Anti-apoptotic and antioxidant mechanisms may underlie the abrogative potential of Ocimum gratissimum Linn. Leaf extract and fractions against trastuzumab-induced cardiotoxicity in Wistar rats.

Clinical use of trastuzumab (TZM), has been widely associated with increased incidence of cardiotoxicity. Ocimum gratissimum Linn. is a household medicinal plant popularly used for treating inflammatory conditions. In this study, we investigated the abrogative potential of 100 mg/kg/day of the ethanol leaf extract of Ocimum gratissimum Linn. (OG) and its petroleum ether (PEOG), ethyl acetate (EAOG) and ethanol (EOG) fractions in TZM intoxicated Wistar rats for 7 days using anthropometric, biochemical, histopathological and immunohistochemical endpoints. In addition, secondary metabolite constituents in OG and its fractions were determined through Gas Chromatography-Mass Spectrometry (GC-MS). The study results showed that oral pretreatments with OG and OG fractions as well as the fixed dose valsartan-lisinopril (VAL-LSP) combination effectively ameliorated and restore nearly normal levels the TZM-altered plasma cardiac troponin I and antioxidant profile which were corroborated by histopathological and immunohistochemical findings as indicated by the inhibition of TZM-induced activation of caspases-3 and - 9 and profound upregulation of BCL-2 expression. Phytoscan of OG and its fractions showed the presence of thymol and in high amount. Overall, our findings revealed the cardioprotective potentials of OG, OG fractions and fixed dose VAL-LSP combination against TZM-induced cardiotoxicity which probably was mediated via abrogation of cardiomyocyte apoptosis and antioxidant mechanisms.

Oxidized dietary lipids induce vascular inflammation and atherogenesis in post-menopausal rats: estradiol and selected antihyperlipidemic drugs restore vascular health in vivo.

BACKGROUND: Thermoxidation of edible oil through deep fat frying results in the generation of several oxidized products that promote lipid peroxidation and ROS production when eaten. Consumption of thermoxidized oil in post-menopausal conditions where the estrogen level is low contributes to cardiovascular disease. This study evaluates the role of estradiol and antihyperlipidemic agents (AHD) in restoring the vascular health of ovariectomized (OVX) rats fed with thermoxidized palm oil (TPO) and thermoxidized soya oil (TSO) diets. METHOD: A total of 10 groups of rats (n = 6) were set up for the experiment. Group I (normal control) rats were sham handled while other groups were OVX to bring about estrogen deficient post-menopausal state. Group II (OVX only) was not treated and received normal rat chow. Groups III-X were fed with either TPO or TSO diet for 12 weeks and treated with estradiol (ETD) 0.2 mg/kg/day, atorvastatin (ATV) 10 mg/kg/day, and a fixed-dose combination of ezetimibe and ATV (EZE 3 mg/kg/day + ATV 10 mg/kg/day). RESULTS: Pro-atherogenic lipids levels were significantly elevated in untreated TSO and TPO groups compared to OVX and sham, resulting in increased atherogenic and Coronary-risk indices. Treatment with Estradiol and AHDs significantly reduced the total cholesterol, triglycerides, low-density lipoprotein cholesterol as well as AI and CRI compared to untreated TSO and TPO groups, whereas TSO and TPO groups showed significant elevation in these parameters compared to Group I values. Moreover, aortic TNF-α levels were extremely elevated in the untreated TSO and TPO compared to Group I. TNF-α levels were significantly reduced in rats treated with AHDs and ETD. Localized oxidative stress was indicated in the aortic tissues of TSO and TPO-fed OVX rats by increased malondialdehyde and decreased glutathione, catalase, and superoxide dismutase levels. This contributed to a depletion in aortic nitric oxide. AHDs and ETD replenished the nitric oxide levels significantly. Histological evaluation of the aorta of TSO and TPO rats revealed increased peri-adventitia fat, aortic medial hypertrophy, and aortic recanalization. These pathologic changes were less seen in AHDs and ETD rats. CONCLUSION: This study suggests that ETD and AHDs profoundly attenuate oxidized lipid-induced vascular inflammation and atherogenesis through oxidative-stress reduction and inhibition of TNF-α signaling.

Nutritional and Pharmaceutical Applications of Under-Explored Knottin Peptide-Rich Phytomedicines.

Phytomedicines reportedly rich in cystine knot peptides (Knottins) are found in several global diets, food/herbal supplements and functional foods. However, their knottin peptide content has largely been unexplored, notably for their emerging dual potentials at both the food and medicine space. The nutritional roles, biological targets and mechanism(s) of activity of these knotted peptides are largely unknown. Meanwhile, knottins have recently been unveiled as emerging peptide therapeutics and nutraceuticals of primary choice due to their broad spectrum of bioactivity, hyper stability, selective toxicity, impressive selectivity for biomolecular targets, and their bioengineering applications. In addition to their potential dietary benefits, some knottins have displayed desirable limited toxicity to human erythrocytes. In an effort to appraise what has been accomplished, unveil knowledge gaps and explore the future prospects of knottins, an elaborate review of the nutritional and pharmaceutical application of phytomedicines rich in knottins was carried out. Herein, we provide comprehensive data on common dietary and therapeutic knottins, the majority of which are poorly investigated in many food-grade phytomedicines used in different cultures and localities. Findings from this review should stimulate scientific interest to unveil novel dietary knottins and knottin-rich nutraceutical peptide drug candidates/leads with potential for future clinical application.

Antidiabetic and antihyperlipidemic effects of aqueous extract of Parquetina nigrescens in streptozotocin-nicotinamide induced type 2 diabetic rats.

BACKGROUND: Parquetina nigrescens is among the evergreen plants native to West Africa. It is used in the management of various ailments including anemia, fever, asthma and diabetes. This study evaluated the antidiabetic and antihyperlipidemic effect of Parquetina nigrescens in streptozotocin-nicotinamide-induced type 2 diabetic rats. METHODS: Type 2 diabetes mellitus was induced in overnight fasted rats with a single intraperitoneal injection of streptozotocin (60 mg/kg), followed by the administration of nicotinamide (120 mg/kg) after an interval of 15 min. Diabetic rats were orally administered with; 200, 400 and 800 mg/kg of aqueous extract of Parquetina nigrescens (AEPN), metformin (180 mg/kg) and glibenclamide (1 mg/kg) for two weeks. The effect of treatments on fasting blood glucose, serum insulin, leptin, adiponectin, homa-ir, lipid profile, body weight, pancreatic antioxidants parameters, hepatic glycogen content, glucose-6-phosphate activity, α-amylase inhibition, α-glucosidase inhibition, lipase inhibition and histology of the organs were evaluated. RESULTS: Data from this study showed that treatment with AEPN produced a significant reduction (p < 0.05) in fasting blood glucose, glucose-6-phosphatase activity, serum lipase, total triglyceride, total cholesterol, low-density lipoproteins, very low-density lipoprotein, atherogenic index, coronary risk index, pancreatic α-amylase, α-glucosidase and lipase activities. Treatment with AEPN also produced a significant (p < 0.05) increase in; glucose tolerance, glycogen content, leptin, adiponectin and pancreatic antioxidants (glutathione, superoxide dismutase, catalase and high-density lipoproteins). The histology of the organ showed regeneration of the pancreatic tissue after treatment with AEPN. CONCLUSIONS: This study showed that AEPN exhibited antidiabetic and antihyperlipidemic activity in streptozotocin-nicotinamide-induced type 2 diabetic rats.

Selected Antihypertensive Agents and Their Fixed-Dose Combinations Effectively Ameliorate Trastuzumab-Mediated Cardiac Dysfunction In Rats.

This study evaluates the therapeutic potentials of selected antihypertensive drugs [valsartan, amlodipine, lisinopril and their fixed-dose combinations (amlodipine + lisinopril) and (valsartan + lisinopril)] in ameliorating trastuzumab (TZM)­induced cardiac dysfunctions in experimental rats. After an ethical clearance for the study was obtained, in-bred young adult female Wistar rats were randomly allotted into 10 groups of 6 rats per group. Group I rats were treated with 10 ml/kg/day sterile water p.o. and 1 ml/kg/day sterile water i.p.; Group II, III and IV rats were orally treated with 5 mg/kg/day VAL and 1 ml/kg/day sterile water i.p., 0.25 mg/kg/day ADP and 1 ml/kg/day sterile water i.p., 0.035 mg/kg/day LSP and 1 ml/kg/day sterile water i.p., respectively. Group V rats were orally pretreated with 10 ml/kg/day of sterile water before i.p. 2.25 mg/kg/day of TZM. Groups VI-VIII rats were equally pretreated with 5 mg/kg/day VAL, 0.25 mg/kg/day ADP, and 0.035 mg/kg/day LSP before i.p. 2.25 mg/kg/day TZM treatment, respectively. Also, Groups IX and X rats were orally pretreated with the fixed-dose combinations of 0.25 mg/kg/day ADP + 0.035 mg/kg/day LSP in dissolved in sterile water and 5 mg/kg/day VAL + 0.035 mg/kg/day LSP before 2.25 mg/kg/day TZM treatment for 7 days. Blood pressure parameters [systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP)] and electrocardiogram (ECG) of the treated rats were measured using non-invasive procedures on days 1 and 7 of the experiment, following which the treated rats were sacrificed humanely under light inhaled diethyl ether and histopathological examination was conducted on all treated rat hearts. Results show that repeated TZM treatment significantly (p<0.05) raised SBP, DBP and MAP values from 115.0 ± 17.1 mmHg, 85.1 ± 15.1 mmHg     and      94.7 ± 15.5 mmHg, respectively on day 1      to 127.7 ± 27.8 mmHg, 87.4 ± 27.3 mmHg       and 100.5 ± 26.4 mmHg, respectively, on day 7. Oral pretreatments with VAL, ADP, LSP and their fixed-dose combinations significantly (p<0.05) attenuated increases in the SBP, DBP and MAP values with the most significant attenuation mediated by the fixed-dose VAL + LSP combination at the SBP, DBP and MAP values of 103.8 ± 20.6        mmHg, 65.5 ± 18.8 mmHg, and 77.9 ± 18.7 mmHg, respectively. TZM treatment also profoundly (p<0.05) prolonged the QT and corrected QT intervals from 85.0 ± 11.5 ms and         161.6 ± 20.3 ms, respectively, on day 1 to 110.2 ± 21.5 ms and 226.5 ± 41.5 ms, respectively, on day 7. However, these QT and corrected QT interval prolongations were effectively and profoundly attenuated by oral pretreatments with VAL, ADP, LSP and their fixed-dose combinations. In addition, TZM cardiotoxicity was characterized by marked vascular and cardiomyocyte congestion and coronary artery microthrombi formation. However, these histopathological changes were reversed with oral pretreatments with ADP, LSP, VAL and fixed-dosed [(ADP + LSP) and (VAL + LSP)] combinations although fixed-dose VAL + LSP was associated with histopathological lesions of coronary arterial wall cartilaginous metaplasia. Overall, this study revealed the promising therapeutic potentials of VAL, ADP, LSP and their fixed-dose combinations as repurposed drugs for the prevention of TZM-mediated cardiac dysfunctions.

Clerodendrum volubile Ethanol Leaf Extract: A Potential Antidote to Doxorubicin-Induced Cardiotoxicity in Rats.

Doxorubicin is widely applied in hematological and solid tumor treatment but limited by its off-target cardiotoxicity. Thus, cardioprotective potential and mechanism(s) of CVE in DOX-induced cardiotoxicity were investigated using cardiac and oxidative stress markers and histopathological endpoints. 50-400 mg/kg/day CVE in 5% DMSO in distilled water were investigated in Wistar rats intraperitoneally injected with 2.5 mg/kg DOX on alternate days for 14 days, using serum troponin I and LDH, complete lipid profile, cardiac tissue oxidative stress marker assays, and histopathological examination of DOX-treated cardiac tissue. Preliminary qualitative and quantitative assays of CVE's secondary metabolites were also conducted. Phytochemical analyses revealed the presence of flavonoids (34.79 ± 0.37 mg/100 mg dry extract), alkaloids (36.73 ± 0.27 mg/100 mg dry extract), reducing sugars (07.78 ± 0.09 mg/100 mg dry extract), and cardiac glycosides (24.55 ± 0.12 mg/100 mg dry extract). 50-400 mg/kg/day CVE significantly attenuated increases in the serum LDH and troponin I levels. Similarly, the CVE dose unrelatedly decreased serum TG and VLDL-c levels without significant alterations in the serum TC, HDL-c, and LDL-c levels. Also, CVE profoundly attenuated alterations in the cardiac tissue oxidative stress markers' activities while improving DOX-associated cardiac histological lesions that were possibly mediated via free radical scavenging and/or antioxidant mechanisms. Overall, CVE may play a significant therapeutic role in the management of DOX-induced cardiotoxicity in humans.

Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity.

Trastuzumab (TZM) is useful in the clinical management of HER2-positive metastatic breast, gastric, and colorectal carcinoma but has been limited by its off-target cardiotoxicity. This study investigates the therapeutic potentials of 0.25 mg/kg/day amlodipine, 0.035 mg/kg/day lisinopril, 5 mg/kg/day valsartan, and their fixed-dose combinations in TZM-intoxicated Wistar rats that were randomly allotted into 10 groups of 6 rats for each group. Group I rats were treated with 10 ml/kg/day sterile water orally and 1 ml/kg/day sterile water intraperitoneally; Groups II, III, and IV rats were orally gavaged with 5 mg/kg/day valsartan and 1 ml/kg/day sterile water intraperitoneally, 0.25 mg/kg/day amlodipine and 1 ml/kg/day sterile water via the intraperitoneal route, 0.035 mg/kg/day lisinopril and 1 ml/kg/day sterile water administered intraperitoneally, respectively. Group V rats were orally treated with 10 ml/kg/day of sterile water prior to intraperitoneal administration of 2.25 mg/kg/day of TZM. Groups VI-VIII rats were equally pretreated with 5 mg/kg/day valsartan, 0.25 mg/kg/day amlodipine, and 0.035 mg/kg/day lisinopril before intraperitoneal 2.25 mg/kg/day TZM treatment, respectively; Groups IX and X rats were orally pretreated with the fixed-dose combinations of 0.25 mg/kg/day amlodipine +0.035 mg/kg/day lisinopril and 5 mg/kg/day valsartan +0.035 mg/kg/day lisinopril, respectively, before TZM treatment. Cardiac injury and tissue oxidative stress markers, complete lipids profile, histopathological, and immunohistochemical assays were the evaluating endpoints. Results showed that repeated TZM treatments caused profound increases in the serum TG and VLDL-c levels, serum cTnI and LDH levels, and cardiac tissue caspase-3 and -9 levels but decreased BCL-2 expression. TZM also profoundly attenuated CAT, SOD, GST and GPx activities, and increased MDA levels in the treated tissues. In addition, TZM cardiotoxicity was characterized by marked vascular and cardiomyocyte congestion and coronary artery microthrombi formation. However, the altered biochemical, histopathological, and immunohistochemical changes were reversed with amlodipine, lisinopril, valsartan, and fixed-dose combinations, although fixed-dose valsartan/lisinopril combination was further associated with hyperlipidemia and increased AI and CRI values and coronary artery cartilaginous metaplasia. Thus, the promising therapeutic potentials of amlodipine, lisinopril, valsartan and their fixed-dose combinations in the management of TZM cardiotoxicity, majorly mediated via antiapoptotic and oxidative stress inhibition mechanisms were unveiled through this study.

Iloneoside: a cytotoxic ditigloylated pregnane glycoside from the leaves of Gongronema latifolium Benth.

Gongronema latifolium Benth (Asclepiadaceae) is an edible-green-leafy vegetable with known medicinal value. A chemical investigation of the 80% methanolic extract of the leaves led to the isolation of a new pregnane glycoside: iloneoside (3-O-[6-deoxy-3-O-methyl-ß-D-allopyranosyl-(1→14)-ß-D-oleandropyranosyl]-11,12-di-O-tigloyl-17ß-marsdenin), together with four known constituents. Their chemical structures were determined by spectroscopic analysis. The isolates were tested for their in vitro growth inhibitory activity against human leukemia HL-60 cells. Iloneoside was the most active and gave apoptotic response. Molecular docking analysis demonstrated that iloneoside could be accommodated within hot spots of anti-apoptotic protein Bcl-2. These results suggest G. latifolium as a reliable source of potent anticancer compounds.