Cellular, Molecular, Pharmacological, and Nano-Formulation Aspects of Thymoquinone: History
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Contributor:
Ambreen Shoaib
,
Shamama Javed
,
Shadma Wahab
,
Lubna Azmi
,
Mohammad Tabish
,
Muhammad H. Sultan
,
Karim Abdelsalam
,
Saad S. Alqahtani
,
Md Faruque Ahmad

The goal of an antiviral agent research is to find an antiviral drug that reduces viral growth without harming healthy cells. Transformations of the virus, new viral strain developments, the resistance of viral pathogens, and side effects are the current challenges in terms of discovering antiviral drugs. The time has come and it is now essential to discover a natural antiviral agent that has the potential to destroy viruses without causing resistance or other unintended side effects. The pharmacological potency of thymoquinone (TQ) against different communicable and non-communicable diseases has been proven by various studies, and TQ is considered to be a safe antiviral substitute. 

  • clinical trial
  • immunity
  • mechanism
  • nanotechnology

1. An Introduction to Thymoquinone and Viral Diseases

Viral diseases are a serious concern worldwide, because of the extreme danger and complexity they pose to human life, due to their ability to cause a rapid outbreak among developing nations [1]. Viruses are intracellular parasites that encompass one of the significant classes of pathogens [2]. Viruses can generate several diseases such as: acquired immunodeficiency syndrome, dengue, Middle East respiratory syndrome, polio, etc. [3][4]. Viruses infect healthy cells and cause apoptosis in infected cells. Among all of these viruses, a small proportion of them cause the depletion of immune cells and, consequently, deteriorate the host’s immune system [5][6].
Developing remedies for viral diseases presents a tremendous challenge due to the easy transformation of viruses, the resistance of viral pathogens, new viral strain developments, side effects, the high cost of medicines, and the development of resistance [7]. The standard therapy for viral infections includes destroying the target pathogen; instead, many therapies inhibit viral development and shorten the length of the disease [8]. In modern times, the emergence of resistance of microbial and viral pathogens against common antimicrobial and antiviral drugs, mostly for respiratory tract infections (RTI), has increased day by day, which is a significant health problem affecting the treatment of these conditions [8]. According to the WHO’s (World Health Organization)’s current list, viruses, especially RNA viruses, are among the top ten health threats globally. The list includes: the influenza pandemic, human immunodeficiency virus, dengue virus, Ebola virus (EBOV), and SARS-COV-2. Other pathogens include Zika virus, various hemorrhagic fevers, Nipah virus, Middle East respiratory syndrome, SARS-COV-2, SARS-CoV, and disease X [9][10][11][12].
Plants have long been used to prevent disease. Botanicals are used to treat around eighty percent of the world’s population. Alternative medicine shows the economic importance of plants [13]. Natural medicinal plants are an essential source of different bioactive and therapeutic compounds with antiviral activities; very few studies have been conducted on various medicinal plants’ antiviral potential [14][15]. Since ancient times, the use of various medicinal plants has been considered to treat human diseases. A medicinal herb can change the pathological and physiological processes used to prevent and treat disease. Recently, there has been a remarkable increase in the therapeutic use of medicinal plants for different diseases, compared with chemical and synthetic drugs, because of their ease of availability without requiring a prescription, less interference from healthcare professionals, their low cost, and the belief that they are associated with fewer adverse effects [16][17]. Natural spices and herbs have been used since time immemorial for their medicinal and therapeutic purposes. These natural therapies are used in the treatment of multiple diseases around the globe. Barrett et al. reported that fifty percent of Americans use herbal and natural remedies to treat ailments [18][19].
N. sativa (Ranunculaceae), also known as black seed, is an herb that is commonly used in the Middle East as a natural food and traditional medicine [20]. Some research and data suggest that black seed and its principal active constituent TQ has significant antioxidant and cytoprotective effects against organ damage. It has antifungal, antiviral, anti-allergic, analgesic, anti-tumor, and antipyretic activity [18][21]. N. sativa oil has been shown to lower viral load in mice infected with cytomegalovirus to an undetectable level in the spleen and liver within ten days after being administered via the intraperitoneal route. This may be due to increasing the function and number of CD T cells and interferon-gamma production [22][23]. In patients (n = 30) infected with HCV (hepatitis C virus), in whom IFN-α/ribavirin drug therapy was contraindicated, a significant improvement was observed in HCV viral load. Moreover, various laboratory parameters have been shown to improve with N. sativa seed oil, including red blood cells, platelet count, and total protein, along with a decrease in postprandial glucose and fasting blood glucose in both non-diabetic and diabetic HCV patients [22][24].

2. Antiviral Properties and Mechanisms of Action of Thymoquinone in Cellular and Molecular Aspects

2.1. Antiviral Properties

TQ is a phytoconstituent having different pharmacological actions along with all emphasis is placed on its antiviral activity. This natural product shows its action as an antiviral agent by decreasing inhibition of viral replication of the virus [25]. It has a high therapeutic index for its target [26]. The other hybrid product of TQ shows synergistic effects among linked pharmacophores [27]. An in vitro model of a TQ–artesunic acid hybrid shows considerably higher antiviral activity from the standard drugs, artesunic acid and ganciclovir [26]. Correspondingly it also exhibits synergistic antiviral activity when co-administered with other phytoconstituents, such as curcumin. Curcumin and TQ show effective actions against a murine cytomegalovirus infection model and avian influenza virus (H9N2 AIV) [28]. A recent study recommended that it modulates IL-8 secretion, tryptophan repressor gene expression, and viral load in coronavirus infections [29]. Furthermore, examination of gene expression reveals a decrease in viral loads following treatments, which in turn affects viral survival within the cell [29]. TQ is undergoing clinical trials for the treatment of infection related to the hepatitis C virus [24].
The potential therapeutic value of TQ in the treatment of SARS-COV-2 has attracted more attention in recent years due to its medical significance. The compound TQ possesses antiviral activity against the coronavirus infection as it has the probable binding at SARS-CoV-2: angiotensin-converting enzyme-2 (ACE-2) interface, and consequently could be predicted as a persuasive inhibitor to interfere with viral-host interactions [30]. This compound can be utilized through the human cell-surface receptor HSPA5 and shows positive action on the virus and thus can be used in patients with high risk to reduce the hazard of SARS-COV-2 [31]. TQ interface binds with the key residues and may dislocate host recognition, which may cure the viral infection. It also inhibits the murine cytomegalovirus replication in infected mice which might be facilitated by an increase in the number and function of macrophages and the production of interferon-gamma [6]. Some studies show that the Black seeds (N. sativa) and their pharmacologically active constituent TQ show potent antiviral mechanisms by inhibiting the proliferation of viruses or by its immunomodulatory effect.

2.2. Mechanisms of Action

TQ is a temperature-sensitive phytoconstituent and hydrophobic too; resulting in poor bioavailability due to its hydrophobicity and low solubility [32]. However, dosage form other than conventional (nano-formulations) increases the efficacy and bioavailability that unveiled remarkable immunomodulatory and antiviral activities at a specific dose [33]. Numerous pharmaceutical formulation research has focused on it because its hydrogel preparations are biologically friendly and provide the continuous release of medicines [34]. It shows its antiviral activity by regulating ROS and NO production [35]. It also reduces cytokine storm-mediated endothelial dysfunction. It also shows inhibitory effects on viral infection and improved multiple organ dysfunction syndrome complications by fixing the redox and immune balances [30]. This is perhaps via the redox mechanism, which may reduce the inflammatory response and systemic oxidative stress. Consequently, TQ reduces the early stage inflammatory biomarkers viz., endothelial cell-specific molecule 1, C-reactive protein, and vascular endothelial growth factor [33]. Remarkably, inflammatory cytokines like- tumor necrosis factor-α (TNF-α), Interleukin-1α, Interleukin 2, Interleukin-6, and Interleukin-10 also augment the inducible nitric oxide synthase-mediated NO production [30].
Besides ROS generation, inflammatory cytokine production by activated phagocytes as a result of the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) also contributes to the oxidative stress associated with virus-induced phagocyte activation. Inhibition of NF-κB can thus suppress inflammatory genes, halt the cytokine storm, and reduce immune cell invasion and activation, protecting tissue and organs from injury [36]. Docking studies suggest that TQ may inhibit SARS-CoV-2 replication by interfering with viral binding to ACE-2 receptors. As a result, it is able to block the virus from entering the host cell and from replicating within the host cell and act as a potent antiviral agent [37][38].

3. Pharmacological Applications of Thymoquinone as an Antiviral Agent

Viral infections can induce apoptotic cell death and reduce host lymphocyte counts. Antioxidants have the potential to inhibit the apoptosis induced by the virus along with they also prevent the replication of the virus in target cells [39]. Therefore, it can be concluded that the antiviral and antioxidant possessions can be linked with each other and that could be a potential source to surmount viral infection [40]. TQ is the active constituent of many plants but is widely found in N. sativa and has different valuable properties [21]. When you focus on the TQ exhibits a broad-spectrum antimicrobial activity (Gram +ve, Gram −ve bacteria, fungi, schistosoma, parasites, and viruses) [6]. The antiviral effect of TQ was investigated in the murine cytomegalovirus model, and the results show that it enhances serum interferon-gamma levels and increases the numbers of CD4+ helper T cells [41]. Therefore, TQ has potential therapeutic applications for diverse pathological conditions, such as antiviral, anticancer, anti-inflammatory, and hepatoprotective interventions.

4. Biopharmaceutical Problems of Thymoquinone

Viral infections are a global health challenge and SARS-COV-2 is the most recent addition to the list of global pandemic outbreaks [42]. Combating viral infections is a big challenge owing to the advent of new viral strains and a high level of genetic variability. These are often resistant to available drug inhibitors, and vaccines, and thus, the need for a new antiviral agent is always urgent and much required in the pharmaceutical market. For any agent to be a good antiviral agent, it should have an effective virucidal mechanism and a broad spectrum of activity against the viruses, and a good safety profile for the users [36]. Nature is a vast source of medicinal compounds derived from diverse organisms, such as plants, bacteria, and animals. However, plants are an essential source of phytochemicals. These phytochemicals have immense potential as medicinal and curative agents. The compendiums of their uses are mentioned in various traditional and alternative systems of medicine. TQ is one such multi-targeted wonder molecule from nature. The USFDA has classified Nigella oil as Generally Recognized as Safe [43]. TQ (2-isopropyl-5-methylbenzo-1,4-quinone) is the main active constituent of the N. sativa plant. The diverse therapeutic benefits of TQ viz. anti-inflammatory, antioxidant, anticancer, hepatoprotective, gastro-protective, antimicrobial, and anti-diabetic are well documented in both in-vitro and in-vivo. [44].
Despite being a wonder molecule of nature, TQ suffers from challenges related to poor biopharmaceutical characteristics and photo-instability. This hinders the potential of TQ, and it has not yet advanced to the clinical trial phase. TQ is a highly hydrophobic agent that has poor aqueous solubility issues [45]. The highly thermolabile nature of TQ, lack of quantification methods in blood and tissues, high hydrophobicity, and high lipophilicity (Log P = 2.54) causes poor formulation characteristics [46]. It is difficult to formulate TQ into formulations (tablets and capsules). In general, the use of herbal drugs in pharmaceutical research and development (R&D) is increasing exponentially in past few decades. The key benefits when utilizing natural prodrugs are that they are stable, economical, and have flexible properties; nevertheless, their main drawbacks include moderate water-solubility, poor oral bioavailability, limited half-life, and non-specific targeting problems. Nanotechnology provides a wide variety of potential solutions to tackle these challenges [47].

5. Nanotechnological Approaches of Thymoquinone for Effective Antiviral Therapy

Infectious diseases are a global burden, such as the unprecedented outbreak of SARS-COV-2 cases left the world crippled with no specific drug or vaccine to treat or prevent it immediately leading to high mortality. Since then researchers are working hard to explore, and identify more and more antiviral agents from natural sources and develop suitable nano-based formulations as antiviral therapeutics. The nanoparticles can address antiviral resistance a problem often associated with the conventional therapeutic approach by their unique properties such as small size, shape, advanced biological and functional properties, large surface-to-volume ratio, surface charges, and surface functionalization characteristics [48]. Nanomedicine by nanotechnology aims to create nanostructures to carry and target nanodrugs effectively. Many nanomaterials have been extensively researched in this regard to prevent viral diseases via the direct association of nanoparticles and viruses. The small size, big surface area, variety of surface modification, and ability to encapsulate drugs with large payload enhances the antiviral efficacies of these nanomaterials. Known for their unique physical and chemicals properties and used quite often for developing novel antiviral agents, recent research has categorized nanomaterials into four types (quantum dots as antiviral agents), metal nanoparticles (gold, silver, zinc oxide, and cobalt nanoparticles as antiviral agents), graphene-based nanoparticles (graphene and its derivatives–graphene oxide and reduced graphene oxide as effective antiviral agents) and photodynamic therapy (PDT for the inactivation of microbes) is the latest advancement in the field [49]. A thorough understanding of the pathogenesis of the viral disease, the virus structure, proteins present on the surface of the virus, and the mechanism of virus entry into host cells are vital in understanding to further fabricate a nanoparticulate formulation that is both safe and effective in the treatment of viral diseases. For a better understanding of the readers, researchers have systematically explained an approach focused on nanotechnology to tackle emerging NIPAH virus infection [50], the antiviral potential of silver nanoparticles against novel coronaviruses have also been addressed intricately by researchers [48], and antiviral potential of silver nanoparticles against African swine fever virus [51], Iron oxide nanozyme catalytically inactivates influenza virus [52]. Various forms of nano-formulations such as inorganic nanoparticles (gold nanoparticles, silver nanoparticles titanium oxide nanoparticles, carbon dots), organic nanoparticles, vesicular delivery systems, and Lipid-based nanoparticles, nanostructured lipid-based structures have been studied for the management of viral infections [53]. Metal nanoparticles’ promise as an auspicious therapy for viral and arboviral outbreak has been well documented [54].
Nanotechnological approaches of different types are required to be applied for encapsulating TQ and improving its oral bioavailability and thus its efficacy. Numerous nano-formulations of TQ have been made in past for improved drug delivery in various human ailments such as Alzheimer’s disease, anticancer, hepatotoxicity [55][56]. The promise of this nutraceuticals as nano-TQ is comprehensively summarized in the literature, along with the benefits and drawbacks of other FDA-approved nanoparticle-based therapeutics [57]. Low water-solubility, poor oral bioavailability, poor penetration in membranes, and non-existence of understanding of its mechanism of action are some of the biopharmaceutical problems associated with TQ and all these are valid reasons behind the development of novel nano-TQ formulations with improved bioavailability [58]. In this section, researchers have tried to summarize the most novel and recent nano-TQ formulations with their characteristic features and improved profiles. TQ-loaded liposomes have been prepared in past for improved stability, bioavailability, and enhanced anticancer activity towards breast cancer [59]. TQ-loaded NLCs were prepared using high-speed homogenization accompanied by ultrasonication, and their in-vitro properties were assessed. TQ-NLCs have higher relative bioavailability than TQ suspension, meaning that the NLC formulation improves bioavailability [60]. Poor oral bioavailability upon oral administration impedes TQ biological activity. TQ-SNEDDS were created by scientists and evaluated for improved hepatoprotective potential. As compared to TQ suspension, optimized SNEDDS formulation of TQ showed improved in-vivo absorption and an increase in relative bioavailability up to 3.87 folds [61]. Modified chitosan-loaded TQ nanocapsules were also prepared recently by the researchers. The optimized nanocapsules had a size between 100 and 300 nm and a zeta potential of +48 mV indicating a more stable profile [62]. A mitochondria-targeted TQ compound was produced in an extremely advanced and novel manner, mitochondrial function in rat liver and yeast cell viability were both studied. Improved antioxidant activity of SkQThy was observed showing good therapeutic potentials [63]. The anticancer potential of TQ has been enhanced by various nanotechnological approaches and researchers have reviewed various TQ-nano-formulations highlighting their superior anticancer efficacy such as in breast cancer [47][56]. In yet another exciting study, inclusion complexes of TQ and hydroxypropyl-β-cyclodextrin were prepared for improved solubility and bioactivity. As compared to free TQ, the complexed TQ had better improved efficacy against allergies and prolonged action with reduced side effects [64]. Non-lamellar liquid crystalline nanoparticles made up of cubosomes and hexosomes are gaining popularity as robust nanocarrier systems for TQ due to their special properties. The lipid composition and drug loading of these nano-self-assemblies have considerable impact on their structural features, morphological characteristics, and size. Cubosomes and hexosomes are vesicular nanostructures possessing “flower-like” features that are ideal for enhancing the solubilization capacity of poorly water-soluble drugs and improving drug delivery through various routes of drug administration.
Recently, nano-dispersions, comprising binary mixtures of glycerol monooleate and vitamin E loaded with TQ, were prepared and characterized by their morphological, structural, and size characteristics [46]. Very recently, TQ-loaded NLCs were once again formulated to improve their poor solubility and oral bioavailability issues. A high-pressure homogenization method was employed, and a particle size of less than 100 nm was achieved for the nanocarriers, which showed stability for up to 24 months of storage. The formulated nanocarrier of TQ was radio-labelled with technetium-99 m before administration to the rats for the in-vivo organ distribution study both by oral and I.V. routes. TQ-NLCs administered orally had a higher relative bioavailability than those administered intravenously, but oral administration had a slower absorption rate than intravenous administration [65]. In yet another recent study, TQ-loaded Soluplus–Solutol HS15 mixed micelles were prepared. In-vitro characterization was carried out and their effects on SH-SY5Y cell migration were studied. The use of nanotechnology to inhibit cancer cell invasion and migration has opened up new avenues for combating neuroblastoma [66]. MSNs (mesoporous silica nanoparticles) have gained much popularity in drug delivery systems in the last few decades for being an effective delivery system for targeted drug delivery. Their low toxicity profile, small particle size, uniform pore size, good biocompatibility, and chemical stability have made them ideal nanocarrier systems for drugs [67]. The mesoporous silica nanoparticles (MSNs) (nanospheres with a size of 100–200 nm in diameter) are known to enhance the solubility profile of drugs. In addition, they have an excellent targeting ability and are capable of loading two or more drugs for dual therapeutic efficiency. These are biocompatible, non-toxic, and also classified as “Generally Recognized as Safe” (GRAS) by the FDA. In a very recent study, MSNs were used as nanocarriers of natural antiviral prodrug complexes of shikimic acid and quercetin. The developed novel nano-formulations were highly effective against the influenza virus H5N1 [68]. A similar approach can be applied to TQ for improving its antiviral efficacy. To further surmount the delivery challenges and biopharmaceutical issues associated with TQ, researchers are working on various other nanosystems. Very recently, phospholipid nanoconstructs were constructed by Rathore et al., 2020 [69]. The optimized nano composition had a size of <100 nm, a spherical morphology (nanospheres), entrapment efficiency of >90%, polydispersity index of 0.55, a controlled-release pattern, and a zeta potential of −0.65 mV. The single dose, upon oral administration, produced a relative bioavailability of 386.03% and improved the hepatoprotective effects as compared to a plain TQ suspension. This nanoconstruct has the potential to be a promising delivery mechanism for increasing the oral bioavailability of this hydrophobic compound. The nanosizing of phytochemicals whose clinical usefulness is restricted due to poor biopharmaceutical attributes is also a novel approach to enhancing their therapeutic efficacy. The nanosizing of curcumin, naringenin, berberine, catechins, TQ, resveratrol, apigenin, baicalin, and many other molecules is evident from the literature [57]. Recently, TQ-loaded SLNs were prepared and tested in rats for their antidepressant activity [70]. Keeping in mind all of the biopharmaceutical issues of TQ, the ideal approach is encapsulation or entrapment of this bioactive compound in a vesicular system such as nanoliposomes and tocosomes, which have greater potentials as advanced vesicular systems of drug delivery. The encapsulation of nutraceuticals improves their stability profile, controls their release characteristics and increases the product shelf life [71]. TQ-loaded cubosomes with a mean particle size of 98 ± 4.10 nm, entrapment competence of 96.60 ± 3.58%, and zeta potential of 31.50 ± 4.20 mV were prepared recently using the emulsification homogenization method. They were evaluated for their in-vitro chemotherapeutic efficacy on MCF-7 and MDA-MB-231 breast cancer cell lines, compared to MCF-10A non-tumorigenic cell lines. The enhanced anti-tumor activity of TQ-loaded cubosomes was observed as compared to free TQ [72].
A nano-based approach to combat viral infection using natural phytoconstituents (TQ) is a new arena and more research is warranted. Nano-TQ-based formulations seem to be a versatile and feasible strategy to conquer viral infections due to the potent antiviral properties of TQ. A well-designed and targeted nano-TQ system against the viral proteins that facilitate the spread of infections could help prohibit the spread of viral infections. A nano-TQ-based antiviral nanomedicine with improved antiviral activity is a prerequisite in this regard to protect mankind from these rapidly emerging viral infections. With the nano-based formulation approach, it is much easier and more promising to bridge the gap between the occurrences of disease, a cure, and improved and biomedical applications of agents. Nanoproducts with improved bioavailability, bio-degradability, biocompatibility, tunability, targetability, and specificity are the expected outcomes in this regard. Thus, more and more nanotechnological approaches could be applied to make more nano-TQ formulations with improved bioavailability and enhanced antiviral efficacies in the near future.

This entry is adapted from the peer-reviewed paper 10.3390/molecules28145435

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