An updated review on phytochemistry and molecular targets of Withania somnifera (L.) Dunal (Ashwagandha).

Withania somnifera (L.) Dunal belongs to the nightshade family Solanaceae and is commonly known as Ashwagandha. It is pharmacologically a significant medicinal plant of the Indian sub-continent, used in Ayurvedic and indigenous systems of medicine for more than 3,000 years. It is a rich reservoir of pharmaceutically bioactive constituents known as withanolides (a group of 300 naturally occurring C-28 steroidal lactones with an ergostane-based skeleton). Most of the biological activities of W. somnifera have been attributed to two key withanolides, namely, withaferin-A and withanolide-D. In addition, bioactive constituents such as withanosides, sitoindosides, steroidal lactones, and alkaloids are also present with a broad spectrum of therapeutic potential. Several research groups worldwide have discovered various molecular targets of W. somnifera, such as inhibiting the activation of nuclear factor kappa-B and promoting apoptosis of cancer cells. It also enhances dopaminergic D2 receptor activity (relief in Parkinson's disease). The active principles such as sitoindosides VII-X and withaferin-A possess free radical properties. Withanolide-D increases the radio sensitivity of human cancer cells via inhibiting deoxyribonucleic acid (DNA) damage to non-homologous end-joining repair (NHEJ) pathways. Withanolide-V may serve as a potential inhibitor against the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to combat COVID. The molecular docking studies revealed that the withanolide-A inhibits acetyl-cholinesterase in the brain, which could be a potential drug to treat Alzheimer's disease. Besides, withanolide-A reduces the expression of the N-methyl-D-aspartate (NMDA) receptor, which is responsible for memory loss in epileptic rats. This review demonstrates that W. somnifera is a rich source of withanolides and other bioactive constituents, which can be used as a safe drug for various chronic diseases due to the minimal side effects in various pre-clinical studies. These results are interesting and signify that more clinical trials should be conducted to prove the efficacy and other potential therapeutic effects in human settings.

Natural product inspired leads in the discovery of anticancer agents: an update.

Natural products have emerged as major leads for the discovery and development of new anti-cancer drugs. The plant-derived anti-cancer drugs account for approximately 60% and the quest for new anti-cancer agents is in progress. Anti-cancer leads have been isolated from plants, animals, marine organisms, and microorganisms from time immemorial. The process of semisynthetic modifications of the parent lead has led to the generation of new anti-cancer agents with improved therapeutic efficacy and minimal side effects. The various chemo-informatics tools, bioinformatics, high-throughput screening, and combinatorial synthesis are able to deliver the new natural product lead molecules. Plant-derived anticancer agents in either late preclinical development or early clinical trials include taxol, vincristine, vinblastine, topotecan, irinotecan, etoposide, paclitaxel, and docetaxel. Similarly, anti-cancer agents from microbial sources include dactinomycin, bleomycin, mitomycin C, and doxorubicin. In this review, we highlighted the importance of natural products leads in the discovery and development of novel anti-cancer agents. The semisynthetic modifications of the parent lead to the new anti-cancer agent are also presented. Further, the leads in the preclinical settings with the potential to become effective anticancer agents are also reviewed.Communicated by Ramaswamy H. Sarma.

Skimmia anquetilia N.P. Taylor and Airy Shaw (Rutaceae): A Critical Appriasal of its Ethnobotanical and Pharmacological Activities.

Skimmia anquetilia N.P. Taylor and Airy Shaw (Rutaceae) is a perennial, aromatic, gregarious wild ornamental shrub native to the Western Himalaya. The plant is used in the traditional medicinal system to treat copious health conditions like rheumatism, fever, inflammation, headache, influenza, body-ache, clearing of the nose, diabetes, lowering the body temperature, smallpox, wounds, burns, snake, and scorpion bites. Phytochemical and gas chromatography-mass spectrometer (GC-MS) analysis of S. anquetilia showed the presence of alkanes, alkenes, carboxylic acids, fatty acids, and their esters, simple coumarins, terpenes, phenylpropanoid, and so on. These active principles exhibit a wide array of pharmacological effects, including anti-inflammatory, antioxidant, anti-cancerous, anti-feedant, and antibacterial properties. Most pharmacological studies were based on the essential oil and the crude extracts of the plant and the bioactive compounds responsible for the bioefficacy have not been well-identified. Further investigations are required to transform the experience-based claims on the use of S. anquetilia in traditional medicine practices into evidence-based information. Detailed in-vitro and in-vivo studies on the mechanisms of action of pure bioactive compounds and more elaborate toxicity studies to ensure plant safety for human use should be conducted. This review recapitulates the current status of its use in the ethnobotany, phytochemistry, and pharmacological activities. It also offers a critical assessment of the plant's existing information which would help to recuperate its potential as a source for drug development of lead molecules.

Phytochemical screening and antibacterial activity of Skimmia anquetilia N.P. Taylor and Airy Shaw: A first study from Kashmir Himalaya.

The present study aimed to explore the antibacterial activity of various organic root extracts of Skimmia anquetilia N.P. Taylor and Airy Shaw and the identification of major functional groups and phytoconstituents through fourier transform infrared spectrometer (FTIR) and gas chromatography-mass spectrometer (GC-MS). The extracts were evaluated for antibacterial activity against multidrug-resistant (MDR) strains viz., Pseudomonas aeruginosa (MTCC424), Escherichia coli (MTCC739), Klebsiella pneumoniae (MTCC139), Salmonella typhi (MTCC3224), and Staphylococcus aureus (MTCC96). ESKAPE pathogens such as S. aureus, K. pneumoniae, and P. aeruginosa are responsible for a majority of all healthcare acquired infections. The ethyl acetate extract showed the highest zone of inhibition against P. aeruginosa (18 mm) followed by S. aureus (17 mm). The minimum inhibitory concentration (MIC) of ethyl acetate extract against strain of S. aureus (4 mg mL-1) demonstrated therapeutically significant antibacterial activity. The FTIR spectra of root extracts revealed the occurrence of functional characteristic peaks of alcohols, carboxylic acids, aromatic compounds, alkanes, alkenes, and amines that indicates the presence of various metabolites in the extracts. The GC-MS investigation led to the identification of diverse phytoconstituents in each of the extracts with varying concentrations and molecular masses. The highest number of compounds were identified from the methanol extract (112), followed by n-hexane extract (88) and ethyl acetate extract (74). The most predominant compounds were 5, 10-pentadecadien-1-ol, (Z,Z)-(33.94%), n-hexadecanoic acid (13.41%) in n-hexane extract, 5,10-pentadecadien-1-ol, (Z,Z)-(10.48%), 1-hexyl-2-nitrocyclohexane (7.94%) in ethyl acetate extract, and 1-hexyl-2-nitrocyclohexane (15.43%), cis,cis,cis-7,10,13-hexadecatrienal (13.29%) in methanol extract. The results of the present study will create a way for the invention of plant-based medicines for various life-threatening microbial infections using S. anquetilia, which may lead to the development of novel drugs against drug-resistant microbial infections.

Phytochemical Profiling and Antibacterial Activity of Methanol Leaf Extract of Skimmia anquetilia.

Skimmia anquetilia is a plant species native to the Western Himalaya region that has tremendous potential for phytochemical activities. This study aimed to identify bioactive compounds and assess the antibacterial activity of S. anquetilia. To determine the major bioactive chemicals in the methanol leaf extract of S. anquetilia, we used a gas chromatography-mass spectrometer (GC-MS). The presence of 35 distinct phytoconstituents was discovered using GC-MS, which could contribute to the therapeutic capabilities of this plant species. The most predominant compound was 2R-acetoxymethyl-1,3,3-trimethyl-4t-(3-methyl-2-buten-1-yl)-1t-cyclohexanol (23.9%). Further, the leaf extract was evaluated for antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, and Staphylococcus aureus. The extract showed the highest zone of inhibition against E. coli (19 mm) followed by P. aeruginosa (18 mm) and K. Pneumoniae (17 mm) at 160 mg mL-1. The minimum inhibitory concentration (MIC) of methanol extract against the strain of P. aeruginosa (2 mg mL-1) demonstrated significant antibacterial activity. The findings of the present study highlight the potential of S. anquetilia for the development of herbal medicines for the treatment of various pathogenic infections.

Role of Environmental Toxicants on Neurodegenerative Disorders.

Neurodegeneration leads to the loss of structural and functioning components of neurons over time. Various studies have related neurodegeneration to a number of degenerative disorders. Neurological repercussions of neurodegeneration can have severe impacts on the physical and mental health of patients. In the recent past, various neurodegenerative ailments such as Alzheimer's and Parkinson's illnesses have received global consideration owing to their global occurrence. Environmental attributes have been regarded as the main contributors to neural dysfunction-related disorders. The majority of neurological diseases are mainly related to prenatal and postnatal exposure to industrially produced environmental toxins. Some neurotoxic metals, like lead (Pb), aluminium (Al), Mercury (Hg), manganese (Mn), cadmium (Cd), and arsenic (As), and also pesticides and metal-based nanoparticles, have been implicated in Parkinson's and Alzheimer's disease. The contaminants are known for their ability to produce senile or amyloid plaques and neurofibrillary tangles (NFTs), which are the key features of these neurological dysfunctions. Besides, solvent exposure is also a significant contributor to neurological diseases. This study recapitulates the role of environmental neurotoxins on neurodegeneration with special emphasis on major neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

Invivo hepatoprotective potential of extracts obtained from floral spikes of Prunella vulgaris L.

BACKGROUND: Prunella vulgaris, commonly known as self-heal, has been extensively used in the traditional system of medicines. The plant has been found to contain a number of bioactive molecules including those having radical scavenging property which indicates its potential for the treatment of those diseases which are induced by free radical damage like drug-induced hepatotoxicity. OBJECTIVE: The current study was undertaken to investigate the flavonoid and total phenolic content and evaluate the hepatoprotective potential of various extracts obtained from floral spikes of P. vulgaris. MATERIAL AND METHODS: Flavonoid and otal phenolic contents were obtained from the standard curves of Gallic acid as per the reported methods. The extent of hepatotoxicity induced by paracetamol (500 mg/kg b.w, p.o daily for 14 days), hepatoprotective potential of extracts (200 mg/kg b.w/day, orally) and standard drug silymarin (50 mg/kg b.w/day, orally) were evaluated by analyzing various biochemical parameters like Serum Glutamic Oxaloacetic Transaminase, Serum Glutamic Pyruvic Transaminase, Alkaline Phosphatase, Total Proteins, Total and Direct Bilirubin and detailed histopathology of rat livers. RESULTS: Methanolic extract showed higher quantity of flavonoids and total phenolic content followed by ethanolic, hydroalcoholic and aqueous extracts. Treatment of rats with extracts showed a highly significant reduction in the enzyme activities of Serum Glutamic Oxaloacetic Transaminase, Serum Glutamic Pyruvic Transaminase, Alkaline Phosphatase, and serum levels of Total, Direct Bilirubin (P < 0.01) and highly significant elevation in Total Proteins (P < 0.01) when compared with the toxic control group. This was further confirmed by histopathological evaluation, where almost normal hepatic architecture or very less hepatic damage was observed in groups treated with extracts and silymarin compared to paracetamol treated group. Results from biochemical and histopathological evaluation indicated that among the extracts methanolic extract was most effective. CONCLUSION: From the results, it can be concluded that the extracts obtained from floral spikes of P. vulgaris possess highly significant hepatoprotective activity which could be attributed to its radical scavenging potential and hepatic regeneration. This is further authenticated by the presence of phenolic and flavonoids which are known to possess radical scavenging properties.

Raloxifene potentiates the effect of fluoxetine against maximal electroshock induced seizures in mice.

The evidence to guide clinicians regarding rationale polytherapy with current antiepileptic drugs (AEDs) is lacking, and current practice recommendations are largely empirical.  The excessive drug loading with combinatorial therapies of existing AEDs are associated with escalated neurotoxicity, and that emergence of pharmacoresistant seizures couldn't be averted. In pursuit of judicious selection of novel AEDs in combinatorial therapies with mechanism based evidences, standardized dose of raloxifene, fluoxetine, bromocriptine and their low dose combinations, were experimentally tested for their impact on maximal electroshock (MES) induced tonic hind limb extension (THLE) in mice. Hippocampal neuropeptide Y (NPY) levels, oxidative stress and histopathological studies were undertaken. The results suggest the potentiating effect of 4 mg/kg raloxifene on 14 mg/kg fluoxetine against MES induced THLE, as otherwise monotherapy with 4 mg/kg raloxifene was unable to produce an effect. The results also depicted better efficacy than carbamazepine (20 mg/kg), standard AED. Most profoundly, MES-induced significant (P < 0.001) reduction in hippocampal NPY levels, that were escalated insignificantly with the duo-drug combination, suggesting some other mechanism in mitigation of electroshock induced seizures. These results were later corroborated with assays to assess oxidative stress and neuronal damage. In conclusion, the results demonstrated the propitious therapeutic benefit of duo-drug low dose combination of drugs; raloxifene and fluoxetine, with diverse mode of actions fetching greater effectiveness in the management of generalized tonic clonic seizures (GTCS).

The Synergistic Effect of Raloxifene, Fluoxetine, and Bromocriptine Protects Against Pilocarpine-Induced Status Epilepticus and Temporal Lobe Epilepsy.

The present antiepileptic drugs pose several problems in the management of seizures owing to their meager neuroprotective potential, adverse effects on bone, detrimental effects on cognitive function, chronic toxicity, drug interactions, side effects including aggression, agitation, and irritability and sometimes exacerbation of seizures. We followed up progressive preclinical investigation in mice against pilocarpine (PILO)-induced status epilepticus (SE) and temporal lobe epilepsy (TLE). To determine the response of raloxifene (RF) (4 and 8 mg/kg), fluoxetine (FT) (14 and 22 mg/kg), bromocriptine (BC) (6 and 10 mg/kg), and their low-dose combinations, oral treatment was scheduled for 28 days followed by PILO (300 mg/kg, i.p). The response was stalked for intensive behavioral monitoring of convulsions, hippocampal neuropeptide Y (NPY), and oxidative stress discernment along with histomorphological studies. The resultant data confirmed the therapeutic potential of triple drug combination of raloxifene (4 mg/kg) with fluoxetine (14 mg/kg) and bromocriptine (6 mg/kg) compared to monotherapy with raloxifene (4 mg/kg), and bromocriptine (6 mg/kg) as otherwise monotherapy with fluoxetine (14 mg/kg) was ineffective to suppress convulsions; an effect better than sodium valproate (300 mg/kg), a standard AED, was validated. Most profoundly, PILO-induced compensatory increases in hippocampal NPY levels (20.01%), which was escalated (100%) with the triple drug combination. The same pattern of results was superseded for oxidative stress indices and neuronal damage. The results for the first time demonstrate the propitious role of triple drug combination in the management of SE and TLE. Therapeutically, this enhancing profile of drugs fosters a safer and more effective drug-combination regimen. Graphical abstract.

Amelioration of the cyclophosphamide induced genotoxic damage in mice by the ethanolic extract of Equisetum arvense.

In the present study, we evaluated the potential of the plant E. arvense against the cytotoxic and mutagenic effects induced by cyclophosphamide (chemotherapeutic agent) in the bone marrow cells of mice using the Chromosome assay (CA) and Mitotic index (MI) in vivo as the biomarkers. The study was performed following 3 protocols: pre-treatment, simultaneous treatment and post-treatment with the ethanolic extract of the plant. The results demonstrated that the plant extract was not cytotoxic and mutagenic and has a protective effect against the mutagenicity induced by cyclophosphamide in pre, simultaneous and post treatments and against its cytotoxicity as well. Because of its ability to prevent chromosomal damage, E. arvense is likely to open an interesting field concerning its possible use in clinical applications, most importantly in cancer as a chemopreventive agent or even as a coadjuvant to chemotherapy to reduce the side effects associated with it.

Effect of Naringenin (A naturally occurring flavanone) Against Pilocarpine-induced Status Epilepticus and Oxidative Stress in Mice.

BACKGROUND: Epilepsy is a disorder of the central nervous system characterized by recurrent seizures. It is a very common disease in which approximately 30% of patients do not respond favourably to treatment with anticonvulsants. Oxidative stress is associated with neuronal damage arising from epileptic seizures. The present study investigated the effects of naringenin in pilocarpine-induced epilepsy in mice. Naringenin, one of the most frequently occurring flavanone in citrus fruits, was evaluated for its shielding effect against the pilocarpine induced behavioural, oxidative and histopathological alterations in rodent model of epilepsy. METHODOLOGY: Epilepsy was induced by giving pilocarpine (300mg/kg) and sodium valproate (300mg/kg) was given as standard anti-epileptic drug Pilocarpine was administered (300 mg /kg body weight) intraperitoneally to the mice on 15th day while naringenin was administered orally (20 and 40 mg/kg body weight) for 15 days prior to administration of pilocarpine. RESULTS: The intraperitoneal administration of pilocarpine enhanced lipid peroxidation, caused reduction in antioxidant enzymes, viz., catalase, superoxide dismutase and glutathione reductase. Treatment of mice orally with naringenin (20 mg/kg body weight and 40 mg/kg body weight) resulted in a significant decrease in lipid peroxidation. There was significant recovery of glutathione content and all the antioxidant enzymes studied. Also in case of behavioural parameters studied, naringenin showed decrease in seizure severity. All these changes were supported by histological observations, which revealed excellent improvement in neuronal damage. CONCLUSION: The higher dose of naringenin was more potent in our study and was comparable to the standard drug (sodium valproate) in effectiveness. SUMMARY: Naringenin ameliorated the development of ROS formation in hippocamus.Naringenin helped in recovery of antioxidant enzymes.Naringenin decreased seizure severity.Naringenin treatment reduced lipid peroxidation. Abbreviations used: 6-OHDA: 6-hydroxydopamine, AED: Anti epileptic drugs, AIDS: Acquired immune deficiency syndrome, ANOVA: Analysis of variance, ATP: Adenosine triphosphate, CA: Cornu ammonis, CAT: Catalase, DG: Dentate gyrus, EDTA: Ethylenediamine tetra acetic acid, GR: Glutathione reductase, GSH: Glutathione reduced, HCl: Hydrochloric acid, IL-1ß: Interleukin 1 beta, LPO: Lipid peroxidation, MDA: Malondialdehyde, NADPH: Nicotinamide adenine dinucleotide phosphate, PMS: post mitochondrial supernatant, SE: Status epilepticus, SEM: Standard error of the mean, SOD Superoxide dismutase, TBA: Thiobarbituric acid, TBARS: Thiobarbituric acid reactive substance, TLE: Temporal lobe epilepsy, TNF-α: Tumor necrosis factor alpha.

Plants used to treat skin diseases.

Skin diseases are numerous and a frequently occurring health problem affecting all ages from the neonates to the elderly and cause harm in number of ways. Maintaining healthy skin is important for a healthy body. Many people may develop skin diseases that affect the skin, including cancer, herpes and cellulitis. Some wild plants and their parts are frequently used to treat these diseases. The use of plants is as old as the mankind. Natural treatment is cheap and claimed to be safe. It is also suitable raw material for production of new synthetic agents. A review of some plants for the treatment of skin diseases is provided that summarizes the recent technical advancements that have taken place in this area during the past 17 years.

Preliminary phytochemical, acute oral toxicity and antihepatotoxic study of roots of Paeonia officinalis Linn.

OBJECTIVE: To carry out a preliminary phytochemical, acute oral toxicity and antihepatotoxic study of the roots of Paeonia officinalis (P. officinalis) L. METHODS: Preliminary phytochemical investigation was done as per standard procedures. Acute oral toxicity study was conducted as per OECD 425 guidelines. The antihepatotoxic activity of aqueous extract of root of P. officinalis was evaluated against carbon tetrachloride (CCl4) induced hepatic damage in rats. Aqueous extract of P. officinalis at the dose levels of 100 and 200 mg/kg body weight was administered daily for 14 d in experimental animals. Liver injury was induced chemically, by CCl4 administration (1 mL/kg i.p.). The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum alkaline phosphatase (SALP), total bilirubin and total protein (TP) along with histopathological studies. RESULT: Phytochemical screening revealed that the roots of P. officinalis contain alkaloids, tannins, saponins, glycosides, carbohydrates, flavonoids, terpenes, steroids and proteins. The aqueous extract did not cause any mortality up to 2 000 mg/kg. In rats that had received the root extract at the dose of 100 and 200 mg/kg, the substantially elevated AST, ALT, SALP, total bilirubin levels were significantly lowered, respectively, in a dose dependent manner, along with CCl4 while TP levels were elevated in these groups. Histopathology revealed regeneration of the livers in extract treated groups while Silymarin treated rats were almost normal. CONCLUSIONS: The aqueous extract of P. officinalis is safe and possesses antihepatotoxic potential.

Role of natural herbs in the treatment of hypertension.

Hypertension (HTN) is the medical term for high blood pressure. It is dangerous because it makes the heart work too hard and contributes to atherosclerosis (hardening of arteries), besides increasing the risk of heart disease and stroke. HTN can also lead to other conditions such as congestive heart failure, kidney disease, and blindness. Conventional antihypertensives are usually associated with many side effects. About 75 to 80% of the world population use herbal medicines, mainly in developing countries, for primary health care because of their better acceptability with human body and lesser side effects. In the last three decades, a lot of concerted efforts have been channeled into researching the local plants with hypotensive and antihypertensive therapeutic values. The hypotensive and antihypertensive effects of some of these medicinal plants have been validated and others disproved. However, ayurvedic knowledge needs to be coupled with modern medicine and more scientific research needs to be done to verify the effectiveness, and elucidate the safety profile of such herbal remedies for their antihypertensive potential.