Corrigendum: A natural sustained-intestinal release formulation of red chili pepper extracted capsaicinoids (Capsifen®) safely modulates energy balance and endurance performance: a randomized, double-blind, placebo-controlled study.

[This corrects the article DOI: 10.3389/fnut.2024.1348328.].

A natural sustained-intestinal release formulation of red chili pepper extracted capsaicinoids (Capsifen®) safely modulates energy balance and endurance performance: a randomized, double-blind, placebo-controlled study.

Introduction: Overweight and obesity are major public health concerns, with a sharp increase in prevalence over the last few decades. The primary cause is an imbalance between calorie intake and expenditure due to a rise in calorie-rich processed food and reduced physical activity. Energy balance in humans involves complex processes including thermogenesis, a crucial factor in regulating energy expenditure. Methods: In this randomized, double-blinded, placebo-controlled three-arm three-sequence study, we investigated the efficacy of Capsifen® (CapF), a pungency-masked sustained-intestinal release formulation of red chili extract, on energy expenditure, fat oxidation, and endurance using the Quark C-PET system in healthy overweight participants, with and without exercise. In the study, 105 healthy participants were randomized to receive either placebo, CapF 100 mg/day, or CapF 200 mg/day for 28 days. Results: CapF demonstrated a dose-dependent response to increased energy expenditure and fatty acid oxidation with a concomitant reduction in body weight. Both CapF 100 and CapF 200 also increased the time to exhaustion. Discussion: These results demonstrate the plausible efficacy of CapF in energy expenditure and physical performance in otherwise healthy adults who have a high body mass index. Clinical trial registration: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MjQzNTg=&Enc=&userName=CTRI/2018/04/013157 dated 04 October 2018.

Exploring the short-term influence of a proprietary oil extract of black cumin (Nigella sativa) on non-restorative sleep: a randomized, double-blinded, placebo-controlled actigraphy study.

Background: Nigella sativa (black cumin, or black seed) is popularly known as the seed of blessings in the Arab system of medicine. Though not widely recommended for sleep, a unique proprietary black cumin extract (BlaQmax®/ThymoDream™; BCO-5) has been shown to be helpful in the management of stress and sleep issues. Methods: This randomized, double-blind, placebo-controlled trial aimed to investigate the efficacy of BCO-5 on the sleep quality of volunteers characterized with a self-reported non-restorative sleep disorder. Healthy male and female participants (n = 70), aged 18-65 years (BMI 22-28 Kg/m2) were randomized to either placebo or BCO-5 (n = 35/group). Both interventions were supplemented at 200 mg/day for seven days. Actigraphy and a validated restorative sleep questionnaire (RSQ-W) were used to monitor the influence of BCO-5 on sleep. Results: Compared to placebo, BCO-5 significantly improved sleep quality, as evidenced by both intra-group and inter-group analyses of the actigraphy data. The relative improvements observed were sleep efficiency (7.8%, p < 0.001), total sleep time (19.1%, p < 0.001), sleep onset latency (35.4%; p < 0.001), and wake-after-sleep-onset (22.5%; p < 0.001) compared with placebo. BCO-5 also improved sleep by 75.3% compared to baseline (p < 0.001) and by 68.9% compared to placebo (p < 0.001), when monitored by RSQ-W. BCO-5 was well-tolerated with no reports of side effects or toxicity. Conclusion: BCO-5 significantly improved non-restorative sleep in seven days, indicating its potential role as a natural sleep aid.

Brain regional pharmacokinetics following the oral administration of curcumagalactomannosides and its relation to cognitive function.

OBJECTIVE: Though a number of bioavailable formulations of curcuminoids have been reported and available commercially as nutraceuticals for brain health, systematic informations on their blood-brain-barrier permeability and brain tissue distribution have not been reported. The present study was aimed to investigate the brain regional pharmacokinetics of curcuminoids following both single dose and repeated dose oral administration of a self-emulsifying food-grade formulation of curcuminoids using fenugreek galactomannan hydrogel scaffold as 'curcumagalactomannosides' (CGM), and its influence on cognitive functions in comparison with unformulated natural curcuminoids (NC) in Wistar rats. METHODS: CGM was given to animals in single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the concentration of total curcuminoids at various parts of brain was evaluated at different time points using Ultra-performance liquid chromatography/electrospray ionization triple quadruple tandem mass spectroscopy (UPLC-ESI-MS/MS) system. Another set of animals were also fed with CGM at single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the behavioural studies were conducted using open field test and radial arm maze. RESULTS: UPLC-ESI-MS/MS analyses of plasma revealed significant absorption of unconjugated (free) curcuminoids upon both single and repeated dose administration of CGM with maximum concentrations of 173.34 ± 27.12 ng/mL and 223.22 ± 32.73 ng/mL, respectively. Further analysis of brain tissues demonstrated significant blood-brain-barrier permeability. Brain regional pharmacokinetics (AUC, Cmax and t1/2) indicated a relative distribution order of hippocampus > striatum > cerebellum > cerebral cortex > brain stem. Supplementation of CGM for 28 days also offered significant (p < 0.05) improvement in locomotor activity and reduction in spatial memory errors as compared to NC. The NC treatment also improved the behaviour better than the vehicle-treated group. CONCLUSION: CGM could distribute significant amount of free curcuminoids, in brain especially in the hippocampus at both single and repeated dose administration with an elimination half-life of 2.6 h. CGM also showed a positive impact in behaviour of animals in comparison with normal unformulated curcuminoids.

Natural self-emulsifying reversible hybrid-hydrogel delivery (N'SERH) of tocopherol enhances bioavailability and modulates alcohol-induced reproductive toxicity in rats.

Alpha-tocopherol (α-Toc), an antioxidant vitamin, has been widely prescribing in the treatment of infertility, in spite of its limited oral bioavailability. The present study describes the enhanced bioavailability and efficacy of a novel 'natural self-emulsifying reversible hydrogel' (N'SERH)-based oral delivery form of α-Toc-rich sunflower oil (Tα-fen) using fenugreek galactomannan hydrogel scaffold (hybrid-FENUMATTM ). Tα-fen was characterised by FTIR, SEM, TEM and DLS as a hybrid-hydrogel powder. The bioavailability study on thirty (n = 30) male Sprague Dawley rats randomised into two groups indicated 4.84-fold increase in the oral bioavailability when the formulation was provided at 15 mg/kg b. wt. of α-Toc by oral gavage. The efficacy study on 24 animals randomised into four groups as control, ethanol treated (4 mg/kg b. wt.), ethanol+unformulated, UTα (15 mg/kg b. wt.) and ethanol+formulation, Tα-fen (15 mg/kg b. wt.) revealed significant improvement (*p < 0.05) and reversal of alcohol-induced reproductive toxicity as evident from the enhanced sperm count, motility and viability parameters, testosterone levels, fructose content, and SDH activity and plasma antioxidant status among Tα-fen-treated rats, compared with unformulated, UTα-treated group. Histopathology further confirmed the reversal of the alterations in the testes morphology of Tα-fen-treated animals, indicating its promising potential in the treatment of reproductive health issues.

All trans retinoic acid modulates TNF-α and CYP2E1 pathways and enhances regression of ethanol-induced fibrosis markers in hepatocytes and HSCs in abstaining rodent model.

Context: Our previous studies showed that all trans retinoic acid (ATRA) ameliorates alcohol-induced toxicity. Hence, we evaluated the efficacy of ATRA and abstention in the regression of alcohol-induced hepatotoxicity. Materials and methods: After ethanol administration to rats for 90 days, the regression of alcohol-induced toxicity was studied by supplementing ATRA at a dose of 100 µg/kg body weight for 30 days. It was also compared with animals in abstention. Results and discussion: Ethanol administration enhanced oxidative stress, activated HSCs and increased collagen deposition. All these alterations were reversed to a certain extent by ATRA supplementation. Conclusions: ATRA had better efficacy than just abstention in reducing ethanol-induced toxicity. The mechanism might be downregulation of CYP2E1, leading to reduced oxidative stress in the hepatocytes and thus impeding NFκB activation, cytokine production, activation of HSC and resulting in the reduction of inflammation and remodelling of fibrosis by modulating MMP and TIMP.

Safety and Efficacy of Ferula asafoetida in Functional Dyspepsia: A Randomized, Double-Blinded, Placebo-Controlled Study.

Despite the availability of various synthetic drugs for the treatment of functional dyspepsia (FD), the side effects and their cost have always created a great interest in the search for novel natural alternatives for the management of gut disorders. The present contribution reports the safety and efficacy of the kitchen spice asafoetida (Ferula asafoetida) in FD for the first time. In the double-blinded, placebo-controlled study, 43 subjects diagnosed to have moderate to severe discomforts of nonulcer FD were randomized to receive hard-shell capsules (250 mg × 2/day) of either placebo (n=22) or a food-grade formulation of asafoetida (Asafin) (n=21) for 30 days. When evaluated by a set of validated indexing tools (GSRS, GDSS, and NDI), almost 81% in the Asafin group showed significant (p < 0.01) improvement in the overall score and quality of life as compared to the placebo. At the end of the study, 66% of subjects in the Asafin group remained symptoms-free. Although the symptoms score improved significantly in both the groups (from -5.67 to -25.29 in Asafin group versus -1.55 to -6.0 in the placebo; p ≤ 0.001), the relative percentage of subjects in the Asafin group with more than 80% reduction in various symptoms were: bloating (58%), appetite (69%), postprandial fullness (74%) motion sickness (75%), and digestion (77%) as compared to less than 10% nonspecific improvement in the placebo group. All the subjects remained safe with no adverse events or variations in haematological and biochemical parameters. The study was registered at http://ctri.nic.in/ (CTRI/2018/ 01/011149).

All Trans Retinoic Acid Attenuates Markers of Neuroinflammation in Rat Brain by Modulation of SIRT1 and NFκB.

Alcohol abuse affects several neurological pathways and causes significant alterations in the brain. Abstention from alcohol causes only a marginal decrease in oxidative stress and neuro inflammation. Our previous studies had shown that an active metabolite of vitamin A, all trans retinoic acid (ATRA), ameliorates alcohol induced toxicity. Hence in the present study we investigated whether ATRA regressed alcohol induced neuroinflammation. We focused on the role of silent mating type information regulation 2 homolog 1(SIRT1) and nuclear factor kappa-B (NFκB). Animals were administered with ethanol at a daily dose of (4 g/kg body weight) for 90 days. On the 91st day ethanol administration was stopped and animals were divided into ethanol abstention (A) and ATRA supplementation group (ATRA + A) (100 µg/kg body weight) and maintained for 30 days. Ethanol exposure increased markers of oxidative stress, inflammation and the activities of alcohol and acetaldehyde dehydrogenases and reduced the expression of SIRT1 in the whole brain.The ethanol induced altered expressions of NFκB and SIRT1 were modulated by supplementation of ATRA. Abstention also reduced toxicity, but to a lower extent in comparison with supplementation of ATRA. Our results seemed to suggest that ATRA regressed the mediators of ethanol induced neuroinflammation by reducing oxidative stress and by regulating the expression of NFκB and SIRT1. The ameliorative potential of ATRA was much higher than abstention.

Atorvastatin modulates drug transporters and ameliorates nicotine-induced testicular toxicity.

We studied the changes in mRNA expressions of influx and efflux transporters, blood-testis-barrier proteins (BTB) and key apoptotic genes in the testis of rats coadministered with nicotine and atorvastatin. Rats were divided into four groups: (i) control, (ii) atorvastatin (10 mg/kg b.wt), (iii) nicotine (0.6 mg/kg b.wt) and (iv) atorvastatin (10 mg/kg b.wt) + nicotine (0.6 mg/kg b.wt). Atorvastatin was given by oral intubation and nicotine by intraperitoneal injection. After 60 days of treatment, expressions of key apoptotic genes involved in both intrinsic and extrinsic pathways; solute carrier influx transporters SLCOB1, SLC22A1 and efflux transporter ABCB1 associated with transport of atorvastatin and nicotine, and proteins of BTB were assayed. Nicotine administration activated apoptosis and downregulated SLCOB1, which transport atorvastatin. Atorvastatin administration suppressed apoptotic pathway and downregulated SLC22A1, transporter of nicotine. Coadministration of atorvastatin with nicotine downregulated expressions of apoptotic genes. The combined administration of atorvastatin and nicotine reduced the influx of both atorvastatin and nicotine and enhanced the efflux of these drugs thereby altering the microenvironment of testis and improving testicular function. We conclude that atorvastatin-mediated alterations of BTB and drug transporters might have played a significant role in ameliorating nicotine-induced testicular toxicity.

All trans retinoic acid (ATRA) mediated modulation of N-methyl D-aspartate receptor (NMDAR) and Kruppel like factor 11 (KLF11) expressions in the mitigation of ethanol induced alterations in the brain.

BACKGROUND: Damaging effects that chronic ethanol exposure causes to the brain and the neurons are well documented. Ethanol and its toxic metabolites increase the oxidative stress in brain. Chronic exposure to ethanol leads to upregulation of N-methyl D-aspartate receptors (NMDAR) and also activates Kruppel like factor 11 (KLF11) mediated death cascade and thereby neurodegeneration. OBJECTIVE: Ethanol depletes vitamin A stores. But supplementation of vitamin A exacerbates ethanol induced toxicity since alcohol and its metabolites are competitive inhibitors of the enzymes involved in the metabolism of vitamin A. Hence, in this study we investigated the impact of co-administration of ethanol and all trans retinoic acid (ATRA), active metabolite of vitamin A, on ethanol induced alterations to the brain. MATERIALS AND METHODS: Male Sprague Dawley rats, adolescent, were grouped as follows and maintained for 90 days. I - Control, II - Ethanol (4 g/kg b.w.), III - ATRA (100 µg/kg b.w.), IV - Ethanol (4 g/kg b.w.), +ATRA (100 µg/kg b.w.). Oxidative stress and the mRNA expression of various receptors for the neurotransmitter involved in glutamergic, serotonergic and gabaergic pathways were studied in the brain homogenate. RESULTS: Ethanol treatment was shown to decrease brain weight and it was increased on ATRA treatment. Increase in oxidative stress due to ethanol treatment was also brought down on ATRA administration. Ethanol induced upregulation of NMDAR and KLF11 was also downregulated on ATRA supplementation. The alterations in the levels of neurotransmitters and the expression of their receptors due to ethanol treatment also were ameliorated on ATRA supplementation. CONCLUSION: Our results show that ATRA supplementation mitigates the ethanol induced alterations in the brain by reducing oxidative stress in the brain with concurrent suppression of NMDAR and KLF11 expression leading to enhanced catabolism of neurotransmitters.

Protective effect of ascorbic acid against ethanol-induced reproductive toxicity in male guinea pigs.

The present study was undertaken to elucidate the effect of ascorbic acid on alcohol-induced reproductive toxicity and also to compare it with that of abstention. A total of thirty-six male guinea pigs were divided into two groups and were maintained for 90 d as control and ethanol-treated groups (4 g/kg body weight (b.wt.)). After 90 d, ethanol administration was stopped and animals in the control group were divided into two groups and then maintained for 30 d as the control and control+ascorbic acid groups and those in the ethanol-treated group as ethanol abstention and ethanol+ascorbic acid (25 mg/100 g b. wt.) groups. Animals treated with ethanol showed a significant decline in sperm quality (P<0·001), decreased activity of steroidogenic enzymes (P<0·05) and reduced serum testosterone (P<0·05), luteinising hormone and follicle-stimulating hormone levels, decrease in the activity of testicular succinate dehydrogenase, adenosine triphosphatase, sorbitol dehydrogenase and reduction in fructose content (P<0·05). It also caused an increase in testicular malondialdehyde levels (P<0·05) and decrease in the levels of glutathione content (P<0·001) of testes. Ascorbic acid levels in testes and plasma were also reduced (P<0·001) in ethanol-fed animals. Ascorbic acid supplementation altered all these parameters and produced a better and faster recovery from alcohol-induced reproductive toxicity than abstention. The mechanism of action of ascorbic acid may be by reducing the oxidative stress and improving antioxidant status, which eventually changed the microenvironment of testes and enhanced the energy needed for motility of sperms, improved the sperm morphology and elevated the testosterone and gonadotropin levels.