Combination Chemotherapy with Selected Polyphenols in Preclinical and Clinical Studies-An Update Overview.

This review article describes studies published over the past five years on the combination of polyphenols, which are the most studied in the field of anticancer effects (curcumin, quercetin, resveratrol, epigallocatechin gallate, and apigenin) and chemotherapeutics such as cisplatin, 5-fluorouracil, oxaliplatin, paclitaxel, etc. According to WHO data, research has been limited to five cancers with the highest morbidity rate (lung, colorectal, liver, gastric, and breast cancer). A systematic review of articles published in the past five years (from January 2018 to January 2023) was carried out with the help of all Web of Science databases and the available base of clinical studies. Based on the preclinical studies presented in this review, polyphenols can enhance drug efficacy and reduce chemoresistance through different molecular mechanisms. Considering the large number of studies, curcumin could be a molecule in future chemotherapy cocktails. One of the main problems in clinical research is related to the limited bioavailability of most polyphenols. The design of a new co-delivery system for drugs and polyphenols is essential for future clinical research. Some polyphenols work in synergy with chemotherapeutic drugs, but some polyphenols can act antagonistically, so caution is always required.

The Role of Mitochondria in Phytochemically Mediated Disease Amelioration.

Mitochondrial dysfunction may cause cell death, which has recently emerged as a cancer prevention and treatment strategy mediated by chemotherapy drugs or phytochemicals. However, most existing drugs cannot target cancerous cells and may adversely affect normal cells via side effects. Mounting studies have revealed that phytochemicals such as resveratrol could ameliorate various diseases with dysfunctional or damaged mitochondria. For instance, resveratrol can regulate mitophagy, inhibit oxidative stress and preserve membrane potential, induce mitochondrial biogenesis, balance mitochondrial fusion and fission, and enhance the functionality of the electron transport chain. However, there are only a few studies suggesting that phytochemicals could potentially protect against the cytotoxicity of some current cancer drugs, especially those that damage mitochondria. Besides, COVID-19 and long COVID have also been reported to be correlated to mitochondrial dysfunction. Curcumin has been reported bringing a positive impact on COVID-19 and long COVID. Therefore, in this study, the benefits of resveratrol and curcumin to be applied for cancer treatment/prevention and disease amelioration were reviewed. Besides, this review also provides some perspectives on phytochemicals to be considered as a treatment adjuvant for COVID-19 and long COVID by targeting mitochondrial rescue. Hopefully, this review can provide new insight into disease treatment with phytochemicals targeting mitochondria.

The Impact of Curcumin on Immune Response: An Immunomodulatory Strategy to Treat Sepsis.

Primary and secondary immunodeficiencies cause an alteration in the immune response which can increase the rate of infectious diseases and worsened prognoses. They can also alter the immune response, thus, making the infection even worse. Curcumin is the most biologically active component of the turmeric root and appears to be an antimicrobial agent. Curcumin cooperates with various cells such as macrophages, dendritic cells, B, T, and natural killer cells to modify the body's defence capacity. Curcumin also inhibits inflammatory responses by suppressing different metabolic pathways, reduces the production of inflammatory cytokines, and increases the expression of anti-inflammatory cytokines. Curcumin may also affect oxidative stress and the non-coding genetic material. This review analyses the relationships between immunodeficiency and the onset of infectious diseases and discusses the effects of curcumin and its derivatives on the immune response. In addition, we analyse some of the preclinical and clinical studies that support its possible use in prophylaxis or in the treatment of infectious diseases. Lastly, we examine how nanotechnologies can enhance the clinical use of curcumin.

Anti-viral drug discovery against monkeypox and smallpox infection by natural curcumin derivatives: A Computational drug design approach.

Background: In the last couple of years, viral infections have been leading the globe, considered one of the most widespread and extremely damaging health problems and one of the leading causes of mortality in the modern period. Although several viral infections are discovered, such as SARS CoV-2, Langya Henipavirus, there have only been a limited number of discoveries of possible antiviral drug, and vaccine that have even received authorization for the protection of human health. Recently, another virial infection is infecting worldwide (Monkeypox, and Smallpox), which concerns pharmacists, biochemists, doctors, and healthcare providers about another epidemic. Also, currently no specific treatment is available against Monkeypox. This research gap encouraged us to develop a new molecule to fight against monkeypox and smallpox disease. So, firstly, fifty different curcumin derivatives were collected from natural sources, which are available in the PubChem database, to determine antiviral capabilities against Monkeypox and Smallpox. Material and method: Preliminarily, the molecular docking experiment of fifty different curcumin derivatives were conducted, and the majority of the substances produced the expected binding affinities. Then, twelve curcumin derivatives were picked up for further analysis based on the maximum docking score. After that, the density functional theory (DFT) was used to determine chemical characterizations such as the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), softness, and hardness, etc. Results: The mentioned derivatives demonstrated docking scores greater than 6.80 kcal/mol, and the most significant binding affinity was at -8.90 kcal/mol, even though 12 molecules had higher binding scores (-8.00 kcal/mol to -8.9 kcal/mol), and better than the standard medications. The molecular dynamic simulation is described by root mean square deviation (RMSD) and root-mean-square fluctuation (RMSF), demonstrating that all the compounds might be stable in the physiological system. Conclusion: In conclusion, each derivative of curcumin has outstanding absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. Hence, we recommended the aforementioned curcumin derivatives as potential antiviral agents for the treatment of Monkeypox and Smallpox virus, and more in vivo investigations are warranted to substantiate our findings.

Curcumin Confers Anti-Inflammatory Effects in Adults Who Recovered from COVID-19 and Were Subsequently Vaccinated: A Randomized Controlled Trial.

COVID-19 infection and vaccination offer disparate levels of defense against reinfection and breakthrough infection. This study was designed to examine the effects of curcumin supplementation, specifically HydroCurc (CURC), versus placebo (CON) on circulating inflammatory biomarkers in adults who had previously been diagnosed with COVID-19 and subsequently received a primary series of monovalent vaccine doses. This study was conducted between June 2021 and May 2022. Participants were randomized to receive CURC (500 mg) or CON capsules twice daily for four weeks. Blood sampling was completed at baseline and week-4 and analyzed for biomarkers. Linear regression was utilized to examine the between-group differences in post-trial inflammatory biomarker levels, adjusting for baseline and covariates including age, sex, race/ethnicity, and interval between COVID-19 diagnosis and trial enrollment. The sample (n = 31) was 71% female (Age 27.6 ± 10.4 y). The CURC group exhibited significantly lower post-trial concentrations of proinflammatory IL-6 (ß = -0.52, 95%CI: -1.03, -0.014, p = 0.046) and MCP-1 (ß = -0.12, 95%CI: -0.23, -0.015, p = 0.027) compared to CON, adjusting for baseline and covariates. Curcumin intake confers anti-inflammatory activity and may be a promising prophylactic nutraceutical strategy for COVID-19. These results suggest that 4 weeks of curcumin supplementation resulted in significantly lower concentrations of proinflammatory cytokines in adults who recovered from COVID-19 infection and were subsequently vaccinated.

Prediction and Verification of Curcumin as a Potential Drug for Inhibition of PDCoV Replication in LLC-PK1 Cells.

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus (CoV) that causes lethal watery diarrhea in neonatal pigs and poses economic and public health burdens. Currently, there are no effective antiviral agents against PDCoV. Curcumin is the active ingredient extracted from the rhizome of turmeric, which has a potential pharmacological value because it exhibits antiviral properties against several viruses. Here, we described the antiviral effect of curcumin against PDCoV. At first, the potential relationships between the active ingredients and the diarrhea-related targets were predicted through a network pharmacology analysis. Twenty-three nodes and 38 edges were obtained using a PPI analysis of eight compound-targets. The action target genes were closely related to the inflammatory and immune related signaling pathways, such as the TNF signaling pathway, Jak-STAT signaling pathway, and so on. Moreover, IL-6, NR3C2, BCHE and PTGS2 were identified as the most likely targets of curcumin by binding energy and 3D protein-ligand complex analysis. Furthermore, curcumin inhibited PDCoV replication in LLC-PK1 cells at the time of infection in a dose-dependent way. In poly (I:C) pretreated LLC-PK1 cells, PDCoV reduced IFN-ß production via the RIG-I pathway to evade the host's antiviral innate immune response. Meanwhile, curcumin inhibited PDCoV-induced IFN-ß secretion by inhibiting the RIG-I pathway and reduced inflammation by inhibiting IRF3 or NF-κB protein expression. Our study provides a potential strategy for the use of curcumin in preventing diarrhea caused by PDCoV in piglets.

Therapeutic potential of curcumin in ARDS and COVID-19.

Curcumin is a safe, non-toxic, readily available and naturally occurring compound, an active constituent of Curcuma longa (turmeric). Curcumin could potentially treat diseases, but faces poor physicochemical and pharmacological characteristics. To overcome these limitations, we developed a stable, water-soluble formulation of curcumin called cyclodextrin-complexed curcumin (CDC). We have previously shown that direct delivery of CDC to the lung following lipopolysaccharides exposure reduces acute lung injury (ALI) and effectively reduces lung injury, inflammation and mortality in mice following Klebsiella pneumoniae. Recently, we found that administration of CDC led to a significant reduction in angiotensin-converting enzyme 2 and signal transducer and activator of transcription 3 expression in gene and protein levels following pneumonia, indicating its potential in treating coronavirus disease 2019 (COVID-19). In this review, we consider the clinical features of ALI and acute respiratory distress syndrome (ARDS) and the role of curcumin in modulating the pathogenesis of bacterial/viral-induced ARDS and COVID-19.

The effectiveness of nano-curcumin on patients with COVID-19: A systematic review of clinical trials.

The main aim of the current study was to summarize the findings of available clinical studies to assess nano-curcumin's influence on COVID patients. A comprehensive online search was performed in Scopus, PubMed, ISI Web of Science, and Google Scholar until March 2022 to identify trials that investigated the effects of nano-curcumin in patients with COVID-19. Eight studies comprising 569 patients were included in this review. Compared with placebo, nano-curcumin had no significant effect on C-reactive protein (CRP) and high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). However, gene expression of IL-6 and gene expression as well as secretion of interleukin-1 beta (IL-1ß) significantly decreased following nano-curcumin intervention. Nano-curcumin had beneficial effects on fever, cough, chills, myalgia, and olfactory and taste disturbances. The duration of hospitalization and mortality rate were significantly lower in the nano-curcumin group compared with the control group. Lymphocyte count was significantly increased after curcumin supplementation. Nano-curcumin also had favorable effects on O2 saturation, sputum, chest pain, wheeze, and dyspnea in patients with COVID-19. No major adverse effects were reported in response to nano-curcumin supplementation. In summary, the results of this systematic review of clinical trials suggested that nano-curcumin supplementation has beneficial effects on inflammation, respiratory function, disease manifestations, and complications in patients with COVID-19 viral infection.

Curcumin-piperine co-supplementation and human health: A comprehensive review of preclinical and clinical studies.

Curcumin is extracted from the rhizomes Curcuma longa L. It is known for its anti-inflammatory and anti-oxidant activities. Despite its safety and potential for use against various diseases, curcumin's utility is restricted due to its low oral bioavailability. Co-administration of curcumin along with piperine could potentially improve the bioavailability of curcumin. The present review aimed to provide an overview of the efficacy and safety of curcumin-piperine co-supplementation in human health. The findings of this comprehensive review show the beneficial effects of curcumin-piperine in improving glycemic indices, lipid profile and antioxidant status in diabetes, improving the inflammatory status caused by obesity and metabolic syndrome, reducing oxidative stress and depression in chronic stress and neurological disorders, also improving chronic respiratory diseases, asthma and COVID-19. Further high-quality clinical trial studies are needed to firmly establish the clinical efficacy of the curcumin-piperine supplement.

Antiinflammatory Activities of Curcumin and Spirulina: Focus on Their Role against COVID-19.

Nutraceuticals have for several years aroused the interest of researchers for their countless properties, including the management of viral infections. In the context of the COVID-19 pandemic, studies and research on the antiviral properties of nutraceuticals have greatly increased. More specifically, over the past two years, researchers have focused on analyzing the possible role of nutraceuticals in reducing the risk of SARS-CoV-2 infection or mitigating the symptoms of COVID-19. Among nutraceuticals, turmeric, extracted from the rhizome of the Curcuma Longa plant, and spirulina, commercial name of the cyanobacterium Arthrospira platensis, have assumed considerable importance in recent years. The purpose of this review is to collect, through a search of the most recent articles on Pubmed, the scientific evidence on the role of these two compounds in the fight against COVID-19. In the last two years many hypotheses, some confirmed by clinical and experimental studies, have been made on the possible use of turmeric against COVID-19, while on spirulina and its possible role against SARS-CoV-2 infection information is much less. The demonstrated antiviral properties of spirulina and the fact that these cyanobacteria may modulate or modify some mechanisms also involved in the onset of COVID-19, lead us to think that it may have the same importance as curcumin in fighting this disease and to speculate on the possible combined use of these two substances to obtain a synergistic effect.

Optimization of Anti-SARS-CoV-2 Treatments Based on Curcumin, Used Alone or Employed as a Photosensitizer.

Curcumin, the bioactive compound of the spice Curcuma longa, has already been reported as a potential COVID-19 adjuvant treatment due to its immunomodulatory and anti-inflammatory properties. In this study, SARS-CoV-2 was challenged with curcumin; moreover, curcumin was also coupled with laser light at 445 nm in a photodynamic therapy approach. Curcumin at a concentration of 10 µM, delivered to the virus prior to inoculation on cell culture, inhibited SARS-CoV-2 replication (reduction >99%) in Vero E6 cells, possibly due to disruption of the virion structure, as observed using the RNase protection assay. However, curcumin was not effective as a prophylactic treatment on already-infected Vero E6 cells. Notably, when curcumin was employed as a photosensitizer and blue laser light at 445 nm was delivered to a mix of curcumin/virus prior to the inoculation on the cells, virus inactivation was observed (>99%) using doses of curcumin that were not antiviral by themselves. Photodynamic therapy employing crude curcumin can be suggested as an antiviral option against SARS-CoV-2 infection.

Curcumin partly prevents ISG15 activation via ubiquitin-activating enzyme E1-like protein and decreases ISGylation.

The expression of the ubiquitin-like molecule interferon-stimulated gene 15 kDa (ISG15) and post-translational protein modification by ISG15 (ISGylation) are strongly activated by interferons or pathogen infection, suggesting that ISG15 and ISGylation play an important role in innate immune responses. More than 400 proteins have been found to be ISGylated. ISG15 is removed from substrates by interferon-induced ubiquitin-specific peptidase 18 or severe acute respiratory syndrome coronavirus 2‒derived papain-like protease. Therefore, maintaining strong ISGylation may help prevent the spread of coronavirus disease 2019 (COVID-19). However, it is unknown whether nutrients or chemicals affect ISGylation level. Curcumin is the major constituent of turmeric and functions as an immunomodulator. Here, we investigated the effect of curcumin on ISGylation. MCF10A and A549 cells were treated with interferon α and curcumin after which the expression levels of various proteins were determined. The effect of curcumin on ubiquitylation was also determined. Curcumin treatment was found to reduce ISGylation in a dose-dependent manner. The findings suggested that curcumin partly prevents disulfide bond-mediated ISG15 dimerization directly or indirectly, thereby increasing monomer ISG15 levels. Reduced ISGylation may also occur via the prevention of ISG15 activation by ubiquitin-activating enzyme E1-like protein. In conclusion, curcumin treatment was found to reduce ISGylation, suggesting that it may contribute to severe COVID-19. This is the first study to report a relationship between ISGylation and a food component.

The Efficacy of Traditional Medicinal Plants in Modulating the Main Protease of SARS-CoV-2 and Cytokine Storm.

Selected traditional medicinal plants exhibit therapeutic effects in coronavirus disease (Covid-19) patients. This review aims to identify the phytochemicals from five traditional medicinal plants (Glycyrrhiza glabra, Nigella sativa, Curcuma longa, Tinospora cordifolia and Withania somnifera) with high potential in modulating the main protease (Mpro) activity and cytokine storm in Covid-19 infection. The Mpro binding affinity of 13 plant phytochemicals were in the following order: Withanoside II>withanoside IV>withaferin A>α-hederin>withanoside V>sitoindoside IX>glabridin>liquiritigenin, nigellidine>curcumin>glycyrrhizin>tinocordiside>berberine. Among these phytochemicals, glycyrrhizin, withaferin A, curcumin, nigellidine and cordifolioside A suppressed SARS-CoV-2 replication and showed stronger anti-inflammatory activities than standard Covid-19 drugs. Both preclinical and clinical evidences supported the development of plant bioactive compounds as Mpro inhibitors.

Molecular Modeling and Simulation Analysis of Antimicrobial Photodynamic Therapy Potential for Control of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enter the host cells by binding the viral surface spike glycoprotein (SG) to angiotensin-converting enzyme 2. Since antiviral photodynamic therapy (aPDT) has been described as a new method for inhibiting viral infections, it is important to evaluate whether it can be used as a photoactivated disinfectant to control COVID-19. In this in silico study, SARS-CoV-2-SG was selected as a novel target for curcumin as a photosensitizer during aPDT to exploit its physicochemical properties, molecular modeling, hierarchical nature of protein structure, and functional analysis using several bioinformatics tools and biological databases. The results of a detailed computational investigation revealed that SARS-CoV-2-SG is most similar to 6VXX_A, with 100% query cover and identity. The predicted structure of SARS-CoV-2-SG displayed that it is a protein with a positive charge and random coil dominates other secondary structures located outside the viral cell. The protein-protein interaction network showed that SARS-CoV-2-SG interacted with ten potential interacting partners. In addition, primary screening of binding modes through molecular docking showed that curcumin desires to bind and interact with residues of SARS-CoV-2-SG as the main site to enhance the yield of aPDT. Overall, the computer simulation reveals that SARS-CoV-2-SG can be a suitable target site for interaction with curcumin during aPDT.

Evaluating the Effects of Curcumin on the Cytokine Storm in COVID-19 Using a Chip-Based Multiplex Analysis.

SARS-CoV-2 can stimulate the expression of various inflammatory cytokines and induce the cytokine storm in COVID-19 patients leading to multiple organ failure and death. Curcumin as a polyphenolic compound has been shown to have anti-inflammatory properties and inhibit the release of numerous pro-inflammatory cytokines. We present multiplex analysis using the Evidence Investigator biochip system to determine the effect of curcumin on serum level of cytokines which are typically elevated in cytokine storm events, including tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and IL-10.

Curcumin and Its Analogs as a Therapeutic Strategy in Infections Caused by RNA Genome Viruses.

The use of natural resources for the prevention and treatment of diseases considered fatal to humanity has evolved. Several medicinal plants have nutritional and pharmacological potential in the prevention and treatment of viral infections, among them, turmeric, which is recognized for its biological properties associated with curcuminoids, mainly represented by curcumin, and found mostly in rhizomes. The purpose of this review was to compile the pharmacological activities of curcumin and its analogs, aiming at stimulating their use as a therapeutic strategy to treat infections caused by RNA genome viruses. We revisited its historical application as an anti-inflammatory, antioxidant, and antiviral agent that combined with low toxicity, motivated research against viruses affecting the population for decades. Most findings concentrate particularly on arboviruses, HIV, and the recent SARS-CoV-2. As one of the main conclusions, associating curcuminoids with nanomaterials increases solubility, bioavailability, and antiviral effects, characterized by blocking the entry of the virus into the cell or by inhibiting key enzymes in viral replication and transcription.

Nanocurcumin Potently Inhibits SARS-CoV-2 Spike Protein-Induced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial Cells.

Interleukin-mediated deep cytokine storm, an aggressive inflammatory response to SARS-CoV-2 virus infection in COVID-19 patients, is correlated directly with lung injury, multi-organ failure, and poor prognosis of severe COVID-19 patients. Curcumin (CUR), a phenolic antioxidant compound obtained from turmeric (Curcuma longa L.), is well-known for its strong anti-inflammatory activity. However, its in vivo efficacy is constrained due to poor bioavailability. Herein, we report that CUR-encapsulated polysaccharide nanoparticles (CUR-PS-NPs) potently inhibit the release of cytokines, chemokines, and growth factors associated with damage of SARS-CoV-2 spike protein (CoV2-SP)-stimulated liver Huh7.5 and lung A549 epithelial cells. Treatment with CUR-PS-NPs effectively attenuated the interaction of ACE2 and CoV2-SP. The effects of CUR-PS-NPs were linked to reduced NF-κB/MAPK signaling which in turn decreased CoV2-SP-mediated phosphorylation of p38 MAPK, p42/44 MAPK, and p65/NF-κB as well as nuclear p65/NF-κB expression. The findings of the study strongly indicate that organic NPs of CUR can be used to control hyper-inflammatory responses and prevent lung and liver injuries associated with CoV2-SP-mediated cytokine storm.

Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron, an in silico study.

BACKGROUND: Omicron (B.1.1.529), a variant of SARS-CoV-2 is currently spreading globally as a dominant strain. Due to multiple mutations at its Spike protein, including 15 amino acid substitutions at the receptor binding domain (RBD), Omicron is a variant of concern (VOC) and capable of escaping vaccine generated immunity. So far, no specific treatment regime is suggested for this VOC. METHODS: The three-dimensional structure of the Spike RBD domain of Omicron variant was constructed by incorporating 15 amino acid substitutions to the Native Spike (S) structure and structural changes were compared that of the Native S. Seven phytochemicals namely Allicin, Capsaicin, Cinnamaldehyde, Curcumin, Gingerol, Piperine, and Zingeberene were docked with Omicron S protein and Omicron S-hACE2 complex. Further, molecular dynamic simulation was performed between Crcumin and Omicron S protein to evaluate the structural stability of the complex in the physiological environment and compared with that of the control drug Chloroquine. RESULTS: Curcumin, among seven phytochemicals, was found to have the most substantial inhibitory potential with Omicron S protein. Further, it was found that curcumin could disrupt the Omicron S-hACE2 complex. The molecular dynamic simulation demonstrated that Curcumin could form a stable structure with Omicron S in the physiological environment. CONCLUSION: To conclude, Curcumin can be considered as a potential therapeutic agent against the highly infectious Omicron variant of SARS-CoV-2.