Current Insights on the Photoprotective Mechanism of the Macular Carotenoids, Lutein and Zeaxanthin: Safety, Efficacy and Bio-Delivery.

Ocular health has emerged as one of the major issues of global health concern with a decline in quality of life in an aging population, in particular and rise in the number of associated morbidities and mortalities. One of the chief reasons for vision impairment is oxidative damage inflicted to photoreceptors in rods and cone cells by blue light as well as UV radiation. The scenario has been aggravated by unprecedented rise in screen-time during the COVID and post-COVID era. Lutein and Zeaxanthin are oxygenated carotenoids with proven roles in augmentation of ocular health largely by virtue of their antioxidant properties and protective effects against photobleaching of retinal pigments, age-linked macular degeneration, cataract, and retinitis pigmentosa. These molecules are characterized by their characteristic yellow-orange colored pigmentation and are found in significant amounts in vegetables such as corn, spinach, broccoli, carrots as well as fish and eggs. Unique structural signatures including tetraterpenoid skeleton with extensive conjugation and the presence of hydroxyl groups at the end rings have made these molecules evolutionarily adapted to localize in the membrane of the photoreceptor cells and prevent their free radical induced peroxidation. Apart from the benefits imparted to ocular health, lutein and zeaxanthin are also known to improve cognitive function, cardiovascular physiology, and arrest the development of malignancy. Although abundant in many natural sources, bioavailability of these compounds is low owing to their long aliphatic backbones. Under the circumstances, there has been a concerted effort to develop vegetable oil-based carriers such as lipid nano-emulsions for therapeutic administration of carotenoids. This review presents a comprehensive update of the therapeutic potential of the carotenoids along with the challenges in achieving an optimized delivery tool for maximizing their effectiveness inside the body.

Lutein and zeaxanthin are the two most abundant natural xanthophylls (oxygenated carotenoids) with a linear C40 tetraterpene/isoprenoid lycopene-based backbone.Presence of extensive conjugation (more than 10 double bonds) enable these molecules to act as accessory light harvesting pigments apart from chlorophyll.More importantly, the xanthophylls prevent photobleaching of the pigments and proteins in the Light Harvesting Complex (LHC) by sequestering the excess unutilized blue light and preventing triplet chlorophyll associated formation of Reactive Oxygen Species.In human eye, lutein, zeaxanthin along with mesozeaxanthin constitute the three macular pigments forming the so called "yellow spot" of the macula and are implicated in maintaining the redox balance, homeostasis and normal physiology of the eyes.However, unlike plants, xanthophylls must be acquired from dietary sources such as colored leafy vegetables and egg yolk.Increase in the number of eye diseases in the aging population coupled with insufficient bioavailability of xanthophylls has mandated the industrial production of supplements enriched in xanthophylls.The bioavailability and delivery of xanthophylls can be significantly enhanced by suspension in a blend of extra-virgin olive oil and other vegetable oils.

Clinical Evaluation of a Novel, Patented Green Coffee Bean Extract (GCB70®), Enriched in 70% Chlorogenic Acid, in Overweight Individuals.

OBJECTIVE: Obesity and overweight are challenging health problems of the millennium that lead to diabetes, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Green coffee bean exhibited significant promise in healthy weight management, potentiating glucose-insulin sensitization and supporting liver health. The safety and efficacy of a novel, patented water-soluble green coffee bean extract (GCB70® enriched in 70% total chlorogenic acid and <1% caffeine) was investigated in 105 participants for 12 consecutive weeks. An institutional review board and Drugs Controller General (India) (DCGI) approvals were obtained, and the study was registered at ClinicalTrials.gov. METHOD: Body weight, body mass index (BMI), waist circumference, lipid profile, plasma leptin, glycosylated hemoglobin (HbA1c), and total blood chemistry were assessed over a period of 12 weeks of treatment. Safety was affirmed. RESULTS: GCB70 (500 mg BID) supplementation significantly reduced body weight (approximately 6%; p = 0.000**) in approximately 97% of the study population. About a 5.65% statistically significant reduction (p = 0.000**) in BMI was observed in 96% of the study volunteers. Waist circumference was significantly reduced by 6.77% and 6.62% in 98% of the male and female participants, respectively. Plasma leptin levels decreased by 13.6% in 99% of the study population as compared to the baseline value. Upon completion of 12 weeks' treatment, fasting glucose levels decreased by 13.05% (p = 0.000**) in 79% of the study population. There was a statistically significant decrease in HbA1c levels in both male and female participants (p = 0.000**), while 86.7% of the study participants showed a statistically significant decrease in thyroid-stimulating hormone (TSH) levels (p = 0.000**). The mean decrease in TSH levels on completion of the treatment was 14.07% in the study population as compared to baseline levels. Total blood chemistry analysis exhibited broad-spectrum safety. CONCLUSIONS: This investigation demonstrated that GCB70 is safe and efficacious in healthy weight management.

A Placebo-Controlled, Double-Blind Clinical Investigation to Evaluate the Efficacy of a Patented Trigonella foenum-graecum Seed Extract "Fenfuro®" in Type 2 Diabetics.

BACKGROUND: Trigonella foenum-graecum (Fenugreek) is an extensively researched phytotherapeutic for the management of Type 2 diabetes without any associated side effects. The major anti-diabetic bioactive constituents present in the plant are furostanolic saponins, which are more abundantly available in the seed of the plant. However, the bioavailability of these components depends on the method of extraction and hence formulation of the phytotherapeutic constitutes a critical step for its success. OBJECTIVE: The present study reports the efficacy of a novel, patented fenugreek seed extract, Fenfuro®, containing significant amount of furostanolic saponins, in an open-labelled, two-armed, single centric study on a group of 204 patients with Type 2 diabetes mellitus over a period of twelve consecutive weeks. RESULTS: Administration of Fenfuro® in the dosage of 500 mg twice daily along with metformin and/or sulfonylurea-based prescribed antidiabetic drug resulted in a reduction of post-prandial glucose by more than 33% along with significant reduction in fasting glucose, both of which were greater than what resulted for the patient group receiving only Metformin and/or Sulfonylurea therapy. Fenfuro® also resulted in reduction in mean baseline HOMA index from 4.27 to 3.765, indicating restoration of insulin sensitivity which was also supported by a significant decrease in serum insulin levels by >10% as well as slight reduction in the levels of C-peptide. However, in the case of the Metformin and/or Sulfonylurea group, insulin levels were found to increase by more than 14%, which clearly indicated that drug-induced suppression of glucose levels instead of restoration of glucose homeostasis. Administration of the formulation was also found to be free from any adverse side effects as there were no changes in hematological profile, liver function and renal function. CONCLUSION: The study demonstrated the promising potential of this novel phytotherapeutic, Fenfuro®, in long-term holistic management of type-2 diabetes.

Revisiting the Multifaceted Therapeutic Potential of Withaferin A (WA), a Novel Steroidal Lactone, W-ferinAmax Ashwagandha, from Withania Somnifera (L) Dunal.

Withania somnifera (L.) Dunal, abundant in the Indian subcontinent as Ashwagandha or winter cherry, is a herb of unprecedented therapeutic value. The number of ailments for which crude Ashwagandha extract can be used as a preventive or curative is practically limitless; and this explains why its use has been in vogue in ancient Ayurveda since at-least about four thousand years. The therapeutic potential of Ashwagandha mainly owes from its reservoir of alkaloids (isopelletierine, anaferine), steroidal lactones (withanolides) and saponins with an extra acyl group (sitoindoside VII and VIII). Withaferin A is an exceptionally potent withanolide which is found in high concentrations in W. somnifera plant extracts. The high reactivity of Withaferin A owes to the presence of a C-28 ergostane network with multiple sites of unsaturation and differential oxygenation. It interacts with the effectors of multiple signaling pathways involved in inflammatory response, oxidative stress response, cell cycle regulation and synaptic transmission and has been found to be significantly effective in inducing programmed cell death in cancer cells, restoring cognitive health, managing diabetes, alleviating metabolic disorders, and rejuvenating the overall body homeostasis. Additionally, recent studies suggest that Withaferin A (WA) has the potential to prevent viral endocytosis by sequestering TMPRSS2, the host transmembrane protease, without altering ACE-2 expression. The scope of performing subtle structural modifications in this multi-ring compound is believed to further expand its pharmacotherapeutic horizon. Very recently, a novel, heavy metal and pesticide free formulation of Ashwagandha whole herb extract, with a significant amount of WA, termed W-ferinAmax Ashwagandha, has been developed. The present review attempts to fathom the present and future of this wonder molecule with comprehensive discussion on its therapeutic potential, safety and toxicity.Key teaching pointsWithania somnifera (L.) Dunal is a medicinal plant with versatile therapeutic values.The therapeutic potential of the plant owes to the presence of withanolides such as Withaferin A.Withaferin A is a C-28 ergostane based triterpenoid with multiple reactive sites of therapeutic potential.It is effective against a broad spectrum of ailments including neurodegenerative disorders, cancer, inflammatory and oxidative stress disorders and it also promotes cardiovascular and sexual health.W-ferinAmax Ashwagandha, is a heavy metal and pesticide free Ashwagandha whole herb extract based formulation with significant amount of Withaferin A.

A critical assessment of the whole plant-based phytotherapeutics from Withania somnifera (L.) Dunal with respect to safety and efficacy vis-a-vis leaf or root extract-based formulation.

Withania somnifera (L.) Dunal, popularly known as Ashwagandha or Indian ginseng, is well acclaimed for its health-enhancing effects, including its potent immunomodulatory, anti-inflammatory, neuroprotective, and anti-tumorigenic properties. The prime biological effectors of these attributes are a diverse group of ergostane-based steroidal lactones termed withanolides. Withanones and withanosides are distributed differentially across the plant body, whereas withanolides and withanones are known to be more abundant in leaves, while withanosides are found exclusively in the roots of the plants. Standardized W. somnifera extract is Generally Recognized as Safe (GRAS)-affirmed, however, moderate to severe toxic manifestations may occur at high dosages. Withaferin A, which also happens to be the primary bioactive ingredient for the effectiveness of this plant. There have been contrasting reports regarding the distribution of withaferin A in W. somnifera. While most reports state that the roots of the plant have the highest concentrations of this phytochemical, several others have indicated that leaves can accumulate withaferin A in proportionately higher amounts. A comprehensive survey of the available reports suggests that the biological effects of Ashwagandha are grossly synergistic in nature, with many withanolides together mediating the desired physiological effect. In addition, an assorted formulation of withanolides can also neutralize the toxic effects (if any) associated with withaferin A. This mini-review presents a fresh take on the recent developments regarding the safety and toxicity of the plant, along with a critical assessment of the use of roots against leaves as well as whole plants to develop therapeutic formulations. Going by the currently available scientific evidence, it is safe to infer that the use of whole plant formulations instead of exclusively root or leaf recipes may present the best possible option for further exploration of therapeutic benefits from this novel medicinal plant.HighlightsTherapeutic potential of withanolides owes to the presence of α,ß unsaturated ketone which binds to amines, alcohols, and esters and 5ß, 6ß epoxy group which react with side chain thiols of proteins.At concentrations above NOAEL (no observed adverse effect level), the same mechanisms contribute towards toxicity of the molecule.Although withanosides are found exclusively in roots, whole plants have higher contents of withanones and withanolides.Whole plant-based formulations have other metabolites which can nullify the toxicity associated with roots.Extracts made from whole plants, therefore can holistically impart all therapeutic benefits as well as mitigate toxicity.

Safety and Efficacy of Furosap®, a Patented Trigonella foenum-graecum Seed Extract, in Boosting Testosterone Level, Reproductive Health and Mood Alleviation in Male Volunteers.

BACKGROUND: The medicinal herb fenugreek (Trigonella foenum-graecum) seeds, fortified with dietary fibers and furostanolic saponins including protodioscin, have demonstrated a significant contribution to human health. In our laboratories, Furosap®, a patented 20% protodioscin-enriched extract was developed from fenugreek seeds. OBJECTIVE: In an open-label, one-arm, single-center longitudinal study, we examined the safety and efficacy of Furosap® on free and total testosterone levels, fasting blood sugar, blood pressure, sperm count, motility and morphology, dihydroepiandrosterone sulfate (DHEA-S), sexual health, reflex erection, mood alleviation, mental alertness, and total blood chemistry analyses over a period of 12 weeks in healthy male volunteers. METHODS: Institutional Ethics Committee approvals and Clinicaltrials.gov registration were obtained. Effect of Furosap® (500 mg/day) was examined of free and total testosterone levels, sperm count, motility and morphology, sexual health, mood and mental alertness, and total blood chemistry analyses in 100 healthy volunteers (age 35-60 Y) over a period of 12 consecutive weeks. RESULTS: No changes were observed in body weight and BMI. Both systolic and diastolic blood pressure, and DHEA levels significantly decreased. Free and bound testosterone levels improved significantly at 12 weeks of treatment. Sperm motility significantly increased at 8- and 12-weeks of treatment, while abnormal sperm morphology significantly decreased at 12-weeks of treatment. Mental alertness, mood, and reflex erection score significantly alleviated. An age-induced increasing effect was observed. Furthermore, cardiovascular health and libido significantly improved. Blood chemistry analyses exhibited broad spectrum safety. A decreasing trend was observed in total cholesterol, triglycerides, and VLDL levels, while an increasing trend was observed in HDL level at 12 weeks of treatment. LDL level decreased significantly at 12-weeks of treatment. No adverse events were observed. CONCLUSION: Results demonstrate that Furosap® is safe and effective in improving testosterone levels, cardiovascular health, healthy sperm profile, mental alertness in human male volunteers.

Beneficial Effects of a Novel Fenugreek Seed Extract (Trigonella foenum-graecum, Furocyst®) in Women with Polycystic Ovary Syndrome (PCOS): A Follow-up Compliance Clinical Investigation.

INTRODUCTION: Polycystic Ovary Syndrome (PCOS) is an endocrine disorder which accounts for infertility around the world. The disease is characterized by elevated secretion of androgens in the women which results in enlargement of ovaries with accumulation of fluid filled cysts, irregular menstrual cycles, and hirsutism. This study reports the efficacy of a patented, standardized Trigonella foenum-graecum extract (Furocyst®) as an effective phytotherapeutic for effective management of PCOS. OBJECTIVE: This randomized one-arm study assessed the efficacy of Furocyst® in 107 female volunteers over a period of 12 consecutive weeks. METHOD: Following approvals of the Institutional Ethical Committee and clinicaltrials.gov, 107 female volunteers (age: 18-45 years) were recruited. Subjects consumed Furocyst® capsules (1,000 mg/day p.o.) over a period of 12 consecutive weeks. Physical (Sonographic scan, Hirsutism Score, Menstrual cycle, Body Weight, BMI, Height, Waist Circumference and Blood Pressure) and biochemical parameters (LH/FSH ratio, TSH, Prolactin, Fasting insulin, Fasting Glucose, triglyceride, cholesterol, HOMA Index, free and total testosterone, 2-hour GTT, DHEAS) were assessed at the beginning of the study as well as at intervals of 4 weeks till 12 weeks to determine the efficacy of Furocyst® on PCOS induced damage on reproductive and endocrine system. RESULTS: Furocyst® treatment induced >40% reduction of mean cyst sizes in both ovaries with corresponding reduction of in ovarian volumes. LH:FSH ratio was also significantly improved with corresponding reduction in total testosterone and prolactin levels. As a result of improvement in endocrine function, menstrual cycle became regular in the subjects. Furocyst® also reduced the severity of other associated ailments such as insulin resistance, dyslipidemia, and improved liver function significantly. CONCLUSIONS: This study reinstated the efficacy of Furocyst® as a safe phytotherapeutic to reverse the effects of PCOS inflicted damage on the female reproductive system without any adverse events.

Effect of Dietary Pyrroloquinoline Quinone Disodium Salt on Cognitive Function in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study.

BACKGROUND: Cognitive dysfunctions are increasing alarmingly around the world, and researchers are exploring preventive measures for improving brain performance. Pyrroloquinoline quinone (PQQ), a naturally occurring coenzyme in foods, exhibits potent antioxidant activity, and improves diverse functions which include mitochondrial activation, growth, repair, protection of nerve cells by increased expression of nerve growth factor (NGF) and NGF receptors; and suppression of fibril formation and aggregation of amyloid ß. OBJECTIVE: This randomized, double-blind, placebo-controlled, parallel-group clinical investigation (RCT) evaluated the efficacy and safety of PQQ disodium salt powder (mnemoPQQ®) for improved cognitive function after 12 weeks of supplementation in healthy Japanese male and female (age 40 to <80 Y). METHODS: 64 healthy subjects were randomly assigned to receive either mnemoPQQ® (PQQ disodium salt: 21.5 mg/day) or a placebo over a period of 12 weeks. The efficacy of mnemoPQQ® on cognitive performance (memory, attention, judgment, and cognitive flexibility) was examined using Cognitrax as the primary outcome (primary endpoint), and forgetfulness questionnaire (DECO: Deterioration Cognitive Observee) and Mini-Mental State Examination-Japanese (MMSE-J) as the secondary outcome (secondary endpoint). RESULTS: A total of 58 subjects (placebo = 31; Age = 70.91 ± 3.06 Y; mnemoPQQ® group = 27; Age = 72.10 ± 3.77 Y) completed the study over a period of 12 weeks of supplementation. Significant improvements were observed on the Cognitrax's cognitive function domain score on "composite memory", "verbal memory", "reaction time", "complex attention", "cognitive flexibility", "executive function", and "motor speed" in the mnemoPQQ® group as compared to the placebo group. The DECO and the MMSE-J scores were also significantly improved in the mnemoPQQ® group. No adverse events were observed. CONCLUSIONS: Study demonstrates that supplementation of PQQ disodium salt is useful in improving memory, attention, judgment, and cognitive function, in middle-aged to elderly population, who feel they have become more forgetful because of aging.

VMP35 MNC, a novel iron-free supplement, enhances cytoprotection against anemia in human subjects: a novel hypothesis.

BACKGROUND: The American Society of Hematology reported that according to the National Heart, Lung, and Blood Institute (NHLBI) anemia is the most common blood disorder, which affects more than 3 million Americans, while the Global Burden of Disease 2016 (GBD 2016) reported that iron deficiency anemia (IDA) is the leading cause of anemia, which affects 1.93 billion people worldwide. Anemia is intricately linked to chronic inflammation, chronic kidney disease, gastrointestinal and gynecological malignancies, and autoimmune disorders. Hemorrhagic anemia results in substantial loss of blood, which causes significant alterations in all blood parameters, including reduced iron. The other type of anemia is chronic anemia syndrome (CAS), which is a constellation of disorders and chronic inflammatory events caused by an increasing anaerobic/acidic environment (promoting the growth of anaerobic organisms), inducing a defensive expenditure of alkalinizing buffers in hemoglobin (i.e. histidine), to prevent a dangerous lowering of blood pH. In this process, iron is cleaved from heme groups and transferred out of blood circulation into other organs, like the liver, appearing to be IDA, where excessive accumulation can lead to hemochromatosis, also known as 'iron overload anemia'. DESIGN: A pilot clinical study was conducted in 38 subjects (men = 10; women = 28; age = 22-82 years) to evaluate the rate of absorption and effects on blood of VMP35 multi-nutrient complex (MNC), a non-iron containing liquid nutraceutical supplement. Subjects consumed either placebo or VMP35 (30 mL) over a period of 0, 5, or 30 min. METHODS: Changes in peripheral blood smears from 38 subjects were observed using live blood cell imaging (LBCI) with phase contrast microscopy. Adverse events were rigorously monitored. RESULTS: VMP35 caused positive changes in the blood, including morphological, hematological (including restoration of hemoglobin), and rheological changes following 5 min of administration, which were sustained for at least 30 min. CONCLUSION: Overall, the non-iron containing VMP35 can induce improvements in blood properties and potential benefits for subjects even with compromised digestive systems. No adverse events were reported. Further research studies are in progress to explore the mechanistic insight.

Efficacy of FurosapTM, a novel Trigonella foenum-graecum seed extract, in Enhancing Testosterone Level and Improving Sperm Profile in Male Volunteers.

Background: Dietary fiber rich fenugreek (Trigonella foenum-graecum) seeds have exhibited cardioprotective, hypolipidemic and other health benefits. Furosap (FS), an innovative, patented, 20% protodioscin-enriched extract was developed in our laboratory from fenugreek seeds. This study examined the free and total testosterone levels, sperm profile and morphology, sexual health, mood and mental alertness, and broad spectrum safety parameters of FS in 50 male volunteers following supplementation over a period of 12 weeks. Methods: Institutional Review Board (IRB) and other regulatory approvals were obtained for our study. This one-arm, open-labelled, multi-center study was conducted in 50 male volunteers (age: 35 to 65 years) over a period of 12 weeks to determine the efficacy of FS (500 mg/day/subject) on free and total testosterone levels, sperm profile, sperm morphology, libido and sexual health, mood and mental alertness, and broad spectrum safety parameters. Results: Free testosterone levels were improved up to 46% in 90% of the study population. 85.4% of the study population showed improvements in sperm counts. Sperm morphology improved in 14.6% of volunteers. Majority of the subjects enrolled in the study demonstrated improvements in mental alertness and mood. Furthermore, cardiovascular health and libido were significantly improved. Extensive safety parameters were evaluated which included blood chemistry data. No significant changes were observed in serum lipid function, cholesterol, triglyceride, HDL and LDL levels, hemogram (CBC), hepatotoxicity and nephrotoxicity. Conclusion: Overall, the results demonstrate that FS, enriched in 20% protodioscin, is safe and effective in attenuating testosterone levels, healthy sperm profile, mental alertness, cardiovascular health and overall performance in human subjects.

Efficacy of a Novel Fenugreek Seed Extract (Trigonella foenum-graecum, Furocyst) in Polycystic Ovary Syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is one of the most prevalent hormonal disorders among women of reproductive age causing irregular menstrual cycles, excessive body or facial hair, miscarriage and infertility. The latter being a most common PCOS symptoms. Because the symptoms are seemingly unrelated to one another, PCOS is often overlooked and undiagnosed. The present study is an open label, one-arm, non-randomized, post-marketing surveillance study in 50 premenopausal women (18-45 years, BMI<42) diagnosed with PCOS using a novel Trigonella foenum-graecum seed extract (fenugreek seed extract, Furocyst, 2 capsules of 500 mg each/day) extract, enriched in approximately 40% furostanolic saponins, over a period of 90 consecutive days. The study was conducted to determine its efficacy on the reduction of ovarian volume and the number of ovarian cysts. Ethical committee approval was obtained for this study. Furocyst treatment caused significant reduction in ovary volume. Approximately 46% of study population showed reduction in cyst size, while 36% of subjects showed complete dissolution of cyst. It is important to mention that 71% of subjects reported the return of regular menstrual cycle on completion of the treatment and 12% of subjects subsequently became pregnant. Overall, 94% of patients benefitted from the regimen. Significant increases in luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels were observed compared to the baseline values. Extensive blood chemistry, hematological and biochemical assays demonstrated the broad-spectrum safety. Furocyst caused significant decrease in both ovarian volume and the number of ovarian cysts. Serum ALT, BUN and CK were assessed to demonstrate the broad-spectrum safety of Furocyst. No significant adverse effects were observed. In summary, Furocyst was efficacious in ameliorating the symptoms of PCOS.

Safety and efficacy of a novel Prunus domestica extract (Sitoprin, CR002) on testosterone-induced benign prostatic hyperplasia (BPH) in male Wistar rats.

The efficacy of a novel Prunus domestica bark extract (Sitoprin, CR002) was investigated on testosterone propionate (TP)-induced benign prostatic hyperplasia (BPH) in male Wistar rats. BPH was induced by daily subcutaneous administration of TP (3.0 mg/kg) over a period of 15 days (interim sacrifice group) and for an additional 21 days (terminal sacrifice group). We evaluated the dose-dependent efficacy (0, 50, 100 and 200 mg/kg body weight/day) of CR002 and a control group against BPH, and compared with a reference standard Prunus africana extract (CR001). Extensive clinical examinations were carried out on days 1, 7, 14, 21, 28 and 35 of treatment period to determine the onset, duration and severity of clinical signs. Clinical pathology, hematology, biochemistry and histopathology were performed on days 15 and 35, prior to necropsy. Animals were fasted overnight prior to blood collection. Prostate glands and tissues were examined. On day 36, histopathology of ventral prostrate of control rats demonstrates single layer of columnar mucin secreting epithelial cells along with a lumen occupied with eosinophilic secretion. In contrast, CR002 and CR001 groups (100 and 200 mg/kg/day) exhibited no hyperplasia and proliferation of epithelial cells. Prostate histopathology of these treated groups was comparable with control rats. The hyperplasia and hypertrophy of prostrate was reduced to single-layered cell indicating the efficacy of CR002 and CR001. Overall, results demonstrate that CR002 exhibits therapeutic efficacy/activity in TP-induced BPH in rats, which is comparable to CR001.

Safety, efficacy and toxicological evaluation of a novel, patented anti-diabetic extract of Trigonella Foenum-Graecum seed extract (Fenfuro).

Safety and anti-diabetic efficacy of a novel, proprietary Trigonella foenum-graecum seed extract [novel fenugreek extract (FE), Fenfuro™, CR0010810) enriched in furostanolic saponins (>60% w/w, HPLC) were assessed. Concerning safety, we undertook studies dealing with acute oral toxicity, 28-d sub-chronic toxicity and Ames' bacterial reverse mutation assay that revealed no toxicity. Concerning efficacy, we examined beneficial effects of the extract on rats with type 2 diabetes (T2D). Male Sprague-Dawley rats received a high-fat diet for 2 weeks followed by streptozotocin (STZ, 35 mg/kg i.p.) to produce T2D. Seven days post-STZ, rats showing ≥300 mg/dl fasting plasma glucose level (PGL) were included in the study. FE (150- or 450- mg/kg p.o.) and glipizide (5 mg/kg p.o.) were administered once daily for 20 d and then twice daily for another 10 d (total 30 d). Blood samples were collected at 0, 10, 20 and 30 d of treatment and estimated for fasting plasma triglyceride (PTG), total cholesterol and insulin levels. After 30 d, FE and glipizide-treated diabetic animals were treated in combination with or without metformin (100 mg/kg) twice daily for another 10 d. FE did not influence body weight, feed and water intake. FE (150 mg/kg p.o.) reduced PTG levels in T2D rats by 22%, 24.6% and 29% at 10, 20 and 30 d of treatment, respectively, while glipizide (5 mg/kg p.o.) reduced the PTG levels by 57.4%, 46.2% and 39.4% at these time points. FE (450 mg/kg) treatment in STZ-induced diabetic rats produced significant hypoglycemic activity (approximately 31.5%) as compared to insulin (48.2% with 1 U/kg i.p.). FE (150 mg/kg p.o.) and metformin (100 mg/kg p.o.) combined produced significant reduction (20.7%) of PGL in T2D rats. No adverse effects were observed. We conclude after extensive in vitro and in vivo safety and efficacy studies that FE is safe and effective in treating T2D.

Free radical scavenging, antioxidant and cancer chemoprevention by grape seed proanthocyanidin: an overview.

A large number of investigations have demonstrated a broad spectrum of pharmacological and therapeutic benefits of grape seed proanthocyanidins (GSP) against oxidative stress and degenerative diseases including cardiovascular dysfunctions, acute and chronic stress, gastrointestinal distress, neurological disorders, pancreatitis, various stages of neoplastic processes and carcinogenesis including detoxification of carcinogenic metabolites. GSP exhibited potent free radical scavenging abilities in both in vitro and in vivo models. GSP exerted significant in vivo protection against structurally diverse drug and chemical-induced hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity and spleentoxicity. GSP also protected against idarubicin and 4-hydroxyperoxy-cyclophosphamide-induced cytotoxicity toward human normal liver cells. GSP exhibited selective cytotoxicity toward selected human cancer cells, while enhancing the growth and viability of normal cells. GSP exhibited potent modulatory effects of pro-apoptotic and apoptotic regulatory bcl-XL, p53, c-myc, c-JUN, JNK-1 and CD36 genes. Long-term exposure to GSP may serve as a novel chemoprotectant against three stages of DMN-induced liver carcinogenesis and tumorigenesis including initiation, promotion and progression. GSP may selectively protect against oxidative stress, genomic integrity and cell death patterns in vivo. These results demonstrate that GSP may serve as a novel therapeutic intervention against carcinogenesis.

Water-soluble undenatured type II collagen ameliorates collagen-induced arthritis in mice.

Earlier studies have reported the efficacy of type II collagen (C II) in treating rheumatoid arthritis (RA). However, a few studies have investigated the ability of the antigenic collagen to induce oral tolerance, which is defined as active nonresponse to an orally administered antigen. We hypothesized that water-soluble undenatured C II had a similar effect as C II in RA. The present study was designed to examine the oral administration of a novel, water-soluble, undenatured C II (commercially known as NEXT-II) on collagen-induced arthritis (CIA) in mice. In addition, the underlying mechanism of NEXT-II was also identified. After a booster dose (collagen-Freund's complete adjuvant), mice were assigned to control CIA group, or NEXT-II treatment group, to which saline and NEXT-II were administered, respectively. The arthritis index in the NEXT-II group was significantly lower compared with the CIA group. Serum IL-6 levels in the NEXT-II group were significantly lower compared with the CIA group, while serum IL-2 level was higher. Furthermore, oral administration of NEXT-II enhanced the proportion of CD4+CD25+T (Treg) cells, and gene expressions of stimulated dendritic cells induced markers for regulatory T cells such as forkhead box p3 (Foxp3), transforming growth factor (TGF)-ß1, and CD25. These results demonstrated that orally administered water-soluble undenatured C II (NEXT-II) is highly efficacious in the suppression of CIA by inducing CD4+CD25+ Treg cells.

Cardioprotective efficacy of a novel antioxidant mix VitaePro against ex vivo myocardial ischemia-reperfusion injury.

Circumstantial evidence frequently implicates oxygen-derived free radicals and oxidative stress as mediators of myocardial ischemia/reperfusion (I/R) injury. Therefore, external supplementation of natural antioxidants plays a main role as cardioprotective compounds. This study was designed to evaluate the cardioprotective effect of VitaePro (70 mg/kg body weight, 21 days), a novel antioxidant mix of astaxanthin, lutein and zeaxanthin in a rat ex vivo model of ischemia/reperfusion injury. The cardioprotective effect of VitaePro was also compared with vitamin E (70 mg/kg body weight, 21 days) treatment. Rats were randomized into control I/R (CIR), VitaePro I/R (VPIR) and Vitamin E I/R (VEIR). After 21 days of oral treatment, isolated hearts from each group were subjected to 30 min of ischemia followed by 2 h of reperfusion. In the VPIR group compared to CIR and VEIR groups at 2 h of reperfusion, increased left ventricular functional recovery, such as left ventricular developed pressure (92.7 ± 0.7 vs. 85.3 ± 0.3 and 89.4 ± 1.2 mm Hg), dp/dt max (2518.7 ± 77.9 vs. 1962.5 ± 24 and 2255.7 ± 126.6 mm Hg/s), and aortic flow (21.5 ± 1.36 vs. 4.4 ± 0.6 and 13.2 ± 1.02 ml/min) were observed. The infarct size (27.68 ± 1.7 vs. 45.4 ± 1.8 and 35.4 ± 0.6%), apoptotic cardiomyocytes (61.7 ± 10.6 vs. 194.1 ± 14.8 and 118.7 ± 15.4 counts/100 HPF) and thiobarbituric acid reactive substances levels (80 ± 3 vs. 127 ± 5 and 103 ± 2 nM/mg tissue) also were decreased in VPIR group when compared to CIR and VEIR. As evidenced by the data, administration of vitamin E offered substantial cardioprotection to I/R injury, but VitaePro enhanced cardioprotection significantly more than vitamin E treatment. Taken in concert, the results of this study suggests that the oral ingestion of VitaePro protects myocardium from ischemia/reperfusion injury by decreasing oxidative stress and apoptosis, which may be of therapeutic benefit in the treatment of cardiovascular complications. However, further in vivo animal and human intervention studies are warranted before establishing any recommendations about usage of VitaePro for human cardiovascular complications.

Safety assessment of a calcium-potassium salt of (-)-hydroxycitric acid.

The safety of Garcinia cambogiaextract, its active ingredient (-)-hydroxycitric acid (HCA), and the marketed weight management formula, Super CitriMax(®) (HCA-SX), is supported by numerous in vitro and animal experimental studies as well as several clinical studies. HCA-SX has been shown to reduce appetite, inhibit fat synthesis, and decrease body weight. A series of toxicological tests including acute, short-term, and sub-chronic studies as well as teratogenicity/reproduction and genotoxicity studies were performed on HCA-SX. In the acute oral toxicity study, administration of a single dose of 5,000 mg/kg of HCA-SX did not reveal any significant changes for all examined tissues. Following the high dose safety testing, there were no remarkable changes or differences observed in any of the experimental conditions monitored. There were no macroscopic abnormalities for any examined tissues at scheduled necropsies. On the basis of these findings, the consumption of HCA-SX at dose level of up to 4667 mg/day is considered safe.

Safety and toxicological evaluation of AlgaeCal (AC), a novel plant-based calcium supplement.

The present study was conducted to examine the safety of a novel plant-based calcium supplement, derived from marine algae and containing high levels of calcium, magnesium, and other bone supporting minerals (commercially known as AlgaeCal (AC)). The present study evaluated the broad-spectrum safety of AC using a variety of toxicological assays including acute oral, acute dermal, primary skin irritation, and primary eye irritation toxicity. Under the conditions of the study, the acute oral LD(50) of AC was found to be greater than 5000 mg/kg body weight in rats, while the single acute dermal LD(50) was greater than 2000 mg/kg body weight. The primary skin irritation index of AC was found to be 0.4 and classified as slightly irritating to the skin. In primary eye irritation studies, the maximum mean total score of AC was observed to be 13.7 and classified as mildly irritating to the eye. Furthermore, another independent set of studies was conducted to obtain preliminary data for the teratogenic effects of AC in pregnant rats likely to arise from repeated gestational exposure, via oral gavage, over a test period of implantation through gestation (gestation days 5-19). Under the conditions of this pilot study, the effect of daily administration of AC by oral gavage at dose levels of 0, 500, 2500, and 5000 mg/kg/day during gestation days 5-19 of a 21-day pregnancy has appeared to result in no adverse toxicological effects to the pregnant rat or its developing offspring. A slight, non-significant increase in the incidence of incomplete sterna ossification (5(th) center) was observed. Under the conditions of the study, a no-observed-adverse effect level (NOAEL) of 5000 mg/kg/day of AC during pregnancy of the rat was observed. Overall, no significant toxicities of AC were observed in these toxicity models. Therefore, the results from the current study demonstrate a broad-spectrum safety profile of AC.

Comparative effects of a novel plant-based calcium supplement with two common calcium salts on proliferation and mineralization in human osteoblast cells.

Calcium is an essential mineral to support bone health and serves as a major therapeutic intervention to prevent and delay the incidence of osteoporosis. Many individuals do not obtain the optimum amount of calcium from diets and depend on bioavailable calcium supplements. The present study was conducted to examine the effect of a novel plant-based calcium supplement, derived from marine algae, and contains high levels of calcium, magnesium, and other bone supporting minerals [commercially known as AlgaeCal (AC)], on proliferation, mineralization, and oxidative stress in cultured human osteoblast cells, and compared with inorganic calcium carbonate and calcium citrate salts. Cultured human fetal osteoblast cells (hFOB 1.19) were treated with AC (0.5 mg/ml, fixed by MTT assay), calcium carbonate, or calcium citrate. These cells were harvested after 4 days of treatment for ALP activity, PCNA expression, and DNA synthesis, and 2 days for Ca(2+) deposition in the presence and absence of vitamin D3 (5 nM). The ability of AC to reduce H(2)O(2) (0.3 mM)-induced oxidative stress was assessed after 24 h of treatment. ALP activity was significantly increased with AC treatment when compared to control, calcium carbonate, or calcium citrate (4.0-, 2.0-, and 2.5-fold, respectively). PCNA expression (immunocytochemical analysis), DNA synthesis (4.0-, 3.0-, and 4.0-fold, respectively), and Ca(2+) deposition (2.0-, 1.0-, and 4.0-fold, respectively) were significantly increased in AC-treated cells when compared with control, calcium carbonate, or calcium citrate treatment. These markers were further enhanced following additional supplementation of vitamin D3 in the AC-treated group cells. AC treatment significantly reduced the H(2)O(2)-induced oxidative stress when compared to calcium carbonate or calcium citrate (1.5- and 1.4-fold, respectively). These findings suggest that AC may serve as a superior calcium supplement as compared to other calcium salts tested in the present study. Hence, AC may be developed as a novel anti-osteoporotic supplement in the near future.

Nutrigenomic basis of beneficial effects of chromium(III) on obesity and diabetes.

Insulin resistance has been shown to be the major contributing factor to the metabolic syndrome, which comprises a cluster of risk factors for metabolic aberrations such as obesity, dyslipidemia, hypertension, and hyperglycemia. Additionally, insulin resistance has been associated with the occurrence of cardiovascular disease and type 2 diabetes. Epidemiological studies indicate that obesity and diabetes have become alarmingly prevalent in recent years. Substantial evidence suggests that dietary interventions and regular exercise greatly improve body mass index and lipid profile as well as alleviate insulin resistance. Therefore, dietary supplements such as insulin-sensitizing agents may be beneficial in the prevention and treatment of obesity and type 2 diabetes. Numerous in vitro and in vivo studies suggest that chromium supplements, particularly niacin-bound chromium or chromium-nicotinate, may be effective in attenuating insulin resistance and lowering plasma cholesterol levels. Utilizing the powerful technology of nutrigenomics to identify the genes regulated by chromium supplementation may shed some light on the underlying mechanisms of chromium-gene interactions, and thus provide strategies to mitigate and prevent insulin-resistance-related disorders.