Cissus quadrangularis extract mitigates diabetic cardiomyopathy by inhibiting RAAS activation, inflammation and oxidative stress.

BACKGROUND: Diabetic cardiomyopathy (DCM) is an age-related disease, and its progression is accompanied by hyperglycaemia, cardiac dysfunction, and myocardial structural and functional abnormalities. Cissus quadrangularis, a traditional medicinal plant, contains polyphenols, flavonoids, phytosterols, carbohydrates and ascorbic acid. It is used to treat osteoporosis, asthma, haemorrhoids and menstrual disorders.Objective: In the current research, we have investigated the effect of ethanolic extract of C. quadrangularis (EECQ) against a high-fat diet (HFD)/streptozotocin-induced DCM by estimating cardiac biomarkers, inflammatory markers and Reactive oxygen species (ROS) production. MATERIAL AND METHODS: Rats were fed with an HFD for 12 weeks, followed by single-shot low-dose streptozotocin (35 mg/kg; i.p.). The treatment was performed by EECQ (200 mg/kg/day, orally) for six weeks. RESULTS: The extract EECQ improves glucose, insulin tolerance tests and hypercholesteremia. DCM is characterized by cardiac dysfunction, cardiac biomarkers CKMB and LDH, which were attenuated by the EECQ treatment. The hypertrophic biomarker ANP, BNP expression and cardiomyocyte surface area were decreased by EECQ. Moreover, EECQ also alleviated the biomarkers Angiotensin II and renin level. EECQ also reduced oxidative stress, ROS production and cardiac inflammation. CONCLUSIONS: Thus, these findings suggested that EECQ could be used as a possible therapeutic regiment to treat DCM.

Cissus quadrangularis ameliorates hyperglycaemia, hyperinsulinemia and hyperlipidaemia.Cissus quadrangularis mitigates cardiac dysfunction.Cissus quadrangularis decreases RAAS activation, thereby down-regulates ANP, BNP expression.Cissus quadrangularis alleviates ROS propagated oxidative stress and apoptosis.

Ethanolic extract of Cissus quadrangularis improves vasoreactivity by modulation of eNOS expression and oxidative stress in spontaneously hypertensive rats.

BACKGROUND: Endothelial dysfunction is related to the reduced bioavailability of nitric oxide (NO) and plays a significant role in developing hypertension. The intake of a diet rich in antioxidants decreases the threat of hypertension. Cissus quadrangularis possesses antioxidant, anti-inflammatory, and hypocholesterolemic activities. However, to date, no studies have been performed to explore this plant's antihypertensive and vasorelaxant activity. Herein, we investigated the chronic effect of C. quadrangularis on blood pressure as well as vascular function in hypertensive rats. METHODS: Male spontaneously hypertensive rats (SHR) were randomly divided into two groups. Normotensive Wistar rats were taken as the control group. The treatment was done using ethanolic extract of C. quadrangularis (EECQ) at a dose of 200 mg/kg. RESULTS: The administration of EECQ for six weeks reduced the systolic blood pressure, mean arterial blood pressure, and heart rate. It also alleviated the cardiac and renal hypertrophy indices. Supplementation of EECQ improved the endothelium-dependent aortic vasodilation induced by acetylcholine. It restored the NO level and endothelial NO synthase expression in the aorta. Subsequently, the extract alleviates the oxidative stress and inflammatory markers in SHR rats. CONCLUSION: Thus, in the present study, the chronic treatment of EECQ to genetically hypertensive rats improved endothelium-dependent relaxation in addition to its antihypertensive effect by eNOS activation and inhibition of ROS production, inflammation.

Regulatory safety pharmacology and toxicity assessments of a standardized stem extract of Cassia occidentalis Linn. in rodents.

Cassia occidentalis Linn (CO) is an annual/perennial plant having traditional uses in the treatments of ringworm, gastrointestinal ailments and piles, bone fracture, and wound healing. Previously, we confirmed the medicinal use of the stem extract (ethanolic) of CO (henceforth CSE) in fracture healing at 250 mg/kg dose in rats and described an osteogenic mode of action of four phytochemicals present in CSE. Here we studied CSE's preclinical safety and toxicity. CSE prepared as per regulations of Current Good Manufacturing Practice for human pharmaceuticals/phytopharmaceuticals and all studies were performed in rodents in a GLP-accredited facility. In acute dose toxicity as per New Drug and Clinical Trial Rules, 2019 (prior name schedule Y), in rats and mice and ten-day dose range-finding study in rats, CSE showed no mortality and no gross abnormality at 2500 mg/kg dose. Safety Pharmacology showed no adverse effect on central nervous system, cardiovascular system, and respiratory system at 2500 mg/kg dose. CSE was not mutagenic in the Ames test and did not cause clastogenicity assessed by in vivo bone marrow genotoxicity assay. By a sub chronic (90 days) repeated dose (as per OECD, 408 guideline) study in rats, the no-observed-adverse-effect-level was found to be 2500 mg/kg assessed by clinico-biochemistry and all organs histopathology. We conclude that CSE is safe up to 10X the dose required for its osteogenic effect.

Evaluation of anti-hypertensive activity of Ulmus wallichiana extract and fraction in SHR, DOCA-salt- and L-NAME-induced hypertensive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulmus wallichiana Planchon (Himalayan Elm), a traditional medicinal plant, used in fracture healing in folk tradition of Uttarakhand, Himalaya, India. It is also used as diuretic. U. rhynchophylla, native to China, known as Gou Teng in Chinese medicine, is used for hypertension (WHO). U. macrocarpa has antihypertensive and vasorelaxant activity. However, no detailed studies related to hypertension have been reported previously, so we have explored the antihypertensive activity of U. wallichiana. AIM OF THE STUDY: To investigate the pharmacological effect of ethanolic extract (EE) and butanolic fraction (BF) of U. wallichiana in hypertensive rats. MATERIALS AND METHODS: SHR, DOCA-salt- and L-NAME-induced hypertension models were used. Treatment was performed by oral administration of EE and BF of U. wallichiana (500mg/kg/day and 50mg/kg/day) for 14 days. Then blood pressure was measured by non-invasive blood pressure (NIBP) measurement technique. Invasive blood pressure (IBP) was also reported to support the NIBP data. Concentrations of plasma renin, angiotensin II (Ang II), nitrate/nitrite (NO), cGMP were estimated. Angiotensin-converting enzyme (ACE) activity and ROS activity were also estimated. RESULTS: Blood pressure was significantly higher in SHR as compared to normotensive wistar group (170.59±0.83mmHg vs 121.54±1.24mmHg, respectively). SBP was increased in DOCA-salt induced group compared to their control (132.77±3.90mmHg vs 107.85±5.95mmHg, respectively) and L-NAME-induced group compared to their control (168.55±5.07mmHg vs 113.03±4.13mmHg, respectively). The treatment of extract and fraction of U. wallichiana significantly decreased the blood pressure in SHR+EE (151.26±1.85mmHg, p<0.001), SHR+BF (140.44±1.16mmHg, p<0.001); DOCA+EE (113.43±5.44mmHg, p<0.05), DOCA+BF (105.09±5.12mmHg, p<0.05) and L-NAME+EE (119.76±4.39mmHg, p<0.001), L-NAME+BF (117.50±7.27mmHg, p<0.001) compared to their respective diseased control groups. The plasma renin, Ang II and ACE activity were also significantly decreased and augmented the NO and cGMP levels. It also down regulated the expression of Renin, ACE, NOS3 and TGF-ß1 at mRNA levels. CONCLUSIONS: The EE and BF probably reducing the BP via Renin-angiotensin-aldosterone system and NO/cGMP signaling pathway. The decrease in blood pressure may be due to presence of quercetin analogue flavonoids (2S,3S)-(+)-3',4',5,7-tetrahydroxydihydroflavonol-6-C-ß-D-glucopyranoside; 6-Glucopyranosyl-3,3',4',5,7-pentahydroxyflavone; 6-Glucopyranosyl-4',5,7-trihydroxyflavanone and (2S,3S)-(+)-4',5,7-trihydroxydihydroflavonol-6-C-ß-D-glucopyranoside, may be due to its antioxidant activity. Thus EE and BF of U. wallichiana found to have the potential ability to be used as herbal medicament to treat hypertension.

Cardioprotective Effect of Ulmus wallichiana Planchon in ß-Adrenergic Agonist Induced Cardiac Hypertrophy.

Ulmus wallichiana Planchon (Family: Ulmaceae), a traditional medicinal plant, was used in fracture healing in the folk tradition of Uttarakhand, Himalaya, India. The present study investigated the cardioprotective effect of ethanolic extract (EE) and butanolic fraction (BF) of U. wallichiana in isoprenaline (ISO) induced cardiac hypertrophy in Wistar rats. Cardiac hypertrophy was induced by ISO (5 mg/kg/day, subcutaneously) in rats. Treatment was performed by oral administration of EE and BF of U. wallichiana (500 and 50 mg/kg/day). The blood pressure (BP) and heart rate (HR) were measured by non-invasive blood pressure measurement technique. Plasma renin, Ang II, NO, and cGMP level were estimated using an ELISA kit. Angiotensin converting enzyme activity was estimated. BP and HR were significantly increased in ISO group (130.33 ± 1.67 mmHg vs. 111.78 ± 1.62 mmHg, p < 0.001 and 450.51 ± 4.90 beats/min vs. 347.82 ± 6.91 beats/min, respectively, p < 0.001). The BP and HR were significantly reduced (EE: 117.53 ± 2.27 mmHg vs. 130.33 ± 1.67 mmHg, p < 0.001, BF: 119.74 ± 3.32 mmHg vs. 130.33 ± 1.67 mmHg, p < 0.001); HR: (EE: 390.22 ± 8.24 beats/min vs. 450.51 ± 4.90 beats/min, p < 0.001, BF: 345.38 ± 6.79 beats/min vs. 450.51 ± 4.90 beats/min, p < 0.001) after the treatment of EE and BF of U. wallichiana, respectively. Plasma renin, Ang II, ACE activity was decreased and NO, cGMP level were increased. The EE and BF of U. wallichiana down regulated the expression of ANP, BNP, TNF-α, IL-6, MMP9, ß1-AR, TGFß1 and up regulated NOS3, ACE2 and Mas expression level, respectively. Thus, this study demonstrated that U. wallichiana has cardioprotective effect against ISO induced cardiac hypertrophy.

Effect of homeopathic Lycopodium clavatum on memory functions and cerebral blood flow in memory-impaired rats.

BACKGROUND: Lycopodium clavatum (Lyc) is a widely used homeopathic medicine for the liver, urinary and digestive disorders. Recently, acetyl cholinesterase (AchE) inhibitory activity has been found in Lyc alkaloid extract, which could be beneficial in dementia disorder. However, the effect of Lyc has not yet been explored in animal model of memory impairment and on cerebral blood flow. AIM: The present study was planned to explore the effect of Lyc on learning and memory function and cerebral blood flow (CBF) in intracerebroventricularly (ICV) administered streptozotocin (STZ) induced memory impairment in rats. MATERIALS AND METHODS: Memory deficit was induced by ICV administration of STZ (3 mg/kg) in rats on 1st and 3rd day. Male SD rats were treated with Lyc Mother Tincture (MT) 30, 200 and 1000 for 17 days. Learning and memory was evaluated by Morris water maze test on 14th, 15th and 16th day. CBF was measured by Laser Doppler flow meter on 17th day. RESULTS: STZ (ICV) treated rats showed impairment in learning and memory along with reduced CBF. Lyc MT and 200 showed improvement in learning and memory. There was increased CBF in STZ (ICV) treated rats at all the potencies of Lyc studied. CONCLUSION: The above study suggests that Lyc may be used as a drug of choice in condition of memory impairment due to its beneficial effect on CBF.

Withania somnifera shows a protective effect in monocrotaline-induced pulmonary hypertension.

CONTEXT: Withania somnifera (Linn.) Dunal (Solanaceae), a clinically used herbal drug in Ayurveda, shows potent antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective effects. However, the efficacy of W. somnifera in pulmonary hypertension (PH), a cardiopulmonary disorder, remains unexplored. OBJECTIVE: The present study investigates the effect of W. somnifera root powder on monocrotaline (MCT)-induced PH in rats. MATERIALS AND METHODS: In preventive studies, W. somnifera root powder (50 and 100 mg/kg/d, p.o.) was administered from day 1 following single administration of MCT (60 mg/kg, s.c.) in Sprague-Dawley (SD) rats. After 35 d, right ventricular pressure (RVP) was measured in anesthetized rats. Various physical markers of right ventricular hypertrophy (RVH) were measured in isolated hearts. Markers of endothelial function, inflammation, and oxidative stress were estimated in lung homogenate. Vasoreactivity of pulmonary arteries was also studied. In therapeutic treatment, W. somnifera (50 and 100 mg/kg/d, p.o.) was administered from day 21 to 35 post-MCT administration. RESULTS: Preventive treatment with 50 and 100 mg/kg W. somnifera significantly reduced the RVP (32.18 ± 1.273 mm Hg and 29.98 ± 1.119 mm Hg, respectively, versus 42.96 ± 1.789 mm Hg of MCT) and all markers of RVH in MCT-challenged rats. There was an improvement in inflammation, oxidative stress and endothelial dysfunction, and attenuation of proliferative marker and apoptotic resistance in lungs. Therapeutic treatment with W. somnifera (100 mg/kg) also reduced RVP and RVH. DISCUSSION: This study demonstrated that W. somnifera significantly protected against MCT-induced PH due to its antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective properties.

LPS induces mediators of neuroinflammation, cell proliferation, and GFAP expression in human astrocytoma cells U373MG: the anti-inflammatory and anti-proliferative effect of guggulipid.

Neuroinflammation has been considered to be an integrated part of human neurodegenerative diseases. In this study, we examined the effect of guggulipid on cell proliferation, nitrite release, interleukin IL-6 and IL-1 beta release, and expression of COX-2 and glial fibrillary acidic protein (GFAP) in LPS-stimulated U373MG cells. LPS significantly stimulated human astrocytoma cells U373MG by up-regulating these neuroinflammatory mediators. Guggulipid alone had no effect on the cell proliferation of U373MG cells. The up regulation in nitrite release, cell proliferation, and release of IL-6 and IL-1 beta in LPS stimulated human astrocytoma cells were dose-dependently inhibited by co-treatment with guggulipid. The expression level of COX-2 and GFAP proteins was up regulated by LPS but the increased level of COX-2 and GFAP was significantly down regulated by treatment with guggulipid. These data indicate that guggulipid has a modulatory effect on all these parameters, which might explain its beneficial effect in the treatment of neuroinflammation-associated disorders directly relating to human aspects.

Standardized Extract of Bacopa monniera Attenuates Okadaic Acid Induced Memory Dysfunction in Rats: Effect on Nrf2 Pathway.

The aim of the present study is to investigate the effect of standardized extract of Bacopa monnieri (memory enhancer) and Melatonin (an antioxidant) on nuclear factor erythroid 2 related factor 2 (Nrf2) pathway in Okadaic acid induced memory impaired rats. OKA (200 ng) was administered intracerebroventricularly (ICV) to induce memory impairment in rats. Bacopa monnieri (BM-40 and 80 mg/kg) and Melatonin (20 mg/kg) were administered 1 hr before OKA injection and continued daily up to day 13. Memory functions were assessed by Morris water maze test on days 13-15. Rats were sacrificed for biochemical estimations of oxidative stress, neuroinflammation, apoptosis, and molecular studies of Nrf2, HO1, and GCLC expressions in cerebral cortex and hippocampus brain regions. OKA caused a significant memory deficit with oxidative stress, neuroinflammation, and neuronal loss which was concomitant with attenuated expression of Nrf2, HO1, and GCLC. Treatment with BM and Melatonin significantly improved memory dysfunction in OKA rats as shown by decreased latency time and path length. The treatments also restored Nrf2, HO1, and GCLC expressions and decreased oxidative stress, neuroinflammation, and neuronal loss. Thus strengthening the endogenous defense through Nrf2 modulation plays a key role in the protective effect of BM and Melatonin in OKA induced memory impairment in rats.

Protective effect of fruits of Morinda citrifolia L. on scopolamine induced memory impairment in mice: a behavioral, biochemical and cerebral blood flow study.

ETHNOPHARMACOLOGICAL RELEVANCE: Noni (Morinda citrifolia L.) is widely used for different illnesses including CNS disorders. Recently Noni has been reported to prevent amyloid beta induced memory impairment in mice. However, the influence of Noni on cholinergic system has not been explored so far. Therefore, present study was designed to investigate effect of Noni fruit on memory, cerebral blood flow (CBF), oxidative stress and acetylcholinesterase (AChE) activity in scopolamine induced amnesia model. MATERIALS AND METHODS: Mice were orally treated with ethanolic extract of Noni fruit and chloroform, ethyl acetate and butanol fractions of ethanolic extract for three days. Scopolamine was administered 5 min prior to acquisition trial and memory function was evaluated by passive avoidance test. CBF was measured by laser doppler flowmetry. AChE activity and oxidative stress parameters were estimated in mice brain at the end of behavioral studies. Further, effect of ethanolic extract and its fractions (5-400 µg/ml) on AChE activity was measured in vitro. RESULTS: Scopolamine caused memory impairment along with reduced CBF, increased AChE activity and oxidative stress in mice brain. Ethanolic extract of Noni fruits and its chloroform and ethyl acetate fractions significantly improved memory and CBF. However, butanol fraction had no effect. Further, increased oxidative stress and AChE activity following scopolamine was significantly attenuated by ethanolic extract of Noni and its fractions. Moreover ethanolic extract and its fractions showed dose dependent inhibition of AChE activity in vitro. CONCLUSION: These observations suggest that Noni may be useful in memory impairment due to its effect on CBF, AChE and oxidative stress.

Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow.

AIMS: The aim of the present study is to investigate the effect of curcumin on cerebral blood flow (CBF), memory impairment, oxidative stress and cholinergic dysfunction in intracerebral (IC) streptozotocin (STZ) induced memory impairment in mice. MAIN METHODS: Memory impairment was induced by STZ (0.5mg/kg, IC) administered twice with an interval of 48h in mice. Memory function was assessed by Morris water maze and passive avoidance test. CBF was measured by Laser Doppler Flowmetry (LDF). To study the preventive effect, curcumin (10, 20 and 50mg/kg, PO) was administered for 21days starting from the first dose of STZ. In another set of experiment, curcumin was administered for 7days from 19th day after confirming STZ induced dementia to observe its therapeutic effect. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain on day 21. KEY FINDINGS: The major finding of this study is that STZ (IC) caused a significant reduction in CBF along with memory impairment, cholinergic dysfunction and enhanced oxidative stress. Curcumin dose dependently improved CBF in STZ treated mice together with amelioration of memory impairment both in preventive and therapeutic manner. SIGNIFICANCE: The present study clearly demonstrates the beneficial effects of curcumin, the dietary staple of India, on CBF, memory and oxidative stress which can be exploited for dementia associated with age related vascular and neurodegenerative disorders.