A review: traditional herbs and remedies impacting pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons, leading to misbalance and loss of coordination. Current therapies are claimed only for symptomatic relief, on long-term use, which causes alteration in basal ganglia, and give rise to various adverse effects like dyskinesia and extra pyramidal side effects, which is reversed and proved to be attenuated with the help of various herbal approaches. Therefore, in order to attenuate the dopaminergic complications, focus of current research has been shifted from dopaminergic to non-dopaminergic strategies. Herbs and herbal remedies seems to be a better option to overcome the complications associated with current dopaminergic therapies. In recent years, various herbs and herbal remedies based on Ayurveda, traditional Chinese and Korean remedies, have become the target of various researches. These herbs and their bioactive compound are being extensively used to treat PD in India, China, Japan, and Korea. The major focus of this current review is to analyze preclinical studies with reference to various herbs, bioactive compounds, and traditional remedies for the management of Parkinson disorder, which will give an insight towards clinical trials.

The War against Tuberculosis: A Review of Natural Compounds and Their Derivatives.

Tuberculosis (TB), caused by the bacterial organism Mycobacterium tuberculosis, pose a major threat to public health, especially in middle and low-income countries. Worldwide in 2018, approximately 10 million new cases of TB were reported to the World Health Organization (WHO). There are a limited number of medications available to treat TB; additionally, multi-drug resistant TB and extensively-drug resistant TB strains are becoming more prevalent. As a result of various factors, such as increased costs of developing new medications and adverse side effects from current medications, researchers continue to evaluate natural compounds for additional treatment options. These substances have the potential to target bacterial cell structures and may contribute to successful treatment. For example, a study reported that green and black tea, which contains epigallocatechin gallate (a phenolic antioxidant), may decrease the risk of contracting TB in experimental subjects; cumin (a seed from the parsley plant) has been demonstrated to improve the bioavailability of rifampicin, an important anti-TB medication, and propolis (a natural substance produced by honeybees) has been shown to improve the binding affinity of anti-TB medications to bacterial cell structures. In this article, we review the opportunistic pathogen M. tuberculosis, various potential therapeutic targets, available therapies, and natural compounds that may have anti-TB properties. In conclusion, different natural compounds alone as well as in combination with already approved medication regimens should continue to be investigated as treatment options for TB.

Pentacyclic triterpenes: New tools to fight metabolic syndrome.

BACKGROUND: Metabolic syndrome is a combination of dysregulated cardiometabolic risk factors characterized by dyslipidemia, impaired glucose tolerance, insulin resistance, inflammation, obesity as well as hypertension. These factors are tied to the increased risk for type-II diabetes and cardiovascular diseases including myocardial infarction in patients with metabolic syndrome. PURPOSE: To review the proposed molecular mechanisms of pentacyclic triterpenes for their potential use in the metabolic syndrome. METHODS: PubMed, Science Direct, and Google Scholar database were searched from commencement to April 2018. Following keywords were searched in the databases with varying combinations: "metabolic syndrome", "pentacyclic triterpenes", "transcription factors", "protein kinase", "lipogenesis", "adipogenesis", "lipolysis", "fatty acids", "gluconeogenesis", "cardiovascular", "mitochondria", "oxidative stress", "pancreas", "hepatic cells", "skeletal muscle", "3T3-L1", "C2C12", "obesity", "inflammation", "insulin resistance", "glucose uptake", "clinical studies" and "bioavailability". RESULTS: Pentacyclic triterpenes, such as asiatic acid, ursolic acid, oleanolic acid, 18ß-glycyrrhetinic acid, α,ß-amyrin, celastrol, carbenoxolone, corosolic acid, maslinic acid, bardoxolone methyl and lupeol downregulate several metabolic syndrome components by regulating transcription factors, protein kinases and enzyme involved in the adipogenesis, lipolysis, fatty acid oxidation, insulin resistance, mitochondria biogenesis, gluconeogenesis, oxidative stress and inflammation. CONCLUSION: In vitro and in vivo studies suggests that pentacyclic triterpenes effectively downregulate various factors related to metabolic syndrome. These phytochemicals may serve as promising candidates for clinical trials for the management of metabolic syndrome.

Targeting the DNA Repair Endonuclease ERCC1-XPF with Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) and Its Prodrug to Enhance Cisplatin Efficacy in Human Cancer Cells.

The 5'-3' structure-specific endonuclease ERCC1/XPF (Excision Repair Cross-Complementation Group 1/Xeroderma Pigmentosum group F) plays critical roles in the repair of cisplatin-induced DNA damage. As such, it has been identified as a potential pharmacological target for enhancing clinical response to platinum-based chemotherapy. The goal of this study was to follow up on our previous identification of the compound NSC143099 as a potent inhibitor of ERCC1/XPF activity by performing an in silico screen to identify structural analogues that could inhibit ERCC1/XPF activity in vitro and in vivo. Using a fluorescence-based DNA-endonuclease incision assay, we identified the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) as a potent inhibitor of ERCC1/XPF activity with an IC50 (half maximal inhibitory concentration) in the nanomolar range in biochemical assays. Using DNA repair assays and clonogenic survival assays, we show that EGCG can inhibit DNA repair and enhance cisplatin sensitivity in human cancer cells. Finally, we show that a prodrug of EGCG, Pro-EGCG (EGCG octaacetate), can enhance response to platinum-based chemotherapy in vivo. Together these data support a novel target of EGCG in cancer cells, namely ERCC1/XPF. Our studies also corroborate previous observations that EGCG enhances sensitivity to cisplatin in multiple cancer types. Thus, EGCG or its prodrug makes an ideal candidate for further pharmacological development with the goal of enhancing cisplatin response in human tumors.

Embelin Attenuates Intracerebroventricular Streptozotocin-Induced Behavioral, Biochemical, and Neurochemical Abnormalities in Rats.

Embelin, the main active constituent of Embelia ribes, has been reported to possess various pharmacological actions, including anti-inflammatory, antioxidant, anticonvulsant, and neuroprotective. The present study was designed to investigate neuroprotective mechanisms and therapeutic potential of embelin against intracerebroventricular streptozotocin (ICV-STZ)-induced experimental sporadic dementia in rats. STZ was infused bilaterally at the dose of (3 mg/kg/1 µl/1 min) ICV on day first and third. Spatial and non-spatial memory was evaluated using Morris water maze and object recognition task in rats. Embelin (2.5, 5, and 10 mg/kg, i.p.) was administrated for 14 days from seventh day onwards after first ICV-STZ infusion in rats. On day 22, rats were sacrificed and hippocampal brain regions were used to identify biochemical, neurochemical, and neuroinflammatory alterations. STZ-infused rats showed significant learning and memory deficit which was associated with an increase in oxidative stress (lipid peroxidation and nitrite), compromised antioxidant defense (reduced glutathione), neurotransmitter alterations (AChE, dopamine, noradrenaline, 5-hydroxytryptamine, gama amino butyric acid, and glutamate), and elevation in neuroinflammatory cytokine (IL-1 ß, IL-6, and TNF-α) levels. Embelin dose dependently attenuated STZ-induced cognitive deficit and biochemical alterations and restored hippocampal neurochemical levels. The observed protective effect might be attributed to the antioxidant and anti-inflammatory potential of embelin and its ability to restore hippocampal neurochemistry. Thus, the outcomes of the current study suggest therapeutic potential of embelin in cognitive disorders such as sporadic Alzheimer's disease (SAD).

Anti-hyperalgesic and anti-nociceptive potentials of standardized grape seed proanthocyanidin extract against CCI-induced neuropathic pain in rats.

BACKGROUND: Neuropathic pain is associated with severe chronic sensory disturbances characterized by spontaneous pain, increased responsiveness to painful stimuli (hyperalgesia) and pain perceived in response to non-noxious stimuli (allodynia). Morphine is effective treatment for neuropathic pain but produces tolerance on chronic use. The present study was designed to explore the anti-nociceptive and anti-hyperalgesic effect of grape seed extract using sciatic nerve ligation-induced neuropathic pain in rats. METHODS: Chronic constructive injury (CCI) was performed under anesthesia, on one side leg exposed by making a skin incision, and chromic gut ligatures were tied loosely around the sciatic nerve at 1 mm intervals. The treatment with grape seed proanthocyanidin extract (GSPE) (100 and 200 mg/kg, p.o.) was initiated on 7th day post-surgery and continued for next 14 days. Morphine (10 mg/kg, s.c.) alone and morphine in combination with GSPE (100 mg/kg, p.o.) were administered in CCI rats for 5 days starting from 7th day. On 3rd, 7th, 14th and 21st day, behavioral parameters (mechanical allodynia and thermal hyperalgesia) were assessed. Then the animals were killed on 22nd day and biochemical parameters [reduced glutathione (GSH), lipid peroxidation (LPO), catalase, nitrite, superoxide dismutase (SOD)] were assessed. RESULTS: Ligation of the sciatic nerve significantly induced mechanical allodynia and thermal hyperalgesia and induces oxidative stress (increase in LPO and nitrite) and decline of anti-oxidant enzyme levels (catalase, SOD, GSH) in sciatic nerve homogenate. GSPE (100 and 200 mg/kg, p.o.) attenuated all the behavioural and biochemical parameters. Morphine also significantly reversed the symptoms of neuropathic pain but produced tolerance after 5 days. Further, co-treatment of GSPE (100 mg/kg) with morphine (10 mg/kg, s.c.) in CCI rats significantly reversed the morphine tolerance and enhanced its anti-hyperalgesic effect as compared to the morphine-alone-treated group. CONCLUSIONS: In the present set of experiments, GSPE showed a significant anti-hyperalgesic and anti-nociceptive effect in rats.

Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer's disease.

Cyclic nucleotides viz., cAMP/cGMP has been well known to play important role in cellular function and deficiency in their levels has been implicated in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease (AD). Phosphodiesterases (PDE) are the enzymes involved in the metabolism of cyclic nucleotides and the inhibition of phosphodiesterases is considered to be viable strategy to restore the level of cyclic nucleotides and their functions in the brain. Various synthetic PDE inhibitors had been used clinically for various disorders and also suggested to be useful candidates for treating neurological disorders. However, side effects of these synthetic PDE inhibitors have limited their use in clinical practice. Natural plant extracts or their bio-active compounds are considered to be safe and are widely acceptable. During the last decade, many plant extracts or their bio-active compounds were tested pre-clinically for PDE inhibitory activity and are reported to be equally potent in inhibiting PDE's, as that of synthetic compounds. The present review is aimed to discuss the potential plant extract/compounds with PDE inhibitory activity and critically discuss their potential role in Alzheimer's disease.

Effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart.

Hyperlipidemia is regarded as independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia-/reperfusion (I/R)-induced injury. Hyperlipidemia attenuates the cardioprotective response of ischemic preconditioning (IPC). The present study investigated the effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat hearts. Hyperlipidemia was induced in rat by feeding high-fat diet (HFD) for 6 weeks then the serum lipid profile was observed. In experiment, the isolated Langendorff rat heart preparation was subjected to 4 cycles of ischemic preconditioning (IPC), then 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was elaborated morphologically by triphenyltetrazolium chloride (TTC) staining and biochemically by lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) release from coronary effluent and left ventricular collagen content. However, the effect of zinc supplement, i.e., zinc pyrithione (10 µM) perfused during reperfusion for 120 min, significantly abrogated the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart whereas administration of chelator of this zinc ionophore, i.e., N,N,N',N'-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN; 10 µM), perfused during reperfusion 2 min before the perfusion of zinc pyrithione abrogated the cardioprotective effect of zinc supplement during experiment in hyperlipidemic rat heart. Thus, the administration of zinc supplements limits the infarct size, LDH, and CK-MB and enhanced the collagen level which suggests that the attenuated cardioprotective effect of IPC in hyperlipidemic rat is due to zinc loss during reperfusion caused by ischemia/reperfusion.

Attenuating effect of standardized lyophilized Cinnamomum zeylanicum bark extract against streptozotocin-induced experimental dementia of Alzheimer's type.

BACKGROUND: The Cinnamomum zeylanicum (CZ; family Lauraceae) bark, an important spice, has also been used traditionally for nervous stress, as a nervine tonic, and as a stimulant. Therefore, the present study was designed to evaluate the effect of the standardized lyophilized aqueous extract of CZ bark (LCZE) on learning and memory in rodents at 50, 100, and 200 mg/kg, p.o. dose levels against streptozotocin (STZ)-induced memory impairment. METHODS: LCZE was standardized based on the cinnamaldehyde content using high-performance thin-layer chromatography (HPTLC). The effect on learning and memory was evaluated using two widely used behavioral models, the Morris water maze (MWM) test and the object recognition test (ORT). The effect of LCZE on the acetylcholinesterase (AChE) activity and oxidative stress parameters in the cerebral cortex and hippocampus of rat brain was also evaluated. RESULTS: LCZE significantly (p<0.05) and dose-dependently attenuated STZ-induced cognitive deficit in both models in comparison to only STZ-treated animals. In the MWM test, LCZE (100 and 200 mg/kg) significantly decreased the transfer latency and increased the time spent by the animals in target quadrant. Similarly in the ORT, the LCZE-treated animals exhibited an improved discrimination between a familiar object and a novel object, indicating the reversal of STZ-induced memory impairment. LCZE also restored STZ-induced alteration in AChE activity and oxidative stress parameters in both brain parts. CONCLUSIONS: The results clearly indicate toward the memory-enhancing effect of LCZE, which could be due to the synergistic effect of anti-AChE and antioxidant activities.

Ameliorating effect of lyophilized extract of Butea frondosa leaves on scopolamine-induced amnesia in rats.

CONTEXT: Butea frondosa (BF) Roxb. & Koen. (syn. B. monosperma Lam.) (Fabaceae) leaves have been used in folklore medicine for the treatment of diabetes, conjunctivitis, gastrointestinal tract, and central nervous system disorders such as anxiety, amnesia, etc. OBJECTIVE: To evaluate the effect of lyophilized hydroalcoholic extract of BF leaves (BFLE) at 100, 200 and 400 mg/kg, p.o., for its memory enhancing activity against scopolamine-induced amnesia in rats. MATERIALS AND METHODS: Antiamnesic effect of the BFLE was evaluated using Morris water maze and object recognition test models. The effect of BFLE on acetylcholinesterase activity and malondialdehyde and glutathione levels were also evaluated in brain homogenate. RESULT: BFLE ameliorates scopolamine-induced amnesia in both the models with maximum effect at 400 mg/kg. BFLE (400 mg/kg) decreased escape latency and increased time spent in target quadrant (24.2 and 42.5 s, respectively) in comparison to scopolamine (82 and 18.2 s, respectively) in the Morris water maze task. In the object recognition test, BFLE produced significant increase in ability to discriminate between novel and familiar objects. The highest investigated dose of BFLE (400 mg/kg), produced a significant decrease in acetylcholinesterase activity and malondialdehyde levels, and improves glutathione levels in comparison to scopolamine. Moreover, this effect of BFLE at 400 mg/kg was comparable to that of standard, donepezil. CONCLUSION: BFLE exhibited significant antiamnesic activity in rats thereby validating its folklore use.

Preferred binding orientations of phenacetin in CYP1A1 and CYP1A2 are associated with isoform-selective metabolism.

Human cytochromes P450 1A1 and 1A2 play important roles in drug metabolism and chemical carcinogenesis. Although these two enzymes share high sequence identity, they display different substrate specificities and inhibitor susceptibilities. In the present studies, we investigated the structural basis for these differences with phenacetin as a probe using a number of complementary approaches, such as enzyme kinetics, stoichiometric assays, NMR, and molecular modeling. Kinetic and stoichiometric analyses revealed that substrate specificity (k(cat)/K(m)) of CYP1A2 was approximately 18-fold greater than that of CYP1A1, as expected. Moreover, despite higher H2O2 production, the coupling efficiency of reducing equivalents to acetaminophen formation in CYP1A2 was tighter than that in CYP1A1. CYP1A1, in contrast to CYP1A2, displayed much higher uncoupling, producing more water. The subsequent NMR longitudinal (T1) relaxation studies with the substrate phenacetin and its product acetaminophen showed that both compounds displayed similar binding orientations within the active site of CYP1A1 and CYP1A2. However, the distance between the OCH2 protons of the ethoxy group (site of phenacetin O-deethylation) and the heme iron was 1.5 Å shorter in CYP1A2 than in CYP1A1. The NMR findings are thus consistent with our kinetic and stoichiometric results, providing a likely molecular basis for more efficient metabolism of phenacetin by CYP1A2.