Withania somnifera , commonly known as Ashwagandha, is a widely recognized medicinal plant in India, belonging to the family Solanaceae, used in Ayurveda due to its diverse therapeutic properties. The roots of Ashwagandha are considered the most active part of the plant, for its biological and pharmacological effects. However, very little scientific evidence regarding its safety assessment has been published. Thus, the objective of the present study was to assess the safety of the standardized extract of Ashwagandha, known as Shagandha, which is prepared from the roots of Ashwagandha containing 2.5% Withanolides, analysed using a USP method (HPLC). The GLP studies for acute, subacute, subchronic, reproductive, bacterial reverse mutation assay, and mammalian erythrocyte micronucleus test were conducted following the test guidelines established by the Organization for Economic Cooperation and Development (OECD). Treatment with Shagandha (Ashwagandha Root Extract-ARE) did not result in any toxicologically significant changes regarding abnormal clinical signs or behavioral changes, body weight, reproductive and developmental parameters, or gross and histopathological changes. Additionally, the results of genotoxicity as evaluated by the in vitro reverse mutation assay and in vivo micronucleus test in mice demonstrated that ARE did not induce any genotoxic effects. These findings indicate that the oral administration of ARE is safe in rodents, non-mutagenic, with no adverse effects under experimental conditions.

Oroxylum indicum extract (OIE), prepared from its dried bark, known for neuroprotective and cognitive health support, is evaluated. Oroxylum indicum, the Indian Trumpet Tree, is traditionally known for its numerous medicinal benefits. Almost every part of the plant has been traditionally applied to treat many conditions such as stomachache, rheumatism, jaundice, cough, pharyngitis, acute and chronic bronchitis. Various researchers have demonstrated biological activities including antioxidant, and anti-inflammatory, immunomodulatory, analgesic, anti-cancer, anthelmintic, hepatoprotective, antiulcer, anti-diarrheal, cardioprotective, anti-diabetic, anti-epileptic, wound healing, properties. Since very little scientific evidence was available on safety assessment of OIE, a detailed toxicological evaluation of OIE was executed to ensure its safety for human administration and to harness its potential therapeutic applications. The present study evaluated the acute, subacute, subchronic, and reproductive toxicity of OIE in rodents. Also, the mutagenic potential was evaluated with the bacterial reverse mutation assay and the mammalian bone marrow micronucleus test. No treatment-related study findings were observed, and a No Observed Adverse Effect Level of 400 mg/kg body weight was established in subacute, subchronic, reproductive/developmental toxicity studies. In addition, the findings of genotoxicity as evaluated by in vitro bacterial reverse mutation assay, and in vivo mammalian bone marrow micronucleus test in mice showed that OIE did not induce any mutagenic effects. Henceforth, this toxicological evaluation confirms that oral administration of OIE was found to be safe in rodents, non-mutagenic, without any adverse effects. This study positively impacts in encouraging the use of OIE in various therapeutic applications ensuring its safety.

In recent years, metabolic syndrome has been a growing health concern across the world. The role of nutraceuticals and functional foods in this area has a significant place due to the adverse effects of contemporary modes of treatment. CurCousin® is a nutritional ingredient containing bioactive Calebin A, (analog of Curcumin) with self-affirmed GRAS status. CurCousin® has been a clinically studied dietary supplement ingredient with a positive impact on body weight, lipid levels and metabolic health. Bioenhancers play an important role in increasing the bioavailability of the active in turn enhancing efficacy as well as reducing the dosage required to achieve the therapeutic effect. This study investigated the possible pharmacokinetic interaction between CurCousin® at two different doses (2.25 and 4.5 mg/kg) in the presence and absence of BioPerine® (0.27 mg/kg), a natural bioenhancer in Sprague-Dawley rats. The results revealed that the addition of BioPerine® into CurCousin® (2.25 mg/kg) half the dose when administered enhances the bioavailability and was equipotent to CurCousin® (4.5 mg/kg) double the dose without BioPerine®. Thus, leading to future clinical studies to evaluate its improved pharmacological efficacy as well as reduced therapeutic dosage.

There has been keen interest on herbs and phytoconstituents with hepatoprotective property to help restore healthy liver function. Ayurveda, the ancient Indian traditional system of medicine mentions about Curcuma longa, Garcinia indica and Piper nigrum which are reported to have hepatoprotective activity. Apart from supporting metabolism, liver plays pivotal role in numerous bodily processes, immune functions to digestion, detoxification, and storage of nutrients. Factors such as sedentary lifestyle, viral infections, drugs/chemicals, high calorie diet, excess intake of alcohol etc have adverse impact on normal functioning of liver. Development of novel herbal combination with standards of safety and efficacy can help manage liver ailments and protect liver health. LivLonga (R) is a polyherbal combination of scientifically validated ingredients- curcuminoids, garcinol and piperine to support healthy liver function. The present work was conducted to evaluate toxicity of LivLonga (R) using in vivo models when administered orally. The acute, subacute, and subchronic toxicity studies were carried out in accordance with the test guidelines established by the Organization for Economic Cooperation and Development. A single-dose acute oral toxicity produced no toxic effects after 14 days of treatment. Four-week (subacute) and 3-months (subchronic) oral toxicity studies were conducted and observed no abnormal clinical signs, no alterations in the body weight, hematology and biochemical parameters or gross and histopathological changes. Thus, oral administration of LivLonga (R) showed no signs of toxicity when dosed orally to rats, with a no observed adverse effect level (NOAEL) of 600 mg/kg/day.

Introduction/Background: Curcuma longa, a plant native to the Indian subcontinent has a variety of biological activities. Curcumin is the most abundant and biologically active compound with many therapeutic properties. Demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) - the two other bioactive components present in Curcuma longa, besides curcumin, are collectively termed curcuminoids. Apart from the well-known curcumin, BDMC also has been reported to possess promising biological and pharmacological effects, but very little scientific evidence on its safety assessment has been published. Objective: The present study was undertaken to determine the safety of pure BDMC from Curcuma longa extract in rodents which comprises of general toxicity (both four weeks and three months duration), reproductive/developmental toxicity and genotoxicity studies. Methods: The Good Laboratory Practice studies were carried out in accordance with the test guidelines established by the Organization for Economic Cooperation and Development.Results: No treatment-related adverse findings were seen in general toxicity testing and a no observed adverse effect level (NOAEL) of 1000 mg/kg/day was established after four weeks (sub-acute) and three-months (sub-chronic) dosing. Evaluation of fertility, embryo-fetal, and post-natal reproductive and developmental parameters also showed no adverse findings with a NOAEL of 1000 mg/kg/day established. The results of genotoxicity as evaluated by in vitro reverse mutation assay, and in vivo micronucleus test in mice indicate that BDMC did not induce any genotoxic effects. Conclusion: Oral administration of BDMC is safe in rodents and non-mutagenic, with no adverse effects under experimental conditions.

The present work was carried out to investigate the toxic effects of Activated Curcumin C3 Complex (AC3®) through the methods of acute, subacute, subchronic, reproductive/developmental toxicity, and genotoxicity when administered orally in experimental rodents. The studies were carried out in line with OECD principles of good laboratory practice. A single-dose acute oral toxicity study was conducted on female Wistar rats that produced no toxic effects after 14 days (the observation period) of treatment. Subacute, subchronic, and reproductive/developmental studies were conducted in Wistar rats, divided equally into vehicle control, 125, 250, and 500 mg/kg dose groups along with recovery groups for vehicle control and high dose. In all the studies, there were no abnormal clinical signs/behavioral changes, reproductive and developmental parameters, or gross and histopathological changes. Likewise, no alteration was found in the body weight, hematology, and other biochemical parameters. Also, it did not show mutagenicity in the in vitro AMES test or clastogenicity and aneugenicity in the in vivo micronucleus test, indicating that AC3® did not induce any genotoxic effects. This revealed that oral administration of AC3® is safe in rodents, nonmutagenic, and had no observed adverse effects under experimental conditions.

Obesity, a condition accompanying abnormal or excessive accumulation of fat in the body has become a major public health concern globally. Various herbs hailed from traditional systems of medicine like Ayurveda have gained importance in recent years to combat obesity. One such herb Cyperus rotundus (nutgrass), is known for its beneficial effects in obesity, in Ayurveda. Cirpusins® a patented extract from the dried rhizomes of Cyperus rotundus (standardized for minimum of 6% total identified stilbenes - Piceatannol, Scirpusin A & Scirpusin B) and BioPerine®, a bioavailability enhancer, obtained from the dried fruits of Piper nigrum (standardized to minimum 95% piperine). In this study, we examined the pharmacokinetic profile and bioavailability of Cirpusins® in Sprague-Dawley rats at two different doses (45 and 90 mg/kg) in the presence and absence of BioPerine® respectively. The results signifies that addition of BioPerine® (0.45 mg/kg) with Cirpusins® (45 mg/kg) enhances the bioavailability by reducing the effective dose of Cirpusins® (90 mg/kg) to half.

'TAF' fraction from the methanol-water extract of Barleria prionitis Linn. was evaluated for anti-inflammatory and anti-arthritic activities against different acute and chronic animal test models. It exhibited significant anti-inflammatory activity against different inflammagens like carrageenan, histamine and dextran. The anti-inflammatory activity in adrenalectomised rats was maintained showing that the effect of fraction 'TAF' is not activated by the pituitary-adrenal axis. Significant anti-arthritic activity was observed in adjuvant-induced polyarthritis test in rats. 'TAF' also showed inhibition of vascular permeability and leucocytes migration in vivo into the site of inflammatory insult.Ibuprofen (Cadilla India Ltd., Mumbai) was used as a standard reference drug. The oral (p.o.) LD(50) was more than 3000mg/kg, with no signs of abnormalities or any mortality observed for 15 days after single-dose drug administration. The intraperitoneal (i.p.) LD(50) was found to be 2530mg/kg (+/-87mg/kg S.E.) [Proceedings of Society of Experimental Biological Medicine 57 (1944) 261].

Purpose Obesity is a complex medical problem that increases the risk of other diseases like diabetes, cardiovascular diseases, and fatty liver disease. The present study evaluated the efficacy and safety of Cyperus rotundus rhizome extract (CRE), standardized to contain Piceatannol, Scirpusin A, and Scirpusin B (5% total Stilbenoids) in overweight individuals. The mechanism of activity was evaluated in a diet-induced mice model of obesity and adipocytes in vitro. Materials and Methods The efficacy, safety, and tolerability of CRE were evaluated in 30 obese individuals with a BMI of 30 to 40 kg/m2 for 90 days in a randomized, double-blind, parallel-group, placebo-controlled study. In vitro studies were carried out in differentiated 3T3 L1 adipocytes, and the therapeutic efficacy was evaluated in high-fat diet-induced obese mice. Results The pilot clinical study showed a reduction in body weight with a significant decrease in waist circumference and BMI. The serum lipid profile showed a significant improvement in CRE-treated individuals. The extract was well tolerated, and no adverse effects were reported at the end of the study. CRE showed a dose-dependent adipogenesis reduction in vitro with an IC50 value of 9.39 μg/mL, while oral administration of CRE reduced weight gain in diet-induced obese mice. The efficacy in mice was associated with reduced levels of leptin, corticosteroids, and serum lipid levels, with no adverse effects. Conclusion CRE has anti-adipogenic properties, is safe for human consumption, and effectively manages weight and hypercholesterolemia in overweight individuals.

Glycation is a non-enzymatic biochemical reaction between reducing sugars and amino acids, causing the crosslinking and rearrangement of glycated proteins, leading to irreversible formation of Advanced Glycation End products (AGEs). Glycation is an activity that occurred both endogenously in our body and exposed to it through our diet as well, which contributed to the pool of AGEs and their pathology. AGEs played important role in various health conditions including and not limited to, hyperglycemia, inflammation, Alzheimer’s disease, cardiovascular health and, ageing itself. While the formation of AGEs is irreversible, its formation can be inhibited or slowed down by natural products, which have anti-glycation activity. In this study, we explored the antiglycation activity of commercial herbal extracts of Artocarpus lakoocha and Pterocarpus marsupium using a competitive fluorescence assay. Both Artocarpus lakoocha and Pterocarpus marsupium extracts show highest anti-glycation activity (84.6–100%) after background correction, in a range of 10 to 100 mg/ml.

Though there are several studies on efficacy of Boswellia serrata on various indications, safety studies of the extract are very few or inadequate.Also, Boswellia serrata extract is usually intended for long term use so potential cytotoxic, genotoxic or mutagenic activity testing of the extract is important.Further, mutagenicity tests help to reduce the genetic or carcinogenetic hazards to humans as several studies showed the connection between mutagenicity and carcinogenicity 13 .In the present study, we have conducted the in vivo acute toxicity study, 90 days sub chronic study, Mammalian Bone Marrow Chromosome Aberration Test and Mammalian Bone Marrow ABSTRACT Boswellia serrata is a branching tree found abundantly in India, Boswellic acids extracted from resin of plant is used in inflammatory conditions, arthritis and hyperlipidaemia.However, any supplement used for long term use needs to be tested for potential mutagenicity and toxicity.Thus, we assessed the mutagenicity of Boswellia serrata extract by Mammalian Bone Marrow Chromosome Aberration Test and Mammalian Bone Marrow Micronucleus Test and in vitro Bacterial Reverse Mutation Test.Further we assessed in vivo toxicity by acute toxicity study and 90 days sub chronic toxicity study of Boswellia serrata extract.None of the mutagenic assays showed any increase in mutagenicity above background.Also, the acute oral toxicity and sub chronic toxicity study revealed that Boswellia serrata extract was not lethal to animals up to 2000mg/kg/day when observed for 14 days and 600mg/kg/day when observed for 90 days.Therefore, these data provide evidence that the Boswellia tested have no cytotoxic potency and are not mutagenic.Thus, our findings contribute to the risk assessment of preparations containing Boswellia serrata extract.

ALPAlkaline Phosphotase ALTAlanine Transaminase ANOVAAnalysis of Variance APAP – Acetaminophen (paracetamol) ASTAspartate Transaminase CPSEACommittee for the Purpose of Control and Supervision of Experiments on Animals CTLCytotoxic T Lymphocyte DMNDimethylnitrosamine ECMExtracellular Matrix ELISAEnzyme Linked Immune-sorbent Assay GCGarcinol GSH-Glutathione ICAMIntercellular Adhesion Molecule ILInterleukin JNK c-Jun N-terminal kinases LDHLactate dehydrogenase LPLipid Peroxidation LPSLipopolysaccharide NAPQIN-acetyl-p-benzoquinone imine NKNatural Killer ROSReactive Oxygen Species SDStandard Deviation TGF Transforming Growth Factor ThT helper cell TLRToll-like Receptor TNFTumor Necrosis Factor

Tetrahydrocurcumin (THC) is a major metabolite of curcumin, which is obtained from Curcuma longa. THC has various benefits and overcomes the bioavailability issue of curcumin. To establish it as a pharmacologically active molecule, its safety profile has to be determined. Thus, the present study aimed to determine the preclinical safety profile of THC in a 90-day subchronic and reproductive/developmental toxicity study in Wistar rats. THC at oral doses of 100, 200, and 400 mg/kg was administered daily for 90 days. Rats in the recovery group were kept for 14 days after treatment termination. The animals were observed for treatment-related morbidity, mortality, and changes in clinical signs, clinical pathology, and histopathology. In the reproductive/developmental toxicity study, THC at 100, 200, and 400 mg/kg was administered orally to rats and the reproductive/developmental parameters in adult male and female rats and pups were observed. THC at up to 400 mg/kg/day of did not have any significant effect on all parameters in male and female rats in both toxicity studies. Thus, 400 mg/kg/day can be considered as the no-observed-adverse-effect-level of THC in rats.

The present study was taken up to evaluate the single dose acute toxicity, 28 days and 90 days repeated dose toxicity and reproductive/developmental toxicity of standardized 40% Garcinol in experimental rodents. The studies were conducted in compliance with OECD principles of good laboratory practice, guidelines for testing of chemicals no.420, 407, 408 and 421 respectively. Single dose acute oral toxicity was conducted on female Wistar rats as sighting study step-I (300 mg/kg) & sighting study step-II (2000 mg/kg) and main study (2000 mg/kg). Sub-acute, sub-chronic and reproductive/developmental studies were conducted in Wistar rats divided equally in vehicle control, 20, 50 and 100 mg/kg dose group along with recovery groups for vehicle control and high dose. Reproductive/developmental study was carried out for minimum of 28 days and in females during pregnancy and 4 days post partum. There were no abnormal clinical signs/behavioural changes, reproductive and developmental parameters, gross and histopathological changes as well as no alteration in the body weight, body temperature, haematology and other biochemical parameters in all the four studies. 40% Garcinol has a low toxicity profile in rodents and had no observed effects under experimental conditions used.

Novel 9-alpha-hydroxy-11-keto-beta-boswellic acid analogues constituted with versatile functionality at ring A have been synthesized for the first time from 3-O-acetyl-11-keto beta boswellic acid (AKBBA) and described herein. The anti-malarial potential of endoperoxide benzyl ester was evaluated against the malarial parasite and exhibited reasonable anti-malarial activity (2 mu M). Anti-inflammatory potential of all new analogues was examined against proinflammatory cytokine, Tumor Necrosis Factor-alpha (TNF-alpha) and one of them was found to possess similar activity as that of AKBBA.

Alzheimer's disease (AD) is a chronic disorder that slowly worsens and impairs the person's memory, learning, reasoning, judgment, communication and familiar tasks with loss of orientation, AD is characterized clinically by cognitive deficit and pathologically by the deposition of beta amyloid plaques, neurofibrillary tangles, associated with degeneration of the cholinergic forebrain. Withanone (WS-2), a compound isolated from root extract of Withania somnifera at doses administered orally/day to wistar rats for duration of 21 days showed significant improvement in the cognitive skill by inhibiting amyloid beta-42 and attenuated the elevated levels of pro-inflammatory cytokines like TNF alpha, IL-1 beta, IL-6, MCP-1, Nitric oxide, lipid peroxidation and both [3- and y secretase enzymatic activity. Administration of WS-2 also significantly reversed the decline in acetyl choline and Glutathione (GSH) activity. None of the treatments that are available today alter the underlying causes of this terminal disease. Few preliminary clinical treatments have demonstrated that some plant medicines do ameliorate and improve memory and learning in patients with mild-to-moderate AD. WS-2 showed promise in AD treatment because of cognitive benefits and more importantly, mechanisms of action with respect to the fundamental pathophysiology of the disease, not limited to the inhibition of AChE, but also include the modification of A beta processing, protection against oxidative stress and anti-inflammatory effects.

3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

A series of 3, 5-disubstituted-4, 5-dihydro-1H-pyrazoles have been synthesized under solvent free microwave irradiation method by the condensation of α, β-unsaturated ketones with hydrazine and its differently substituted derivatives. The chemical structures of the compounds were characterized by elemental analysis and spectroscopic data. All the synthetics were evaluated for their anti-inflammatory activity under in vivo conditions. The present study describes the potential of these pyrazole ring containing scaffolds to assess the TNF α (Tumor Necrosis Factor-alpha) and IL-1β (Interleukin-1 beta) inhibitory potential. TNF-α and IL-1β are inflammatory cytokines that are pro-inflammatory in nature and play a major role in inflammatory cascades of many pathologically dreadful diseases ranging from neurodegenerative disorders to autoimmune diseases such as rheumatoid arthritis.

The present study was undertaken to study the potential of Taraxacum officinale aqueous extract (aerial part; TO-10) to maintain immune homeostasis in normal and chronic restraint stress and cyclosporine-A-induced immune suppressed mice. Immune restorative effect of test drug was evaluated first in normal and then in immune-compromised mice using flow cytometer and Elisa techniques. TO-10 enhanced the expression of T-cell subsets and CD28, CD69 and CD80/CD86 co-stimulatory molecules in sheep red blood corpuscles (SRBCs)-immunized mice. Flow cytometric analysis revealed that TO-10 upregulated the expression of Th1 cytokines, IL-2, IFN-gamma and IL-12, and regularized the increased expression of IL- 10 in chronically stressed animals. It also normalized the elevated corticosterone levels, and reversed the chronic stress-induced hypertrophy of adrenal glands and atrophy of spleen and thymus. The results show that TO-10 is also able to maintain immune homeostasis in normal and immune-compromised conditions. Chicoric acid, a major constituent of TO-10, seems to be responsible for skewing to Th1 immune polarization as shown by its stimulatory effect on the expression of IFN-gamma and IL-2 in phorbol 12-myristate 13-acetate + ionomycin stimulated peripheral blood mononuclear cells (PBMCs).