Health Promotion Effects of Dietary Pterostilbene: Comparison
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Pterostilbene (PTS), a natural analog of resveratrol is a compound most abundantly found in blueberries. PTS is produced by several plant species such as peanuts and grapes. While resveratrol has been extensively studied for its antioxidant properties, recent evidence also points out the diverse therapeutic potential of PTS. Several studies have identified the robust pharmacodynamic features of PTS, including better intestinal absorption and elevated hepatic stability than resveratrol. Indeed, due to its higher bioavailability paired with reduced toxicity compared to other stilbenes, PTS has become an attractive drug candidate for the treatment of several disease conditions, including diabetes, cancer, cardiovascular disease, neurodegenerative disorders, COVID-19 and aging. 

  • pterostilbene
  • resveratrol
  • antioxidant
  • bioavailability
  • cancer
  • diabetes

1. Pterostilbene

Pterostilbene (PTS) (trans-3,5-dimethoxy-4′-hydroxystilbene), a dimethyl ether analog of resveratrol, is a natural polyphenol [1]. Several plants produce PTS as a secondary metabolite to respond to environmental challenges including UV radiation, drought, fluctuating temperature extremes, grazing pressures, and fungal infections. PTS also serves as an important mediator of disease resistance [2][3]. Similar to resveratrol, PTS also behaves as a phytoalexin, providing crucial anti-pathogenic defense to plants [4][5]. The daily consumption of PTS is determined by its dietary intake. Based on the type of blueberry ingested, the content of PTS is estimated to range from 99 ng to 520 ng/gram of fruit [6]. Though berries are the most evident source of PTS, it has been reported to be present in various other food sources, including peanuts.
As a natural dietary component, PTS has been documented to exhibit an increased bioavailability compared to other stilbene compounds [7][8]. Various studies have demonstrated the effect of PTS in countering oxidative damage and inflammation, imparting preventive and therapeutic benefits in experimental disease models [4][7][9]. Indeed, through its antioxidant and anti-inflammatory activity, PTS has been reported to inhibit pathogenic pathways associated with carcinogenesis, hematologic diseases, neurological disorders, vascular dysfunction, aging disorders, and diabetes [7].
Among the identified polyphenols, resveratrol has been determined to exhibit relatively poor oral bioavailability and undergoes rapid first-pass metabolism. On the contrary, methylated polyphenols such as PTS have been documented to possess better intestinal absorption and elevated hepatic stability. Considering the potential drawbacks that are exhibited due to the unfavorable pharmacodynamics of resveratrol, much focus has shifted towards understanding the therapeutic potential of PTS. 

2. Therapeutic Properties of PTS

Various therapeutic properties of PTS have been documented since its discovery. The phytonutrient is reported to have potent anti-cancer, anti-inflammatory, immunomodulatory, anti-diabetic, antioxidant, analgesic, anti-obesity, neuroprotective, and anti-aging properties [9] (Figure 1).
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Figure 1. Therapeutic properties of PTS in various disease conditions.

2.1. Anti-Cancer Activity of PTS

PTS has been reported to be beneficial in preventing and treating cancer by regulating pro-apoptotic or non-apoptotic anti-cancer effects [10]. Drug-metabolizing enzymes play a crucial role in the development of cancer. These enzymes mediate the metabolic activation of several pro-carcinogens and are involved in the inactivation and activation of anti-cancer drugs. CYP1A1 and CYP1B1 are members of the cytochrome P450 superfamily and have important roles in cancer progression. PTS acts as an efficient inhibitor of CYP1A1, CYP1A2, and CYP1B2 in a competitive manner. The anti-proliferative mechanisms of PTS are seen in different concentrations for different cell types [3].
Rimando et al. studied the cancer chemopreventive activity of PTS using a mouse mammary gland model, and showed that PTS (ED50 = 4.8 µM) markedly reduced DMBA-induced mammary alveolar precancerous lesions through its peroxy-radical scavenging antioxidant activity [11]. In mutant p53-breast cancer cell lines MDA-MB-231 and T-47D, PTS facilitated the reduction of oncogenic β-catenin, mTOR, and mutant p53, as well as increased the expression of the pro-apoptotic Bax protein [12]. Moreover, in MDA-MB-231 xenograft mouse models, PTS suppressed the epithelial-to-mesenchymal transition (EMT) through the upregulation of miR-205 and led to reduction in pro-EMT src signaling [13]. Notably, PTS exhibited additive anti-cancer effects in combination with other natural compounds. A combination of α-tocopherol succinate (42 and 99 IU/kg) and PTS (40 μg/kg) attenuated the invasive capability of MDA-MB-231 cells [14]. The treatment of ER-positive breast cancer with a combination of tamoxifen (5 μM) and PTS (10 and 20 μM) also exhibited additive effects. In the studied cell lines (MCF7 and ZR-751), the suppression of cancer cell proliferation along with an elevation in apoptotic activity was observed when this combination was employed [15].
In the human colorectal adenocarcinoma cell line HT-29, PTS (≥10 µM) inhibited cell proliferation while inducing G1 cell arrest. Moreover, PTS treatment stimulated apoptosis through the attenuation of the STAT3 and AKT kinase signaling pathways [16]. In a rodent model of azoxymethane (AOM)-induced colon cancer, the intake of PTS (40 ppm) through the diet for 45 weeks led to a reduction in tumorigenesis and diminished the levels of proliferating cell nuclear antigen (PCNA), cyclin D1, and β-catenin [17]. PTS was also observed to mediate the anti-cancer effect through the stimulation of Nrf2 signaling and its target genes (HO-1 and GR), which counter the effect of NF-κB-mediated pro-inflammatory signaling. Studies have shown that the overexpression of iNOS and COX-2 is markedly correlated with the progression of colon cancer. Notably, in an in vitro study using the HT-29 colon cancer model, PTS inhibited the transcriptional expression of augmented iNOS levels and moderated the inhibition of COX-2 in a concentration-dependent manner [17][18].
PTS in combination with quercetin at 20 mg/kg/day inhibited the metastatic activity in B16-F10 melanoma by reducing the adhesion of B16-F10 cells to the endothelium, and also by downregulating the levels of anti-apoptotic protein Bcl-2 in cancerous cells [19]. PTS (10 to 50 μM) suppressed the cancer cell proliferation and initiated apoptotic signaling through the induction of lysosomal membrane permeabilization in A375 melanoma cells [20]. Moreover, through the attenuation of iNOS and COX-2 expression, PTS prevented DMBA- and TPA-induced skin tumor formation [21]. Similarly, in rodent models of UVB-induced skin cancer, PTS provided protection by prominently inducing Nrf2-mediated antioxidant signaling, resulting in glutathione level maintenance, and the improved activities of catalase, SOD, and GPX [22]. Intravenously administered PTS suppressed human melanoma and pancreatic cancer growth in small animals. Evidence indicates an indirect mechanism of cancer growth inhibition, where PTS inhibits pituitary adrenocorticotropic hormone production, mediates the downregulation of glucocorticoid receptors, and stimulates the Nrf2-dependent anti-cancer antioxidant defense system [23][24].
Multiple myeloma (MM) models, xenograft mouse models for hematological cancers, and several diffuse large B-cell lymphoma (DLBCL) models have been utilized to study the anti-cancer effect of PTS [25][26]. In the DLBCL cell line, the viability of the cancer cells was largely dependent on the concentration of PTS and was associated with reduced mitochondrial membrane potential, elevated free-radical generation, and caspase-mediated apoptosis when PTS was intravenously administered [25]. In MM cell lines, a similar concentration-dependent suppression of the proliferation of cancer cells was observed through increased caspase activation, further highlighting the anti-cancer properties of PTS [26]. Additionally, PTS treatment was reported to show benefits against Cholangiocarcinoma (CCA), also known as biliary tract cancer, as evidenced by its cytotoxic effects, mediated through autophagy and the inhibition of CCA tumor growth, in two different CCA cell lines [27].
In endometrial cancer cells, the combination of PTS and megestrol acetate produced a synergistic effect through the inhibition of cell-cycle regulators, including cyclin D1, cyclin B1, and CDK4 [28]. Furthermore, PTS suppresses cell-cycle progression and apoptosis in ovarian cancer cells (OVCAR-8 and Caov-3 cells) through the inhibition of the STAT3 pathway. PTS decreased the expression of cell-cycle and anti-apoptotic proteins involved in the STAT3 pathway, including Mcl-1, Bcl-2, and cyclin D1 [29].
There are scientific reports on the therapeutic potential of PTS in attenuating hepatocellular carcinoma (HCC), which is the second-most prominent cause of cancer-related mortality. In a recent study, PTS treatment was reported to inhibit tumor growth and cell proliferation in a dose-dependent manner in an animal model of HCC [30]. A combination of diethylnitrosamine and carbon tetrachloride was used to induce HCC in mouse livers. PTS treatment was demonstrated to upregulate caspase-3 activity, and thereby induce apoptosis in HCC tumor tissue. Interestingly, PTS was identified to reduce HCC proliferation through a reduction in SOD2, and through the induction of ROS-mediated mitochondrial apoptotic pathways [30]. Further, it was observed that PTS conferred protection against HCC proliferation, and inhibited Hepatitis B virus proliferation in several HCC cell lines. Of note, PTS exhibited antiviral and anti-cancer activity in HCC cells that were resistant to Sorafenib (anti-cancer drug) and Lamivudine (antiretroviral drug) [31]. Importantly, the researchers identified that PTS exhibited anti-cancer and anti-retroviral effects through the potent inhibition of ribonucleotide reductase (RR), which plays a critical role in cellular DNA synthesis. Additionally, PTS treatment was demonstrated to markedly inhibit the growth of an HCC xenograft in nude mice with minimal toxicity [31]. PTS was reported to suppress the invasion and growth of HCC by down-regulating the expression of Metastasis-Associated Protein 1 (MTA1) and histone deacetylase 1 (HDAC1) while upregulating the acetylation of the tumor suppressor protein PTEN [32].

2.2. Anti-Diabetic Activity of PTS

Diabetes is a chronic multisystemic metabolic disease characterized by uncontrolled sugar levels due to insufficient secretion and the improper action of insulin [33]. Various rodent models have demonstrated the anti-diabetic effect of PTS. The compound has been reported to strongly influence glucose homeostasis by decreasing systemic glucose levels while increasing insulin concentrations [3][34]. Indeed, the findings from the researchers' lab indicated that PTS treatment markedly regulated blood glucose by improving insulin secretion in STZ-induced diabetic mice [35]. In particular, the researchers observed that PTS-mediated glucose regulation is achieved by regulating glucose metabolism enzymes in the liver of STZ-induced diabetic mice [35]. The oral administration of PTS to diabetic rats elevated the levels of the hepatic glycolytic enzyme hexokinase, reduced the levels of glycogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase, and thereby improved the peripheral utilization of glucose [36]. PTS also improved the antioxidant capacity in diabetic rats by upregulating GST, SOD, GPX, and catalase levels and counteracting ROS accumulation [34]. These mechanisms protect renal and hepatic cells from the deleterious effects of hyperglycemia-induced oxidative stress. Hence, PTS exhibits anti-diabetic activity by reducing hyperglycemia, but it also protects liver and kidney cells from hyperglycemia-associated damage [34].
While investigating PTS-mediated protection against β-cell apoptosis in STZ-induced diabetic rodents, it was demonstrated that PTS treatment improved glucose homeostasis while attenuating the pro-inflammatory cytokine response. The cytoprotection of β-cells by PTS treatment was conferred by an Nrf2-mediated mechanism, as evidenced by the attenuation of caspase-3 activity and the BAX/Bcl-2 ratio. An inhibition of iNOS, and a reduction in nitric oxide (NO) synthesis in the diabetic pancreas was also observed after PTS treatment. Notably, PTS alleviated the function of pancreatic β-cell cells and improved cell survival in the background of cytokine stress, thereby preventing the pathogenic features of STZ-induced diabetes [37]. Furthermore, a proteomic study demonstrated the molecular mechanisms involved following PTS administration in diabetic rodents by employing electrospray ionization tandem mass spectrometry (LC-MS/MS). The findings indicated that the administration of PTS normalized the levels of 315 proteins that were modulated in diabetic mice. Outstandingly, a major proportion of these proteins were involved in the regulation of redox imbalance, the antioxidative stress response, the unfolded protein response, and ER degradation pathways, indicating that PTS treatment plays a crucial role in the rehabilitation of defective metabolic processes and stress sensors in diabetes [38].
Lipid peroxidation is a characteristic of diabetes, and lipid peroxidation products can damage DNA and contribute to extra-pancreatic tissue damage in diabetes. PTS significantly reduced lipid peroxidation levels and was reported to scavenge DPPH free radicals and peroxyl radicals (ROO*). In a tertiary-butyl hydroperoxide (TBHP)-induced oxidative damage rodent model, free radicals, including hydroxyl, superoxide, and hydrogen peroxide, were attenuated by PTS in a concentration-dependent manner [39]. Notably, in diabetic-nephropathy-induced rats, PTS ameliorated renal damage by dampening the NF-κB inflammatory signaling pathway and inhibiting oxidative stress [40]. Diabetic retinopathy is associated with pathogenic alterations in the structure of the retina, mediated through high glucose levels. PTS treatment reduced the ROS generation while increasing the antioxidant SOD levels to scavenge free radicals and attenuate the progression of diabetic retinopathy [41].

2.3. Therapeutic Effect of PTS in Liver Diseases

Liver fibrosis is the consequence of overt accumulation of extracellular matrix proteins, resulting in the scarring of hepatic tissue and the marked disruption of hepatic vasculature, which can ultimately lead to cirrhosis [42]. Along with an increased risk of mortality, cirrhosis is also a risk factor for developing hepatocellular carcinoma [42]. Studies employing both acute and chronic liver injury models have identified the alleviation of liver injury following the administration of PTS. Of note, PTS treatment to a dimethylnitrosamine (DMN)-induced liver fibrosis model in Sprague-Dawley rats reduced DMN-induced changes, and attenuated pro-fibrogenic hepatic stellate cell activation. PTS also exhibited hepatoprotective activity through the inhibition of TGF-b1/Smad signaling [43].
NAFLD is a chronic progressive liver disorder in metabolic syndromes caused by excessive fat accumulation (hepatic steatosis). PTS administration in Zucker rats showed reduced insulin resistance, and attenuated hepatic triacylglycerol levels, thus reducing liver steatosis. Importantly, treatment with PTS reduced hepatic steatosis from grade 2 to grade 1. Of note, PTS was observed to reduce the triacylglycerol synthesis capacity of the liver through a reduction in fatty acid disposal, and through the inhibition of triacylglycerol synthesis enzymes such as DGAT2. The PTS-treated rats had improved fatty acid profiles, attributed to its delipidating effect [44]. Furthermore, PTS and its derivative 3′-Hydroxy-pterostilbene reduced NAFLD pathogenesis induced by free fatty acids and a fat-rich diet through the upregulation of SIRT1/AMPK, and insulin signaling pathways and the downregulation of the protein expression of SREBP-1, which results in the activation of the β-oxidation of fatty acids and the consequent reduction in fatty acid synthesis. Moreover, PTS was also observed to promote the growth of vital beneficial microbiota, such as Oscillospira, while down-regulating the population of potentially pathogenic bacteria, such as Allobaculum, Phascolarctobacterium, and Staphylococcus [45].
Zhang et al. employed an IUGR-induced liver injury model which exhibited increased circulating alanine transaminase activity, elevated hepatocyte apoptosis rate, and marked ROS accumulation. PTS administration reduced these pathogenic processes by preventing the accumulation of hepatic superoxide anions, 8-hydroxy-2 deoxyguanosine, and 4-hydroxynonenal-modified protein by stimulating the translocation of Nrf2 to the nucleus and inducing the antioxidant enzyme SOD2 [46]. Further, in a study investigating the efficacy of PTS against obesity, it was found that PTS formed three hydrogen bonds with the amino acids of PPAR-α, thereby inducing its expression in the livers of BBPX hamsters and lowering the plasma LDL concentration [47].

2.4. Effects of PTS on Diseases of the Central Nervous System

The anti-inflammatory and antioxidant properties of PTS have been reported to be therapeutic for the aging brain. Evidence from experimental studies indicates that PTS confers protective benefits against Alzheimer’s disease (AD) and vascular dementia [48]. PTS treatment potently modulated cognitive impairment and cellular stress. This effect was closely linked to the presence of methoxy groups, which increases lipophilicity. It also positively modulated cellular stress markers by upregulating PPAR-α expression [49].
Joseph et al. administered PTS to rats at various doses and measured its concentration in blood plasma and brain tissue (hippocampus). The amount of PTS in the hippocampus was directly related to the intake of PTS and alleviated cognitive function through the modulation of neural plasticity and motor activity. When administered at high doses, the compound was detected in the serum and brain tissue; however, low doses were only found in the serum and not detected in brain tissue [48]. More dose studies are needed to further understand the threshold dosage for PTS to cross the BBB.
The induction of the pro-inflammatory NF-kB signaling pathway is a vital pathogenic component in neurodegenerative diseases. Through the downregulation of NF-kB, PTS limited the inflammatory response in the CNS [49]. Cerebral ischemia/reperfusion injury is a period of impaired blood supply to the brain during an ischemic stroke. Five days of PTS treatment (10 mg/kg) in a common carotid artery occlusion model markedly elevated the membrane potential of mitochondria, and induced cytochrome c expression, as well as complex I and IV activity. PTS attenuated the ROS generated by mitochondria and reduced the cytochrome c levels in the cytosol. Considering that HO-1 signaling exhibits protection in Parkinson’s, Alzheimer’s, and other neurodegenerative diseases, the upregulation of HO-1 expression by PTS exhibited cerebral protective effects [50].
PTS confers neuroprotection to neuronal Sh-SY5Y cells by reviving estrogen-receptor-α-induced signaling [51]. A reduction in high-glucose-induced CNS injury and mitochondrial-dysfunction-derived oxidative stress was observed upon PTS administration due to the activation of Nrf2 in hippocampal neuronal cells [52]. However, high doses of PTS or resveratrol inhibited the physiological immune response to pathogens [53][54][55]. Further dose-dependent studies are needed to identify the appropriate PTS dose to achieve the therapeutic effect in CNS disorders.

2.5. Effects of PTS on Cardiovascular Diseases

PTS treatment was demonstrated to reduce atherosclerosis and myocardial infarction in animal models of cardiovascular diseases. PTS treatment lowered plasma lipoproteins and cholesterol, protecting vascular endothelial cells from oxidation, and promoting cytoprotective macroautophagy [7]. pTeroPure, a highly purified trans-PTS patented by Chromadex, Irvine, CA, has been proven to significantly reduce blood pressure in adults [2]. The combination of PTS and hydroxypropyl-β-cyclodextrin improved cardiac function in an experimental monocrotaline (MCT)-induced/arterial-hypertension-provoked right-heart-failure model through the induction of the antioxidative response. In particular, PTS enabled the rehabilitation of glutathione metabolism, and restored redox homeostasis in the right ventricle of MCT-treated rats. At higher doses, PTS attenuated lipoperoxidation and total phospholamban while increasing the levels of sarcoplasmic reticulum calcium ATPase (SERCA) in the right ventricles of diseased rodents [56].
An elevation of mechanical stress in the endothelium puts the heart at risk of injury to its vasculature and thrombogenesis, which is worsened by oxidative stress. The endogenous antioxidative response of the vascular system is responsible for exerting a protective effect by attenuating oxidative damage; however, the antioxidant capacity may become exhausted due to increased and chronic exposure to ROS, creating an imbalance between oxidant and antioxidant activities. In an ischemia/reperfusion-induced myocardial damage experimental model, PTS showed a cardioprotective effect by reducing myocardial peroxynitrite, superoxide production, malondialdehyde content, and NADPH oxidase enzyme expression and by increasing the antioxidant SOD activity to protect against oxidative stress [57].
The unchecked proliferation of vascular smooth muscle cells leads to atherosclerosis, and the consequent development of vascular stenosis [58]. In atherosclerosis, PTS has been reported to exhibit protective effects through the modulation of vascular smooth muscle cells (VSMCs) and endothlial cells through the blocking of an Akt (a serine/threonine kinase)-dependent pathway. In a platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation model, PTS treatment downregulated the promoters of DNA synthesis and VSMC proliferation, including cyclin-dependent kinase (CDK)-2, CDK-4, cyclin E, cyclin D1, retinoblastoma (Rb), and proliferative cell nuclear antigen (PCNA) [59].

2.6. Effects of PTS on Aging

Polyphenols have been extensively documented to protect against aging and age-related diseases such as atherosclerosis, arthritis, cataracts, osteoporosis, diabetes, and neurodegenerative and cardiovascular disorders. Studies reported that PTS acted as an anti-aging agent by regulating hallmark aging features, including oxidative damage, inflammation, telomere attrition, and cell senescence [60]. Owing to its ability to cross the BBB, PTS can localize within the brain, and provide potential therapeutic benefits against age-related neurodegenerative disorders [53]. Indeed, PTS countered lipopolysaccharide-induced microglial activation in rodents, and ameliorated learning and memory impairments [61]. PTS was also demonstrated to effectively reverse aging-associated behavioral deficits in rats. Indeed, the concentration of PTS in the rat hippocampus was directly correlated with dopamine release and working memory [48]. Employing the SAMP8 mouse, which is increasingly being recognized as an effective model of accelerated aging in the background of sporadic and age-related Alzheimer's disease, Chang et al. demonstrated that dietary doses of PTS exhibited more potency when compared to resveratrol in modulating cognitive behavior and cellular stress [49]. Moreover, PTS was also reported to extend the lifespan of SAMP8 mice, an effect attributed to c-Jun N-terminal protein kinase inhibition [62].
Ocular surface inflammation is a multifactorial disease that is particularly prevalent among the elderly. PTS has been reported to restore the imbalance between oxygenases and antioxidative enzymes through the attenuation of COX-2 and the upregulation of SOD1 and peroxiredoxin-4 (PRDX4) activities in the background of hyperosmotic stress [63]. PTS treatment is associated with a reduction in oxidative damage mediators, including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), aconitase-2, and 8-hydroxydeoxyguanosine (8-OHdG) levels, in a human corneal epithelial cell model induced by hyperosmotic medium stress [63]. Blueberry consumption has been reported to prolong the lifespan and improve thermo-tolerance in C. elegans [64]. In D. melanogaster, blueberry extracts upregulated the expression of the antioxidant enzymes SOD and catalase, which were mainly attributed to lifespan extension [65]. Dietary supplementation with blueberries, which contain polyphenols such as PTS, alleviated the damaging effect of aging on motor behavior and neuronal signaling and lowered the amyloid-beta content in a transgenic AD rodent model [66]. In an open-label, single-arm, monocentric study investigating the efficacy of Pon skin brightening and PTS anti-aging, a cream formulation containing 0.4% PTS was highly effective in reducing aging markers, and brightening the skin tone of study participants. Furthermore, employing an in vitro experiment, PTS was reported to exhibit anti-tyrosinase activity and inhibit melanogenesis, which could have contributed to the reduction in the markers of skin aging [67].
Arthritis is characterized by the painful swelling of joints, which worsens with age. In a Freund’s adjuvant (CFA)-induced arthritis model in rats, PTS significantly reduced paw swelling, the arthritic score, and body weight. Interestingly, it also helped restore the healthy gut microbiota ecosystem by reducing the relative abundance of Helicobacter, Desulfovibrio, Lachnospiraceae, and Mucispirillum. Considering the evidence of PTS in suppressing inflammation through intestinal bacteria alterations, studies investigating its therapeutic potential against inflammatory bowel disorders could be of clinical value [68].

2.7. Antibacterial Effect of PTS

PTS behaves as a  natural antibacterial agent due to its low hydrophilicity, enabling them to penetrate hydrophobic biological membranes [69]. PTS with cyclodextrin exerts antimicrobial effects by inducing bacterial cell content leaks, resulting in a reduction in bacterial cell viability. It also inhibits F. nucleatum biofilm formation, making it a potential candidate for treating periodontitis [70]. Bacillus cereus, a foodborne pathogen contaminating uncooked food, was tested with PTS. Following treatment, apoptosis-like cell death (ALD) was induced and increased intracellular ROS in bacterial cells. Additionally, an improvement in the beneficial gut microbiota Bacteroidetes was also documented [71].
PTS, along with gentamicin, was tested against six Gram-positive and Gram-negative bacteria, and the combination was found to be synergistic against three susceptible strains, Staphylococcus aureus ATCC 25923, Escherichia coli O157, and Pseudomonas aeruginosa 15442. However, no significant difference was observed from gentamicin treatment alone. Bacterial growth was fully diminished after 2–8 h treatment with PTS and gentamicin, exhibiting the potential to delay the development of bacterial resistance by utilizing lower concentrations of antibacterial agents [72]. Methicillin-resistant S. aureus (MRSA) is a multi-drug-resistant S. aureus strain, whose biofilm thickness was reduced from 18 to 10 μm when treated with PTS. Topical administration ameliorated the abscess formation induced by MRSA, thereby lowering the bacterial burden and improving the architecture of the skin [73]. PTS has also been used to treat infections with Staphylococcus spp. or Enterococcus faecalis in biofilms due to a reduction in the growth capacity of Gram-positive cocci [69].

2.8. Potential Therapeutic Effects of PTS against COVID-19 Infection

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), triggered a major setback to global human health and the economy [74]. Resveratrol was tested and proved to have effective therapeutic value against MERS-CoV infection by decreasing cell death [75]. Screening studies have indicated that stilbenes inhibit complex formation between the spike protein and ACE-2 receptor, thereby blocking viral entry into the host cell [76]. Based on these studies, stilbene derivatives could be considered important drug candidates for COVID-19 [76]. PTS has been demonstrated to actively inhibit SARS-CoV-2 virus replication in infected African green monkey kidney cells. Antiviral activity was seen for up to five rounds of replication, which indicates a long-lasting therapeutic effect.
Moreover, in human primary bronchial epithelial cells isolated from healthy volunteers, PTS showed an antiviral effect for up to 48 h after infection. These data promote the use of PTS as a potent drug against COVID-19 and warrant further clinical trials to prove its antiviral efficacy early in COVID-19 [74]. Furthermore, PTS, co-administered with zinc, has also been identified as a potential COVID-19 adjuvant therapy for managing moderate–severe disease [77]. However, further clinical trials are required to back the pharmacotherapeutic potential of PTS. COVID-19 patients with comorbidities related to metabolic syndromes, such as diabetes, obesity, hypertension, and cardiovascular disease, have low levels of the HO antioxidant enzyme. Higher HO-1 expression has been associated with reduced susceptibility to COVID-19 infection [78]. Considering that COVID-19 patients are susceptible to the induction of overt inflammatory processes and cytokine storms, PTS treatment could exert anti-inflammatory and cytoprotective effects by increasing HO-1 expression [79].

3. Conclusion and Future Prospects

Several studies that have evaluated PTS for its therapeutic potential have demonstrated its role as a promising candidate drug for health benefits in a broad spectrum of disease conditions. Various experimental studies have confirmed that PTS has anticancer, anti-diabetic, anti-hypertensive, antimicrobial, anti-aging, anti-atherosclerotic, and neuroprotective properties. PTS exerted its beneficial effects mainly by modulating antioxidant, anti-apoptotic, and anti-inflammatory pathways. Even at higher doses, PTS did not exhibit toxicity in animal studies, providing further encouragement to explore the use of the compound in more human clinical trials. However, considering that some of the studies have employed co-administration of PTS in combination with other compounds to improve its therapeutic efficiency, the potential effect of drug interactions should be considered. Although PTS has been identified to exert marked therapeutic benefits, most findings have been proven only in experimental models. Human clinical trials have been largely limited due to the lesser-than-desired bioavailability of the compound. To overcome this limitation, various strategies have been implemented, which involve modifying the administration routes and formulations of PTS ranging from co-crystals, pro-drugs, nanoparticles, lipid-based encapsulation, and beads. The potential effect of many of drug interactions with PTS still remains unclear. Of note, the mode of administration of PTS seems to play an important role in its bioavailability, as the administration of intravenous doses show a higher distribution when compared to oral intake. Further research that carefully considers the dose, drug interactions, administration route, disease-specific formulations, and the short and long-term biomedical implications are warranted before clinical adoption of this promising natural compound.

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