Abstract. The clinical use of doxorubicin (DOX), a potent antineoplastic agent, is limited by its serious side-effects, which include acute and chronic cumulative dose-related cardiotoxicity. Berberine (BER), a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazolium bromide (MTT) assay was used to detect the cell viability of A549, HeLa and HepG2 cells after each cell line was treated with DOX, BER or a combination of DOX and BER for 24 h. Apoptosis was evaluated by acridine orange staining. The results showed that BER and DOX exhibited dose-dependent inhibitory effects on A549 and HeLa cells which were likely mediated by inducing apoptosis. The same result was found in the combination group. Isobologram illustration and combination index (CI) analyses revealed that the combination of DOX and BER generates synergistic effects in A549 (CI=0.61) and HeLa (CI= 0.73) cells. These findings indicate that BER sensitizes cells to the anticancer effects of DOX. IntroductionDoxorubicin (DOX), an anthracycline antibiotic and antineoplastic agent, was first isolated from Streptomyces peucetius (1). DOX is a potent chemotherapeutic agent that is used in the treatment of solid tumors and malignant hematological diseases (2). DOX exerts its antitumor activity by inserting into DNA, leading to double-stranded DNA breaks (DSB), and intercepting DNA topoisomerase II activity (3,4). However, the clinical use of DOX has been largely restricted due to its cardiotoxicity, which may lead to the development of cardiomyopathy and ultimately congestive heart failure (5). The molecular mechanisms underlying DOX-induced cardiotoxicity include the formation of free radicals, activation of transcription factor NF-κB, increased lipid peroxidation and Ca 2+ overloading (6-8). The use of cardioprotective drugs is an alternative approach to reduce the cardiotoxicity of DOX. Pharmacological and clinical attempts to reduce the cardiotoxicity of DOX have had little success thus far. Consequently, it is important to develop a therapy to reduce DOX-induced cardiotoxicity and increase the antitumor effect of DOX.Berberine (BER), a botanical alkaloid, is purified from the roots and bark of the Berberis species (9). BER reportedly possesses multiple biological and pharmacological properties, including anti-diarrheal, anti-fungal, anti-diabetic (10-12), hepatoprotective and cardioprotective effects. The possible mechanism of the hepatoprotective effect is that BER inhibits the activity of CYP 2E1 and CYP 1A2, reduces the production of nitric oxide and lowers the AST and ALT levels in serum (13,14). For the cardioprotective property, BER is known to modulate Cdk9 and cyclin T1 protein expression. BER possesses muscarinic agonist-like properties which may contribute to a reduction in myocardial damage (15-17). BER also suppresses tumor growth through the induction of apoptosis and cell cycle arrest in cancer cells (18)(19)(20)(21). Notably, it has been reported tha...
Doxorubicin, a very potent and often used anti-cancer drug, is largely limited due to the dose-related toxic effects. The present study investigated whether berberine, a natural product alkaloid, can reduce the liver injury induced by doxorubicin. Mice of either gender were randomly divided into four groups: the control group, doxorubicin group, berberine group, and berberine doxorubicin group. In the tests, body weight, general condition and mortality of the mice were observed, and serum alanine aminotransferase and aspartate transaminase levels were determined to evaluate liver function. Furthermore, the liver was excised for determination of the weight changes, as well as histopathological analysis in the tissues. Mortality rate and significant decline in body weight, and increased plasma alanine aminotransferase and aspartate transaminase activities were observed in doxorubicin-treated mice. These changes were significantly prevented by pretreatment with berberine. Histopathological studies showed that doxorubicin caused structural injuries, such as vascular congestion, inflammatory cell infiltration, hepatocellular degeneration and necrosis, fibrosis in the liver. These histopathological changes were largely attenuated by berberine pretreatment. These findings indicate that berberine has the hepatoprotective effect on doxorubicin-induced liver injury in mice.
Arsenic trioxide (As2O3), an effective agent to treat leukemia and other solid tumors, is largely limited by its toxicity. QT prolongation, torsades de pointes and sudden death have been implicated in the cardiotoxicity of As2O3. The present study was designed to assess whether the combination of As2O3 and tetrandrine could generate a more powerful anti-cancer effect. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed for detecting the proliferation of HepG2 and A549 cells treated with tetrandrine and As2O3. Fluorescent microscopy measurements and flow cytometry were carried out to evaluate the apoptosis in HepG2 cells. The cell cycle arrest of HepG2 cells was also determined by flow cytometry. The cell proliferation assay in HepG2 and A549 cells indicated that tetrandrine significantly enhanced the inhibit effect of As2O3. In addition, the following Isobolograms further demonstrated that combining As2O3 with tetrandrine generated synergism action. Tetrandrine also enhanced the apoptosis, necrosis and cell cycle arrest in As2O3-treated HepG2 cells. Our present study showed that tetrandrine can dramatically enhance the anti- cancer effect induced by As2O3. Combining As2O3 with tetrandrine would be a novel strategy to treat cancer in clinical practice.
This study investigated the effects of berberine, a natural alkaloid, on doxorubicin-induced cardiotoxicity in mice. Mice were injected intraperitoneally with saline 10 ml/kg (n = 10), doxorubicin 2.5 mg/kg (n = 10), 60 mg/kg berberine 1 h before doxorubicin 2.5 mg/kg (n = 10), or 60 mg/kg berberine alone (n = 10) every other day for 14 days. Body weight, general condition and mortality were recorded over the 14-day study period. Electro cardiography was performed before the start of treatment and after 14 days and plasma lactate dehydrogenase (LDH) activity was measured after 14 days. At the end of the study period the heart was excised and examined histologically. An increase in mortality, an initial decrease in body weight, increased LDH activity, prolongation of QRS duration and increased myocardial injury were seen in the doxorubicin-treated group compared with the saline control group. These changes were significantly attenuated by pretreatment with berberine. The study suggests that berberine may have a potential protective role against doxorubicin-induced cardiotoxicity in mice.
Objective Proinflammatory cytokines mediate anxiety and depression in various ways, such as immunity, inflammation, and the hypothalamic–pituitary–adrenal axis. This study intended to further explore the linkage of common proinflammatory cytokine levels with anxiety and depression in psoriasis patients. Methods Totally, 150 psoriasis patients and 50 healthy controls (HCs) were included; the serum samples were collected, then common proinflammatory cytokines were measured by ELISA. Hospital Anxiety and Depression Scale (HADS) was assessed. Results HADS‐anxiety (HADS‐A) score, HADS‐depression (HADS‐D) score, TNF‐α, IL‐1β, IL‐6, IL‐12, IL‐17A, and IL‐23 were all increased in psoriasis patients compared to HCs (all p < 0.05). In psoriasis patients, TNF‐α ( p = 0.001), IL‐12 ( p = 0.035), and IL‐17A ( p < 0.001), but not IL‐1β ( p = 0.255), IL‐6 ( p = 0.248), and IL‐23 ( p = 0.216), were positively linked to HADS‐A score. Meanwhile, TNF‐α ( p = 0.007) and IL‐17A ( p = 0.007) were enhanced in psoriasis patients with anxiety in contrast to those without anxiety; whereas IL‐1β ( p = 0.178), IL‐6 ( p = 0.360), IL‐12 ( p = 0.239), and IL‐23 ( p = 0.450) were not different. TNF‐α ( p < 0.001), IL‐1β ( p = 0.013), Il‐17A ( p < 0.001), and IL‐23 ( p = 0.023), but not IL‐6 ( p = 0.143) and IL‐12 ( p = 0.158), were positively linked to HADS‐D score. Concurrently, TNF‐α ( p = 0.015), IL‐17A ( p < 0.001), and IL‐23 ( p = 0.017) were climbed in psoriasis patients with depression by comparison to those without depression; whereas IL‐1β ( p = 0.113), IL‐6 ( p = 0.237), IL‐12 ( p = 0.660) did not differ. Conclusion TNF‐α, IL‐17A, and IL‐23 increments reflect anabatic anxiety and depression in psoriasis patients, uncovering the potency of proinflammatory cytokines measurement for monitoring or even preventing psoriasis patients' anxiety and depression.
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