A novel multi-ingredient supplement significantly improves ocular symptom severity and tear production in patients with dry eye disease: results from a randomized, placebo-controlled clinical trial.

Introduction: Dry eye disease (DED) is multifactorial and characterized by a loss of tear film homeostasis that causes a cycle of tear film instability, tear hyperosmolarity, and inflammation. While artificial tears are the traditional mainstay of treatment, addressing the underlying pathophysiology could relieve symptoms and prevent progression. Increasing evidence indicates a role for oral nutritional supplementation in multiple ophthalmic diseases, including DED. Lutein, zeaxanthin, curcumin, and vitamin D3 have demonstrated protective and anti-inflammatory properties in ocular models. This prospective, randomized, double-blind, parallel, placebo-controlled study evaluated the efficacy and safety of a proprietary blend of lutein, zeaxanthin isomers, curcumin, and vitamin D3 (LCD) as a daily supplement in adult participants with DED. Methods: Participants were randomized to receive one LCD supplement capsule (lutein 20 mg, zeaxanthin isomers 4 mg, curcumin 200 mg curcuminoids, and vitamin D3 600 IU) or placebo per day for 8 weeks (LCD, n=77; placebo, n=78). Primary outcomes were changes in tear volume (Schirmer's test) and ocular symptoms (Ocular Surface Disease Index [OSDI]). Results: The study met its primary endpoints: the LCD group demonstrated significantly better Schirmer's test scores and improvement in overall OSDI score, versus placebo, at Day 56 (p<0.001 for both). Scores for total OSDI, and symptoms and vision domains, significantly improved by Day 14 for LCD versus placebo, (p<0.05 for all) and were maintained to Day 56 (p<0.001). In addition, the LCD group demonstrated significantly improved tear film break-up time (TBUT) and tear film osmolarity, versus placebo, by Day 56 (p<0.001), along with significant improvements in corneal and conjunctival staining (p<0.001 for both), and inflammation (matrix metalloproteinase-9; p<0.001 for each eye). Total Standard Patient Evaluation of Eye Dryness (SPEED) score, and scores for the frequency and severity domains, were significantly improved by Day 14 for LCD versus placebo (p<0.05 for all) and maintained to Day 56 (p<0.001). There was no difference between groups for artificial tear usage. The supplement was well-tolerated. Discussion: Once-daily LCD supplementation significantly improved tear production, stability and quality, reduced ocular surface damage and inflammation, and improved participants' symptoms. LCD supplementation could offer a useful adjunct to artificial tears for patients with DED (NCT05481450).

Impact of a Novel Valerian Extract on Sleep Quality, Relaxation, and GABA/Serotonin Receptor Activity in a Murine Model.

Insomnia is a major global health issue, highlighting the need for treatments that are both effective and safe. Valerian extract, a traditional remedy for sleep problems, offers potential therapeutic options. This research examined the potential sleep-enhancing effects of VA (Valerian Pdr%2) in mice. The study evaluated sleep quality by comparing the impact of the VA extract against melatonin on brain activity, using electrocorticography (ECoG) to assess changes in brain waves. For this purpose, the study utilized two experimental models on BALB/c mice to explore the effects of caffeine-induced insomnia and pentobarbital-induced sleep. In the first model, 25 mice were assigned to five groups to test the effects of caffeine (caffeine, 7.5 mg/kg i.p) alone, caffeine with melatonin (2 mg/kg), or caffeine with different doses of valerian extract (100 or 300 mg/kg) given orally on brain activity, assessed via electrocorticography (ECoG) and further analyses on the receptor proteins and neurotransmitters. In the second model, a different set of 25 mice were divided into five groups to examine the impact of pentobarbital (42 mg/kg) alone, with melatonin, or with the valerian extract on sleep induction, observing the effects 45 min after administration. The study found that ECoG frequencies were lower in groups treated with melatonin and two doses of valerian extract (100 and 300 mg/kg), with 300 mg/kg showing the most significant effect in reducing frequencies compared to the caffeine control group, indicating enhanced sleep quality (p < 0.05). This was supported by increased levels of serotonin, melatonin, and dopamine and higher levels of certain brain receptors in the melatonin and valerian extract groups (p < 0.05). Modulatory efficacy for the apoptotic markers in the brain was also noted (p < 0.05). Additionally, melatonin and both doses of VA increased sleep duration and reduced sleep onset time compared to the pentobarbital control, which was particularly notable with high doses. In conclusion, the findings suggest that high doses (300 mg/kg) of valerian extract enhance both the quantity and quality of sleep through the GABAergic pathway and effectively increase sleep duration while reducing the time to fall asleep in a pentobarbital-induced sleep model in mice.

Beneficial effects of a novel polyherbal formulation on the skeletal muscle antioxidant status, inflammation, and muscle-signaling proteins in exercised rats.

Background/aim: Exhausting exercise can damage muscle tissue due to free radical interactions. It is hypothesized that the increase in free radicals following muscle injury, either due to oxidative damage to biomolecules or the activation of inflammatory cytokines, may lead to secondary muscle damage. This study investigated the effects of a novel joint health formula (JHF) containing bisdemethoxycurcumin-enriched curcumin, 3-O-Acetyl-11-keto-beta-boswellic acid-enriched Boswellia (AKBA), and Ashwagandha on exhaustion time, grip strength, antioxidant status, and muscle-signaling proteins in exhaustively exercised rats. Materials and methods: Twenty-eight rats were divided into four groups: Control (C), exercise (E), E + JHF 100 (100 mg/kg), and E + JHF 200 (200 mg/kg). Results: An increase in time to exhaustion and grip strength was recorded with JHF supplementation in a dose-dependent manner (p < 0.0001). In addition, serum and muscle lactate dehydrogenase, malondialdehyde, myoglobin, creatine kinase, and lactic acid concentrations were decreased in the groups supplemented with JHF, particularly at the high dose of JHF (200 mg/kg) (p < 0.0001 for all). JHF supplementation also increased antioxidant enzyme activities and suppressed the production of inflammatory cytokines compared to the exercise group (p < 0.0001). Moreover, JHF reduced the levels of PGC-1α, p-70S6K1, MAFbx, MuRF1, and p-mTOR proteins in muscle tissue compared to the exercise group (p < 0.05), being more effective at high doses. Conclusion: These findings show that JHF might reduce muscle damage by modulating antiinflammatory, antioxidant, and muscle mass regulatory pathways in exhausted training rats. At the same time, JHF improved exercise performance and grip strength.

Lutein/Zeaxanthin Isomers and Quercetagetin Combination Safeguards the Retina from Photo-Oxidative Damage by Modulating Neuroplasticity Markers and the Nrf2 Pathway.

Exposure to light-emitting diode (LED) light is a primary cause of retinal damage, resulting in vision loss. Several plant-derived substances, such as lutein and quercetagetin (QCG), show promise in supporting eye health. In this study, the impact of lutein/zeaxanthin (L/Z, Lutemax 2020) and QCG were evaluated individually and together in a rat model of LED-induced retinal damage. A total of 63 Wistar rats were allocated into nine groups (n = 7). For 28 days, the rats received L/Z (10 or 20 mg/kg BW), quercetin (QC, 20 mg/kg BW), QCG (10 or 20 mg/kg BW), or a mixture of different lutein and QCG dosages, after which they were exposed to LED light for 48 h. LED exposure led to a spike in serum malondialdehyde (MDA) and inflammatory cytokines, as well as an increase in retinal NF-κB, ICAM, GFAP, and MCP-1 levels (p < 0.0001 for all). It also reduced serum antioxidant enzyme activities and retinal Nrf2, HO-1, GAP43, NCAM, and outer nuclear layer (ONL) thickness (p < 0.0001 for all). However, administering L/Z and QCG, particularly a 1:1 combination of L/Z and QCG at 20 mg/kg, effectively reversed these changes. The treatment suppressed NF-κB, ICAM, GFAP, and MCP-1 while enhancing Nrf2, HO-1, GAP43, and NCAM and preventing ONL thickness reduction in LED-induced retinal damage rats. In conclusion, while LED light exposure caused retinal damage, treatment with L/Z, QC, and QCG, particularly a combined L/Z and QCG regimen, exhibited protective effects on the retina. This is possibly due to the modulation of neuroplasticity markers and nuclear transcription factors in the rats' retinal cells.

Superior Bioavailability of a Novel Lutein and Zeaxanthin Formulation in Healthy Human Subjects.

INTRODUCTION: Lutein (L) and zeaxanthin (Z) are carotenoids that are found in the macula of the human eye and are known to improve visual functions. However, poor bioavailability of supplemental L and Z poses a challenge to achieving significant benefits after consumption. We developed a novel patented formulation of L and Z (Ocusorb®) and demonstrated the improved bioavailability in a pharmacokinetic clinical study. METHODS: Ninety adult human volunteers were recruited in this randomized, double-blind, parallel, comparative bioavailability study. Volunteers were randomly assigned to receive single dose of 10 mg lutein and 2 mg zeaxanthin from test (LZO) or reference (LZC) formulations after breakfast. Blood samples were collected pre-dose at - 48, - 24, and 0 h and at 2, 4, 6, 8, 10, 12, 16, 20, 24, 48, and 72 h post-dose. Serum concentrations of L and Z were quantified by using a validated HPLC method. The LZO and LZC formulations were compared for L and Z on the basis of Cmax, AUC0-72, and AUC0-t. RESULTS: All 90 subjects completed the study. The LZO group demonstrated significantly higher levels of L and Z in serum at several time points as compared to LZC group. The LZO group showed significantly higher bioavailability for lutein (2.5 times higher Cmax, 2.9 times higher AUC0-72, and 3.2 times higher AUC0-t) and zeaxanthin (1.8 times higher Cmax, 2.2 times higher AUC0-72, and AUC0-t) as compared to the LZC group. No safety issues were reported. CONCLUSION: The study results show superior bioavailability of lutein and zeaxanthin from our novel LZO formulation as compared to LZC. The enhanced bioavailability from the LZO formulation can be advantageous for individuals looking to quickly improve their L and Z status and enhance their vision performance. TRIAL REGISTRATION: http://ctri.nic.in/ . Identifier: CTRI/2019/11/022082.

Protective effect of a novel polyherbal formulation on experimentally induced osteoarthritis in a rat model.

Osteoarthritis (OA) is a musculoskeletal disorder mainly found in elderly individuals. Modern treatment of OA, like nonsteroidal anti-inflammatory drugs, corticosteroids, hyaluronic acid injections, etc., is linked to long-term side effects. We evaluated the anti-osteoarthritic properties of a novel joint health formula (JHF) containing Bisdemethoxycurcumin enriched curcumin, 3-O-Acetyl-11-keto-beta-Boswellic acid-enriched Boswellia, and Ashwagandha in monosodium iodoacetate (MIA)-induced knee OA in rats. Twenty-eight female rats were distributed into four groups: Control, OA, OA + JHF (100 mg/kg), and OA + JHF (200 mg/kg). JHF decreased the right joint diameters but increased the paw area and stride length compared to the OA group with no treatment. JHF significantly reduced the arthritic conditions after four weeks of supplementation (p < 0.05). JHF significantly decreased TNF-α, IL-1ß, IL-10, COMP, and CRP in the serum of osteoarthritic rats (p < 0.0001). We observed reduced lipid peroxidation but increased SOD, GSH-Px, and CAT activities in response to JHF treatment in OA animals. JHF down-regulated MMP-3, COX-2, and LOX-5 and improved the histological structure of the knee joint of osteoarthritic rats. JHF demonstrated a protective effect against osteoarthritis, possibly due to anti-inflammatory and antioxidant activity in experimentally induced osteoarthritis in rats, and could be an effective option in the management of OA.

Protective Effect of Allyl Isothiocyanate in an Experimentally Induced Rat Model for Dry Eye Syndrome.

PURPOSE: Growing evidence emphasizes the role of inflammation and oxidative stress in the pathogenesis of Dry Eye Syndrome (DES). Concordantly, the importance of agents targeting the inflammatory cascade and oxidative stress in the treatment is also progressively increasing. Herein, the study has investigated the protective effects and underlying mechanism of allyl isothiocyanate (AITC) on the ocular surface in a benzalkonium chloride (BAC)-induced dry eye rat model. METHODS: A total of twenty-one Wistar albino rats were used to form the following three groups: Control, BAC, BAC + AITC. DES was established by topical application of BAC (four times daily for two weeks) in two groups, of which one group was treated with AITC (10 mg/kg BW daily oral dosage) for four weeks. Rats were monitored by dry eye diagnostic tests during the study period, and eventually, corneal tissues were used to evaluate for histopathologic analyzes and inflammatory and oxidative status. RESULTS: A significant improvement was observed in various histopathologic and ophthalmologic findings, including tear volume, tear film integrity, ocular surface damage, ocular inflammatory signs, corneal thickness, and edema through AITC supplementation. AITC prominently balanced the inflammatory status and oxidative stress by lowering key proinflammatory mediators (NF-κB, TNF-α, IL-1ß, IL-6, and IL-8) and increasing the activities of antioxidant enzymes (SOD, GSH-Px). Also, levels of protective tear proteins, including Muc1, Muc4, and Muc5 were recovered with AITC supplementation. CONCLUSION: AITC alleviates clinical and histopathologic signs related to DES. Antioxidative and anti-inflammatory properties of AITC play a significant role in the mechanism of action.

Next-Generation Ultrasol Curcumin Boosts Muscle Endurance and Reduces Muscle Damage in Treadmill-Exhausted Rats.

Curcumin positively affects performance during exercise and subsequent recovery. However, curcumin has limited bioavailability unless consumed in larger doses. In the current study, we examined the impact of a new formulation of curcumin, Next-Generation Ultrasol Curcumin (NGUC), which is relatively more bioavailable than natural curcumin on exhaustion time, grip strength, muscle damage parameters, and serum and muscle proteins. A total of 28 rats were randomly grouped as control (C, non-supplemented), exercise (E, non-supplemented), E+NGUC100 (supplemented with 100 mg/kg BW NGUC), and E+NGUC200 (supplemented with 200 mg/kg NGUC). Grip strength and exhaustion time were increased with NGUC supplementation (p < 0.0001). Creatine kinase (CK), lactate dehydrogenase (LDH), lactic acid (LA), myoglobin, malondialdehyde (MDA) concentrations were reduced in serum, and muscle tissue in NGUC supplemented groups (p < 0.05). In contrast, NGUC supplementation elevated the antioxidant enzyme levels compared to the non-supplemented exercise group (p < 0.01). Additionally, inflammatory cytokines were inhibited with NGUC administration (p < 0.05). NGUC decreased PGC-1α, p-4E-BP1, p-mTOR, MAFbx, and MuRF1 proteins in muscle tissue (p < 0.05). These results indicate that NGUC boosts exercise performance while reducing muscle damage by targeting antioxidant, anti-inflammatory, and muscle mass regulatory pathways.

Allyl isothiocyanate attenuates LED light-induced retinal damage in rats: exploration for the potential molecular mechanisms.

PURPOSE: Environmental light pollution due to artificial light may increase the rate and severity of retinal diseases, and plant-based nutritional interventions with antioxidant properties have the potential to reverse this phenomenon. We aimed to investigate the potential effects of allyl isothiocyanate (AITC) against white light-emitting diode (LED)-induced retinal degeneration (RD) in the rats. METHODS: Twenty-eight male rats were allocated as: (i) Control, (ii) LED, (iii) LED + AITC (10 mg/kg BW), (iv) LED + AITC (20 mg/kg BW). Rats were administered with AITC for 28 days, followed by two days of intense environmental LED light (750 Lux) exposure to the eyes. Animals were sacrificed immediately at the end of the study, then the blood and eyeballs were taken for the biochemical, western blotting, and histopathology examinations. RESULTS: AITC lowered the serum and retina malondialdehyde (MDA) levels while significantly (p < 0.05) improving the retinal antioxidant enzyme activities in a dose-dependent manner. AITC improved retinal and outer nuclear layer (ONL) thickness as compared to the LED group (p < 0.05). AITC increased the levels of Bax, caspase-3, HO-1, GAP43, and VEGF, while decreasing IL-1ß, IL-6, NF-κB, Bcl-2, GFAP, Grp78, activating ATF4 and ATF6 as compared to the LED group (p < 0.05). CONCLUSION: In conclusion, four weeks of AITC administration to the rats showed specific protective effects against two days of intense LED light-induced retinal damage; through antiinflammatory, antioxidant, anti-apoptotic, and modulating mitochondrial metabolic pathways.

Accumulating evidence to support the safe and efficacious use of a proprietary blend of capsaicinoids in mediating risk factors for obesity.

Obesity is a significant public health concern, and finding safe and effective means for combating this condition is needed. This study investigates the safety and efficacy of supplementation of a blend of capsaicinoids on weight gain, fat mass, and blood chemistry in a high-fat diet (HFD) model of obesity in mice and on adipocyte differentiation and gene expression in 3T3-L1 preadipocytes. High-fat diet (HFD)-fed mice were treated with a proprietary capsaicinoid concentrate (Capsimax®; OmniActive Health Technologies Ltd., India) and compared to orlistat (ORL) and normal chow-fed mice (NC). Mice fed a high-fat diet showed significantly lower weight gain upon Capsimax® (CAP) administration than their HFD counterparts and similar to that observed with ORL animals. In addition, CAP decreased the high-fat diet-induced increases in adipose tissue and epididymal fat pad mass and hypertrophy after 52 days of treatment. Both the CAP and ORL groups had increased plasma concentrations of leptin. CAP extracts decreased triacylglycerol content in 3T3-L1 preadipocytes and decreased markers of adipogenesis including peroxisome proliferator-activated receptor (PPAR-É£) and fatty acid-binding protein 4 (FABP4). Expression of genes involved in lipogenesis such as stearoyl-CoA desaturase (SCD) and fatty acid synthase (FSN) was decreased by CAP in a dose-dependent manner. Thermogenic genes and markers of brown adipose tissue including uncoupling protein 1 (UCP1) and PR domain-containing 16 (Prdm16) were induced by CAP in the preadipocyte cells. These in vivo and in vitro data support that this proprietary capsaicinoid concentrate reduces weight gain and adiposity at least in part through decreasing lipogenesis and increasing thermogenesis.

A Next Generation Formulation of Curcumin Ameliorates Experimentally Induced Osteoarthritis in Rats via Regulation of Inflammatory Mediators.

Osteoarthritis (OA) is a chronic and debilitating disease of the knee joint. OA of the knee is initiated by physical damage and accumulated oxidative stress, followed by an exaggerated inflammation leading to cartilage damage. Currently, no effective and safe therapeutic option capable of restoring articular cartilage tissue and joint architecture is available. We here report a novel and highly bioavailable formulation of curcumin, labeled as Next Generation Ultrasol Curcumin (NGUC), which was 64.7 times more bioavailable than natural 95% curcumin extract as demonstrated in rat bioavailability studies. We further investigated the protective effect of NGUC against monosodium iodoacetate (MIA)-induced knee OA in rats. Analysis of X-ray and histopathological images revealed that NGUC supplementation restored joint architecture and reduced swelling of joints induced by MIA. NGUC treatment caused a significant reduction in the levels of inflammatory mediators such as TNF-α, IL-1ß, IL-6, COMP, and CRP, and expressions of MMP-3, 5-LOX, COX-2, and NFκB in synovial tissue of rats with MIA-induced OA. NGUC also decreased serum MDA level and increased the levels of antioxidant enzymes SOD, CAT, and GPX. Thus, our results indicate that a novel formulation of curcumin with enhanced bioavailability effectively ameliorates the pathophysiology of OA.

Different Doses of ß-Cryptoxanthin May Secure the Retina from Photooxidative Injury Resulted from Common LED Sources.

Retinal damage associated with loss of photoreceptors is a hallmark of eye diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. Potent nutritional antioxidants were previously shown to abate the degenerative process in AMD. ß-Cryptoxanthin (BCX) is an essential dietary carotenoid with antioxidant, anti-inflammatory, and provitamin A activity. It is a potential candidate for developing intervention strategies to delay the development/progression of AMD. In the current study, the effect of a novel, highly purified BCX oral formulation on the rat retinal damage model was evaluated. Rats were fed with BCX for four weeks at the doses of 2 and 4 mg/kg body weight in the form of highly bioavailable oil suspension, followed by retinal damage by exposing to the bright light-emitting diode (LED) light (750 lux) for 48 hrs. Animals were sacrificed after 48 hours, and eyes and blood samples were collected and analyzed. BCX supplementations (2 and 4 mg/kg) showed improvements in the visual condition as demonstrated by histopathology of the retina and measured parameters such as total retinal thickness and outer nuclear layer thickness. BCX supplementation helped reduce the burden of oxidative stress as seen by decreased serum and retinal tissue levels of malondialdehyde (MDA) and restored the antioxidant enzyme activities in BCX groups. Further, BCX supplementation modulated inflammatory markers (IL-1ß, IL-6, and NF-κB), apoptotic proteins (Bax, Bcl-2, caspase 3), growth proteins and factors (GAP43, VEGF), glial and neuronal proteins (GFAP, NCAM), and heme oxygenase-1 (HO-1), along with the mitochondrial stress markers (ATF4, ATF6, Grp78, Grp94) in the rat retinal tissue. This study indicates that oral supplementation of BCX exerts a protective effect on light-induced retinal damage in the rats via reducing oxidative stress and inflammation, also protected against mitochondrial DNA damage and cellular death.

A Novel Integrated Active Herbal Formulation Ameliorates Dry Eye Syndrome by Inhibiting Inflammation and Oxidative Stress and Enhancing Glycosylated Phosphoproteins in Rats.

Dry eye syndrome (DES) is a chronic condition of the eye with insufficient production of tears leading to inadequate lubrication of eyes. Symptoms of DES are associated with discomfort and redness of the eye, blurred vision, and tear film instability which leads to the damaged ocular surface. Inflammation and oxidative stress play a significant role in the pathogenesis of the disease. In this study, the protective effect of different doses (100 or 200 mg/kg) of a novel multi-component oral formulation of lutein/zeaxanthin, curcumin, and vitamin D3 (LCD) was evaluated using a rat model with benzalkonium chloride (BAC)-induced dry eye syndrome. The formulation was administered orally to rats for 4 weeks. We observed a significant improvement in tear volume, tear breakup time, tear film integrity, and reduction in overall inflammation in rats fed with the LCD at dose 200 mg/kg performing better than 100 mg/kg. Furthermore, the formulation helped in lowering oxidative stress by increasing antioxidant levels and restored protective tear protein levels including MUC1, MUC4, and MUC5AC with 200 mg of LCD having the most significant effect. The results strongly suggest that the combination of lutein/zeaxanthin, curcumin, and vitamin-D3 is effective in alleviating the symptoms of dry eye condition with a multi-modal mechanism of action.