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Atherosclerosis is an inflammatory and multifaceted disorder resulting from the accumulation of lipid droplets and several types of immune cells, including macrophages, T and B lymphocytes in the arterial walls. A wide variety of macrophage subtypes with different functions is implicated in the development and progression of atherosclerotic lesions. The prevalence of specific macrophage subtypes, which is influenced by cytokines, mediators, and substances composing atherosclerotic lesions, has been suggested to be an appropriate indicator of transition from a stable to an unstable plaque phenotype. Thus, a better understanding of the mechanisms underlying the differentiation of macrophage subpopulations in relation to the plaque phenotype would help to develop novel approaches aiming at slowing-down the progression of atherosclerotic disease by modulating the polarization of these cells. In addition, many arms of the adaptative immune system, which are regulated by different subtypes of T and B lymphocytes, are involved in atherosclerosis progression and there is an increasing effort to identify immune-modulating therapies targeting either T or B cells with a potential anti-atherosclerotic impact. This paper summarizes the pathophysiology of atherosclerotic disease as it relates to the contribution from the immune system, reviewing the crucial role of macrophages, T and B lymphocytes.

Small ubiquitin-like modifier (SUMO) proteins, as a subgroup of post-translational modifiers, act to change the function of proteins. Through their interactions with different targets, immune pathways, and the responses they elicit, can be affected by these SUMO conjugations. Thus, both a change to protein function and involvement in immune pathways has the potential to promote an efficient immune response to either a pathogenic challenge, or the development of an imbalance that could lead to an autoimmune-based disease. Also, a variety of changes such as mutations and polymorphisms can interfere with common functions of these modifications and move an effective immune response in the direction of an autoimmune disease. The present review discusses the general characteristics of SUMO proteins and focuses on their involvement in rheumatoid arthritis as an autoimmune disease.

Despite incessant research, colon cancer still is one of the most common causes of fatalities in both men and women worldwide. Also, nearly 50% of patients with colorectal cancer show tumor recurrence. Recent investigations have highlighted the involvement of colon cancer stem cells (CCSCs) in cancer relapse and chemoresistance. CCSCs deliver a significant protumorigenic niche through persistent overexpression of self-renewal capabilities. Moreover, CSCs cross network with stromal cells, immune infiltrates, and cyotokine-chemokine, which potentiate their aggressive proliferative potential. Targeting CCSCs through small molecule inhibitors, miRNAs, and monoclonal antibodies (mAbs) in in vivo studies has generated compelling evidence for the effectiveness of these various treatments. This review effectively compiles the role of CCSC surface markers and dysregulated and/or upregulated pathways in the pathogenesis of colorectal cancer that can be used to target CCSCs for effective colorectal cancer treatment.

Curcumin, a naturally occurring phenolic compound isolated from Curcuma longa, has different pharmacological effects, including antiinflammatory, antimicrobial, antioxidant, and anticancer properties. However, curcumin has been found to have a limited bioavailability because of its hydrophobic nature, low-intestinal absorption, and rapid metabolism. Therefore, there is a need for enhancing the bioavailability and its solubility in water in order to increase the pharmacological effects of this bioactive compound. One strategy is curcumin complexation with transition metals to circumvent the abovementioned problems. Curcumin can undergo chelation with various metal ions to form metallo-complexes of curcumin, which may show greater effects as compared with curcumin alone. Promising results with metal curcumin complexes have been observed with regard to antioxidant, anticancer, and antimicrobial activity, as well as in treatment of Alzheimer's disease. The present review provides a concise summary of the characterization and biological properties of curcumin-metal complexes. © 2019 BioFactors, 45(3):304-317, 2019.

Turmeric extracts contain three primary compounds, which are commonly referred to as curcuminoids. They are curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin. While curcumin has been the most extensively studied of the curcuminoids, it suffers from low overall oral bioavailability due to extremely low absorption as a result of low water solubility and instability at acidic pH, as well as rapid metabolism and clearance from the body. However, DMC, which lacks the methoxy group on the benzene ring of the parent structure, has much greater chemical stability at physiological pH and has been recently reported to exhibit antitumor properties. However, the treatment of noncancerous diseases with DMC has not been comprehensively reviewed. Therefore, here we evaluate published scientific literature on the therapeutic properties of DMC. The beneficial pharmacological actions of DMC include anti-inflammatory, neuroprotective, antihypertensive, antimalarial, antimicrobial, antifungal, and vasodilatory properties. In addition, DMC's ability to ameliorate the effects of free radicals and an environment characterized by oxidative stress caused by the accumulation of advanced glycation end-products associated with diabetic nephropathy, as well as DMC's capacity to inhibit the migration and proliferation of vascular smooth muscle cells following balloon angioplasty are also addressed. This review collates the available literature regarding the therapeutic possibilities of DMC in noncancerous conditions.

Malignancy is a significant cause of mortality after organ transplantation. There is an increased rate of malignancy following heart transplantation (HTx) compared to the general population and other organ transplant recipients. Post-HTx patients with a history of malignancy are also at a higher risk of developing new malignancies or exacerbation of their existing malignancies. Mammalian target of Rapamycin inhibitors (mTORIs) are newly introduced immunosuppressive drugs with a unique mechanism of action. By changing the immunosuppressive regimen from classic drugs, especially calcineurin inhibitors (CNIs) to mTORIs, the rate of developing de novo malignancies and the relapse of former malignancies is significantly reduced. However, issues like allograft function, total surveillance of patients, and post-transplantation complications should be considered during the conversion of drug regimens utilizing CNIs to drug regimens employing mTORIs. We reviewed different post-heart transplant maintenance immunosuppressive regimens and their effect on post-HTx malignancies with a focus on mTORIs, compared safety against effectiveness, and gathered conclusions based on our review of the literature, which may lead clinicians to make a better evidence-based decision regarding post-HTx maintenance immunosuppressive drug regimens. Overall, CNI to mTORI conversion in post-HTx maintenance immunosuppressive drug regimens was associated with a reduced rate of developing malignancy in post-HTx patients. Furthermore, nephrotoxicity decreased significantly while using mTORIs in combination with lower doses of CNIs and the rejection rate was equivalent to CNI-only regimens. In conclusion, mTORI-based maintenance immunosuppressive drug regimens seem to be safe and beneficial when considering efficacy vs. adverse effects, and all-cause mortality rates are significantly lower in patients switched to mTORIs when compared to CNI recipients.

Traditional methods of inducing hyperlipidemia in animal models are either costly (genetic manipulation) or it is difficult to control for the effects of other variables. For example, during high-fat feeding, the amount of high-fat diet intake per animal cannot be precisely controlled. The aim of this study was to develop an experimental model of fatty organ degeneration induced by poloxamer 407 (P-407). The study was conducted in 2-month-old, male Sprague-Dawley rats that were administered intraperitoneally with either 10% (w/w) P-407 (1 g/kg) or saline (10 mL/kg) for 4 months. Their lipid profile, organ degeneration due to fat deposition, and body mass were assessed. Intraperitoneal administration of P-407 resulted in significant increases in plasma triglycerides (P ≤ 0.001), total cholesterol (P < 0.001), high-density lipoprotein-cholesterol (P ≤ 0.001), and low-density lipoprotein (P < 0.001) cholesterol. In contrast to the control group, fatty tissue degeneration was observed in the liver, spleen, and kidneys of P-407-treated rats. Positive correlations between fatty tissue degeneration, and the atherogenic index of plasma (P < 0.001) and the ratio of total cholesterol to high-density-lipoprotein (P < 0.001) were identified. In addition, treatment with P-407 for 3 to 4 months caused a significant reduction in body mass relative to controls (P < 0.001). Thus, this study describes the development of a cost-effective experimental rat model of organ degeneration, characterized by fat accumulation in the liver, spleen, and kidneys, which could be used for the study of steatosis and related diseases arising from sustained untreated dyslipidemia. Furthermore, both the atherogenic index of plasma and the ratio of total cholesterol to high-density lipoprotein-cholesterol can be used to predict the risk of fatty tissue degeneration in this model. The study was approval of the University of Jishou Biomedical Research Ethics Committee, China. Key words: atherogenic index of plasma; fatty degeneration; hyperlipidemia; intraperitoneal administration; poloxamer 407; rat model; triglyceride

Effective drug delivery is one of the most important issues associated with the administration of therapeutic agents that have low oral bioavailability. Curcumin is an active ingredient in the turmeric plant, which has low oral bioavailability due to its poor aqueous solubility. One strategy that has been considered for enhancing the aqueous solubility, and, thus, its oral bioavailability, is the use of chitosan as a carrier for curcumin. Chitosan is a biodegradable and biocompatible polymer that is relatively water-soluble. Therefore, various studies have sought to improve the aqueous solubility of chitosan. The use of different pharmaceutical excipients and formulation strategies has the potential to improve aqueous solubility, formulation processing, and the overall delivery of hydrophobic drugs. This review focuses on various methods utilized for chitosan-based delivery of curcumin.

CD47 is a receptor belonging to the immunoglobulin (Ig) superfamily and broadly expressed on cell membranes. Through interactions with ligands such as SIRPα, TSP-1, integrins, and SH2-domain bearing protein tyrosine phosphatase substrate-1 (SHPS-1), CD47 regulates numerous functions like cell adhesion, proliferation, apoptosis, migration, homeostasis, and the immune system. In this aspect, previous research has shown that CD47 modulates phagocytosis via macrophages, the transmigration of neutrophils, and the activation of T-cells, dendritic cells, and B-cells. Moreover, several studies have reported the increased expression of the CD47 receptor in a variety of diseases, including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), bladder cancer, acute myeloid leukemia (AML), Gaucher disease, Multiple Sclerosis and stroke among others. The ubiquitous expression of the CD47 cell receptor on most resident cells of the CNS has previously been established through different methodologies. However, there is little information concerning its precise functions in the development of different neurodegenerative pathologies in the CNS. Consequently, further research pertaining to the specific functions and roles of CD47 and SIRP is required prior to its exploitation as a druggable approach for the targeting of various neurodegenerative diseases that affect the human population. The present review attempts to summarize the role of both CD47 and SIRP and their therapeutic potential in neurodegenerative disorders.

Autoimmune diseases (ADs) are conditions in which the immune system cannot distinguish self from non-self and, as a result, tissue injury occurs primarily due to the action of various inflammatory mediators. Different immunosuppressive agents are used for the treatment of patients with ADs, but some clinical cases develop resistance to currently available therapies. The proteasome inhibitor bortezomib (BTZ) is an approved agent for first-line therapy of people with multiple myeloma. BTZ has been shown to improve the symptoms of different ADs in animal models and ameliorated symptoms in patients with systemic lupus erythematous, rheumatoid arthritis, myasthenia gravis, neuromyelitis optica spectrum disorder, Chronic inflammatory demyelinating polyneuropathy, and autoimmune hematologic diseases that were nonresponsive to conventional therapies. Proteasome inhibition provides a potent strategy for treating ADs. BTZ represents a proteasome inhibitor that can potentially be used to treat AD patients resistant to conventional therapies.

Programmed cell death processes such as apoptosis and autophagy strongly contribute to the onset and progression of cancer. Along with these lines, modulation of cell death mechanisms to combat cancer cells and elimination of resistance to apoptosis is of great interest. It appears that modulation of autophagy and endoplasmic reticulum (ER) stress with specific agents would be beneficial in the treatment of several disorders. Interestingly, it has been suggested that herbal natural products may be suitable candidates for the modulation of these processes due to few side effects and significant therapeutic potential. Ginsenosides are derivatives of ginseng and exert modulatory effects on the molecular mechanisms associated with autophagy and ER stress. Ginsenosides act as smart phytochemicals that confer their effects by up-regulating ATG proteins and converting LC3-I to -II, which results in maturation of autophagosomes. Not only do ginsenosides promote autophagy but they also possess protective and therapeutic properties due to their capacity to modulate ER stress and up- and down-regulate and/or dephosphorylate UPR transducers such as IRE1, PERK, and ATF6. Thus, it would appear that ginsenosides are promising agents to potentially restore tissue malfunction and possibly eliminate cancer.

There is data from individual clinical trials suggesting that procalcitonin (PCT) may be a prognostic factor in the severity of COVID-19 disease. Therefore, this systematic review and meta-analysis was performed to investigate PCT levels in severe COVID-19 patients. We searched Embase, ProQuest, MEDLINE/PubMed, Scopus, and ISI/Web of Science for studies that reported the level of PCT of patient with severe COVID-19. We included all studies regardless of design that reported the level of PCT in patients with severe COVID-19. We excluded articles not regarding COVID-19 or not reporting PCT level, studies not in severe patients, review articles, editorials or letters, expert opinions, comments, and animal studies. Nine studies were included in the analysis. The odds of having more severe COVID-19 disease was higher in subjects with elevated PCT (≥0.05 ng/mL) compared with those having low procalcitonin (0.05 ng/mL) [n = 6, OR(95% CI) = 2.91(1.14, 7.42), p = 0.025). After estimating the mean and standard deviation values from the sample size, median, and interquartile range, a pooled effect analysis indicated higher serum PCT concentrations in patients with severe versus less severe disease [n = 6, SMD(95% CI) = 0.64(0.02, 1.26), p = 0.042]. The results of this study showed that PCT is increased in patients with severe COVID-19 infection.

Drugs are organic compounds, and as a result, their activity, their solubility in plasma, and their distribution to various tissues are all dependent on their physicochemical properties. According to the Bronsted–Lowry theory, an acid is a substance, charged or uncharged, that is capable of donating a proton, and a base is a substance, charged or uncharged, that is capable of accepting a proton. Water can act as both a weak base and a weak acid, which might be another reason for the deviations. According to the pH partition hypothesis, the un-ionized form of a weakly basic or a weakly acidic drug partitions into the lipid bilayer of the membrane. Thus, it is important to be familiar with an expression that relates the percent or fraction of the drug in the ionized and the un-ionized state because of the regional differences in the pH of the gastrointestinal tract. This equation is called the Henderson–Hasselbalch equation.

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that induces caspase-1 activation and the downstream substrates involved with the processing and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and tumor necrosis factor-α (TNF- α). The NLRP3 inflammasome is activated by a wide range of danger signals that derive from metabolic dysregulation. Activation of this complex often involves the adaptor ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. It has been shown that nutraceuticals and medicinal plants have antiinflammatory properties and could be used as complementary therapy in the treatment of several chronic diseases that are related to inflammation, for example, cardiovascular diseases and diabetes mellitus. Herb-based medicine has demonstrated protective effects against NLRP3 inflammasome activation. Therefore, this review focuses on the effects of nutraceuticals and bioactive compounds derived from medicinal plants on NLRP3 inflammasome activation and the possible mechanisms of action of these natural products. Thus, herb-based, natural products/compounds can be considered novel, practical, and accessible agents in chronic inflammatory diseases by inhibiting NLRP3 inflammasome activation.

Mounting scientific evidence over decades has established that atherosclerosis is a chronic inflammatory disorder. Among the potentially critical sources of vascular inflammation during atherosclerosis are the components of pathogenic bacteria, especially lipopolysaccharide (LPS). Toll-like receptor (TLR)-4, expressed on different inflammatory cells involved with the recognition of bacterial LPS, has been recognized to have mutations that are prevalent in a number of ethnic groups. Such mutations have been associated with a decreased risk of atherosclerosis. In addition, epidemiological investigations have proposed that LPS confers a risk factor for the development of atherosclerosis. Gram-negative bacteria are the major source of LPS in an individual's serum, which may be generated during subclinical infections. The major cell receptors on inflammatory cells involved in the pathogenesis of atherosclerosis, like macrophages, monocytes, and dendritic cells (DCs), are CD14, MD-2, and LPS binding protein (LBP). These receptors have been blamed for the development of atherosclerosis through dysregulated activation following LPS recognition. Lipoproteins may also play a role in modulating the LPS-induced inflammatory events during atherosclerosis development. In this review article, we attempt to clarify the role of LPS in the initiation and progression of atherosclerotic lesion development.

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.

Programmed cell death processes such as apoptosis and autophagy strongly contribute to the onset and progression of cancer. Along with these lines, modulation of cell death mechanisms to combat cancer cells and elimination of resistance to apoptosis is of great interest. It appears that modulation of autophagy and endoplasmic reticulum (ER) stress with specific agents would be beneficial in the treatment of several disorders. Interestingly, it has been suggested that herbal natural products may be suitable candidates for the modulation of these processes due to few side effects and significant therapeutic potential. Ginsenosides are derivatives of ginseng and exert modulatory effects on the molecular mechanisms associated with autophagy and ER stress. Ginsenosides act as smart phytochemicals that confer their effects by up-regulating ATG proteins and converting LC3-I to -II, which results in maturation of autophagosomes. Not only do ginsenosides promote autophagy but they also possess protective and therapeutic properties due to their capacity to modulate ER stress and up- and down-regulate and/or dephosphorylate UPR transducers such as IRE1, PERK, and ATF6. Thus, it would appear that ginsenosides are promising agents to potentially restore tissue malfunction and possibly eliminate cancer.

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, children experience mild symptoms compared to adults. However, the precise explanations for this disparity are not clear. Thus, we attempted to identify rational explanations about age-related differences as reported in different studies. Given the incomplete data on SARS-CoV-2, some information has been gathered from other studies of earlier coronavirus or influenza outbreaks. Age-related differences in disease severity are important with regard to diagnosis, prognosis, and treatment of SARS-CoV-2 infections. In addition, these differences impact social distancing needs, since pediatric patients with mild or asymptomatic are likely to play a significant role in disease transmission.

Arterial stiffness describes the increased rigidity of the arterial wall that occurs as a consequence of biological aging and several diseases. Numerous studies have demonstrated that parameters to assess arterial stiffness, especially pulse-wave velocity, are predictive of those individuals that will suffer cardiovascular morbidity and mortality. Statin therapy may be a pharmacological strategy to improve arterial elasticity. It has been shown that the positive benefits of statin therapy on cardiovascular disease is attributable not only to their lipid-lowering capacity but also to various pleiotropic effects, such as their anti-inflammatory, antiproliferative, antioxidant, and antithrombotic properties. Additionally, statins reduce endothelial dysfunction, improve vascular and myocardial remodeling, and stabilize atherosclerotic plaque. The aim of the present review was to summarize the evidence from human studies showing the effects of statins on arterial stiffness.

There is data from individual clinical trials suggesting that procalcitonin (PCT) may be a prognostic factor in the severity of COVID-19 disease. Therefore, this systematic review and meta-analysis was performed to investigate PCT levels in severe COVID-19 patients. We searched Embase, ProQuest, MEDLINE/PubMed, Scopus, and ISI/Web of Science for studies that reported the level of PCT of patient with severe COVID-19. We included all studies regardless of design that reported the level of PCT in patients with severe COVID-19. We excluded articles not regarding COVID-19 or not reporting PCT level, studies not in severe patients, review articles, editorials or letters, expert opinions, comments, and animal studies. Nine studies were included in the analysis. The odds of having more severe COVID-19 disease was higher in subjects with elevated PCT (≥0.05 ng/mL) compared with those having low procalcitonin (

Natural compounds, primarily derived from plants, have been isolated and evaluated as alternative and complementary treatments for cancer. Curcumin has been proven to be beneficial in cancer therapy due to its multiple effects on cell signaling pathways, although the application of curcumin is limited due to its low oral bioavailability. Nanotechnology-based drug delivery systems have been used to overcome limited bioavailability and ensure greater biodistribution after administration. Nano-formulations of curcumin have shown more significant anticancer activity than free curcumin. Among the various nanocarriers, polymeric micelles with inherent stability and ease of formulation are ideal for tumor targeting via the enhanced permeation and retention (EPR) effect. The structure of polymeric micelles is suitable for the encapsulation of hydrophobic or low water-soluble drugs. Additionally, the outer shell of polymeric micelles provides protection against the normal uptake of foreign compounds by the reticuloendothelial system (RES). This review discusses the recent developments in curcumin delivery using polymeric micelles for various cancers.

The most widespread, malignant, and deadliest type of glial tumor is glioblastoma multiforme (GBM). Despite radiation, chemotherapy, and radical surgery, the median survival of afflicted individuals is about 12 months. Unfortunately, existing therapeutic interventions are abysmal. Dexamethasone (Dex), a synthetic glucocorticoid, has been used for many years to treat brain edema and inflammation caused by GBM. Several investigations have recently shown that Dex also exerts antitumoral effects against GBM. On the other hand, more recent disputed findings have questioned the long-held dogma of Dex treatment for GBM. Unfortunately, steroids are associated with various undesirable side effects, including severe immunosuppression and metabolic changes like hyperglycemia, which may impair the survival of GBM patients. Current ideas and concerns about Dex's effects on GBM cerebral edema, cell proliferation, migration, and its clinical outcomes were investigated in this study.

Background: Due to their plasticity, macrophages exert critical effects on both promoting and suppressing inflammatory processes. Pathologic inflammatory conditions are frequently correlated with dynamic alterations in macrophage activation, with classically activated M1 cells associated with the promotion and maintenance of inflammation and M2 cells being linked to the resolution or smouldering of chronic inflammation. Inflammation deputes a common feature of various chronic diseases and the direct involvement in the insurgence and development of these conditions. Macrophages participate in an autoregulatory loop characterizing the inflammatory process, as they produce a wide range of biologically active mediators that exert either deleterious or beneficial effects during the inflammation. Therefore, balancing the favorable ratios of M1/M2 macrophages can help ameliorate the inflammatory landscape of pathologic conditions. Curcumin is a component of turmeric with many pharmacological properties. Objective: Recent results from both in-vivo and in-vitro studies have indicated that curcumin can affect polarization and/or functions of macrophage subsets in the context of inflammation-related diseases. There is no comprehensive review of the impact of curcumin on cytokines involved in macrophage polarization in the context of inflammatory diseases. The present review will cover some efforts to explore the underlying molecular mechanisms by which curcumin modulates the macrophage polarization in distant pathological inflammatory conditions, such as cancer, autoimmunity, renal inflammation, stroke, atherosclerosis, and macrophage-driven pathogenesis. Result: The accumulation of the findings from in vitro and in vivo experimental studies suggests that curcumin beneficially influences M1 and M2 macrophages in a variety of inflammatory diseases with unfavorable macrophage activation. Conclusion: Curcumin not only enhances anti-tumor immunity (via shifting M polarization towards M1 phenotype and/or up-regulation of M1 markers expression) but ameliorates inflammatory diseases, including autoimmune diseases (experimental autoimmune myocarditis and Behcet's disease), nephropathy, chronic serum sickness, stroke, and atherosclerosis.

Glioblastoma multiforme (GBM), as one of the immunosuppressive and common intrinsic brain tumors in adults, remains an intractable malignancy to manage. Since the standard of care for treatment, which includes surgery and chemoradiation, has not provided a sustainable and durable response in affected patients, seeking novel therapeutic approaches to treat GBM seems imperative. Immunotherapy, a breakthrough for cancer treatment, has become an attractive tool for combating cancer with the potential to access the blood-brain-barrier (BBB). In this regard, programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), as major immunological checkpoints, have drawn considerable interest due to their effectiveness in a spectrum of highly-aggressive neoplasms through negative regulation of the T-cell-mediated immune response. Nevertheless, due to the immunosuppressive microenvironment of GBM, the efficacy of these immune checkpoint inhibitors (ICIs), when used as monotherapy, has been unfavorable and lacks sufficient beneficial outcomes for GBM patients. A variety of clinical studies are attempting to evaluate the combination of ICIs (neoadjuvant/adjuvant) and existing treatment guidelines to strengthen their effectiveness; however, the exact mechanism of this signaling axis affects the consequences of immune therapy remains elusive. This review provides an overview of the PD-1/PD-L1 pathway, currently approved ICIs for clinical use, preclinical and clinical trials of PD-1/PD-L1 as monotherapy, and when used concomitantly with other GBM treatments.

The concept of lysosomotropic agents significantly changed numerous aspects of cellular biochemistry, biochemical pharmacology, and clinical medicine. In the present review, we focused on numerous low-molecular and high-molecular lipophilic basic compounds and on the role of lipophagy and autophagy in experimental and clinical medicine. Attention was primarily focused on the most promising agents acting as autophagy inducers, which offer a new window for treatment and/or prophylaxis of various diseases, including type 2 diabetes mellitus, Parkinson’s disease, and atherosclerosis. The present review summarizes current knowledge on the lysosomotropic features of medical drugs, as well as autophagy inducers, and their role in pathological processes.

Introduction Coronavirus disease 2019 (COVID-19) has the characteristics of high transmission, diverse clinical manifestations, and a long incubation period. In addition to infecting the respiratory system, COVID-19 also has adverse effects on the cardiovascular system. COVID-19 causes acute myocardial injuries, as well as chronic damage to the cardiovascular system. Areas covered The present review is aimed at providing current information on COVID-19 and the cardiovascular system. PubMed, Scopus, Science direct, and Google Scholar were searched. Expert opinion It is suggested that heart injury caused by COVID-19 infection might be an important cause of severe clinical phenotypes or adverse events in affected patients. Myocardial damage is closely related to the severity of the disease and even the prognosis in patients with COVID-19. In addition to disorders that are caused by COVID-19 on the cardiovascular system, more protection should be employed for patients with preexisting cardiovascular disease (CVD). Hence, it is very important that once relevant symptoms appear, patients with COVID-19 be rapidly treated to reduce mortality. Thus, early measurements of cardiac damage via biomarkers following hospitalization for COVID-19 infections in a patient with preexisting CVD are recommended, together with careful monitoring of any myocardial injury that might be caused by the infection.Abbreviations: ICU: An intensive care unit; 2019-nCoV: 2019 novel coronavirus; ACEI: ACE inhibitor; ACS: Acute coronary syndrome; ARDS: Acute respiratory distress syndrome; AT1R: Ang II type 1 receptor; ATP: Adenosine triphosphate; ACC: American College of Cardiology; ACE: Angiotensin converting enzyme; Ang II: Angiotensin II; ARB: Angiotensin II receptor blocker; AV block: Atrioventricular block; CAD: Coronary artery disease; CVD: Cardiovascular disease; CT: Computerized tomography; CHF: Congestive heart failure; CHD: Coronary heart disease; CK-MB: Creatine kinase isoenzyme-MB; CRP: C-reactive protein; cTnI: Cardiac troponin I; EAT: Epicardial adipose tissue; ECMO: Extracorporeal membrane oxygenation; FDA: Food and Drug Administration; G-CSF: Granulocyte colony-stimulating factor; HFrEF: HF with a reduced ejection fraction; synhACE2: Human isoform of ACE2; IL: Interleukin; IABP: Intra-aortic balloon counterpulsation; IP10: Interferon γ-induced protein 10 kDa; LPC: Lysophosphatidylcholine; Mas: Mitochondrial assembly receptor; MCP1: Monocyte chemoattractant protein-1; MERS: Middle East respiratory syndrome; MIP1a: macrophage inflammatory protein 1a: MOF: Multiple organ failure; MI: Myocardial infarction; MRI: Magnetic resonance imaging; MYO: Myohe-moglobin; NT-proBNP: N-terminal pro-brain natriuretic peptide; PCPS: Percutaneous cardiopulmonary assistance; rhACE2: Recombinant human ACE2; SARS: Severe acute respiratory syndrome; Th: T helper; RAS: Renin-angiotensin system; TNF-α: Tumor necrosis factor-α; WHO: World Health Organization.

Introducing statins as possible widely-available drugs for the treatment of viral infections requires an in depth review of their antiviral properties. Despite some inconsistency, a large body of literature data from experimental and clinical studies suggest that statins may have a role in the treatment of viral infections due to their immunomodulatory properties as well as their ability to inhibit viral replication. In the present review, the role that statins may play while interacting with the immune system during viral infections and the possible inhibitory effects of statins on different stages of virus cell cycle (i.e., from fusion with host cell membranes to extracellular release) and subsequent virus transmission are described. Specifically, cholesterol-dependent and cholesterol-independent mechanisms of the antiviral effects of statins are reported.

The Wnt signaling pathway appears to activate intracellular signaling transduction in embryonic development, cell migration, hematopoiesis, and several diseases. Wnt signaling is basically recognized as a canonical β-catenin-dependent signaling pathway. However, in recent years, generally three Wnt-mediated pathways have been investigated, which operate independently of β-catenin and include calcium/calmodulin-dependent kinase II and protein kinase C, planar cell polarity, and a third one recruits hetrotrimeric GTP-binding proteins to stimulate phospholipase C and phosphodiesterase. We provide an overview of the noncanonical Wnt signaling pathway and then will focus on canonical Wnt signaling components, Wnt ligands, agonists, and antagonist. This review will also discuss β-catenin, both cytoplasmic and nuclear mechanisms, through signaling transduction, and, as a consequence, we have briefly highlighted potential implications of Wnt/β-catenin in some cancers.

The statin family of drugs are safe and effective therapeutic agents for the treatment of arteriosclerotic cardiovascular disease (CVD). Due to a wide range of health benefits in addition to their cholesterol lowering properties, statins have recently attracted significant attention as a new treatment strategy for several conditions, which are not directly related to normalizing a lipid profile and preventing CVD. Statins exert a variety of beneficial effects on different aspects of oral health, which includes their positive effects on bone metabolism, their anti-inflammatory and antioxidant properties, and their potential effects on epithelization and wound healing. Additionally, they possess antimicrobial, antiviral, and fungicidal properties, which makes this class of drugs attractive to the field of periodontal diseases and oral and dental health. However, to the best of our knowledge, there has been no comprehensive study to date, which has investigated the effects of statin drugs on different aspects of dental and oral health. Therefore, the primary objective of this paper was to review the effect of statins on dental and oral health. Results of our extensive review have indicated that statins possess remarkable and promising effects on several aspects of dental and oral health including chronic periodontitis, alveolar bone loss due to either extraction or chronic periodontitis, osseointegration of implants, dental pulp cells, orthodontic tooth movement, and orthodontic relapse, tissue healing (wound/bone healing), salivary gland function, and finally, anti-cancer effects. Hence, statins can be considered as novel, safe, inexpensive, and widely-accessible therapeutic agents to improve different aspects of dental and oral health.

HMG-CoA reductase inhibitors, or statins, are potent plasma LDL-cholesterol (LDL-c) lowering agents. Since the introduction of the first statin, lovastatin, in 1987, accumulating evidence showed that non-cholesterol lowering effects play an important role in their efficacy to reduce atherosclerotic cardiovascular disease (ASCVD). Thus, these non-LDL-c lowering properties could benefit patients with immune-mediated diseases. Statins and their associated immune-modulating roles have recently received much attention. Different statins have been administered in various experimental and clinical studies focused on autoimmunity. The results indicate that statins can modulate immune responses through mevalonate pathway-dependent and-independent mechanisms. The antiinflammatory and immune-modulating effects include cell adhesion, migration of antigen presenting cells, and differentiation, as well as activation, of T-cells. In various autoimmune diseases (e.g. rheumatoid arthritis, lupus, and multiple sclerosis), promising results have been obtained to date. (C) 2020 Elsevier Inc. All rights reserved.

Curcumin quite possibly represents one of the most diverse therapeutic agents yet isolated from natural sources. Therapeutic benefits of this extraordinary natural compound have been demonstrated during treatment of a variety of diseases, including cancer, inflammatory processes, immunological disorders, Diabetes, and oxidative stress often associated with hyperlipidemia. Due to its unique molecular chemical structure and functional groups, curcumin may bind with and subsequently either inhibit or activate a variety of endogenous biomolecules, including enzymes, receptors, signaling molecules, metals, transcription factors, and even certain proteins located in cell membranes. In fact, curcumin exerts pharmacologically useful effects through non-covalent interactions with biomolecules. With so many varied biological targets, curcumin (a polyphenol) elicits numerous pleiotropic effects, which is therapeutically advantageous owing to the fact that many pathological disease states involve more than one signaling pathway, receptor, protein/enzyme, or gene. In this paper, we will discuss the underlying mechanisms responsible for the chemical interaction of curcumin with selected classes of biomolecules, rather than attempt to provide an exhaustive list of each and every biomolecule with which curcumin may chemically interact.

Visual and retinal function was measured in a mouse model of chemically induced, sustained dyslipidemia to determine the contribution of dyslipidemia to the pathogenesis of retinopathy in the context of metabolic syndrome. Fifteen male C57BL/6Crl mice were divided into three groups. Poloxamer 407 (P-407), 14.5% w/w was delivered at a rate of 6 µl/day by implanted osmotic mini-pumps either subcutaneously (P-407 SQ) or intraperitoneally (P-407 IP) to P-407-treated mice, whereas saline was administered at the same rate to control mice using only the subcutaneous route of administration. Total cholesterol (TC) and true triglyceride (TG) levels were quantified from plasma. Optomotor responses to stimuli of varying spatial frequency or contrast were used to measure visual acuity and contrast sensitivity. Retinal function was determined using Ganzfeld flash electroretinography (ERG). At 32 days, TC for the P-407 IP group was significantly elevated compared to saline controls (169.4 ± 16.5 mg/dl, 0.001

Mannans, which are biological macromolecules of polysaccharide origin and function as immunomodulators, have been shown to stimulate macrophages in vivo by interaction with the mannose receptor. Thus, they can be used to stimulate macrophages in order to effectively remove circulating atherogenic lipoproteins. Our primary aim was to evaluate the hypolipidemic potential of mannans from C. albicans serotype A (mannan A) and serotype B (mannan B) in a murine model of hyperlipidemia. Mannan A and mannan B were shown to significantly (p

Curcumin is a polyphenol natural product isolated from turmeric, interacting with different cellular and molecular targets and, consequently, showing a wide range of pharmacological effects. Recent preclinical and clinical trials have revealed immunomodulatory properties of curcumin that arise from its effects on immune cells and mediators involved in the immune response, such as various T-lymphocyte subsets and dendritic cells, as well as different inflammatory cytokines. Systemic lupus erythematosus (SLE) is an inflammatory, chronic autoimmune-mediated disease characterized by the presence of autoantibodies, deposition of immune complexes in various organs, recruitment of autoreactive and inflammatory T cells, and excessive levels of plasma proinflammatory cytokines. The function and numbers of dendritic cells and T cell subsets, such as T helper 1 (Th1), Th17, and regulatory T cells have been found to be significantly altered in SLE. In the present report, we reviewed the results of in vitro, experimental (pre-clinical), and clinical studies pertaining to the modulatory effects that curcumin produces on the function and numbers of dendritic cells and T cell subsets, as well as relevant cytokines that participate in SLE.

Cardiovascular disease is one of the leading causes of mortality globally. Atherosclerosis is an important step towards different types of cardiovascular disease. The role of oxidized low-density lipoprotein (oxLDL) in the initiation and progression of atherosclerosis has been thoroughly investigated in recent years. Moreover, clinical trials have established that diabetic patients are at a greater risk of developing atherosclerotic plaques. Hence, we aimed to review the clinical and experimental impacts of various classes of antidiabetic drugs on the circulating levels of oxLDL. Metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitors were clinically associated with a suppressive effect on oxLDL in patients with impaired glucose tolerance. However, there is an insufficient number of studies that have clinically evaluated the relationship between oxLDL and newer agents such as agonists of glucagon-like peptide 1 receptor or inhibitors of sodium-glucose transport protein 2. Next, we attempted to explore the multitude of mechanisms that antidiabetic agents exert to counter the undesirable effects of oxLDL in macrophages, endothelial cells, and vascular smooth muscle cells. In general, antidiabetic drugs decrease the uptake of oxLDL by vascular cells and reduce subsequent inflammatory signaling, which prevents macrophage adhesion and infiltration. Moreover, these agents suppress the oxLDL-induced transformation of macrophages into foam cells by either inhibiting oxLDL entrance, or by facilitating its efflux. Thus, the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of antidiabetic agents abrogate changes induced by oxLDL, which can be extremely beneficial in controlling atherosclerosis in diabetic patients.

Atorvastatin calcium (ATV), a cholesterol-lowering agent, suffers from poor systemic availability (14%) after oral administration in addition to other side effects on the gastrointestinal tract, liver and muscle.The goal of the present investigation was to improve ATV bioavailability and overcome complications attendant with peroral administration by developing a new nanovesicular system encapsulating ATV for its delivery via the transdermal route.The vesicular systems were prepared by incorporating different polyethylene glycol fatty acid esters such as Labrasol, Cremophor EL, Gelucire 44/14 and Tween 80 as edge activators (EAs) in the lipid bilayer. The effect of the phosphatidylcholine (PC):EA molar ratio on the physicochemical properties of the vesicles was investigated. The pharmacokinetic studies of the optimized formulation were evaluated in rats. The optimized formulation was tested in poloxamer 407-induced hyperlipidemic rats. The plasma lipid profile, activity of liver enzymes, and oxidative stress parameters were measured using commercially available kits.The results revealed high ATV entrapment efficiency (EE%) ranging from 55.62 to 83.91%. The formulations that contained Labrasol showed the highest EE%. The mean diameter of the vesicles was in the range of 186-583nm. T8 containing Gelucire 44/14 as an EA in the molar ratio of 15:1 (PC:EA) gave the smallest size and exhibited the best permeation parameters across the skin. The pharmacokinetic studies revealed that about three times statistically significant (p0.05) improvement in bioavailability, after transdermal administration of nanotransfersomal ATV gel compared to oral ATV suspension. The transdermal vesicular system exhibited a significant decrease in plasma total cholesterol, triglycerides and LDL cholesterol comparable to oral ATV. Additionally, it lowered the malondialdehyde levels in plasma and abolished the increase in liver enzyme activity.The results obtained suggest that the proposed transdermal vesicular system can serve as a promising alternative means for delivery of ATV.

Exosomes are naturally occurring extracellular vesicles released by most mammalian cells in all body fluids. Exosomes are known as key mediators in cell‐cell communication and facilitate the transfer of genetic and biochemical information between distant cells. Structurally, exosomes are composed of lipids, proteins, and also several types of RNAs which enable these vesicles to serve as important disease biomarkers. Moreover, exosomes have emerged as novel drug and gene delivery tools owing to their multiple advantages over conventional delivery systems. Recently, increasing attention has been focused on exosomes for the delivery of drugs, including therapeutic recombinant proteins, to various target tissues. Exosomes are also promising vehicles for the delivery of microRNAs and small interfering RNAs, which is usually hampered by rapid degradation of these RNAs, as well as inefficient tissue specificity of currently available delivery strategies. This review highlights the most recent accomplishments and trends in the use of exosomes for the delivery of drugs and therapeutic RNA molecules., Exosomes are naturally occurring extracellular vesicles released by most mammalian cells in all body fluids. Recently, increasing attention has been focused on exosomes for the delivery of drugs, including therapeutic recombinant proteins, to various target tissues. This review highlights the most recent accomplishments and trends in the use of exosomes for the delivery of drugs and therapeutic RNA molecules. © 2017 Wiley Periodicals, Inc.This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

The oral route of drug administration is the most common and convenient route for dosing statin drugs, and, in fact, most medications, because of ease of drug delivery, patient compliance, and cost-effectiveness. However, the oral administration of statin drugs has disadvantages such as hepatic first-pass metabolism and degradation within the gastrointestinal tract that limit their overall bioavailability. This review introduces several diverse non-oral delivery methods for the administration of statins. These alternative delivery systems and routes of administration are varied and are capable of improving the bioavailability and therapeutic efficacy of statin drugs.

Fungal infections are estimated to be responsible for 1.5 million deaths annually. Global anti-microbial resistance is also observed for fungal pathogens, and scientists are looking for new antifungal agents to address this challenge. One potential strategy is to evaluate currently available drugs for their possible antifungal activity. One of the suggested drug classes are statins, which are commonly used to decrease plasma cholesterol and reduce cardiovascular risk associated with low density lipoprotein cholesterol (LDL-c). Statins are postulated to possess pleiotropic effects beyond cholesterol lowering; improving endothelial function, modulating inflammation, and potentially exerting anti-microbial effects. In this study, we reviewed in-vitro and in-vivo studies, as well as clinical reports pertaining to the antifungal efficacy of statins. In addition, we have addressed various modulators of statin anti-fungal activity and the potential mechanisms responsible for their anti-fungal effects. In general, statins do possess anti-fungal activity, targeting a broad spectrum of fungal organisms including human opportunistic pathogens such as Candida spp. and Zygomycetes, Dermatophytes, alimentary toxigenic species such as Aspergillus spp., and fungi found in device implants such as Saccharomyces cerevisiae. Statins have been shown to augment a number of antifungal drug classes, for example, the azoles and polyenes. Synthetic statins are generally considered more potent than the first generation of fungal metabolites. Fluvastatin is considered the most effective statin with the broadest and most potent fungal inhibitory activity, including fungicidal and/or fungistatic properties. This has been demonstrated with plasma concentrations that can easily be achieved in a clinical setting. Additionally, statins can potentiate the efficacy of available antifungal drugs in a synergistic fashion. Although only a limited number of animal and human studies have been reported to date, observational cohort studies have confirmed that patients using statins have a reduced risk of candidemia-related complications. Further studies are warranted to confirm our findings and expand current knowledge of the anti-fungal effects of statins.

Bortezomib (VELCADE®) is a boronate peptide and first-in-class proteasome inhibitor serving an important role in degenerating several intracellular proteins. It is a reversible inhibitor of the 26S proteasome, with antitumor activity and antiproliferative properties. This agent principally exerts its antineoplastic effects by inhibiting key players in the nuclear factor κB (NFκB) pathway involved in cell proliferation, apoptosis, and angiogenesis. This medication is used in the management of multiple myeloma. However, more recently, it has been used as a therapeutic option for mantle cell lymphoma. While promising, bortezomib has limited clinical applications due to its adverse effects (e.g., hematotoxicity and peripheral neuropathy) and low effectiveness in solid tumors resulting from its poor penetration into such masses and suboptimal pharmacokinetic parameters. Other limitations to bortezomib include its low chemical stability and bioavailability, which can be overcome by using nanoparticles for its delivery. Nanoparticle delivery systems can facilitate the targeted delivery of chemotherapeutic agents in high doses to the target site, while sparing healthy tissues. Therefore, this drug delivery system has provided a solution to circumvent the limitations faced with the delivery of traditional cancer chemotherapeutic agents. Our aim in this review was to describe polymer-based nanocarriers that can be used for the delivery of bortezomib in cancer chemotherapy.

The endoplasmic reticulum (ER) receives unfolded proteins predestined for the secretory pathway or to be incorporated as transmembrane proteins. The ER has to accommodate the proper folding and glycosylation of these proteins and also to properly incorporate transmembrane proteins. However, under various circumstances, the proteins shuttling through the ER can be misfolded and undergo aggregation, which causes activation of the unfolded protein response (UPR). The UPR is mediated through three primary pathways: activating transcription factor-6, inositol-requiring enzyme-1 (IRE1), and PKR-like endoplasmic reticulum kinase, which up-regulate ER folding chaperones and temporarily suppress protein translation. The UPR can be both cytoprotective and/or cytotoxic depending on the duration of UPR activation and the type of host cell. Proteostasis controls stem cell function, while stress responses affect stem cell identity and differentiation. The present review aimed to explore and discuss the effects of the UPR pathways on mesenchymal stem cells.

Several studies have indicated an association between inflammation and the recurrence of Atrial Fibrillation (AF), especially after ablation, which is a therapeutic option leading to local inflammation. On the other hand, each AF can lead to another AF, as a general rule. Thus, preventing recurrences of AF is extremely important for patient outcomes. In this paper, we attempted to review the effect of medicinal agents with anti-inflammatory properties on the prevention of AF recurrence. There are several randomized controlled trials (RCTs) and meta-analyses on the prevention of AF recurrence using agents with anti-inflammatory properties, which include steroids, colchicine, statins, and n-3 fatty acids (n-3 FA). Clinical trials evaluating the efficacy of anti-inflammatory drugs in preventing the recurrence of AF led to inconsistent results for corticosteroids, statins and n-3 FAs. These results may be related to the fact that inflammation is not the only factor responsible for triggering recurrences of AF. For example, the presence of structural, mechanical and electrical remodeling could potentially be the most important factors that trigger recurrences of AF but these factors have not been addressed in most of the reported studies. Therefore, future clinical trials are needed to compare the efficacy of anti-inflammatory drugs in AF patients with, or without other factors. For colchicine, a potent anti-inflammatory drug, there are limited studies. However, all the studies investigating colchicine in the context of AF were consistent and promising, especially when colchicine was used on a short-term basis following ablation in patients with paroxysmal AF. Therefore, colchicine could be a promising candidate for further clinical studies involving recurrent AF.

There is evidence of the critical role of efferocytosis, the clearance of apoptotic cells (ACs) by phagocytes, in vascular cell homeostasis and protection against atherosclerosis. Specific microRNAs (miRs) can regulate atherogenesis by controlling the accumulation of professional phagocytes (e.g., macrophages) and nonprofessional phagocytes (i.e., neighboring tissue cells with the ability to acquire a macrophage-like phenotype) within the arterial wall, the differentiation of phagocytes into foam cells, the efferocytosis of apoptotic foam cells by phagocytes, and the phagocyte-mediated inflammatory response. A better understanding of the mechanisms involved in miR-regulated phagocyte function might lead to novel therapeutic antiatherosclerotic strategies. In this review, we try to shed light on the relationship between miRs and cellular players in the process of efferocytosis in the context of atherosclerotic plaque and their potential as molecular targets for novel antiatherosclerotic therapies.

Atherosclerosis is a chronic, inflammatory disease that mainly affects the arterial intima. The disease is more prevalent in middle-age and older individuals with one or more cardiovascular risk factors, including dyslipidemia, hypertension, diabetes, smoking, obesity, and others. The beginning and development of atherosclerosis has been associated with several immune components, including infiltration of inflammatory cells, monocyte/macrophage-derived foam cells, and inflammatory cytokines and chemokines. Mesenchymal stem cells (MSCs) originate from several tissue sources of the body and have self-renewal and multipotent differentiation characteristics. They also have immunomodulatory and anti-inflammatory properties. Recently, it was shown that MSCs have a regulatory role in plasma lipid levels. In addition, MSCs have shown to have promising potential in terms of treatment strategies for several diseases, including those with an inflammatory component. In this regard, transplantation of MSCs to patients with atherosclerosis has been proposed as a novel strategy in the treatment of this disease. In this review, we summarize the current advancements regarding MSCs for the treatment of atherosclerosis.

Current guidelines recommend statin therapy for all adult patients with coronary artery disease irrespective of sex. Over recent years, some concerns have been raised concerning the effects of statins on endogenous steroid hormones synthesis. The aim of this review was to summarize the effects of statins on endogenous sex hormones in order to clarify their role and safety in different clinical settings. Results suggest that HMG-CoA inhibitors may slightly impair adrenal and/or gonadal steroid hormone production. In men, statins do not cause any clinically-relevant harmful effects on erectile function and spermatogenesis and, in women, statins have beneficial effects in treatment of polycystic ovary syndrome (PCOS). Additional research is needed to provide specific clinical recommendations concerning this topic.

Curcumin, the bioactive polyphenolic ingredient of turmeric, has been extensively studied for its effects on human papilloma virus (HPV) infection as well as primary and malignant squamous cervical cancers. HPV infections, especially those related to HPV 16 and 18 types, have been established as the leading cause of cervical cancer; however, there are also additional contributory factors involved in the etiopathogenesis of cervical cancers. Curcumin has emerged as having promising chemopreventive and anticancer effects against both HPV-related and nonrelated cervical cancers. In this review, we first discuss the biological relevance of curcumin and both its pharmacological effects and pharmaceutical considerations from a chemical point of view. Next, the signaling pathways that are modulated by curcumin and are relevant to the elimination of HPV infection and treatment of cervical cancer are discussed. We also present counter arguments regarding the effects of curcumin on signaling pathways and molecular markers dysregulated by benzo(a)pyrene (Bap), a carcinogen found in pathological cervical lesions of women who smoke frequently, and estradiol, as two important risk factors involved in persistent HPV-infection and cervical cancer. Finally, various strategies to enhance the pharmacological activity and pharmacokinetic characteristics of curcumin are discussed with examples of studies in experimental models of cervical cancer. © 2016 BioFactors, 43(3):331-346, 2017.