p<0.01) with the highest activity being observed at the 400mg/kg dosage level (1.66±0.81g vs. 4.54±0.51g control, p=0.01). B. biternata extract had significant effects on intestinal motility in the charcoal meal test compared to the control group (43.61±4.42% vs. 60.54±3.33%: p<0.05). B. biternata extract had a significant effect on PGE2 induced enteropooling (3.06±0.07ml vs. 4.74±0.10ml; p<0.001). The freeze dried extracts of B. biternata had a significant negative effect on the contractility of the isolated rabbit jejunum (p<0.001). The effects of the extract were significantly attenuated by tamsulosin (53.94±4.20% vs. 80.57±4.09%; p<0.01) and naloxone (53.94±4.20% vs. 73.89±7.26%; p<0.05). Yohimbine (p>0.05) and propranolol (p>0.05) however did not have any significant effect on the contractile activity of the extract. CONCLUSIONS: The freeze dried extract of B. biternata possess significant antidiarrheal activity in both in vitro and in vivo models which appears to be mediated by modulating both the intestinal motility as well as the secretory activity. The results of this study also validate its traditional use as an antidiarrheal remedy.

Pattern, knowledge and practices of HbA1C testing among diabetic patients in a Kenyan tertiary referral hospital.

BACKGROUND: Glycated haemoglobin (HbA1C) measurement is the currently accepted gold standard biochemical indicator of long-term glycemic control in diabetic patients. The level of knowledge as well as the frequency of use of this test among diabetic patients in Kenya is unknown. The current study aimed to document this among patients attending the diabetes clinic at a national referral hospital in Kenya. METHODS: One hundred and ninety eight diabetic patients (59 male and 139 female) attending the outpatient diabetes clinic at the Kenyatta National Hospital were interviewed on their level of knowledge and use of the HbA1C test, as well as their last HbA1C level. The respondent answers were tabulated, analyzed and summarized. The sample mean, standard deviation and percentages were calculated. RESULTS: Of the 198 patients interviewed, 11 (5.6%) had type I diabetes mellitus (DM) while 187 (94.4%) had type II DM. One hundred and thirty four patients (67.7%) had heard of the HbA1C test while 64 patients (32.3%) had never heard of the test. Forty patients (20.2%) had at one point done the test while 158 (79.8%) had never done the test. The mean HbA1C level of the 40 patients who had at any one time done the test was 8.5 ± 1.7%, with more than 90% having HbA1C > 8%. CONCLUSION: Using self-reported accounts, the current study indicates inadequate knowledge and infrequent testing of HbA1C among diabetic outpatients in Kenya. This lack of knowledge and awareness may lead to increased susceptibility to the development of diabetic complications, and potentially higher healthcare costs among these patients. It is our recommendation that policy makers focus on strategies that address HbA1C test accessibility in Kenya, including financial coverage by the national insurance to access the test in public facilities, so as to effectively monitor and combat DM.