Clinical Quickies (Jan-Feb-March 2024)

1. Randomized Controlled Data Shows That Antenatal Vitamin D Supplementation Can Likely Prevents Atopic Eczema In The Offspring
2. Could Oral Nicotinamide Ribose Supplementation Have A Role In Preventing Neurodegenerative Diseases?
3. Palmitoylethanolamide (PEA) May Be An Optional Acute Migraine Treatment
4. Red Light Treatment Seems To Reduce Blood Sugar Elevation After A Glucose Challenge 
5. Ketogenic Diet May Be Considered For Patients With Autosomal Dominant Polycystic Kidney Disease
6. Apple Cider Vinegar Seems to Help Weight Loss in Obese Young Adults
7. Psilocybin-Containing Mushroom Extracts Outperforms Synthetic Psilocybin in Mice Study
8. Pilot Study Shows That Bitter Ginger Improves Quality Of Life In Cancer Patients With No Treatment Options
9. Black Seed Cream Seems As Effective As Cortecosteroids Gel In Managing Oral Lichen Planus
10. Early Administration of Ginkgo Biloba Extract Improves Cognitive Function In Acute Ischemic Stroke Patients
11. Black Seed Cream May Help Diabetic Peripheral Neuropathy
12. Sunflower Seed Extract Helps Fat Loss In Obese Adults

1. Randomized Controlled Data Shows That Antenatal Vitamin D Supplementation Can Likely Prevents Atopic Eczema In The Offspring

BACKGROUND: Evidence linking prenatal maternal vitamin D supplementation with the offspring’s risk of atopic eczema is inconsistent, with most data coming from observational studies.

OBJECTIVES: To examine the influence of maternal cholecalciferol supplementation during pregnancy on the risk of atopic eczema in the offspring at ages 12, 24 and 48 months.

METHODS: Within the UK Maternal Vitamin D Osteoporosis Study (MAVIDOS) double-blind, randomized placebo-controlled trial, we examined the relationship of maternal vitamin D supplementation during pregnancy with offspring atopic eczema at ages 12, 24 and 48 months. In MAVIDOS, pregnant women were allocated to either cholecalciferol 1000 IU per day or matched placebo, taken from around 14 weeks’ gestation until delivery, with the primary outcome of neonatal whole-body bone mineral content. The prevalence of atopic eczema in the offspring was ascertained at ages 12 (n = 635), 24 (n = 610) and 48 (n = 449) months, based on the UK Working Party criteria for the definition of atopic dermatitis. The trial was registered with ISRCTN (82927713) and EudraCT (2007-001716-23).

RESULTS: The characteristics of mothers and offspring were similar between the intervention and placebo groups, apart from longer breastfeeding duration in the intervention group. Adjusting for breastfeeding duration, offspring of mothers who received cholecalciferol 1000 IU daily had a lower odds ratio (OR) of atopic eczema at age 12 months [OR 0·55, 95% confidence interval (CI) 0·32-0·97, P = 0·04]; this effect weakened and was not statistically significant at ages 24 months (OR 0·76, 95% CI 0·47-1·23) or 48 months (OR 0·75, 95% CI 0·37-1·52). The statistical interaction of intervention and breastfeeding duration in relation to eczema at age 12 months was not significant (P = 0·41), but stratification showed reduced infantile eczema risk in the intervention group for infants breastfed for ≥ 1 month (OR 0·48, 95% CI 0·24-0·94, P = 0·03) but not in those breastfed for < 1 month (OR 0·80, 95% CI 0·29-2·17, P = 0·66).

CONCLUSIONS: Our data provide the first randomized controlled trial evidence of a protective effect of antenatal cholecalciferol supplementation on the risk of infantile atopic eczema, with the effect potentially being via increased breast milk cholecalciferol levels. The findings support a developmental influence on atopic eczema, and point to a potentially modifiable perinatal influence on atopic eczema. What is already known about this topic? There are currently no antenatal interventions proven to reduce the incidence of infantile atopic eczema in the general population. However, observational studies have led to speculation that antenatal vitamin D supplementation may be beneficial.

El-Heis S, et al. Maternal antenatal vitamin D supplementation and offspring risk of atopic eczema in the first 4 years of life: evidence from a randomized controlled trial. Br J Dermatol. 2022 Nov;187(5):659-666. doi: 10.1111/bjd.21721. Epub 2022 Aug 3.

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2. Could Oral Nicotinamide Ribose Supplementation Have A Role In Preventing Neurodegenerative Diseases?

ABSTRACT: Declining nicotinamide adenine dinucleotide (NAD+ ) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. Experimental therapies aimed at boosting brain NAD+ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD+ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD+ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD+ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD+ levels in NEVs and decreases NEV levels of Aβ42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin-Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood-based window into monitoring the physiologic response of NR in the brain.

Vreones M, et al. Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. Aging Cell. 2023 Jan;22(1):e13754. doi: 10.1111/acel.13754. Epub 2022 Dec 14.

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3. Palmitoylethanolamide (PEA) May Be An Optional Acute Migraine Treatment

ABSTRACT: Migraines are a common neurological disorder that generally affects young to middle-aged adults and females more than males. Various treatment options are available; however, these can cause undesirable side effects. Therefore, alternative treatments with minimal side effects are still being investigated. Palmitoylethanolamide (PEA) is a signalling lipid known to have anti-inflammatory and analgesic properties. Previous prophylactic research has reported PEA supplementation to decrease pain associated with migraines. Upon commencement of migraine symptoms, participants were supplemented with either 600 mg of PEA (Levagen+) or a placebo (maltodextrin). Once a dose was taken, participants recorded a visual analogue scale (VAS) for pain every 30 min for 4 h or until the migraine resolved. If the migraine had not resolved 2 h post-dose, participants were instructed to take a second dose. Levagen+ supplementation resolved more headaches after 2- and 8 h, had a lower VAS for pain score at 1.5 and 4 h, and reduced rescue medication use significantly more than a placebo. No adverse events were reported in either group. Overall, PEA was safe and effective in reducing migraine pain, duration, and medication use in an otherwise healthy adult population.

Briskey D, et al. Effectiveness of Palmitoylethanolamide (Levagen+) Compared to a Placebo for Reducing Pain, Duration, and Medication Use during Migraines in Otherwise Healthy Participants-A Double-Blind Randomised Controlled Study. Pharmaceuticals (Basel). 2024 Jan 23;17(2):145. doi: 10.3390/ph17020145.

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4. Red Light Treatment Seems To Reduce Blood Sugar Elevation After A Glucose Challenge 

ABSTRACT: Mitochondria regulate metabolism, but solar light influences its rate. Photobiomodulation (PBM) with red light (670 nm) increases mitochondrial membrane potentials and adenosine triphosphate production and may increase glucose demand. Here we show, with a glucose tolerance test, that PBM of normal subjects significantly reduces blood sugar levels. A 15 min exposure to 670 nm light reduced the degree of blood glucose elevation following glucose intake by 27.7%, integrated over 2 h after the glucose challenge. Maximum glucose spiking was reduced by 7.5%. Consequently, PBM with 670 nm light can be used to reduce blood glucose spikes following meals. This intervention may reduce damaging fluctuations of blood glucose on the body.

Powner MB, Jeffery G. Light stimulation of mitochondria reduces blood glucose levels. J Biophotonics. 2024 Feb 20:e202300521. doi: 10.1002/jbio.202300521. Online ahead of print.

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5. Ketogenic Diet May Be Considered For Patients With Autosomal Dominant Polycystic Kidney Disease

ABSTRACT: Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized, controlled trial, is intended to provide clinical translation of these findings (NCT04680780). Sixty-six patients were randomized to a KDI arm (ketogenic diet [KD] or water fasting [WF]) or the control group. Both interventions induce significant ketogenesis on the basis of blood and breath acetone measurements. Ninety-five percent (KD) and 85% (WF) report the diet as feasible. KD leads to significant reductions in body fat and liver volume. Additionally, KD is associated with reduced kidney volume (not reaching statistical significance). Interestingly, the KD group exhibits improved kidney function at the end of treatment, while the control and WF groups show a progressive decline, as is typical in ADPKD. Safety-relevant events are largely mild, expected (initial flu-like symptoms associated with KD), and transient. Safety assessment is complemented by nuclear magnetic resonance (NMR) lipid profile analyses.

Cukoski S, et al. Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD-a randomized controlled trial. Cell Rep Med. 2023 Nov 21;4(11):101283. doi: 10.1016/j.xcrm.2023.101283. Epub 2023 Nov 7.

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6. Apple Cider Vinegar Seems to Help Weight Loss in Obese Young Adults

BACKGROUND AND AIMS: Obesity and overweight have become significant health concerns worldwide, leading to an increased interest in finding natural remedies for weight reduction. One such remedy that has gained popularity is apple cider vinegar (ACV).

OBJECTIVE: To investigate the effects of ACV consumption on weight, blood glucose, triglyceride and cholesterol levels in a sample of the Lebanese population.

MATERIALS AND METHODS: 120 overweight and obese individuals were recruited. Participants were randomly assigned to either an intervention group receiving 5, 10 or 15 mL of ACV or a control group receiving a placebo (group 4) over a 12-week period. Measurements of anthropometric parameters, fasting blood glucose, triglyceride and cholesterol levels were taken at weeks 0, 4, 8 and 12.

RESULTS: Our findings showed that daily consumption of the three doses of ACV for a duration of between 4 and 12 weeks is associated with significant reductions in anthropometric variables (weight, body mass index, waist/hip circumferences and body fat ratio), blood glucose, triglyceride and cholesterol levels. No significant risk factors were observed during the 12 weeks of ACV intake.

CONCLUSION: Consumption of ACV in people with overweight and obesity led to an improvement in the anthropometric and metabolic parameters. ACV could be a promising antiobesity supplement that does not produce any side effects.

Abou-Khalil R, et al. Apple cider vinegar for weight management in Lebanese adolescents and young adults with overweight and obesity: a randomised, double-blind, placebo-controlled study. BMJ Nutrition, Prevention & Health 2024;e000823. doi: 10.1136/bmjnph-2023-000823

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7. Psilocybin-Containing Mushroom Extracts Outperforms Synthetic Psilocybin in Mice Study

ABSTRACT: Psilocybin, a naturally occurring, tryptamine alkaloid prodrug, is currently being investigated for the treatment of a range of psychiatric disorders. Preclinical reports suggest that the biological effects of psilocybin-containing mushroom extract or “full spectrum” (psychedelic) mushroom extract (PME), may differ from those of chemically synthesized psilocybin (PSIL). We compared the effects of PME to those of PSIL on the head twitch response (HTR), neuroplasticity-related synaptic proteins and frontal cortex metabolomic profiles in male C57Bl/6j mice. HTR measurement showed similar effects of PSIL and PME over 20 min.

Brain specimens (frontal cortex, hippocampus, amygdala, striatum) were assayed for the synaptic proteins, GAP43, PSD95, synaptophysin and SV2A, using western blots. These proteins may serve as indicators of synaptic plasticity. Three days after treatment, there was minimal increase in synaptic proteins. After 11 days, PSIL and PME significantly increased GAP43 in the frontal cortex (p = 0.019; p = 0.039 respectively) and hippocampus (p = 0.015; p = 0.027) and synaptophysin in the hippocampus (p = 0.041; p = 0.05) and amygdala (p = 0.035; p = 0.004). PSIL increased SV2A in the amygdala (p = 0.036) and PME did so in the hippocampus (p = 0.014). In the striatum, synaptophysin was increased by PME only (p = 0.023). There were no significant effects of PSIL or PME on PSD95 in any brain area when these were analyzed separately.

Nested analysis of variance (ANOVA) showed a significant increase in each of the 4 proteins over all brain areas for PME versus vehicle control, while significant PSIL effects were observed only in the hippocampus and amygdala and were limited to PSD95 and SV2A. Metabolomic analyses of the pre-frontal cortex were performed by untargeted polar metabolomics utilizing capillary electrophoresis – Fourier transform mass spectrometry (CE-FTMS) and showed a differential metabolic separation between PME and vehicle groups.

The purines guanosine, hypoxanthine and inosine, associated with oxidative stress and energy production pathways, showed a progressive decline from VEH to PSIL to PME. In conclusion, our synaptic protein findings suggest that PME has a more potent and prolonged effect on synaptic plasticity than PSIL. Our metabolomics data support a gradient of effects from inert vehicle via chemical psilocybin to PME further supporting differential effects. Further studies are needed to confirm and extend these findings and to identify the molecules that may be responsible for the enhanced effects of PME as compared to psilocybin alone.

Shahar O, et al. Effect of chemically synthesized psilocybin and psychedelic mushroom extract on molecular and metabolic profiles in mouse brain. Mol Psychiatry. 2024 Feb 20. doi: 10.1038/s41380-024-02477-w. Online ahead of print.

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8. Pilot Study Shows That Bitter Ginger Improves Quality Of Life In Cancer Patients With No Treatment Options

INTRODUCTION: Zerumbone is a natural compound found in bitter ginger plants (Zingiber zerumbet) that shows antiproliferative, antioxidant, anti-inflammatory, and analgesic properties. We aimed to investigate the role of zerumbone in improving the quality of life and symptom control in cancer patients with no treatment options.

METHODS: We conducted a pilot, non-randomized, single-center, open prospective, and systematic study on the use of 400 mg of zerumbone twice a day.

RESULTS: The study included 35 patients (mean age, 68 years; 64% men), of which 16 completed the eight-week study. The intention-to-treat population showed no significant changes in weight or sleep quality over the eight-week study. Assessments performed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) showed significant improvements in the quality of life in the global (p = 0.072), activity (p = 0.0393), social (p = 0.0001), and emotional (p = 0.0023) dimensions. The Hospital Anxiety and Depression Scale (HADS) questionnaire scores showed significant improvement in anxiety (p = 0.032) and depression (p = 0.021), while the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire scores also indicated a significant improvement (p = 0.001). Bitter ginger showed low toxicity.

CONCLUSIONS: Bitter ginger showed promising results in improving the quality of life and reducing symptoms of anxiety and depression in the study population. A randomized placebo-controlled study is necessary to confirm these results. This trial was registered under the number FMABC: CAAE – 93459418.00000082, at ISRCTN (BIOMED CENTRAL) NUMBER 4388 (03/07/23) and at Plataforma Brasil (https://plataformabrasil.saude.gov.br/login.jsf).

Vieira de Queiroz L, et al. Bitter ginger (Zingiber zerumbet) for patients with solid tumors with no treatment options: A pilot clinical study. Complement Ther Med. 2024 Mar:80:103021. doi: 10.1016/j.ctim.2024.103021. Epub 2024 Jan 8.

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9. Black Seed Cream Seems As Effective As Cortecosteroids Gel In Managing Oral Lichen Planus

OBJECTIVES: The aim of this study is to evaluate and compare the efficacy of Nigella sativa (75% v/v) cream and clobetasol propionate (0.05% w/w) gel for the management of oral lichen planus (OLP).

STUDY DESIGN: Sixty clinically diagnosed cases of OLP were stratified into moderate cases or severe cases based on burning sensation before getting allocated to group I receiving Nigella sativa cream and group II receiving clobetasol propionate gel, two times a day for 45 days. Patients were examined every 15 days for a change in burning sensation and size of the lesion using the numeric pain rating scale (NRS) and a standard Vernier caliper, respectively. Statistical tests including Mann-Whitney U, Wilcoxon signed-rank, Friedman’s, Dunn’s post hoc, unpaired t, paired t, one-way repeated measures ANOVA, and Bonferroni’s post hoc were applied.

RESULTS: There was a statistically significant reduction in the burning sensation as well as the size of the lesion in both groups (P ≤ 0.05). There was an 87.8% (moderate cases) and 85.7% (severe cases) reduction in the mean NRS scores on the 45th day in group I when compared to the 96.5% (moderate cases) and 93.48% (severe cases) in group II. There was a 92.9% (moderate cases) and 90.7% (severe cases) reduction in the size of the lesion in group I when compared to the 92.6% (moderate cases) and 93.1% (severe cases) in group II.

CONCLUSION: The topical application of Nigella sativa cream was effective and comparable to clobetasol propionate 0.05% gel in the management of OLP, without any side effects. Hence, this study recommends the use of topical Nigella sativa cream therapy in the management of OLP.

CLINICAL RELEVANCE: The current mainstay of treatment for OLP is the administration of topical or systemic corticosteroids, which are known to cause side effects, demanding a search for an alternative. Nigella sativa oil cream could be a safe, promising, cost-effective, adjunctive, or alternative modality. Clinical trial registration number: CTRI/2020/07/026745 (India).

Kumar S L, et al. Comparative evaluation of the efficacy of Nigella sativa (75% v/v) cream and clobetasol propionate (0.05% w/w) gel in oral lichen planus-a double-blinded randomized control trial. Oral Maxillofac Surg. 2024 Mar;28(1):225-234. doi: 10.1007/s10006-022-01130-6. Epub 2022 Dec 22.

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10. Early Administration of Ginkgo Biloba Extract Improves Cognitive Function In Acute Ischemic Stroke Patients

BACKGROUND: Ginkgo diterpene lactone meglumine (GDLM) could improve the functional outcome in patients with acute ischemic stroke (AIS). This study aimed to investigate the efficacy of GDLM on cognitive function in patients with AIS.

METHODS: This is a predefined exploratory analysis of the Efficacy and Safety of Ginkgo Diterpene Lactone Meglumine in Acute Ischemic Stroke trial, which was primarily designed to investigate the efficacy and safety of GDLM versus placebo on functional outcome at 100 centers in China. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) test. The primary outcomes were changes of MoCA from baseline to Day 14 and Day 90 after randomization.

RESULTS: A total of 3163 patients with completed data on MoCA were enrolled. There was statistically significant difference of changes in MoCA scores between the GDLM group and the placebo group from baseline to Day 14 (mean difference, 0.31; 95% confidence interval [CI], 0.08-0.53; P = 0.007) and to Day 90 after randomization (mean difference, 0.47; 95% CI, 0.22-0.72; P < 0.001). Additionally, GDLM was associated with a higher proportion of patients who reached a clinically significant level of improvement in MoCA from baseline to Day 14 (odds ratio [OR], 1.25; 95% CI, 1.08-1.44; P = 0.002) and Day 90 after randomization (OR, 1.21; 95% CI, 1.03-1.41; P = 0.02). Specially, GDLM could significantly improve the scores of visuo-spatial and executive function and language.

CONCLUSIONS: In this predefined analysis of patients with AIS, GDLM could improve the 14-day and 90-day cognitive function compared with the placebo.

Tian X, et al. Efficacy of ginkgo diterpene lactone meglumine on cognitive function in patients with acute ischemic stroke: a predefined exploratory analysis of a multicenter, double-blind, randomized controlled trial. J Neurol. 2024 Mar 12. doi: 10.1007/s00415-024-12272-w. Online ahead of print.

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11. Black Seed Cream May Help Diabetic Peripheral Neuropathy

BACKGROUND: Diabetic neuropathy is one of the most common complications of diabetes. The synthetic drugs available in the market have side effects and limitations for diabetic patients, the vast majority of whom are in the upper age group. In this regard, based on Persian medicinal sources, Nigella sativa (N. sativa) has proved to have beneficial effects on neuropathic pain and neurological disorders. In this study, the effect of N. sativa is investigated topically in patients with diabetic neuropathy.

METHODS: This study was performed as a double-blind clinical trial on 120 neuropathic patients. The patients were divided into three groups. The first group received a topical N. sativa product as an ointment, the second group was given a topical placebo, and the third received 300 mg gabapentin capsules. The blindness was done in first and second groups. Diabetic neuropathy was assessed before the study using the Michigan Neuropathy Screening Instrument (MNSI). In addition, neuropathy symptoms were evaluated after the trial using the MNSI questionnaire.

RESULTS: The data were elicited from the patients’ answers to a number of questions in the Michigan questionnaire. There were statistically significant differences between the group that received the topical N. sativa product and the other two groups in terms of legs and feet numbness (p value = 0.001), burning pain in feet or legs (p value = 0.001), muscle cramps in feet or legs (p value = 0.001), prickling fleeing in feet or legs (p value = 0.001), hurting of the skin when the bed covers touch it (p value = 0.005), aggravated symptoms at night (p value = 0.001) and hurting feelings in the legs when walking (p value = 0.032). However, the three studied groups were not statistically different in distinguishing hot water from cold water.

CONCLUSION: According to the results of this study, the topical use of N. sativa, compared to the current drugs, has acceptable improving effects on diabetic neuropathic patients. 

Khodaie SA, et al. Topical Nigella sativa L. product: a new candidate for the management of diabetic peripheral neuropathy. Inflammopharmacology. 2024 Feb;32(1):551-559.doi: 10.1007/s10787-023-01338-2. Epub 2023 Nov 13.

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12. Sunflower Seed Extract Helps Fat Loss In Obese Adults

ABSTRACT: Obesity is an important public health problem and socioeconomic burden. We hypothesized that an intake of sunflower seed extract (SUN-CA) would decrease body fat and then investigated the effects and safety of SUN-CA intake on body fat in adults with obesity as an option for obesity treatment.

In this double-blind, randomized, placebo-controlled study, 100 adults with body mass indices of 25 to 31.9 kg/m2 were assigned to groups that received SUN-CA (n = 50) or a placebo (n = 50) and received 1 tablet/day containing 500 mg of SUN-CA or the placebo over a 12-week period. The primary endpoint was the change in mass and percentage of body fat. The group that received SUN-CA daily showed decreases in body fat mass greater than those in the placebo group (-0.9 ± 1.8 kg vs. -0.1 ± 1.4 kg, P = .043). In addition, body weight, body mass index, and hip circumference improved after the intake of SUN-CA relative to the changes in the placebo group. There was no intergroup differences in the prevalence of adverse events.

The accumulation of excess body fat improved through the intake of 500 mg/day of SUN-CA containing 100 mg of chlorogenic acids for 12 weeks in adults with obesity without causing serious adverse side effects. SUN-CA could be an effective and safe management option for obesity. The trial was registered at Clinical Research Information Service (CRIS: https://cris.nih.go.kr/cris/index/index.do) as KCT0005733.

Kim HN, et al. Sunflower seed extract supplementation reduces body fat in adults with obesity: A double-blind, randomized, placebo-controlled trial. Nutr Res. 2024 Feb:122:113-122. doi: 10.1016/j.nutres.2023.12.004. Epub 2023 Dec 17.

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