There is now evidence that major depression is accompanied by lowered serum zinc, an immune-inflammatory biomarker. However, the effect of anti-inflammatory drugs as adjuvant to antidepressants on serum zinc and copper in relation to pro- and anti-inflammatory cytokines are not studied. The aim of the present work is to examine the effects of treatment with sertraline with and without ketoprofen on serum levels of zinc and copper in association with immune-inflammatory biomarkers in drug-naïve major depressed patients. We measured serum zinc and copper, interleukin (IL)-1β, IL-4, IL-6, IL-18, interferon (IFN)-γ, and transforming growth factor (TGF)-β1 in 40 controls and 133 depressed patients. The clinical efficacy of the treatment was measured using the Beck Depression Inventory-II (BDI-II) at baseline and 8 weeks later. In drug-naïve major depressed patients we found significantly reduced baseline levels of serum zinc and copper in association with upregulation of all cytokines, indicating activation of the immune-inflammatory responses system (IRS) as well as the compensatory immune regulatory system (CIRS). Treatment with sertraline significantly increased zinc and decreased copper levels, while ketoprofen did not have a significant add-on effect on zinc but attenuated the suppressant effects of sertraline on copper levels. During treatment, there was a significant inverse association between serum zinc and activation of the IRS/CIRS. The improvement in the BDI-II during treatment was significantly associated with increments in serum zinc coupled with attenuation of the IRS/CIRS. In conclusion, lower serum zinc is a hallmark of depression, while increments in serum zinc and attenuation of the immune-inflammatory response during treatment appear to play a role in the clinical efficacy of sertraline. Intertwined changes in zinc levels and the immune response play a role in the pathophysiology of major depression and participate in the mechanisms underpinning the clinical efficacy of antidepressants.

Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of pro-inflammatory and immune-regulatory cytokines and cytokine-induced stimulation of indoleamine-2,3-dioxygenase (IDO). There is also some evidence that anti-inflammatory drugs may have a clinical efficacy in MDD.The aim of this study is to examine the clinical effects of an eight-week combinatorial treatment of ketoprofen (a nonsteroidal anti-inflammatory drug) combined or not with sertraline, on serum levels of IDO, interferon (IFN)-γ, interleukin (IL)-4 and transforming growth factor (TGF)-β1 in association with changes in the Beck-Depression Inventory-II (BDI-II). The study included 140 MDD patients and 40 normal controls. The pre-treatment serum levels of IDO, IFN-γ, TGF-β1 and IL-4 were significantly higher in MDD patients compared with the control group. Treatment with sertraline with or without ketoprofen significantly reduced the increased baseline production of all 4 biomarkers to levels which were similar as those of normal controls. Ketoprofen add-on had a significantly greater effect on IDO and BDI-II as compared with placebo. The reductions in IDO, IL-4 and TGF-β1 during treatment were significantly associated with those in the BDI-II.In conclusion, the clinical efficacy of both sertraline + ketoprofen may be ascribed at least in part to attenuated IDO levels and immune-inflammatory responses in MDD. Moreover, add-on treatment with ketoprofen may augment the efficacy of sertraline by attenuating IDO. However, these treatments may also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) immune subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD, while enhancing the compensatory immune-regulatory system (CIRS).

HCC is a highly aggressive malignancy with limited treatment options. In this study, novel conjugates, of NSAIDs - Ibuprofen and Ketoprofen with oleanolic acid oximes derivatives (OAO) were synthesized and their activity as modulators of signaling pathways involved in HCC pathogenesis was evaluated in normal THLE-2 liver cells and HCC derived HepG2 cells. The results demonstrated that conjugation with OAO derivatives reduces the cytotoxicity of parent compounds in both cell lines. In THLE-2 cells treatment with conjugates resulted in increased activation of the Nrf2-ARE pathway. An opposite effect was observed in HepG2 cells. In the later reduction of NF-κB was observed along with modulation of MAPK signaling pathways (AKT, ERK, p38, p70S6K, and JNK). Moreover, STAT3, STAT5, and CREB transcription factors on protein levels were significantly reduced as a result of treatment with IBU- and KET-OAO derivatives conjugates. The most active were conjugates with OAO-morpholide. Overall, the findings of this study demonstrate that IBU-OAO and KET-OAO derivatives conjugates modulate the key signaling pathways involved in hepatic cancer development. Their effect on specific signaling pathways varied depending on the structure of the conjugate. Since the conjugation of IBU and KET with OAO derivatives reduced their cytotoxicity, the conjugates may be considered good candidates for the prevention of liver cancer.