2.3.2. Stomach

The risk of gastric cancer is associated with genetics and dietary factors such as high consumption of smoked, salted, and nitrated foods combined with low intake of fruits and vegetables [42]. The anticancer mechanisms of fruit consumption in gastric cancer are complex; however, two studies have found that both blueberry juice and pterostilbene inhibit carcinogenesis of gastric cells. Boivin and colleagues demonstrated that juice from velvet leaf blueberry, low-bush blueberry, and high-bush blueberry, all inhibited cell proliferation of gastric adenocarcinoma cells [17]. Velvet leaf blueberry juice exerted the most significant antiproliferative effect, and high-bush blueberry juice exhibited the least significant effect. However, there was no significant correlation between antiproliferation rates and antioxidant capacity of blueberry juices leading to the conclusion that blueberries may have variable effects upon several carcinogenic mechanisms independent of antioxidant potential. Similarly, in a study performed by Pan and colleagues, pterostilbene treatment inhibited cell proliferation in a dose-dependent manner and induced apoptosis by increasing cytochrome C, Bad, Bax, and caspases 1, 2, 3, 8, and 9 in gastric adenocarcinoma cells in vitro [43].
Utilization of blueberry juice and pterostilbene to decrease gastric cancer risk and mitigate progression of malignant tumors may be a feasible option in the future. Additional research to examine the effects of blueberry juice and pterostilbene on gastric cancer should include clinical trials to assess the antioxidant and anticancer effects of blueberry-derived pterostilbene in human subjects.

2.3.3. Colon

The etiology of colon cancer is complex and involves dynamic dietary and genetic and inflammatory components [44]. Epidemiological studies have conclusively shown that chronic inflammation predisposes to high rates of colon cancer, and it has been established that diets low in fiber, fruits, and vegetables increase colon cancer risks [44]. The role of OS in the pathogenesis of colon cancer is not fully understood; however, it has been theorized that inflammation and OS interact in a positive feedback loop leading to aberrant cellular signaling and carcinogenesis. Such theories suggest that dietary antioxidants play a key role in the mitigation of colonic inflammation and colon cancer. In multiple studies, pterostilbene exhibited antioxidant properties and significantly inhibited colon cancer [45]. The anticancer effects of pterostilbene are comparable to the findings of Seeram et al. and Boivin et al. who demonstrated the inhibitory effects of blueberry compounds on colon cancer in vitro [16, 17].
Suh et al. and Chiou et al. found that pterostilbene treatment downregulated the inflammatory enzymes nitric oxide synthetase (iNOS) and cyclooxygenase-2 (COX-2), which stimulate production of proinflammatory cytokines and induce proliferation of colon cancer cells [46, 47]. Both enzymes are upregulated by OS and implicated in the progression of colonic tumorigenesis. The findings indicate that iNOS and COX-2 may be direct and indirect targets of pterostilbene’s antioxidant activity in inflammation-mediated colon cancer. Chiou and colleagues also found that pterostilbene decreased expression of aldose reductase (AR), an OS protein, and increased expression of the antioxidant enzymes, GR and hemeoxygenase-1 (HO-1), through NF-E2-related factor 2(Nrf2) upregulation [47]. The transcription factor Nrf2 plays a critical role in regulation of mucosal inflammation and Nrf2 deficient mice have been shown to express increased mucosal inflammation, and OS. The results suggest that pterostilbene exerts its antioxidant effects through multiple interrelated mechanisms.
In addition to anti-inflammation and antioxidation, Chiou et al. and Suh et al. found that pterostilbene treatment inhibited colon cancer proliferation, which is consistent with the research of Remsberg et al. and Priego et al. [12, 48]. Pterostilbene treatment increased expression of the antioxidants, catalase, GPx, GR, and TR-1 by less than 2-fold and downregulated Bcl-2, a proto-oncogene implicated in colon cancer proliferation [48]. The effects of pterostilbene were most significant upon antioxidant SOD2 expression, producing a 5.7-fold increase in enzyme activity [48]. Some authors have proposed that chemotherapeutic regimens target SOD2 as an additional mechanism for tumor suppression making pterostilbene a potential chemotherapeutic agent [49]. Priego and colleagues also found that pterostilbene treatment when combined with quercetin, radiotherapy, and the chemotherapy regimen FOLFOX (oxaliplatin, leucovorin, and 5-fluorouracil) produced tumor regression in rats [48]. The overall evidence suggests that pterostilbene possesses potent anti-inflammatory, antioxidant, and anticarcinogenic properties ideal for the eradication of cancerous colon cells.
The antioxidant properties of pterostilbene may help to explain how blueberry consumption contributes to reduced risk of colon cancer in humans. Pterostilbene’s modulation of antioxidant activity may also facilitate anti-inflammatory and anticarcinogenic mechanisms that confer clinical benefits in inflammatory bowel disease and colorectal malignancies. Additional studies are warranted to investigate the preventive and therapeutic effects of pterostilbene in diseases of the colon.

2.4. Hematology

Hemolytic disorders include a broad spectrum of hereditary and acquired conditions that range from mild to severe clinical outcomes [50]. Hemolytic anemias, irrespective of etiology, are exacerbated by exposure to ROS, which produces both internal and external damage to red blood cells (RBCs), accelerating the process of hemolysis. Studies have shown that ROS-induced hemolysis is a modifiable event that can be alleviated with antioxidant treatment [51]. Specifically, treatments with blueberry extract and pterostilbene have been shown to protect RBCs against ROS-induced hemolysis indicating a possible therapeutic effect in the treatment of hemolytic anemia.
Youdim and colleagues conducted experiments both in vitro and in vivo to assess the antioxidant capacity of blueberry-derived polyphenolic components in vulnerable RBCs [51]. The results of experiments performed in vitro show that low-bush blueberry treatment reduced rates of ROS formation at 6 and 24 hours after H2O2 treatment in a time- and concentration-dependent manner. In vivo, oral blueberry supplementation produced significant inhibition of H2O2-induced ROS formation at 6 and 24 hours similar to the results obtained in vitro. Serum analysis of blueberry fed rats revealed detectable levels of anthocyanins present at 1- and 6-hour intervals but not at 24 hours, indicating a short-term protective effect. The findings of the study suggest that oral blueberry supplementation protects RBCs against ROS formation after exposure to H2O2.
The relationship between antioxidant activity and ROS-induced RBC damage was further explored by Mikstacka and colleagues that studied the antioxidant effects of pterostilbene in RBCs that were treated with 2,2-azobis 2-amidinopropane dihydrochloride (AAPH), a known free radical generator that causes OS in RBCs leading to hemolysis [52]. The authors found that pterostilbene treatment inhibited AAPH-induced hemolysis and AAPH-induced depletion of the antioxidant enzyme GSH. Moreover, pterostilbene treatment was found to inhibit H2O2-induced lipid peroxidation, an initiator of OS that produces autoxidation in RBCs [53].
It has been postulated that blueberries and its component pterostilbene protect RBCs against OS by scavenging H2O2, altering the harmful effects of ROS and increasing antioxidant activity. The short-term benefits of pterostilbene are observable in RBCs up to 24 hours but long-term effects have not been studied. Currently, it is undetermined whether oral supplementation with blueberries or pterostilbene is able to prevent hemolytic episodes in humans. Future research is needed to elucidate the antioxidant enhancing mechanisms of pterostilbene and prevention of hemolysis in clinical trials.

2.5. Hepatopancreaticobiliary

2.5.1. Liver

Chronic liver disease (CLD) is an end-stage process that results from conditions like Wilson’s disease, hemochromatosis, and primary biliary cirrhosis, in addition to infection, alcoholism, and nonalcoholic steatohepatitis (NASH) [54]. The pathogenesis of CLD is complex but follows a consistent model of progression from acute hepatic cellular injury to apoptosis, necrosis, inflammation, and irreversible fibrosis that can culminate in cancer [54]. In experimental studies, OS is a common mediator in the progression of hepatic injury to sustained inflammation and fibrosis regardless of disease etiology. For example, studies have shown that models of CLD due to viral hepatitis, NASH, alcoholism, and excess deposition of copper or iron, all share common pathways of increased OS combined with reduced antioxidant capacity [54]. An imbalance of oxidation, measured by increased ROS, H2O2, and , can alter critical transcriptional and translational cell signaling leading to increased proliferation and eventually fibrosis of hepatic cells. The combined effect of increased OS and reduced antioxidant capacity is deleterious because it potentiates and amplifies structural damage in a time-dependent manner leading to permanent cellular and parenchymal hepatic impairment.