Consistent with the results using black

Consistent with the results using black tea or its extract, major ingredients in black tea including TFs and EGCG inhibited the induction of NF-κB [61] and thus were able to reduce inflammation mediators. By blocking NF-κB, TF1 inhibited tumor necrosis factor (TNF)-α-mediated interleukin (IL)-8 gene [62] and the expression of LPS-induced interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM)-1 via the modulation of MAPKs signaling [63,64]. By modulation multiple transcription factors including NF-κB, AP-1 and CREB, TF2 treatment suppressed TPA-induced inflammatory gene expression in Caco-2 cells, such as COX-2, TNF-α, ICAM-1, and iNOS. It also reduced COX-2 promoter activity [31]. Oral administration of TF2a reduced levels of pro-inflammatory cytokines, including IL-12, IFN-γ, and tumor TNF-α in type IV allergy in male ICR mice [65]. Various in vitro and in vivo models demonstrated the anti-inflammatory effects of TF3. Similar to TF1 and TF2, suppression of NF-κB by TF3 inhibited LPS-induced iNOS expression in RAW264.7 macrophage [66]. In TPA-induced mouse ear edema model, TF3 showed stronger inhibitory effect than other tea polyphenols in reducing of IL-6, prostaglandin E2 (PGE2), and LTB4 levels [67]. Oral administration of TF3 decreased both gene and protein levels of TNF-α, IL-12, interferon (IFN)-γ and iNOS in trinitrobenzene sulfonic antioxidants (TNBS)-induced colitis animal model [68]. TF3 suppressed IL-16 and CXC chemokine ligand 10 (CXCL10) production by targeting multiple signaling pathways in human gingival fibroblasts [69,70], which play a critical role in sustaining inflammatory response in the pathogenesis of periodontal disease [71]. Mononuclear cell infiltration and osteoclast activation have been linked to bone loss [52]. Black tea extract feeding effectively preserved and restored skeletal health by reducing osteoclast activation and oxidative stress caused by mononuclear cells in rats [72]. Osteoporosis is a common complication associated with chronic liver disease [73]. In high fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH) model, consumption of black tea extract ameliorated bone skeletal dysfunctional changes, including bone turnover and density [74]. In addition, it was found that TF3 and EGCG inhibited the formation and differentiation of osteoclasts through decreasing gene expression of MMP-2 and MMP-9 as well as their enzymatic activities. These results supported the role of black tea polyphenols in preventing the degeneration of the matrix in bone and cartilage [75]. Delayed onset muscle soreness (DOMS) frequently occurs in athlete after high intensity exercise. Muscle soreness, which is initiated by muscle damage, is usually noted at 24h post-exercise and can last as long as 5–7 d post-exercise. The muscle damage elicits inflammatory and oxidative responses that may exacerbate muscle injury and prolong the time to regeneration [76]. In a human trial study of healthy athletes engaging in high intensity anaerobic exercise, supplement with TF2-enriched black tea extract significantly reduced DOMS, increased glutathione (GSH)/oxidized glutathione (GSSG) ratio and performance [76]. These results are consistent with the molecular actions of black tea polyphenols that they activate transcription factor Nrf2, which up-regulates protective detoxifying and antioxidant enzymes including enzyme for glutathione biosynthesis and metabolism to maintain glutathione levels [19]. Activation of Nrf2 also attenuates the NF-κB mediated inflammatory response [77], which may play a significant role in anti-inflammatory effects of black tea.
Effects of black tea in obesity and metabolic syndrome Obesity is a highly prevalent condition and regarded as a risk factor for cardiovascular disease, hypertension and metabolic syndrome, fatty liver disease, type 2 diabetes and chronic kidney disease [78]. Obesity is currently considered a chronic inflammatory disorder that promotes the development of insulin resistance and diabetes [77]. In a high fat diet (HFD) induced obesity animal model, drinking black tea or its extract decreased body fat [79], and improved hyperglycemia and glucose intolerance [79] (Table 6). Consumption of black tea up-regulated glucose transporters type 4 (GLUT4) in muscle that resulted in increased glucose uptake and improved glucose intolerance [79]. It also suppressed C/EBPβ expression in perirenal fat that implicated in adipocyte differentiation and fat accumulation [80]. Dietary feeding black tea polyphenol extract also suppressed HFD- or high sucrose-induced increased liver lipid content or dyslipidemia in animals [81]. The potential mechanisms include decreased hepatic fatty acid synthase (FAS) and increased AMP-activated protein kinase (AMPK) activity [82]. AMPK is the key cellular energy sensor that regulates glucose and lipid metabolisms and is the drug target of anti-diabetic drug such as metformin [83,84] and lipid-lowering drug, statins [84]. Activation of AMPK leads to increased glucose uptake via up-regulation of glucose transporters, turning off anabolic pathways including decreased fatty acid synthase for lipid synthesis and increased catabolic pathways in cells [83]. In agreement with the in vivo results, in vitro study showed that theaflavins and EGCG treatment strongly reduced intracellular total lipid, triglyceride, and cholesterol levels in fatty acid (FA)-overloaded liver cell line through activating AMPK signaling pathway [85], and TF1 was found to inhibit both gene and protein expression of FAS in vitro that may reduce cell lipogenesis [26].