Citrus aurantium (Bitter Orange)

Background and purposeOverweight and obesity are critical public health issues linked to chronic diseases such as type 2 diabetes and cardiovascular conditions. Moro orange juice extract has emerged as an alternative for promoting weight loss and improving body composition among overweight adults. Therefore, we conducted a systematic review and meta-analysis to evaluate its effectiveness and potential role in obesity management.AimTo evaluate the effectiveness of Moro orange juice extract supplementation on weight-related outcomes in overweight and obese adults.MethodsWe systematically searched PubMed, Embase, and Cochrane for randomized controlled trials (RCTs) comparing Moro orange juice extract with placebo in overweight adults. Our primary outcomes were changes in body weight and body mass index (BMI). Secondary outcomes included waist circumference, fat mass, and lean mass.ResultsThree RCTs involving 252 participants were included in our analysis. The extract significantly reduced body weight (mean difference (MD) -2.08 kg; 95% confidence interval (CI) -3.50, -0.67; I2 = 0%; p < 0.01) and fat mass (MD -1.53 kg; 95% CI -2.92, -0.15; I2 = 0%; p = 0.03), the pooled analysis of waist circumference presented heterogeneous point estimates (MD -3.25 kg; 95% CI -6.44, -0.07; I2 = 99%; p = 0.05). No significant effects were observed on lean mass.ConclusionMoro orange juice extract may result in weight and fat mass reduction in overweight and obese adults. However, additional research is needed to determine the optimal dosage, duration of supplementation, and underlying mechanisms.

The recovery and reuse of agro-industrial by-products (AIBP) in livestock feeding fully align with the goals set by the European Union, aimed at achieving climate neutrality by 2050. The literature contains many studies related to the inclusion of these products in ruminant diets, with particular interest in those rich in bioactive substances, such as polyphenols, which can provide various benefits to both animals and productions. However, the reported results, particularly regarding milk production and quality, are highly variable, depending on numerous factors such as species, inclusion level, polyphenol dose, other diet ingredients etc. The objective of this study was to evaluate the effects of dietary supplementation with AIBP rich in polyphenols on milk production and composition, and fatty acid profile in dairy sheep and goat. The systematic search was conducted using Scopus, Web of Science, and PubMed databases. Only studies with sheep and goat were included. The data analysed were extracted from 41 scientific papers and the considered AIBP came from grape, olive, tomato, citrus, cocoa and coffee processing. The effects of AIBP were analysed using random-effects statistical models to examine the standardised mean difference between AIBP and control treatment. The heterogeneity was then explored by a meta-regression. A meta-regression was also used to test the effect of the dosage of polyphenols in the diet (g of polyphenols/kg of diet). A test for subgroup differences was carried out through a meta-analysis considering the by-product type. Supplementation with AIBP did not affect the milk yield either in sheep and goat. Supplementation with AIBP in sheep diet led to an increase in monounsaturated fatty acids (MUFA), oleic acid (OA, C18:1cis-9), vaccenic acid (VA, C18:1trans-11), and to a decrease in saturated fatty acids (SFA). Polyunsaturated fatty acids (PUFA), PUFA n-3, VA, and linolenic acid (C18:3 n3) increased in response to the dosage of polyphenols in sheep diet. In goat, the inclusion of by-products in the diet led to a decrease in SFA and an increase in MUFA, VA, LNA, and rumenic acid (RA, C18:2cis-9,trans-11), while the dosage was never signifi

The present systematic review and dose-response meta-analysis was conducted to synthesize existing data from randomized clinical trials (RCTs) concerning the impact of citrus flavonoids supplementation (CFS) on endothelial function. Relevant RCTs were identified through comprehensive searches of the PubMed, ISI Web of Science, and Scopus databases up to May 30, 2023. Weighted mean differences and their corresponding 95% confidence intervals (CI) were pooled utilizing a random-effects model. A total of eight eligible RCTs, comprising 596 participants, were included in the analysis. The pooled data demonstrated a statistically significant augmentation in flow-mediated vasodilation (FMD) (2.75%; 95% CI: 1.29, 4.20; I2 = 87.3%; p < 0.001) associated with CFS compared to the placebo group. Furthermore, the linear dose-response analysis indicated that each increment of 200 mg/d in CFS led to an increase of 1.09% in FMD (95% CI: 0.70, 1.48; I2 = 94.5%; p < 0.001). The findings from the nonlinear dose-response analysis also revealed a linear relationship between CFS and FMD (Pnon-linearity = 0.903, Pdose-response <0.001). Our findings suggest that CFS enhances endothelial function. However, more extensive RTCs encompassing longer intervention durations and different populations are warranted to establish more precise conclusions. © 2024 John Wiley & Sons Ltd.

Dyslipidaemia is a metabolic anomaly which has been related to numerous morbidities. Orange juice (OJ) is a popular flavonoid-rich drink consumed worldwide. Due to the existing controversies regarding its impact on blood lipids, we decided to investigate the impact of OJ supplementation on lipid profile parameters. Major scientific databases (Cochrane library, Scopus, PubMed and Embase) were searched. Pooled effects sizes were reported as weighted mean difference (WMD) and 95 % confidence intervals (CIs). Out of 6334 articles retrieved by the initial search, 9 articles met our inclusion criteria. Overall, supplementation with OJ did not exert any significant effects on blood levels of TG (WMD -1·53 mg/dl, 95 % CI -6·39, 3·32, P = 0·536), TC (WMD -5·91 mg/dl, 95 % CI -13·26, 1·43, P = 0·114) or HDL-C (WMD 0·61 mg/ dl, 95 % CI -0·61, 1·82, P = 0·333). OJ consumption did reduce LDL-C levels significantly (WMD -8·35 mg/dl, 95 % CI -15·43, -1·26, P = 0·021). Overall, we showed that the consumption of OJ may not be beneficial in improving serum levels of TG, TC or HDL-C. Contrarily, we showed that daily intake of OJ, especially more than 500 ml/d, might be effective in reducing LDL-C levels. In the light of the existing inconsistencies, we propose that further high-quality interventions be conducted in order to make a solid conclusion. © The Author(s) 2023.

Fruits, flowers, leaves, essential oils, hydrosols, and juices of citrus spp. Are utilized to prepare various forms of food products. Along with their nutritional values, in the health industry, different parts of the plants of the citrus genus have been used as supplements or remedies to prevent or control diseases. This review focused on reported meta-analyses and clinical trials on the health benefits of citrus plants as functional foods. Also, chemical compounds of various citrus species were reviewed. The following information sources were used for data collection: Google Scholar, the Web of Science, Scopus, and PubMed. Various keywords, including "citrus AND chemical compounds," "citrus AND phytochemicals," "citrus species," "citrus AND meta-analysis," "nutritional and therapeutical values of citrus spp.," "clinical trials AND citrus," "clinical trials AND Rutaceae," "health benefits of citrus spp.," "citrus edible or non-edible applications," and scientific names of the citrus plants were utilized to collect data for the review. The scientific name and common name of all twenty-eight citrus species, along with any of the above keywords, were also searched in the mentioned databases. Scientific papers and data sources were sought to review and discuss the citrus plant's nutritional and therapeutic importance. Several meta-analyses and clinical trials have reported beneficial effects of citrus spices on a variety of cancer risks, cardiovascular risk factors, neurologic disorders, urinary tract conditions, and gastrointestinal tract conditions. They have shown anxiolytic, antimicrobial, and pain-alleviating effects. Some of them can be helpful in managing obesity and cardiovascular risk factors.

Synephrine has been used to promote weight loss; however, its safety and efficacy have not been fully established. The goals of our study were to give an overview of the safety and efficacy of p-synephrine, to systematically evaluate its efficacy regarding weight loss and to assess its safety, focusing on its cardiovascular side effects in a meta-analysis. PubMed, the Cochrane Library, Web of Science and Embase were searched for relevant studies. Only placebo-controlled, human clinical trials with synephrine intervention were included in the meta-analysis. The meta-analysis was reported according to the PRISMA guidelines using the PICOS format and taking into account the CONSORT recommendations. Altogether, 18 articles were included in the meta-analysis. Both systolic and diastolic blood pressure (DBP) increased significantly after prolonged use (6.37 mmHg, 95% CI: 1.02-11.72, p = 0.02 and 4.33 mmHg, 95% CI: 0.48-8.18, p = 0.03, respectively). The weight loss in the synephrine group was non-significant after prolonged treatment, and it did not influence body composition parameters. Based on the analyzed clinical studies, synephrine tends to raise blood pressure and heart rate, and there is no evidence that synephrine can facilitate weight loss. Further studies are needed to confirm evidence of its safety and efficacy.

Hesperidin is a prominent flavanone found in citrus fruits that has a broad range of biological effects, including anti-inflammatory and antioxidant capabilities. The study's objective was to evaluate the effects of hesperidin supplementation on anti-inflammatory and antioxidant parameters such as MDA, TAC, GSH, SOD, and CAT; CRP, TNF-α, IL-6, and IL-4 levels respectively, by analyzing human intervention trials. Google Scholar, PubMed, grey literature databases, and the ClinicalTrials website were scanned to identify eligible studies. For the meta-analysis, eighteen studies were chosen. Hesperidin supplementation had significant lowering effect on not only CRP, IL-6, and IL-4 levels but also MDA level (Meta-regression analysis revealed a non-significant direct relationship between hesperidin dosage and chance in CRP, IL-6, and MDA levels. As a result, it can be said that hesperidin supplementation contributes to the inflammatory and antioxidant response, but this contribution is independent of dosage.

OBJECTIVES: The cognitive-protective effects related to the consumption of a variety of fruits are supported by several intervention studies. This systematic review and meta-analysis compared the magnitude of effects following chronic (≥1 week) consumption of frozen, freeze-dried powder including extracts and juices of fruits, covering berries, cherries and citrus, on cognition and mood in adults. METHODS: PubMed, Web of Science, Scopus, and psycARTICLES were searched from inception until February, 2021. Inclusion criteria were randomised controlled trials assessing memory, executive function, psychomotor speed, mood and mini mental state examination in adult participants ≥18 years of age. Cognition was tested by global or domain specific tasks. RESULTS: Out of 13,861 articles identified, 16 papers were included; 11 studies provided suitable data for meta-analysis. Fourteen studies reported improvement or trend for improvement in cognition, five studies assessed mood and one study supplementing grape juice found trend for mood improvement. From the meta-analysis, cherry juice supplementation was suggested to improve psychomotor speed by -0.37 of standardised mean difference (95% CI [-0.74, 0.01]) in reaction time (P = 0.05). CONCLUSIONS: The meta-analysis did not sufficiently support a role for fruits or fruit forms to improve cognition and mood. © 2022. The Author(s).

Previous investigations exploring the effects of orange juice (OJ) as a nutrient-dense beverage on cardiovascular risk factors were inconsistent. We aimed to conduct a systematic review and meta-analysis of randomized controlled clinical trials to determine the effectiveness of OJ intake on major cardiometabolic markers including anthropometric indices, blood pressure, lipid profile, inflammation, and glycemic control markers. PubMed, Scopus, and ISI Web of Science were searched from inception until January 2021. Fifteen eligible trials with 639 participants were included in the present study. The meta-analysis showed that OJ intake significantly reduces circulating total cholesterol levels (10 trials; weighted mean difference [WMD] = -6.84 mg/dl; 95% CI: -12.38 to -1.29; p = .01) and homeostatic model assessment for insulin resistance (four trials; WMD = -0.39, 95% CI: -0.77 to -0.006; p = .04) compared to control group. The analyses failed to reveal a significant effect of OJ intake on other cardiometabolic risk factors (p > .05). This review suggests that the intake of OJ might be associated with improved serum total cholesterol and insulin sensitivity. Due to low-to-moderate quality of meta-evidence, our results must be interpreted with caution and more well-designed studies are still needed to confirm the current findings. © 2021 John Wiley & Sons Ltd.

BACKGROUND: The current evidence-base regarding the effect of hesperidin (a flavanone found in citrus fruits) on body composition is equivocal. OBJECTIVE: We conducted a meta-analysis on the effect of orange juice and/or hesperidin supplementation on anthropometric measures in randomized controlled trials (RCTs). MATERIALS AND METHODS: A systematic search of PubMed and Scopus was performed up to February 2020. The overall estimates and their 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Eleven eligible RCTs, with 512 individuals, were included in this study. The meta-analysis showed that orange juice and/or hesperidin had no significant effect on body weight [weighted mean difference (WMD) = -0.31 kg; 95% CI, -1.44 to 0.82, P = 0.592], body mass index [WMD = 0.11 kg/m2; 95% CI, -0.33 to 0.56, P = 0.617], fat mass [WMD = 0.14 kg; 95% CI, -0.95 to 1.22, P = 0.807], percentage body fat [WMD = -0.70%; 95% CI, -2.58 to 1.18, P = 0.463] and waist circumference [WMD = 0.07 cm; 95% CI, -1.16 to 1.30, P = 0.588]. CONCLUSION: The present study revealed that there is no significant beneficial effect of orange juice and/or hesperidin supplementation on anthropometric measures. The authors advocate that more high-quality clinical trials are needed to better discern the potential efficacy of orange juice and/or hesperidin.

The impact of fruit juices on postprandial glucose response (PPGR) remains controversial due to their free sugar content. The aim of this study was to investigate the effect of the fruit matrix in 100% orange juice (OJ) on PPGR. In this randomized crossover trial, we compared the intake of 300 mL of 100% OJ to sugar-matched drinks with reduced (50% OJ) or no (0% OJ) fruit matrix and a glucose control (25 g sugar) in healthy young males. We characterised the juices for nutrients and (poly)phenols and measured glucose and insulin over 2 hours. We also analysed interindividual variability and performed a post-hoc cluster analysis of the participants based on the different responses to the drinks. Metabolomics was used to further explore plasma differences between clusters. Differences in incremental area under the curve (iAUC) with the 100% OJ and 50% OJ against the 0% OJ did not reach significance, but the 100% OJ significantly lowered the glucose peak (Cmax) compared to 0% OJ and reduced glucose levels at 15 minutes (C15 min) compared to 50% OJ and 0% OJ. High interindividual variability was expressed as 'high responders' with larger differences in Cmax between 100% OJ and 0% OJ than 'low responders' as well as differences in the 60 min plasma metabolomes, particularly in OJ-derived metabolites like dihydroferulic acid glucuronide. The OJ fruit matrix attenuates postprandial glucose peaks and rate of glucose rise in healthy young males. The occurrence of responder groups with differentiated plasma metabolomes underscores the importance of considering both the food matrix and individual physiological differences when assessing the glycemic impact of fruit juices.

Grapefruit juice (GFJ) is a known inhibitor of intestinal cytochrome P450 3A (CYP3A) metabolism leading to increased exposure to CYP3A substrates such as tacrolimus. The extended-release tacrolimus formulation Envarsus (LCPT) exhibits prolonged absorption throughout the entire GI tract. Although a clinically significant drug-drug interaction occurs with immediate-release tacrolimus formulations, this has not been evaluated with extended-release formulations. This study assessed the impact of GFJ on LCPT in adult kidney transplant patients. Eleven adult kidney transplant recipients on a stable dose of LCPT were enrolled in a randomized crossover study. Participants were administered either GFJ or water during each pharmacokinetic visit, with midazolam used as a positive control. A washout period of 2-4 weeks was included between visits. Tacrolimus concentrations were determined using validated LC-MS/MS methods. Tacrolimus AUC0-24 was 28% higher with GFJ (GMR = 1.28, 90% CI 1.12-1.44) and Cmax was 73% higher (GMR = 1.73, 90% CI 1.46-2.00) compared to control. GFJ exhibited a clinically meaningful interaction with LCPT. However, the magnitude appears less than those reported with immediate-release formulations, suggesting the extended absorption profile of LCPT may affect susceptibility to drug interactions in the intestine. © 2026 The Author(s). Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

BACKGROUND: Recurrent urolithiasis is a major clinical challenge, with more than 50% of patients experiencing recurrence within 5 years. While potassium citrate effectively reduces recurrence, poor adherence due to cost and gastrointestinal side effects limits its long-term use. Citrus-based interventions, such as lime juice, have shown potential in enhancing urinary citrate and alkalinity but require further validation. This study evaluated the efficacy of a lime-based phytochemical-rich regimen (LPR) in preventing stone recurrence and reducing urinary inflammation in post-operative urolithiasis patients. OBJECTIVE: This multicenter, double-blind, randomized controlled trial aimed to evaluate the efficacy and safety of a novel lime-based preparation called LPR in preventing kidney stone recurrence over 24 months. METHODS: In a double-blind, randomized, placebo-controlled, multicenter trial, 173 patients with calcium oxalate urolithiasis who had undergone successful stone removal were enrolled from six hospitals in Thailand. Participants were randomized to receive either LPR or placebo for 24 months. The primary outcome was the incidence of stone recurrence confirmed by computerized topography (CT). Secondary outcomes included changes in urinary protein excretion and urinary interleukin-8 (IL-8) level, a pro-inflammatory cytokine implicated in renal inflammation and stone formation. Kaplan-Meier survival analysis and multivariate Cox regression were used to assess recurrence risk. RESULTS: Of 173 enrolled participants, 151 completed the study. The recurrence rate at 2 years was significantly lower in the LPR group (14%) compared to placebo (45%) (p < 0.001). Kaplan-Meier analysis demonstrated a hazard ratio (HR) of 0.24 (95% CI: 0.13-0.44; log-rank p < 0.0001) favoring LPR. Among completers, LPR significantly reduced urinary IL-8 level (p = 0.017) and 24-hour urinary protein excretion (p = 0.032) compared to baseline and placebo. No serious adverse events were reported, and adherence was high in both groups. CONCLUSION: LPR, a lime-based supplement rich in citrate and flavonoids, significantly reduced the 2-year recurrence rate of calcium oxalate stones by appro

14. JAMA Neurol. 2025 Dec 1;82(12):1235-1242. doi: 10.1001/jamaneurol.2025.3905. Transcutaneous Peripheral Nerve Stimulation for Essential Tremor: A Randomized Clinical Trial. Ondo WG(1), Lv W(2), Zhu X(3), Hu Y(4), Isaacson SH(5), Yuan Y(6), Espay AJ(7), Kreitzman D(8), Kuo SH(9), Brillman S(10

BACKGROUND: Breast cancer (BC) is the second most common cancer globally and the most prevalent among women. Chemotherapy, a primary treatment, frequently induces distressing side effects like nausea and vomiting. This study evaluated the efficacy of Citrus aurantium inhalation aromatherapy in reducing chemotherapy-induced nausea and vomiting (CINV) in women with BC. METHODS: In this CONSORT-compliant parallel-group randomized controlled trial (registered at IRCT: 20240305061177N1), 92 BC patients at Motahari Clinic were randomly allocated (between April to August 2024) to an aromatherapy group (n = 46) or a control group (n = 46). Alongside standard antiemetic medications, the aromatherapy group inhaled two drops of C. aurantium essential oil applied to the philtrum, while the control group received sunflower oil. The Rhodes Index assessed nausea, vomiting, and retching over five days. RESULTS: Significant reductions in mean total scores for nausea, vomiting, and retching were observed in the aromatherapy group compared to the control group from days 3 to 5 (P < 0.05), with no significant differences on days 1 and 2. Total symptom scores significantly decreased from Day 1 to Day 5 in the aromatherapy group while the control group showed no change. CONCLUSION: C. aurantium aromatherapy significantly alleviated CINV during the delayed phase (days 3-5). Given its safety, affordability, and accessibility, this intervention offers a promising complementary approach for managing CINV in BC patients. TRIAL REGISTRATION: This trial was registered with the Iranian Registry of Clinical Trials (IRCT20240305061177N1, march 17, 2024). © 2025. The Author(s).

Currently, there is great interest in the use of pectins for prebiotic treatment of food allergy. Hence, the effects of two different esterified pectins - low methoxyl citrus-derived pectin (CP-DElow) and high methoxyl apple-derived pectin (AP-DEhigh) - were evaluated in peach allergic patients due to sensitization to lipid transfer proteins (LTPs). This study analyzed the systemic immune response, the gut microbiota composition (using 16S rRNA gene sequencing), and microbial-derived metabolome, including short-chain fatty acids (SCFAs) and bile acids (BAs). Prebiotic treatment with both pectins was safe and induced a significant clinical increase in allergen tolerance in more than 50 % of patients. Additionally, CP-DElow and AP-DEhigh groups exhibited a distinctive systemic proteomic profile characterized by a decrease in various inflammatory cytokines compared to Placebo. Regarding microbiota, CP-DElow induced an increase in Bacteroides_H genus and Roseburia intestinalis species, whereas AP-DEhigh was associated with an increase in Bifidobacterium and Succinivibrio genera, and Faecalibacterium prausnitzii species. Reduced concentrations of branched SCFAs were observed after both treatments compared to Placebo. Likewise, fecal levels of microbial-derived secondary BAs were modified by pectin supplementation. Multi-omics integration revealed distinctive signatures in pectin- and placebo-treated patients. This study suggests that pectin treatment is a promising and safe option for LTP allergy.

BACKGROUND AND OBJECTIVE: Guidelines recommend single-dose antimicrobial prophylaxis (AMP) for transurethral resection (TURP) and photoselective vaporization (PVP) of the prostate. As guideline adherence is low and 3-d AMP is given frequently, we aimed to assess the noninferiority of a single dose compared with 3-d AMP by comparing the incidence of urinary tract infections (UTIs) within 30 d. METHODS: A double-blind, multicenter, randomized, noninferiority trial was conducted comparing single-dose with 3-d AMP in patients assigned to TURP and PVP, assuming a 9% event rate for a clinical diagnosis of a UTI with a 4.4% noninferiority margin. KEY FINDINGS AND LIMITATIONS: From anticipated 1574 patients, 728 were recruited and 621 randomized patients were analyzed fully. The study was preliminary stopped due to delayed recruitment and was analyzed exploratively. Following single-dose AMP, 11.0% of patients (95% confidence interval [CI] 7.9%, 15.0%; 33/300) had a clinical diagnosis of UTIs, compared with 8.5% (95% CI 5.8%, 12.1%; 26/307) receiving 3-d AMP (between-group difference 2.5% [95% CI -2.2%, 7.5%]). The rates of UTIs supported by bacteriuria were lower without any difference between groups (single-dose AMP: 3.3% [95% CI 1.8%, 6.0%]; 3-d AMP: 3.3% [95% CI 1.8%, 5.9%]; between-group difference 0.08% [95% CI -2.97%, 3.16%]). Adverse events were rare. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this randomized trial of transurethral prostate surgery patients, 11.0% of those on single-dose AMP and 8.5% on 3-d AMP were diagnosed with UTIs. The smaller than planned sample size precludes a definite interpretation favoring either group. Diagnoses of UTIs based on symptoms and bacteriuria reduced the overall rates and group differences.

BACKGROUND/OBJECTIVES: Sugar-sweetened beverages are associated with an increased risk of obesity and type 2 diabetes (T2DM) and show clear differential metabolic responses compared with 100% fruit juice, which is unsweetened by law. This study investigated whether the postprandial glycaemic response following a standardized breakfast differed when accompanied by 100% orange juice, equivalent whole orange, or a sugar-sweetened control beverage in individuals with well-controlled T2DM. SUBJECTS/METHODS: Fifteen individuals with T2DM (60 ± 6 y; BMI 28.7 ± 5.0 kg/m², HbA1C 49 ± 3 mmol/mol (6.6 ± 0.3%)) participated in this randomized cross-over trial. They consumed a standardized breakfast served with either 250 mL of 100% orange juice, a sugar-sweetened orange-flavoured beverage or whole orange pieces with identical total sugar content. Postprandial glycaemic and insulinaemic responses were checked during 4 h. RESULTS: Following a single intake, no significant differences were found in acute glucose or insulin responses (expressed as total or incremental area under the curve or peak values; ptreatment > 0.05, respectively) when either whole orange pieces, orange juice or a sugar-sweetened control beverage were consumed with a standard high carbohydrate meal. Capillary glucose responses did not differ between conditions (ptreatment > 0.05). CONCLUSION: Acute glycaemic control in individuals with well-controlled T2DM is not significantly influenced by serving orange juice, whole orange pieces or a sugar-sweetened beverage with a standard high-carbohydrate meal. © 2025. The Author(s).

BACKGROUND AND PURPOSE: Postoperative pain and blood pressure are common patient complaints. This study examined the effects of Citrus Aurantium (CA) on pain and blood pressure in patients undergoing hand reconstructive surgery. METHODS: A double-blind, randomized clinical trial was conducted with 76 patients. The control group received a placebo, while the intervention group received CA essential oil. Blood pressure and pain levels were recorded before the intervention, and at 30 minutes and one-hour post-surgery. Data collection used blood pressure sheets, numerical visual pain scales, and demographic questionnaires. RESULT: The intervention group showed significantly greater pain reduction than the control group (p = 0.001), with CA increasing the likelihood of pain reduction by 1.73 times (Exp(B) = 1.73). Systolic and diastolic blood pressure significantly decreased post-intervention (p = 0.001, p = 0.005), but differences were not significant after 30 minutes and one hour after (p > 0.05). CA increased the likelihood of systolic blood pressure reduction by 16.87 times (Exp(B) = 16.78), with no effect on diastolic pressure. CONCLUSION: CA facilitates pain and blood pressure reduction in aromatherapy, suggesting its use as a simple, inexpensive, and noninvasive method for postoperative pain management.

Recent studies underscore the therapeutic potential of citrus polymethoxylated flavonoids-such as tangeretin, sinensetin, and nobiletin-in attenuating inflammation, mitigating oxidative stress, and enhancing metabolic health in individuals with obesity. This randomized, double-blind, placebo-controlled clinical trial assessed the effects of a functional orange juice enriched with flavonoids (200 mL/day) combined with a low-calorie diet over six weeks in 44 obese participants. All subjects adhered to a hypocaloric diet and were randomly assigned to receive either flavonoid-enriched juice (n = 22) or placebo juice (n = 20). Both groups experienced significant reductions (p < 0.05) in weight, body mass index (BMI), fat mass, and waist circumference. However, the flavonoid-enriched juice group showed more pronounced improvements in metabolic biomarkers, including significant decreases in low-density lipoprotein cholesterol (LDL-C) and glycated hemoglobin (A1c) levels. Critically, the intervention enhanced systemic antioxidant defense, evidenced by increased total antioxidant capacity and upregulation of glutathione peroxidase 1 (GPX1), an essential enzyme that reduces hydrogen peroxide and lipid hydroperoxides. This suggests a direct impact on cellular redox homeostasis. Additionally, the enriched juice group exhibited reduced levels of pro-inflammatory cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), indicating an anti-inflammatory effect. Favorable modulation of adipokines was also observed, with elevated adiponectin-a hormone associated with improved insulin sensitivity-and decreased leptin and plasminogen activator inhibitor-1 (PAI-1), both linked to obesity-related inflammation and thrombosis risk. These findings suggest that dietary supplementation with flavonoid-enriched orange juice, in conjunction with caloric restriction, can enhance antioxidant defenses, reduce inflammation, and improve key metabolic parameters in obese individuals.

Cisplatin (DDP) is a widely used chemotherapeutic agent for ovarian cancer (OC) therapy. However, the adverse effects and frequent resistance to DDP make its therapeutic efficacy suboptimal. Combination treatment with an agent capable of overcoming DDP resistance may be a promising solution. Here, we conducted a drug library screen for agents that increase DDP efficiency in a trained DDP-resistant OC cell line (SKOV3/DDP). Diosmetin (Dio), a natural flavonoid abundant in olive leaves and citrus fruits, was identified to synergize with DDP to reduce OC cell growth through apoptosis both in vitro and in vivo, as evidenced by increased expression of the proapoptotic proteins Cleaved-Caspase3 and Cleaved-PARP, as well as decreased expression of the antiapoptotic protein BCL-2 in SKOV3/DDP cells. Mechanistically, compared with Dio or DDP treatment alone, combined Dio and DDP treatment suppressed the MAPK signaling pathway, represented by reduced phosphorylation of JNK, ERK, and P38. These findings demonstrated that Dio potentiates the anticancer effects of DDP both in vitro and in vivo, indicating that Dio is a promising adjuvant for OC treatment. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Cisplatin (CSP) is a first-line chemotherapeutic for laryngeal squamous cell carcinoma (LSCC), but its clinical effectiveness is limited by resistance and toxicity. Hesperidin (HESP), a citrus flavonoid, may enhance chemotherapeutic efficacy through pro-apoptotic properties. This study investigated the involvement of the transient receptor potential melastatin-2 (TRPM2) channel in the HESP-mediated potentiation of CSP-induced cytotoxicity in human laryngeal carcinoma (Hep-2) cells. Hep-2 cells were treated with CSP (25 µM), HESP (25 µM), or their combination for 24 h. The findings showed that the combined application of HESP and CSP reduced cell viability by approximately 50% (p < 0.001), which was the lowest compared to CSP alone. Western blot analysis revealed that TRPM2 protein expression was higher in the CSP+HESP group compared to the control group (p < 0.001). This synergistic treatment resulted in an increase in ROS production and a decrease in MDA levels, accompanied by a reduction in cellular GSH levels (p < 0.001). Furthermore, the combination therapy increased pro-inflammatory cytokines such as IL-1β and TNF-α (p < 0.001). Functional analyses showed that HESP treatment enhanced CSP-induced Ca2+ influx and altered mitochondrial membrane potential (p < 0.001). The pharmacological inhibition of TRPM2 with ACA and 2-APB reversed these effects, restoring redox balance and reducing cellular damage. In conclusion, HESP amplifies CSP-induced apoptosis in Hep-2 cells through TRPM2-dependent oxidative stress, Ca2+ dysregulation, and mitochondrial dysfunction. These findings identify TRPM2 as a mechanistic mediator of HESP-enhanced chemosensitivity in LSCC.

OBJECTIVE: Hepatocellular carcinoma (HCC), the most common form of liver cancer, often develops in individuals with chronic liver diseases, especially cirrhosis. Cisplatin (Cisp), a chemotherapy agent commonly used in HCC treatment, is effective but is known to damage normal cells, including fibroblasts. Hesperetin (HST), a citrus flavanone found abundantly in citrus fruits, has demonstrated antioxidant, anti-inflammatory, and anticancer properties. This study aimed to investigate the synergistic cytotoxic effects and selective induction of senescence by HST in combination with Cisp in HepG2 cancer cells and NIH-3T3 fibroblast cells. METHODS: The cytotoxic effects of HST were assessed using the MTT assay to determine cell viability. The antiproliferative properties were evaluated using colony formation assays. Senescence was assessed using SA-β-gal staining, while flow cytometry was used to analyze cell cycle distribution and apoptosis. Protein expression related to proliferation and apoptosis was determined via Western blot analysis. RESULTS: MTT assay results indicated that both HST and Cisp reduced HepG2 cell viability in a dose-dependent manner, with IC50 values of 258 ± 2.47 µM and 5 ± 1.83 µM, respectively. Their combination (HST: 33-130 µM; Cisp: 0.6-2.5 µM) showed synergistic effects (combination index, CI < 1) co-treatment with HST (65 and 130 µM) significantly enhanced senescence in HepG2 cells. Clonogenic assays showed inhibition of colony formation, supported by reduced expression of p-ERK1/2 and Cyclin D1. Flow cytometry revealed increased apoptosis and G2/M phase arrest, with upregulation of Bax and caspase-3, and downregulation of Bcl-xL. In NIH-3T3 cells, HST showed minimal cytotoxicity (IC50 > 500 µM), and co-treatment with Cisp reduced senescence markers. CONCLUSION: These results suggest that HST and Cisp co-treatment synergistically reduces cancer cell viability while protecting normal fibroblasts from senescence, supporting its potential as a co-chemotherapeutic agent in HCC treatment, while also serving as a protective agent against senescence in healthy tissues.

Mosquitoes have been claimed as the deadliest animals around the globe that cause severe fatal diseases and affect millions of people worldwide. Nowadays, it is well-understood that plant-based products can be used as alternatives to the synthetic insecticides to control a wide range of vectors and pests. The plant derived essential oils, the subject of considerable research and these natural bioactive compounds may replace synthetic insecticides in the consumer markets. Therefore, to enhance the larvicidal toxicity of essential oils, the combined bioassay of leaves and peels essential oils of Citrus limetta, C. limon and C. reticulata were evaluated by using WHO protocol. The findings of present study revealed that all the combinations demonstrated the synergistic effect with combined factor ranging from 1.02 to 1.34 and increased lethal values ranging from 2.09 to 33.90% against both the target species. The highest combined bioefficacy was achieved by CMLEO-CMPEO (1:1) with lowest LC50 values, 12.18 and 21.85 ppm against Anopheles stephensi and Culex quinquefasciatus, respectively after 24 h of exposure. Hence, these different combinations of Citrus essential oils were proved as more toxic and have great capability for the development of a botanical insecticidal formulation to combat the mosquitoes' populations.

BACKGROUND: p-Synephrine (p-Syn), a natural alkaloid isolated from Citrus aurantium L., promotes fat oxidation and is therefore widely used as a weight loss dietary supplement. It was recently reported to exert a potent antidepressant effect. However, its molecular targets remain undefined. Gastrodin (Gas), extracted from Gastrodia elata Blume, exerts antidepressant effects by targeting Melatonin Receptor 1A (MT1). PURPOSE: This study aimed to evaluate whether MT1 is a target of p-Syn, and to verify the antidepressant effects of p-Syn and Gas. METHODS: Network pharmacology was applied to predict potential targets and associated signaling pathways for p-Syn and Gas. Molecular Docking simulations were employed to predict the possible binding sites of MT1 with p-Syn. Solvent-induced Protein Precipitation (SIP) and Fluorescence Correlation Spectroscopy (FCS) were employed to validate p-Syn's binding affinity with MT1. Cellular Thermal Shift Assay (CETSA) was used to confirm the predicted key binding sites in exogenously overexpressed site-mutated MT1. of Extracellular regulated protein kinases (ERK) and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) downstream of MT1, following treatment with p-Syn or Gas, or the synergistic use of both, was investigated by Western blotting. RESULTS: Using a network pharmacology approach and in vitro assays, we found that both p-Syn and Gas bind to MT1, activate the ERK/CREB signaling pathway, and up-regulate BDNF. In vivo assays showed that p-Syn alleviated Reserpine (Res)-induced depression-like symptoms in AB zebrafish larvae and C57 mice. Furthermore, p-Syn and Gas showed a remarkable synergistic effect. CONCLUSION: This study identifies a novel target for p-Syn and provides new insights into the antidepressant mechanisms of p-Syn and Gas that may contribute to the clinical application of these compounds in the development of new drugs for the treatment of depression.

OBJECTIVE: Despite of advancements in oncology, classical therapy like chemotherapy, radiotherapy often come with various side effects, including drug resistance and toxicity to healthy cell. Recent studies suggest that various herbal combinations may reinforce therapeutic efficacy through synergism between combined herbs. The present work was carried out to investigate the synergistic effect of Citrullus colocynthis and lemon fruit hydroethanolic combination against ER+ MCF-7 breast cancer cell line in different aspects. METHODS: The cytotoxic effect of herbal extract combination was studied by MTT, while DNA degradation was detected by Propidium Iodide/Acridine Orange assay. The antiangiogenic effect was evaluated by measuring neuropeptides NPYR1 and NPYR5 using a sandwich enzyme immunoassay (ELISA Kit), as they have been shown to play a role in cancer growth. RESULTS: A highly cytotoxic effect of the Citrullus colocynthis and lemon juice combination extract was observed against MCF-7 cancer cell line, with a significant IC50 value and extensive DNA fragmentation, indicating intense apoptotic events. On the other hand, results showed a decreased level of both NPYR1 and NPYR5, suggesting inhibition by the herbal extract combination. Conclusion: It can be concluded that the Citrullus colocynthis and lemon juice combination extract shows high efficiency as a cytotoxic agent against MCF-7 cancer cell line.

Grapefruit juice is a well-established inhibitor of cytochrome P450 (CYP) 3A4, but its effects on other CYP enzymes or organic anion transporting polypeptides (OATPs) are not fully characterized in humans. Recently, lingonberry powder was shown to induce murine CYP enzymes. We investigated the effects of lingonberry powder and grapefruit juice on seven CYP enzymes and two OATPs. Eleven healthy volunteers received three pretreatments three times per day: water for 1 day (control), lingonberry powder for 9 days, and grapefruit juice for 3 days. CYP index drugs (caffeine/CYP1A2, bupropion/CYP2B6, repaglinide/CYP2C8, flurbiprofen/CYP2C9, omeprazole/CYP2C19, dextromethorphan/CYP2D6, midazolam/CYP3A4, and simvastatin/CYP3A4) were administered orally on the study day of each pretreatment (day 1, 10, and 3, respectively). Venous blood samples were collected until 23 hours postdose. The concentrations of index drugs, their metabolites and endogenous OATP1B1 and OATP1B3 biomarkers glycochenodeoxycholate 3-O-glucuronide (GCDCA-3G) and glycochenodeoxycholate 3-sulfate (GCDCA-3S), respectively, were quantified. Grapefruit juice expectedly increased the AUC0-23h values of the CYP3A4 index drugs midazolam and simvastatin (P < 0.01). Additionally, grapefruit juice decreased the hydroxybupropion/bupropion (CYP2B6), 4'-hydroxyflurbiprofen/flurbiprofen (CYP2C9), 5'-hydroxyomeprazole/omeprazole (CYP2C19), and 1'-hydroxymidazolam/midazolam AUC0-23h ratios to 0.57-fold (90% confidence interval: 0.45-0.74), 0.78-fold (0.69-0.87), 0.43-fold (0.36-0.52), and 0.72-fold (0.63-0.84) of control, respectively (P < 0.01). Lingonberry pretreatment did not change any CYP indices. GCDCA-3G and GCDCA-3S concentrations were unaffected by grapefruit juice or lingonberry pretreatment. Collectively, our findings indicate that in addition to inhibiting CYP3A4, repeated grapefruit juice intake causes clinically relevant inhibition of CYP2B6, CYP2C9, and CYP2C19, revealing previously underappreciated interaction risks. Conversely, lingonberry powder is unlikely to induce CYP enzymes in humans. © 2025 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of Ame

Nematodes are diverse parasites affecting humans and animals, with resistance to anthelmintics becoming a major concern due to prolonged drug use. Essential oils (EOs) from plants offer a promising alternative for parasite control. This study evaluated the preclinical efficacy of Citrus aurantium bergamia essential oil (BEO) combined with nitroxynil (NTX) or ivermectin (IVM) against Haemonchus contortus and Trichostrongylus spp., using the larval migration inhibition test (LMIT). Gas chromatography-mass spectrometry identified (+)-limonene (50.5 %), linalyl acetate (21.0 %), and linalool (6.9 %) as BEO's main components. Fecal samples from naturally infected sheep were analyzed via flotation, larval culture, and microscopy to quantify nematode eggs and infective-stage larvae (L3). The Nadi reagent was used to assess histochemical changes in L3 post-migration. BEO exhibited a lethal concentration (LC50) of 24.5 mg/mL, showing concentration-dependent activity. While BEO alone achieved 93.6 % efficacy, combinations with NTX (99.1 %) and IVM showed some synergy effects. At 70.16 mg/mL, BEO efficacy was 92.2 %, increasing to 95.6 % with IVM (P = 0.0802). However, at 160 mg/mL, BEO in combination with IVM showed a small antagonistic interaction, reducing efficacy to 93.87 % (P = 0.6029) when compared to IVM alone (100 %). Nadi reagent staining also revealed concentration-dependent coloration changes in nematodes treated with BEO, suggesting internal compound action. However, further histological analysis is needed to confirm cellular effects and vacuole formation. In conclusion, BEO demonstrated activity against L3 in ruminant nematodes. Three drug combinations exhibited synergy effects, while IVM + BEO exhibited antagonistic effects. These findings highlight BEO's potential as a standalone and as an anthelmintic candidate when used in combination. There is still a need for further research into BEO mechanisms of action, histological and toxic effects in preclinical experiments.

Cervical cancer is a major gynecological malignancy linked to hormonal dysregulation and genetic alterations. Chemotherapy is standard but limited by toxicity and chemoresistance, prompting interest in plant-derived adjuncts. This study examined the anticancer and immunomodulatory effects of Hesperidin (Hes), a citrus flavonoid, with Doxorubicin (DX) in HeLa cervical cancer cells. Cell viability was assessed by MTT assay, apoptotic markers (Bcl-2, Caspase-3) by RT-qPCR, and inflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-γ) by ELISA. Cytokine levels were normalized to 104 viable cells, and mRNA expression of all four cytokines was quantified by RT-qPCR, confirming protein-level changes and showing the strongest IL-6 suppression with Hes+DX. Chou-Talalay combination index (CI) analysis demonstrated synergistic interactions (CI < 1.0) between Hes and DX across all tested concentrations, with strong synergism (CI < 0.7) at medium and high doses, particularly at 48 and 72 h. Hes alone showed dose-dependent cytotoxicity, while the combination markedly increased Caspase-3, reduced Bcl-2, and decreased IL-1β, IL-6, and TNF-α, indicating enhanced intrinsic apoptosis and complementary immunomodulation. These results suggest that Hes augments DX's pro-apoptotic and anti-inflammatory effects, potentially allowing lower chemotherapy doses and reduced systemic toxicity in cervical cancer treatment.

A Crataegus Extract Mixture (CEM) is a combination of extracts from Crataegus pinnatifida leaves and Citrus unshiu peels, well-known herbs used for treating obesity and dyslipidemia. We aimed to investigate the efficacy and safety of a CEM on the body fat and lipid profiles in overweight adults. A 12-week, randomized, double-blind, placebo-controlled, parallel-group trial was conducted on 105 subjects aged 20-60 years with body mass indexes between 25 and 30 kg/m2. Eligible subjects were randomly assigned in a 1:1:1 ratio to receive either a high dose of the CEM (400 mg tid), a low dose of the CEM (280 mg tid), or a placebo. Body fat was evaluated using dual-energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), and anthropometric measurements. The blood lipid and adipokine profiles were measured before and after the administration. After 12 weeks, the reductions in the fat percentages measured by DXA and BIA were significantly greater in the CEM groups than in the placebo group. The CEM also significantly decreased the body weights, body mass indexes, and blood leptin levels. An additional per-protocol analysis revealed that the high dose of the CEM also lowered the blood levels of triglycerides and very low-density lipoprotein cholesterol. No adverse events occurred after the CEM treatment. Our results suggest that CEMs are safe and effective for reducing the body fat and body weight and regulating the blood lipid and leptin levels in overweight or mildly obese individuals.