Efficacy and safety of curcumin therapy for knee osteoarthritis: A Bayesian network meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcumin, a polyphenolic compound extracted from turmeric (Curcuma longa L.), is widely used in traditional Chinese medicine to treat osteoarthritis and rheumatoid arthritis. Clinical and experimental studies show that curcuminoid formulations have considerable clinical application value in the treatment of knee osteoarthritis (KOA). AIM OF THE STUDY: To evaluate the efficacy and safety of curcumin, both alone and in combination with other drugs, in KOA treatment through a Bayesian network meta-analysis (NMA). METHODS: We searched PubMed, Embase and Cochrane Library for randomized controlled trials of curcumin for KOA treatment. The time range of the search was from the establishment of each database to April 26, 2023. The NMAs of outcome indicators were all performed using a random-effects model. NMAs were calculated and graphed in R using MetaInsight and Stata 140 software. Measurement data were represented by the mean difference (MD), while count data were represented by the odds ratio (OR); the 95% confidence interval (CI) of each effect size was also calculated. RESULTS: This study included 23 studies from 7 countries, including 2175 KOA patients and 6 interventions. The NMA results showed that compared with placebo, curcumin significantly reduced the visual analogue scale pain score (MD = -1.63, 95% CI: -2.91 to -0.45) and total WOMAC score (MD = -18.85, 95% CI: -29.53 to -8.76). Compared with placebo, curcumin (OR = 0.17, 95% CI: 0.08 to 0.36), curcumin + NSAIDs (OR = 0.01, 95% CI: 0.00 to 0.13) and NSAIDs (OR = 0.11, 95% CI: 0.02 to 0.47) reduced the use of rescue medication. Compared with NSAIDs, curcumin (OR = 0.51, 95% CI: 0.25 to 0.94) and curcumin + NSAIDs (OR = 0.23, 95% CI: 0.06 to 0.9) had a reduced incidence of adverse reactions. The surface under the cumulative ranking curve results indicated that curcumin monotherapy, curcumin + chondroprotective agents, and curcumin + NSAIDs have good clinical value in KOA treatment. CONCLUSIONS: Curcumin, either alone or in combination with other treatments, is considered to have good clinical efficacy and safety in KOA treatment. Drug combinations containing curcumin may have the dual effect of enhancing efficacy and reducing adverse reactions, but this possibility still needs to be confirmed by further clinical and basic research.

Anti-inflammatory activity of curcumin in a model of L-arginine-induced acute pancreatitis in rats.

BACKGROUND: Acute pancreatitis (AP) is a pathology characterized by activated digestive enzymes to digest pancreatic tissue and inflammation. This study aimed to investigate the effect of curcumin, which has antioxidant and anti-inflammatory properties, on AP and its effectiveness at different doses. METHODS: Forty Sprague Dawley albino male rats, 12 weeks old, weighing 285-320 g, were used in the study. The rats were divided into control, curcumin, AP, low (100 mg/kg), and high (200mg/kg) dose curcumin groups. An experimental pancreatitis model was created with 5 g/kg L-arginine and samples (amylase, lipase, IL-1ß, IL-6, TNF-alpha, CRP, histopathological) were taken after 72 hours. RESULTS: There was no difference between the groups in terms of the weight of the rats (p=0.76). In the AP group, it was observed that the experimental pancreatitis model was successfully created after examination. Laboratory and histopathological examination results in the curcumin-administered groups were regressed compared to the AP group. The decrease in laboratory values was higher in the high-dose curcumin group than in the low-dose (p<0.001). CONCLUSION: Laboratory and histopathological changes occur in AP according to clinical severity. The antioxidant and anti-inflammatory effects of curcumin are known. In the light of this information and according to the results of our study, it has been shown that curcumin is effective in the treatment of AP, and the effect of curcumin increases with the dose increase. Curcumin is effective in treating AP. However, while high-dose curcumin was more effective in inflammatory response than low-dose, it showed similar histopathological results. KEY WORDS: Acute, Curcumin, Cytokines, Inflammation, Pancreatitis.

Efficacy and safety of curcumin in diabetic retinopathy: A protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic retinopathy (DR) is one of the most common complications of diabetes and has become a major global cause of blindness. Curcumin, an extract of Curcuma longa (turmeric), is effective in preventing and treating diabetes. Recent studies have shown that curcumin can delay DR development. However, there has been no systematic review of its treatment of DR. This study will conduct a systematic review and meta-analysis of currently published randomized controlled trials (RCT) of curcumin for treating DR patients to evaluate its efficacy and safety. METHODS: We will search the relevant studies of curcumin in the treatment of DR in PubMed, Medline, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang databases from their respective inception dates to May 2022. A meta-analysis of the data extracted from qualified RCTs will be conducted, including the progression of DR, visual acuity, visual field, macular edema, quality of life, and adverse events. The meta-analysis will be performed using Review Manager 5.4.1 software, and the results will be based on either random-effects or fixed-effects models, depending on the heterogeneity. The Grading of Recommendations, Development, and Evaluation (GRADE) system will be used to evaluate the reliability and quality of evidence. RESULTS: The results of this study will provide sound and high-quality evidence for the efficacy and safety of curcumin in the treatment of DR. CONCLUSION: This study will be the first meta-analysis to comprehensively assess the efficacy and safety of curcumin in the treatment of DR and will provide helpful evidence for the clinical management of this disease. SYSTEMATIC REVIEW REGISTRATION: INPLASY202250002.

Sensitization of GSH synthesis by curcumin curtails acrolein-induced alveolar epithelial apoptosis via Keap1 cysteine conjugation: A randomized controlled trial and experimental animal model of pneumonitis.

INTRODUCTION: Epidemiological studies have reported an association between exposures to ambient air pollution and respiratory diseases, including chronic obstructive pulmonary disease (COPD). Pneumonitis is a critical driving factor of COPD and exposure to air pollutants (e.g., acrolein) is associated with increased incidence of pneumonitis. OBJECTIVES: Currently available anti-inflammatory therapies provide little benefit against respiratory diseases. To this end, we investigated the preventive role of curcumin against air pollutant-associated pneumonitis and its underlying mechanism. METHODS: A total of 40 subjects was recruited from Chengdu, China which is among the top three cities in terms of respiratory mortality related to air pollution. The participants were randomly provided either placebo or curcumin supplements for 2 weeks and blood samples were collected at the baseline and at the end of the intervention to monitor systemic markers. In our follow up mechanistic study, C57BL/6 mice (n = 40) were randomly allocated into 4 groups: Control group (saline + no acrolein), Curcumin only group (curcumin + no acrolein), Acrolein only group (saline + acrolein), and Acrolein + Curcumin group (curcumin + acrolein). Curcumin was orally administered at 100 mg/kg body weight once a day for 10 days, and then the mice were subjected to nasal instillation of acrolein (5 mg/kg body weight). Twelve hours after single acrolein exposure, all mice were euthanized. RESULTS: Curcumin supplementation, with no noticeable adverse responses, reduced circulating pro-inflammatory cytokines in association with clinical pneumonitis as positive predictive while improving those of anti-inflammatory cytokines. In the pre-clinical study, curcumin reduced pneumonitis manifestations by suppression of intrinsic and extrinsic apoptotic signaling, which is attributed to enhanced redox sensing of Nrf2 and thus sensitized synthesis and restoration of GSH, at least in part, through curcumin-Keap1 conjugation. CONCLUSIONS: Our study collectively suggests that curcumin could provide an effective preventive measure against air pollutant-enhanced pneumonitis and thus COPD.

Efficacy and safety of dietary polyphenol supplementation in the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis.

Background: Dietary polyphenol treatment of non-alcoholic fatty liver disease (NAFLD) is a novel direction, and the existing clinical studies have little effective evidence for its therapeutic effect, and some studies have inconsistent results. The effectiveness of dietary polyphenols in the treatment of NAFLD is still controversial. The aim of this study was to evaluate the therapeutic efficacy of oral dietary polyphenols in patients with NAFLD. Methods: The literature (both Chinese and English) published before 30 April 2022 in PubMed, Cochrane, Medline, CNKI, and other databases on the treatment of NAFLD with dietary polyphenols was searched. Manual screening, quality assessment, and data extraction of search results were conducted strictly according to the inclusion and exclusion criteria. RevMan 5.3 software was used to perform the meta-analysis. Results: The RCTs included in this study involved dietary supplementation with eight polyphenols (curcumin, resveratrol, naringenin, anthocyanin, hesperidin, catechin, silymarin, and genistein) and 2,173 participants. This systematic review and meta-analysis found that 1) curcumin may decrease body mass index (BMI), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Triglycerides (TG) total cholesterol (TC), and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) compared to placebo; and curcumin does not increase the occurrence of adverse events. 2) Although the meta-analysis results of all randomized controlled trials (RCTs) did not reveal significant positive changes, individual RCTs showed meaningful results. 3) Naringenin significantly decreased the percentage of NAFLD grade, TG, TC, and low-density lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) but had no significant effect on AST and ALT, and it is a safe supplementation. 4) Only one team presents a protocol about anthocyanin (from Cornus mas L. fruit extract) in the treatment of NAFLD. 5) Hesperidin may decrease BMI, AST, ALT, TG, TC, HOMA-IR, and so on. 6) Catechin may decrease BMI, HOMA-IR, and TG level, and it was well tolerated by the patients. 7) Silymarin was effective in improving ALT and AST and reducing hepatic fat accumulation and liver stiffness in NAFLD patients. Conclusion: Based on current evidence, curcumin can reduce BMI, TG, TC, liver enzymes, and insulin resistance; catechin can reduce BMI, insulin resistance, and TG effectively; silymarin can reduce liver enzymes. For resveratrol, naringenin, anthocyanin, hesperidin, and catechin, more RCTs are needed to further evaluate their efficacy and safety.

Complementary and alternative therapies in skin cancer a literature review of biologically active compounds.

Complementary and alternative medicine or therapies (CAM) are frequently used by skin cancers patients. Patient's self-administration of CAM in melanoma can reach up to 40%-50%. CAMs such as botanical agents, phytochemicals, herbal formulas ("black salve") and cannabinoids, among others, have been described in skin cancer patients. The objective of this review article was to acknowledge the different CAM for skin cancers through the current evidence, focusing on biologically active CAM rather than mind-body approaches. We searched MEDLINE database for articles published through July 2022, regardless of study design. Of all CAMs, phytochemicals have the best in vitro evidence-supporting efficacy against skin cancer including melanoma; however, to date, none have proved efficacy on human patients. Of the phytochemicals, Curcumin is the most widely studied. Several findings support Curcumin efficacy in vitro through various molecular pathways, although most studies are in the preliminary phase. In addition, the use of alternative therapies is not exempt of risks physicians should be aware of their adverse effects, interactions with standard treatments, and possible complications arising from CAM usage. There is emerging evidence for CAM use in skin cancer, but no human clinical trials support the effectiveness of any CAM in the treatment of skin cancer to date. Nevertheless, patients worldwide frequently use CAM, and physicians should educate themselves on currently available CAMs.

Efficacy and Safety of Curcumin and Curcuma longa Extract in the Treatment of Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trial.

Background: Modern pharmacological research found that the chemical components of Curcuma longa L. are mainly curcumin and turmeric volatile oil. Several recent randomized controlled trials (RCT) have shown that curcumin improves symptoms and inflammation in patients with arthritis. Methods: Pubmed, Cochran Library, CNKI, and other databases were searched to collect the randomized controlled trials (RCTs). Then, the risk of bias of RCTs were assessed and data of RCTs were extracted. Finally, RevMan 5.3 was utilized for meta-analysis. Results: Twenty-nine (29) RCTs involving 2396 participants and 5 types of arthritis were included. The arthritis included Ankylosing Spondylitis (AS), Rheumatoid Arthritis (RA), Osteoarthritis (OA), Juvenile idiopathic arthritis (JIA) and gout/hyperuricemia. Curcumin and Curcuma longa Extract were administered in doses ranging from 120 mg to 1500 mg for a duration of 4-36 weeks. In general, Curcumin and Curcuma longa Extract showed safety in all studies and improved the severity of inflammation and pain levels in these arthritis patients. However, more RCTs are needed in the future to elucidate the effect of Curcumin and Curcuma longa Extract supplementation in patients with arthritis, including RA, OA, AS and JIA. Conclusion: Curcumin and Curcuma longa Extract may improve symptoms and inflammation levels in people with arthritis. However, due to the low quality and small quantity of RCTs, the conclusions need to be interpreted carefully.

The efficacy of curcumin-piperine co-supplementation on clinical symptoms, duration, severity, and inflammatory factors in COVID-19 outpatients: a randomized double-blind, placebo-controlled trial.

BACKGROUND: COVID-19 pandemic has made the disease a major global problem by creating a significant burden on health, economic, and social status. To date, there are no effective and approved medications for this disease. Curcumin as an anti-inflammatory agent can have a positive effect on the control of COVID-19 complications. This study aimed to assess the efficacy of curcumin-piperine supplementation on clinical symptoms, duration, severity, and inflammatory factors in patients with COVID-19. METHODS: Forty-six outpatients with COVID-19 disease were randomly allocated to receive two capsules of curcumin-piperine; each capsule contained 500 mg curcumin plus 5 mg piperine or placebo for 14 days. RESULTS: Mean changes in complete blood count, liver enzymes, blood glucose levels, lipid parameters, kidney function, and c-reactive protein (CRP) were not significantly different between the two groups. There was a significant improvement in health status, including dry cough, sputum cough, ague, sore throat, weakness, muscular pain, headache, and dyspnea at week 2 in both curcumin-piperine and placebo groups (P value < 0.05); however, the improvement in weakness was more in the curcumin-piperine group than with placebo group (P value 025). CONCLUSION: The present study results showed that curcumin-piperine co-supplementation in outpatients with COVID-19 could significantly reduce weakness. However, in this study, curcumin-piperine co-supplementation could not significantly affect the other indices, including biochemical and clinical indices. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT20121216011763N46 . 2020-10-31.

Efficacy of a mixed preparation containing piperine, capsaicin and curcumin in the treatment of alopecia areata.

BACKGROUND: Alopecia areata is a common non-scarring alopecia, mainly manifested as sudden localized patchy alopecia. It is currently believed to be related to autoimmune, genetic, emotional stress, and endocrine factors. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of the mixed preparation of piperine, capsaicin, and curcumin on alopecia areata treatment. METHODS: Sixty patients were enrolled in this study and divided into 2 groups randomly: topical treated with the mixed preparation (case) twice daily and 5%minoxidil (control) once daily for 3 months. The degree of hair loss was assessed by SALT and dermoscopy. RESULTS: On the completion of the study, compared with baseline, statistically significant regrowth occurred in both groups (p < 0.05). The mean SALT scores and hair follicle status under trichoscopy at baseline and at the end of 12 weeks in the mixed preparation group and in the minoxidil group were comparable, respectively. The effective rate of mixed preparation group was 63.33% and minoxidil group was 70%. Adverse symptoms were temporary and no serious adverse event occurred. CONCLUSION: Based on our findings, the mixed preparation of piperine, capsaicin, and curcumin is effective in treating alopecia areata, but it has not been shown to be superior to minoxidil in short-term therapy.

Natural compounds as safe therapeutic options for ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. Several conventional treatments for UC such as corticosteroids, immunosuppressive agents, tumor necrosis factor antagonist, integrin blockers, and interleukin antagonist, and salicylates are available but are associated with the various limitations and side-effects. None of the above treatments helps to achieve the ultimate goal of the therapy, i.e., maintenance of remission in the long-term. Natural remedies for the treatment of UC show comparatively less side effects as compared to conventional approaches, and affordable. The current review presents details on the role of herbal drugs in the treatment and cure of UC. Google, PubMed, Web of Science, and Scopus portals have been searched for potentially relevant literature to get the latest developments and updated information related to use of natural drugs in the treatment of UC. Natural products have been used over centuries to treat UC. Some of the essential herbal constituents exhibiting antiulcerogenic activity include gymnemic acid (Gymnema sylvestre), shagoal (Zingiber officinale), catechin (Camellia sinensis), curcumin (Curcuma longa), arctigenin (Arctium lappa), and boswellic acid (Boswellia serrata). Although many plant-derived products have been recommended for UC, further research to understand the exact molecular mechanism is still warranted to establish their usefulness clinically.

Efficacy and safety of adjuvant curcumin therapy in ulcerative colitis: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcumin, an active polyphenol extracted from Traditional Chinese medicine Curcuma longa (turmeric), has shown many health-related benefits and pharmacological effects. Adjuvant curcumin therapy for ulcerative colitis has become increasingly popular, but its efficacy and safety of which is still controversial. The purpose of this study is to evaluate the efficacy and safety of adjuvant curcumin therapy in ulcerative colitis. MATERIALS AND METHODS: The Medline, EMBASE, the Cochrane Library, CNKI, VIP, WanFang, and SinoMed databases were searched from inception to June 2021, to identify all randomized controlled clinical trials with adjuvant curcumin therapy in ulcerative colitis. The primary outcomes were clinical and endoscopic remission, and subgroup analyses were also performed. RESULTS: Six randomized trials with a total of 385 participants were included in this study. Qualified trials recommended that adjuvant curcumin therapy for ulcerative colitis was effective in inducing clinical remission (RR = 2.10, 95% CI 1.13 to 3.89), but not in clinical improvement (RR = 1.62, 95% CI 1.00 to 2.61), endoscopic remission (RR = 4.17, 95% CI 0.63 to 27.71) or endoscopic improvement (RR = 4.13, 95% CI 0.20 to 87.07). Included studies showed that appropriate dosage, formation, longer duration, and topical medication may have a greater potential advantage. No severe adverse effects had been reported. CONCLUSIONS: Available evidence suggested that adjuvant curcumin therapy may be effective for clinical remission in ulcerative colitis patients without causing severe adverse effects. The appropriate methods of administration can achieve better curative effect, which requires further study to verify.

Curcumin and curcumoids: hepatoprotection or hepatotoxicity?

Curcumin (Curcuma longa) and curcumin analogues are plant-based drugs used because of their possible antioxidant and anti-inflammatory. Clinical data on the efficacy of curcumin as a hepatoprotectant are limited, with growing concern for formulations that may potentially increase curcumin hepatotoxicity.

ProspeCtive study to evaluate efficacy, safety and tOlerability of dietary supplemeNT of Curcumin (BCM95) in subjects with Active relapsing MultIple Sclerosis treated with subcutaNeous Interferon beta 1a 44 mcg TIW (CONTAIN): A randomized, controlled trial.

BACKGROUND: multiple sclerosis (MS) is a complex disease sustained by several pathogenic mechanisms. As such, combination therapy strategies, targeting a range of disease mechanisms, might represent the ideal therapeutic approach. Here we investigated the efficacy of curcumin, a naturally occurring poly-phenolic phytochemical with potent anti-inflammatory and antioxidant properties, in subjects under treatment with IFN ß-1a, to test the effects of this combination therapy on clinical and MRI parameters of inflammation and neurodegeneration in relapsing MS (RMS). METHODS: eighty active RMS were prospectively enrolled, randomized (1:1) to either the IFN-curcumin or the IFN-placebo group and followed up longitudinally with clinical and MRI assessments for 24 months. Primary endpoint was the efficacy of curcumin versus placebo as add-on therapy on new/enlarging T2 lesions in RMS subjects under treatment with subcutaneous IFN ß-1a 44 mcg TIW. Efficacy on clinical parameters (relapses and disability progression), other MRI parameters of inflammation (T1 Gd-enhancing lesions, combined unique active-CUA lesions) and neurodegeneration (T1-hypointense lesions, grey matter loss and white matter microstructural damage) as well as safety and tolerability of curcumin were explored as secondary endpoints. RESULTS: ten subjects dropped out from the study by month 12 (6 in the IFN-curcumin group and 4 in the IFN-placebo group), and 27 by month 24 (11 in the IFN-curcumin group and 16 in the IFN-placebo group). Although no between-group difference was present in terms of proportion of subjects free from new/enlarging T2 lesions, a lower proportion of patients with CUA lesions was noted at month 12 in the IFN-curcumin group in comparison with the IFN-placebo group (7.5% vs 17.5%, χ² test p= 0.0167). This result was not confirmed at month 24. The statistical analysis failed to reveal any difference between the two treatment groups - IFN-curcumin and IFN-placebo - in terms of relapses, disability progression, other MRI metrics of inflammation and MRI changes suggestive of ongoing neurodegeneration. No difference in the rate and nature of adverse events was observed between the two treatment groups. CONCLUSION: Although the study drop-out rate was too high to allow definite conclusions, our findings suggest that curcumin might add to IFN ß-1a efficacy on radiological signs of inflammation in MS, while it did not seem to exert any neuroprotective effect as assessed by clinical and MRI parameters. (NCT01514370).

Targeting of cancer cell death mechanisms by curcumin: Implications to cancer therapy.

Cancer is known as a second major cause of death globally. Nowadays, several modalities have been developed for the treatment of cancer. Radiotherapy and chemotherapy are the most common modalities in most countries. However, newer modalities such as immunotherapy and targeted therapy drugs can kill cancer cells with minimal side effects. All anticancer agents work based on the killing of cancer cells. Numerous studies are ongoing to kill cancer cells more effectively without increasing side effects to normal tissues. The combination modalities with low toxic agents are interesting for this aim. Curcumin is one of the most common herbal agents that has shown several anticancer properties. It can regulate immune system responses against cancer. Furthermore, curcumin has been shown to potentiate cell death signalling pathways and attenuate survival signalling pathways in cancer cells. The knowledge of how curcumin induces cell death in cancers can improve therapeutic efficiency. In this review, the regulatory effects of curcumin on different cell death mechanisms and their signalling pathways will be discussed. Furthermore, we explain how curcumin may potentiate the anticancer effects of other drugs or radiotherapy through modulation of apoptosis, mitotic catastrophe, senescence, autophagy and ferroptosis.

Effect of curcumin-pipeine supplementation on clinical status, mortality rate, oxidative stress, and inflammatory markers in critically ill ICU patients with COVID-19: a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: This study aims to investigate the efficacy of curcumin-piperine co-supplementation on oxidative stress factors, clinical symptoms, and mortality rate in patients with coronavirus (COVID-19) admitted to the intensive care unit (ICU). TRIAL DESIGN: This study is a randomized, placebo-controlled, double-blind, parallel-arm clinical trial. PARTICIPANTS: The study participants will be recruited from patients admitted to the ICU of Al-Zahra hospital with a definitive diagnosis of COVID-19. The inclusion criteria are aged between 20 and 75 years, confirmation of COVID-19 based on the PCR test, and admitted to the ICU. The exclusion criteria include the present use of parenteral nutrition support, a history of underlying diseases such as congenital disorders, immune diseases, renal and hepatic insufficiency, and pancreatitis, a history of sensitivity to herbal remedies such as turmeric and pepper, and regular use of anticoagulant drugs such as warfarin. This study will be performed in the Al-Zahra hospital, an academic hospital affiliated with Isfahan University of Medical Sciences, Isfahan, Iran. INTERVENTION AND COMPARATOR: Sixty eligible patients will be randomly assigned, in a 1:1 ratio, to receive curcumin-piperine capsules (three capsules/day; each capsules containing 500 mg curcumin plus 5 mg piperine; in total 1500 mg curcumin and 15 mg piperine/daily) for seven days (n=30) or matching placebo capsules (three capsules/day; each capsules containing 505 mg maltodextrin; totally 1515 mg, maltodextrin/ daily) for same duration (n=30). Capsules will be administered after oral or enteral feeding at 9, 15 and 21 o'clock. MAIN OUTCOMES: The primary outcome is the time from initiation of supplementation (curcumin-piperine or placebo) to normalization of fever, respiratory rate, and blood oxygen saturation. The secondary outcomes are the mortality rate, length of stay in ICU, temperature, levels of blood oxygen saturation, ventilator dependency, respiratory rate, levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), levels of liver markers (ALT, AST, LDH), and levels of kidney function markers (BUN, Creatinine). FOLLOW UP: All of the parameters will be assessed at baseline and end of the study (7 days intervention). In addition, the rate of mortality will be collected after 4 weeks (28 days' mortality in the ICU, 4 weeks follow up). RANDOMISATION: Eligible patients will be randomly assigned to either the intervention group (Curcumin-piperine) or the control group (Placebo). Randomization sequences will be generated using an electronic table of random numbers to allocate the included participants into either control or intervention groups (in a 1:1 ratio) using the stratified block randomization method. Stratification was conducted according to sex (male and female), with a block size of four. The allocation sequences will be prepared by an independent statistician and will be kept inside sealed, opaque, and consecutively numbered envelopes. Participants, investigators, nurses, and physicians will be unaware of the trial-group assignment. BLINDING (MASKING): This study is a double-blind clinical trial (participants, investigators, nurses, and physicians). The curcumin-piperine and placebo supplements will be similar in the terms of texture, taste, color, odor, and weight. Both tablets will be provided in containers that are completely identical in weight, shape, labeling, and packaging. All participants, investigators, nurses, and physicians will be unaware of the trial-group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is estimated at 60 participants, including 30 patients in the intervention group and 30 patients in the placebo group. TRIAL STATUS: The protocol is Version 2, registered on May 13, 2021. Recruitment began May 20, 2021, and is anticipated to be completed by September 20, 2021. TRIAL REGISTRATION: This trial has been registered in Iranian Registry of Clinical Trials (IRCT) with the title of "Evaluation of the effect of curcumin-piperine supplementation in patients with coronavirus admitted to the intensive care unit (ICU): a double-blind clinical trial study". IRCT registration number is IRCT20121216011763N52 . The registration date was May 13, 2021. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (File 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Experimental and clinical studies on radiation and curcumin in human glioma.

PURPOSE: There is progressing evidence for the anti-cancer potential of the natural compound and dietary spice curcumin. Curcumin has been ascribed to be cytotoxic for various tumour cell types, to inhibit cell proliferation and to interfere with the cellular oxidant status. The compound has been notified as a therapeutic agent with radiosensitizing potential in brain tumour therapy. We considered the rationale to combine curcumin with radiation in the treatment of human glioblastoma multiforme (GBM). METHOD: Determination of clonogenic cell survival following exposure of U251 human glioma cells to single dose (1-6 Gy) and fractionated irradiation (5 daily fractions of 2 Gy) without and with curcumin. Additional literature search focused on the interaction between curcumin and radiotherapy in experimental and clinical studies on human glioma. RESULTS: No interaction was found on the survival of U251 human glioma cells after irradiation in combination with curcumin at clinically achievable concentrations. Experimental in vitro and in vivo data together with clinical bioavailability data from the literature do not give evidence for a radiosensitizing effect of curcumin. Reported GBM intratumoural curcumin concentrations are too low to either exert an own cytotoxic effect or to synergistically interact with radiation. Novel approaches are being explored to increase the bioavailability of curcumin and to facilitate transport over the blood-brain barrier, aimed to reach therapeutic curcumin levels at the tumour site. CONCLUSION: There is neither a biological nor clinical rationale for using curcumin as radiosensitizer in the therapy of GBM patients.

Suppressive effects of curcumin on milk production without inflammatory responses in lactating mammary epithelial cells.

BACKGROUND: Curcumin is a naturally occurring polyphenol found in Curcuma longa with multiple therapeutic properties, such as anti-inflammatory, wound healing and anti-cancer effects. Curcuma longa is also used as a galactagogue to improve milk production during lactation. PURPOSE: To assess curcumin could have therapeutic potential for breastfeeding mothers, we investigated whether and how curcumin influences milk production in lactating mammary epithelial cells (MECs) at the cellular and molecular levels. METHODS: We prepared a lactating MEC culture model that produced milk components and formed less-permeable tight junctions (TJs) to investigate the molecular mechanism of curcumin on milk production, TJs, and inflammation in vitro. RESULTS: Curcumin downregulated milk production in lactation MECs concurrently with inactivation of lactogenesis-relating signaling (STAT5 and glucocorticoid receptor). The maintenance of a less-permeable TJ barrier was also confirmed, although the TJ protein claudin-4 increased. Curcumin inactivated NFκB and STAT3 signaling, which are closely involved in inflammatory responses in weaning and mastitis mammary glands. The expression levels of IL-1ß and TNF-α were also decreased by curcumin treatment. Furthermore, curcumin blocked activation of inflammatory signaling by lipopolysaccharide treatment in MECs, similar to those in MECs that were treated with diclofenac sodium. The drastic phosphorylation of ERK was induced by curcumin treatment in the absence of EGF. U0126, an inhibitor of ERK phosphorylation, attenuated the adverse effects of curcumin on lactating MECs. CONCLUSION: The results of the present study suggests that curcumin downregulates milk production via inactivation of STAT5 and GR signaling with concurrent suppression of inflammatory responses via STAT3 and NFκB signaling in MECs. These findings provide new insights into the role of curcumin as a mild suppressor of milk production without inflammatory damages in breastfeeding mothers.

The role of curcumin in aging and senescence: Molecular mechanisms.

Healthy aging and human longevity are intricate phenotypes affected by environmental factors such as physical exercise, diet, health habits, and psychosocial situations as well as genetic factors. Diet and caloric restriction have a crucial role in healthy aging. Curcumin, a polyphenolic compound isolated from the Curcuma longa, has been shown to exert anti-aging characteristics. Recently, investigations on curcumin with regard to aging and age-associated disease in model organisms has described that curcumin and its metabolites, prolong the mean lifespan of some aging model organisms such as C. elegans, D. melanogaster, yeast, and mouse. It has been proposed to have several biological activities, such as antioxidative, anti-inflammatory, anticancer, chemopreventive, and anti-neurodegenerative characteristics. In several studies on various model organisms it has been shown that the lifespan extension via curcumin treatment was connected with enhanced superoxide dismutase (SOD) activity, and also declined malondialdehyde (MDA) and lipofuscin levels. As well as the pivotal role of curcumin on the modulating of major signaling pathways that influence longevity of organisms like IIS, mTOR, PKA, and FOXO signaling pathways. This review defines the use of curcumin in traditional and modern medicine, its biochemistry and biological functions, such as curcumin's anti-aging, anti-cancer, anti-microbial, anti-inflammatory, and anti-oxidant characteristics. Also, the review further describes the role of curcumin in a pharmacological context and new insights on its therapeutic capacity and restrictions. Particularly, the review emphasizes in-depth on the efficiency of curcumin and its mechanism of action as an anti-aging compound and also treating age-related disease.

Nanocurcumin as an Add-on to Antipsychotic Drugs for Treatment of Negative Symptoms in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE/BACKGROUND: It is well documented that one of the pathophysiological mechanisms of negative symptoms in patients with schizophrenia is hypofunction of N-methyl-d-aspartate receptors. This double-blind, placebo-controlled clinical trial was designed to assess the efficacy and safety of nanocurcumin as an adjuvant agent on psychotic symptoms, especially negative symptoms, in patients with chronic schizophrenia. METHODS/PROCEDURES: Fifty-six inpatients with stable chronic schizophrenia and predominant negative symptoms were randomized in a 1:1 ratio to nanocurcumin soft gel capsule (160 mg/d) and control groups, along with their antipsychotic regimen for 16 weeks. The efficacy of treatment was assessed by Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, Clinical Global Impressions-Severity, and Clinical Global Impressions-Improvement scales. Extrapyramidal symptoms were evaluated by Simpson-Angus Scale and Barnes Akathisia Rating Scale. Patients were assessed at baseline and weeks 4, 8, 12, and 16 after the medication started. FINDINGS/RESULTS: No significant differences were observed in demographic or clinical variables between both groups at baseline. The nanocurcumin group showed significantly greater improvement on the negative subscale (P = 0.05), the general psychopathology subscale (P < 0.001), the positive subscale (P = 0.004), total Positive and Negative Syndrome Scale (P < 0.001), Clinical Global Impressions-Severity (P < 0.001), and Clinical Global Impressions-Improvement scores (P < 0.001) in comparison with the control group at the endpoint. Extrapyramidal symptom rating scales and Calgary Depression Scale for Schizophrenia and frequency of other adverse effects were comparable between 2 groups. IMPLICATIONS/CONCLUSIONS: The present study indicates nanocurcumin as a safe and potential adjunctive treatment strategy for treatment of primary negative symptoms of schizophrenia.

Acute liver injury following turmeric use in Tuscany: An analysis of the Italian Phytovigilance database and systematic review of case reports.

AIMS: Several cases of acute non-infectious cholestatic hepatitis recently appeared in Italy following consumption of Curcuma longa-containing dietary supplements. The aim of this research was to describe the Tuscan (Italy) cases of acute hepatitis and to compare them with similar cases of hepatotoxicity published in the literature by performing a systematic review. METHODS: Records of Tuscan cases of acute hepatitis were obtained from the Italian Phytovigilance system. Each spontaneous report was analysed in order to collect all relevant clinical information of patients and information concerning the Curcuma longa-containing dietary supplement. Moreover, both the RUCAM and WHO-UMC systems were used to evaluate the causal relationship between the use of dietary supplement and acute hepatitis. A systematic literature review was performed in MEDLINE and Embase and all case-reports and case-series published in English were included. RESULTS: Seven cases of acute hepatitis occurring in Tuscany up to September 2019 are described. In all cases, hepatotoxicity was associated with Curcuma longa formulations with high bioavailability and high dosage of curcumin/curcuminoids. The causal relationship was also supported by the positive dechallenge observed in most cases. In the 23 cases identified through the systematic review, the majority of patients were concomitantly exposed to at least one other medication and 16 of them experienced a positive dechallenge. CONCLUSIONS: Within the frame of poorly controlled and regulated products, such as dietary supplements, the evaluation of Italian cases of Curcuma longa-induced acute hepatitis and the systematic review of literature confirmed the association between Curcuma longa and liver injury.