The present study was conducted to evaluate effects of cranberry supplementation and weight loss diet on markers of inflammation (TNF-α and CCL-2), oxidative stress (MDA and TAC) and hepatic cell apoptosis (CK-18 M30) in NAFLD patients. Supplementing a weight loss diet with cranberry for a period of 12 weeks could significantly increase TAC. However, changes in other variables remained insignificant. Different studies have been conducted on the effects of cranberry with or without dietary interventions on these markers with different intervention types (extract, juice, tablet, etc), variable doses and different findings.
Cytokine imbalances occur in the “second hit” of NAFLD. Therefore the issue has gained a considerable attention as target for therapeutic interventions [25]. Glisan et al evaluated effects of polyphenol enriched cranberry extract (CBE) on markers of hepatic inflammation in HFD-fed obese rats and found that CBE can decrease hepatic protein levels of TNF-α and CCL-2, as well as hepatic mRNA levels of toll like receptor-4 (TLR-4) and nuclear factor κB (NFκB) [22]. Another study was performed to evaluate possible anti-fibrotic effects of cranberry nutraceuticals in high fat cholesterol diet induced (HFCD)-NAFLD rats. The results showed that cranberry could alleviate markers of oxidative stress (MDA, glutathione, catalase and superoxide dismutase), inflammation (TNF-α, IL-6 and NFκB) and improved markers of insulin resistance [26]. Apoptosis is a key mechanism in the progression of steatosis to NASH and apoptosis markers are related with histologic severity of NAFLD [27]. CK-18 M30 is a well-known substrate of caspase activity during apoptotic hepatocyte death [28] and has been shown to have a high accuracy in differentiating NAFLD from control subjects [29]. Accordingly, in the current study, CK-18 M30 was assessed as a marker of apoptosis which did not significantly change during intervention. Studies regarding anti-apoptotic effects of cranberries are few. However, some studies have been conducted on other polyphenol rich compounds in this area. In a randomized clinical trial, 44 participants were given either 250 ml bayberry juice or placebo, twice a day for 4 wks. Bayberry consumption could significantly improve markers of inflammation and apoptosis including polypeptide specific antigen and CK-18 M30 [30]. In another study, 14 days of dark chocolate consumption, as a source of polyphenols, led to a significant reduction in CK-18 M30 in NAFLD patients [31]. According to findings, multistage processing of fruit extraction leads to a considerable loss in phytochemical content through thermal degradation and polyphenol oxidation which could have been considered as a reason for the null findings. Therefore, future research should focus on comparisons between different forms of cranberry supplements.
On the other hand, a significant improvement in TAC was observed in intervention group which indicates possible anti-oxidative effects of cranberry supplements in NAFLD patients. Oxidative stress is a result of an imbalance between pro-oxidants and anti-oxidants and plays a crucial role in the pathogenesis of NAFLD [32]. A considerable amount of research has been conducted regarding anti-oxidative effects of berries. In one study mulberry treatment in HFD rats significantly suppressed hepatic reactive oxygen species (ROS) overproduction and mitochondrial oxidative stress [33]. Another research team investigated effects of raspberry on obese diabetic (db/db) mice for 8 weeks. The findings showed that raspberry intake could improve antioxidant status and lessen IL-6 in treatment group [34]. Results of a double blind randomized trial showed that 4 weeks supplementation with maqui berry (delphinol) significantly reduced markers of oxidative stress (ox-LDL and urinary F2-isoprostane) in intervention group [35]. Wild blueberry consumption significantly improved postprandial oxidative stress in male subjects. Oxygen radical absorbance capacity (ORAC) assay and the total antioxidant status (TAS) were evaluated as markers of oxidative stress in the study [36]. On the other hand, in a randomized controlled trial, 40 post-menopausal women consumed either 22 grams of blueberry or placebo for 8 weeks. Blood markers of oxidative stress, inflammation and antioxidant defense did not change in blueberry group after 8 weeks [37].
Health benefits of fruits and vegetables have been demonstrated in nutrition not only for their vitamins and minerals, but also their phytochemical components [38]. The American cranberry (species Vaccinium macrocarpon) has been particularly considered a health fruit for centuries [39]. Cranberries as a uniquely rich source of phytochemicals, contain over 150 phytochemicals with flavonoids as the most predominant component. Some cranberry flavonoids include anthocyanins, proanthrocyanidins, catechins, organic acids, resveratrol and flavonols which are responsible for the fruit’s color and sour astringent flavor [40]. Several in vivo animal models have confirmed anticarcinogenic, antiyumorogenic, antiangiogenic, anti-inflammatory and antioxidant properties of cranberry polyphenols [41]. NAFLD has been linked to gut dysbiosis and metabolic endotoxemia which are the initial triggers of inflammatory cascade [42]. NF-kβ is a key regulator in this cascade and has the potential to control the production of pro-inflammatory cytokines including TNF-α and IL-6 [43, 44]. Cranberries as a great source of polyphenols might exert as prebiotics which can have immunomodulatory and anti-inflammatory effects by interacting with gut microbiota [45]. In one study, dietary cranberry supplementation in a mouse model of IBD, not only suppressed colonic levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) but also increased the abundance of beneficial gut bacteria including lactobacillus and bifidobacterium [46]. It has also been shown that phenolic compounds can suppress IL-1β secretion and exert anti-inflammatory effects through inhibition of cyclo-oxygenase and lipoxygenase activity [47]. Antioxidant properties of cranberry are attributed to free radical scavenging properties of polyphenols against ROSs as well as inhibition of lipid and protein oxidation [48]. According to studies, cranberry supplementation has also the potential to decrease NO synthase activity, improve homocysteine levels, and endothelial function, thus suppressing oxidative stress [49].