Efficacy and safety of methylphenidate and ginseng in cancer-related fatigue: a network meta-analysis of randomized controlled trials.

Background: Incidence of cancer-related fatigue (CRF), which can persist 5 to 10 years, is nearly 85% in cancer patients. It severely affects the quality of life and is strongly associated with poor prognosis. As clinical trial data on CRF treated with methylphenidate and ginseng, two potential medicines, has been accumulating, an updated meta-analysis was performed to evaluate and compare the efficacy and safety of the two medicines in CRF. Methods: Randomized controlled trials that investigated methylphenidate or ginseng in the treatment of CRF were identified through a literature search. The primary outcome was CRF relief. Standardized mean difference (SMD) was used to analyze the effect. Results: Eight studies on methylphenidate were included and the pooled SMD was 0.18 [95% confidence interval (95% CI): -0.00 to 0.35, P=0.05]. Five studies on ginseng were included and the SMD was 0.32 (95% CI: 0.17-0.46, P<0.0001). Results of network meta-analysis showed that the order was ginseng, methylphenidate, placebo from high efficacy to low and ginseng was significantly better than methylphenidate (SMD =0.23, 95% CI: 0.01-0.45). Incidences of insomnia and nausea caused by ginseng were significantly lower than those caused by methylphenidate (P<0.05). Conclusions: Both methylphenidate and ginseng can significantly ameliorate CRF. Ginseng may be superior to methylphenidate because ginseng may be more effective and might cause less adverse events. Head-to-head trials with fixed protocol are warranted to identify the optimal medical strategy.

Impacts of ezetimibe on risks of various types of cancers: a meta-analysis and systematic review.

BACKGROUND: Ezetimibe is a widely used medication to reduce the plasma cholesterol level, particularly low-density lipoprotein level. However, its impact on cancer remains controversial. Here, its impacts on risks of various types of cancers were meta-analyzed. METHODS: PubMed and Cochrane Library electronic databases were searched and randomized controlled trials with followed up for at least 24 weeks were selected and included. The experimental group was defined as those patients treated with ezetimibe alone or with other medications, and the control group was defined as those who received a placebo or the matched medication. The number of new cancer cases or cancer-related deaths was extracted. Statistical analysis was performed using Review Manager (version 5.3). RESULTS: Nine trials enrolling 35 222 patients were included in the analyses. Compared with the control group, ezetimibe increased the number of new intestine cancer patients [relative risk (RR), 1.30; 95% confidence interval (CI), 1.02-1.67; P = 0.03] and had a trend to increase the number of new breast cancer patients (RR, 1.39; 95% CI, 0.98-1.98; P = 0.07). There was no significant difference in new hepatobiliary cancer, prostate cancer, skin cancer or cancer of other sites. Ezetimibe did not significantly increase the risk of new cancer in total (RR, 1.03; 95% CI, 0.96-1.11; P = 0.38), cancer-related death (RR, 1.11; 95% CI, 0.98-1.26; P = 0.10) or cancer events (RR, 1.04; 95% CI, 0.97-1.12; P = 0.30). In terms of lipid-lowering effect, ezetimibe significantly reduced total cholesterol and low-density lipoprotein cholesterol, increased high-density lipoprotein cholesterol. CONCLUSION: Ezetimibe may increase the risk of intestine cancer and has a trend of increasing the risk of breast cancer. There is no evidence to support that it increases or decreases the risk of other types.

Efficacy of ginseng oral administration and ginseng injections on cancer-related fatigue: A meta-analysis.

BACKGROUND: Up to 90% of patients who are under the active treatment suffer from cancer-related fatigue (CRF). CRF can persist about 10 years after diagnosis and/or treatment. Accumulating reports support that ginseng and ginseng injections are both potential drugs for the treatment of CRF but few studies put them together for analysis. METHODS: Two reviewers independently extracted data in 3 databases (PubMed, Cochrane Library and China National Knowledge Infrastructure) from their inception to May 24, 2021. The primary outcome was the effect of ginseng in alleviating CRF. The secondary outcome was ginseng in alleviating emotional or cognitive fatigue. Standardized mean difference (SMD) was employed. RESULTS: Twelve studies were included to evaluate efficacy of ginseng oral administration and ginseng injections on CRF. The pooled SMD was 0.40 (95% confidence Interval [95% CI] [0.29-0.51], P < .00001). Six studies were included to evaluate efficacy of ginseng oral administration on CRF and the SMD was 0.29 (95% CI [0.15-0.42], P < .0001). The order was 2000 mg/d, 3000 mg/d, 1000 mg/d and placebo from high efficacy to low. Ten studies were included to evaluate efficacy of ginseng injections on CRF and the SMD was 0.74 (95% CI [0.59-0.90], P < .00001). Emotional fatigue was reported in 4 studies, ginseng oral administration in 2 and ginseng injections in 2. The pooled SMD was 0.12 (95% CI [-0.04 to 0.29], P = .15). Cognitive fatigue was reported in 4 studies focusing on ginseng injections and the SMD was 0.72 (95% CI [0.48-0.96], P < .00001). CONCLUSION: Ginseng can improve CRF. Intravenous injection might be better than oral administration. Ginseng injections may alleviate cognitive fatigue. No evidence was found to support that ginseng could alleviate emotional fatigue.

Protective effects and possible mechanism of 6-gingerol against arsenic trioxide-induced nephrotoxicity based on network pharmacological analysis and experimental validation.

BACKGROUND AND OBJECTIVE: Nephrotoxicity induced by the chemotherapeutic drug arsenic trioxide (ATO) is often overlooked, and the underlying mechanisms remain poorly understood. Based on network pharmacology and experimental validation, this study investigates the protection of 6-gingerol (6G) against ATO-induced nephrotoxicity and the potential mechanisms. METHODS: We screened and collected 6G and disease-related targets and then imported the interaction targets into a String database to construct protein-protein interaction (PPI) networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Mice were injected intraperitoneally with ATO (5 mg/kg) for seven days to induce nephrotoxicity, and then the histological morphology of the kidneys, biochemical indices of serum and tissues, and associated protein expressions were observed. RESULTS: The network pharmacology results revealed that the effects of 6G against nephrotoxicity are closely related to apoptosis, and the MAPKs pathway was screened for validation. In animal experiments, 6G improved the histopathological morphology of the kidneys, reduced the levels of renal function markers, enhanced antioxidant activity, and decreased the levels of inflammation. Furthermore, 6G reduced apoptotic cells in kidney tissues, decreased the levels of Bax and c-Caspase-3, and increased the level of Bcl-2. The results of immunohistochemistry and western blotting revealed that 6G significantly inhibited the expressions of p-p38, p-ERK, and p-JNK. CONCLUSION: The results comprehensively demonstrate the protective effects of 6G against ATO-induced nephrotoxicity. The effects are related to anti-oxidant, anti-inflammatory, and anti-apoptotic properties, possibly through inhibition of the MAPKs pathway.

Protective Effects of 6-Gingerol on Cardiotoxicity Induced by Arsenic Trioxide Through AMPK/SIRT1/PGC-1α Signaling Pathway.

Background and Objective: Arsenic trioxide (As2O3) induced cardiotoxicity to limit the clinical applications of the effective anticancer agent. 6-Gingerol (6G) is the main active ingredient of ginger, a food with many health benefits. The present study aims to investigate the potential pharmacological mechanisms of 6G on As2O3-induced myocardial injury. Methods and Results: Fifty KunMing mice were divided into five groups (n = 10) receiving: 1) physiological saline; 2) 6G (20 mg/kg) alone; 3) As2O3 (5 mg/kg); 4) 6G (10 mg/kg) and As2O3 (5 mg/kg); 5) 6G (20 mg/kg) and As2O3 (5 mg/kg). 6G was given orally and As2O3 was given intraperitoneally once per day for seven consecutive days. Biochemical, histopathological, transmission electron microscopy, ELISA, and western blotting analyses were then performed. Based on the resultant data, As2O3 was found to induce cardiotoxicity in mice. 6G significantly ameliorated As2O3-induced heart injury, histopathological changes, oxidative stress, myocardial mitochondrial damage, inflammation, and cardiomyocyte apoptosis, while reversed As2O3-induced inhibition of the AMPK/SIRT1/PGC-1α pathway. Conclusion: Our experimental results reveal that 6G effectively counteracts As2O3-induced cardiotoxicity including oxidative stress, inflammation and apoptosis, which might be attributed to its activation action on AMPK/SIRT1/PGC-1α signaling pathway.

6-Gingerol exerts a protective effect against hypoxic injury through the p38/Nrf2/HO-1 and p38/NF-κB pathway in H9c2 cells.

Ginger, one of the most widely consumed condiment for various foods and beverages, has many pharmacological effects. 6-gingerol, a naturally occurring phenol, is one of the major pungent constituents of ginger. The purpose of this study was to characterize the effect of 6-gingerol on the p38/Nrf2/HO-1 and p38/NF-κB signaling pathway, as a possible means of combating hypoxia-related oxidative stress. H9c2 cells were chemically induced with CoCl2 to mimic hypoxia-associated cellular damage. Cardiomyocyte injury was assessed by lactate dehydrogenase and creatine kinase. Reactive oxygen species production was assessed by 2',7'-dichlorodihydrofluorescein diacetate. The antioxidative property of 6-gingerol was measured by estimating the activities of superoxide dismutase, catalase, glutathione and glutathione disulfide. Apoptosis was detected by flow cytometry after Annexin V-FITC-propidium iodide double staining. Western blotting was used to evaluate levels of p-p38, p38, cytoplasm p65, nuclear p65, total p65, nuclear Nrf2, total Nrf2, Keap1, HIF-1α, and HO-1. 6-gingerol was able to counter hypoxia-induced cardiomyocyte injury as evidenced by inhibiting the levels of oxidative stress indexes and increasing the percentage of apoptosis. Furthermore, 6-gingerol was able to down-regulate p-p38/p38, nuclear p65, total p65 and Keap1 expression induced by CoCl2 stimulation and increased cytoplasm p65, nuclear Nrf2, total Nrf2, HO-1, and HIF-1α expression. However, treatment with specific Nrf2 inhibitor blunted the activation of Nrf2 signaling and removed the protective effects of 6-gingerol. These experiments provide evidence that 6-gingerol exerts cytoprotective effects, which may be associated with the regulation of oxidative stress and apoptosis, potentially through activating the Nrf2 pathway and inhibiting the p38/NF-κB pathways.

Network meta-analysis and cost-effectiveness analysis of infliximab, cyclosporine and tacrolimus for ulcerative colitis.

BACKGROUND: Assess the efficiency and cost-effectiveness of infliximab, cyclosporine and tacrolimus for the treatment of ulcerative colitis (UC). METHODS: A literature search identified studies that investigated infliximab, cyclosporine or tacrolimus compared with placebo in UC patients. Short-term, long-term remission rates and response rates were employed to assess efficacy. Odds ratios with 95% confidence intervals were analyzed. A Markov model was constructed to simulate the progression in a cohort of patients with UC, with an over 10 years of time horizon, with a discount rate of 3%, and established threshold of €30,000/quality-adjusted life-year (QALY) or ¥82442/QALY. RESULTS: Results of network meta-analysis showed that the order was cyclosporine, tacrolimus, infliximab and placebo from high rate to low with regard to short-term clinical response. The comparison between infliximab versus cyclosporine achieved an incremental cost effectiveness ratio (ICER) of €184435/QALY and ¥531607/QALY, with a 0.34893 QALYs difference of efficacy, and an incremental cost of €64355 and ¥185494. Tacrolimus versus cyclosporine reached an ICER of €44236/QALY and ¥57494/QALY, with a difference of 0.40963 QALYs in efficacy, and a raising cost to €18120 and ¥23551. The probabilistic sensitivity analysis shows that cyclosporine would be cost-effective in the 75.8% of the simulations, tacrolimus in the 24.2%, and infliximab for the 0%. CONCLUSION: Infliximab, cyclosporine and tacrolimus as salvage therapies are efficacious. For long-term of clinical remission, the order of pharmacological agents was tacrolimus, infliximab and cyclosporine from high efficacy to low while no significant difference is seen. In cost-effectiveness analysis, the cyclosporine versus infliximab or tacrolimus is expected to be at best.

Protective effects of safranal on hypoxia/reoxygenation-induced injury in H9c2 cardiac myoblasts via the PI3K/AKT/GSK3ß signaling pathway.

Safranal (SFR), an active ingredient extracted from saffron, exhibits a protective effect on the cardiovascular system. However, the mechanism of SFR against hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury has previously not been investigated in vitro. The aim of the present study was therefore to observe the protective effects of SFR on H/R-induced cardiomyocyte injury and to explore its mechanisms. A H/R injury model of H9c2 cardiac myoblasts was established by administering 800 µmol/l CoCl2 to H9c2 cells for 24 h and reoxygenating the cells for 4 h to induce hypoxia. H9c2 cardiac myoblasts were pretreated with SFR for 12 h to evaluate the associated protective effects. A Cell Counting Kit-8 assay was used for cell viability detection, and the expression levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), glutathione peroxidase (GSH-px), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA) and caspase-3, and the intracellular Ca2+ concentration were measured using the corresponding commercial kits. Levels of reactive oxygen species (ROS) in the cells were detected using 2,7-dichlorodihydrofluorescein diacetate. Flow cytometry was used to determine the degree of apoptosis and the level of mitochondrial membrane potential (MMP). Moreover, the expression levels of phosphorylated (p-)PI3K, AKT, p-AKT, glycogen synthase kinase 3ß (GSK3ß), p-GSK3ß, Bcl-2, Bax, caspase-3 and cleaved caspase-3 were measured using western blot analysis. Results of the present study demonstrated that the H9c2 cardiac myoblasts treated with SFR exhibited significantly improved levels of viability and significantly reduced levels of ROS, compared with the H/R group. Furthermore, compared with the H/R group, SFR treatment significantly increased the MMP levels and antioxidant enzyme levels, including CAT, SOD and GSH-px; whereas the levels of CK-MB, LDH, MDA and intracellular Ca2+ concentration were significantly decreased. Moreover, the results of the present study demonstrated that SFR significantly reduced caspase-3, cleaved caspase-3 and Bax protein expression levels, but upregulated the Bcl-2 protein expression levels. SFR also increased the protein expressions of PI3K/AKT/GSK3ß. In summary, the results suggested that SFR may exert a protective effect against H/R-induced cardiomyocyte injury, which occurs in connection with the inhibition of oxidative stress and apoptosis via regulation of the PI3K/AKT/GSK3ß signaling pathway.

The Mechanism Underlying the Protective Effects of Tannic Acid Against Isoproterenol-Induced Myocardial Fibrosis in Mice.

Tannic acid (TA) belongs to a class of complex water-soluble polyphenolic derivatives that show anticarcinogenic, antiinflammatory, antioxidant, and scavenging activities. Here, we investigate the protective effects of TA against isoproterenol (ISO)-induced myocardial fibrosis (MF) in mice. Mice received TA and ISO dosing and were sacrificed 48 h later. The activities of creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and mitochondria enzymes were measured. Cardiac histopathology was done using H&E, Sirius red, and Masson's Trichrome staining. Immunohistochemical staining was applied to indicate changes in B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and basic fibroblast growth factor (bFGF) protein expressions in cardiac tissue. RT-PCR was used to measure the expression of atrial and brain natriuretic peptides (ANP and BNP, respectively), c-fos, and c-jun. Western blotting was used to measure the expression of nuclear factor-κB (NF-κB) p65, phosphorylated NF-κB p65), toll-like receptor 4 (TLR4), p38, phosphorylated p38, Bax, Bcl-2, and caspase-3. Compared to the ISO group, the TA group had reduced levels of TLR4, p38, p-p38, NF-κB (p65), p-NF-κB (p-p65), caspase-3, Bax, and Bcl-2, as well as CK, CK-MB, and LDH. These results indicate that TA protects against ISO-induced MF, possibly through its ability to suppress the TLR4-mediated NF-κB signaling pathway.

[6]-Gingerol Ameliorates ISO-Induced Myocardial Fibrosis by Reducing Oxidative Stress, Inflammation, and Apoptosis through Inhibition of TLR4/MAPKs/NF-κB Pathway.

SCOPE: [6]-Gingerol is one of the primary pungent constituents of ginger. While [6]-gingerol has many pharmacological effects, its benefits for myocardial fibrosis, including its exact role and underlying mechanisms, remain largely unexplored. The present study is designed to characterize the cardio-protective effects of [6]-gingerol in myocardial fibrosis mice and possible underlying mechanisms. METHODS AND RESULTS: Mice are subcutaneously injected with isoproterenol (ISO, 10 mg kg-1 ) and gavaged with [6]-gingerol (10, 20 mg kg-1 day-1 ) for 14 days. Pathological alterations, fibrosis, oxidative stress, inflammation response, and apoptosis are examined. In ISO-induced myocardial fibrosis, [6]-gingerol treatment decreases the J-point, heart rate, cardiac weight index, left ventricle weight index, creatine kinase (CK), and lactate dehydrogenase serum levels, calcium concentration, reactive oxygen species, malondialdehyde, and glutathione disulfide (GSSG), and increases levels of superoxide dismutase, catalase, glutathione, and GSH/GSSG. Further, [6]-gingerol improved ISO-induced morphological pathologies, inhibited inflammation and apoptosis, and suppressed the toll-like receptor-4 (TLR4)/mitogen-activated protein kinases (MAPKs)/nuclear factor κB (NF-κB) signaling pathways. CONCLUSION: The protective effect of [6]-gingerol in mice with ISO-induced myocardial fibrosis may be related to the inhibition of oxidative stress, inflammation, and apoptosis, potentially through the TLR4/MAPKs/NF-κB signaling pathway.

Tannic acid ameliorates arsenic trioxide-induced nephrotoxicity, contribution of NF-κB and Nrf2 pathways.

BACKGROUND AND PURPOSE: Tannic acid (TA), a group of polyphenolic compounds, has multiple anticancer, antimutagenic, antioxidant and anti-inflammatory activities. However, the effects of TA on arsenic trioxide (ATO)-induced nephrotoxicity are still relatively unknown. This study investigated the protective effects and potential mechanisms of TA on ATO-induced nephrotoxicity in rats. METHODS: Rats were intragastrically administered TA with concurrent ATO infused intraperitoneally over 10 days. Renal morphology changes were observed through light microscopy. The levels of antioxidants and pro-inflammatory factors were measured in the serum and renal tissue, respectively. Further, expression of B-cell lymphoma-2, B-cell lymphoma-extra large, p53, and Bcl-2-associated X protein were measured using an immunohistochemical method. The protein expression of nuclear factor kappa B (NF-κB), nuclear factor-erythroid-2-related factor 2 (Nrf2), and kelch-like ECH-associated protein 1 (Keap1) were measured by Western blot. RESULTS: The data showed that ATO exposure significantly increased the serum nephritic, oxidative stress, apoptosis and inflammatory markers in the renal tissue of rats. Conversely, pretreatment with TA reversed these changes. Furthermore, TA treatment caused a significant decrease in NF-κB expression (P < 0.05), while increasing Nrf2 and Keap1 expressions (P < 0.05). CONCLUSION: TA ameliorates ATO-induced nephrotoxicity, which is related to the inhibition of oxidative stress, inflammation and apoptosis, potentially through the NF-κB/Nrf2 pathway.

Crocin attenuates isoprenaline-induced myocardial fibrosis by targeting TLR4/NF-κB signaling: connecting oxidative stress, inflammation, and apoptosis.

Crocin is isolated from saffron and has multiple activities. There are many reports on its beneficial effects for cardiovascular disease, but crocin's effects on anti-myocardial fibrosis have not yet been reported. This study investigated crocin's effects and potential mechanisms on isoproterenol (ISO)-induced myocardial fibrosis (MF) in mice. Mice were infused intraperitoneally with crocin with concurrent ISO subcutaneous injections over 2 weeks. Electrocardiography, cardiac weight index (CWI), hydroxyproline content, and heart morphology changes were observed. Administration of crocin markedly decreased heart rate, J-point elevation, QRS interval, CWI, and hydroxyproline content in the myocardial tissues, and improved heart pathologic morphology. Versus the control group, the ISO group showed an increase in lactate dehydrogenase and creatine kinase activities and malondialdehyde content. Meanwhile, superoxide dismutase, catalase, and glutathione contents decreased in the ISO group; crocin caused a significant reduction in oxidative stress levels in ISO-induced MF. ISO led to a significant increase in interleukin-1 and -6 and tumor necrosis factor-α in addition to nuclear factor kappa B (NF-κB) (p65) and toll-like receptor (TLR) 4 expressions. Crocin treatment suppressed these inflammatory cytokine expressions. Moreover, crocin treatment caused a significant decrease in connective tissue growth factor and transforming growth factor-ß1 mRNA levels in addition to a decrease in B cell lymphoma-2, Bcl-2-associated X protein, caspase-3, and cleaved caspase-3 expressions. Crocin has a protective effect on ISO-induced MF, which may be associated with the TLR4/NF-κB (p65) signal transduction pathway.

Cardioprotective effects of glycyrrhizic acid involve inhibition of calcium influx via L-type calcium channels and myocardial contraction in rats.

Glycyrrhizic acid (GA) is one of the main active components in licorice and has often been reported to have cardioprotective effects. However, the underlying cellular mechanisms remain unclear. The aim of this study is to verify the protective effects of GA against isoproterenol (ISO)-induced myocardial ischemia injury in rats. Another aim is to explore the cellular mechanisms based on the L-type Ca2+ channel, myocardial cell contraction, and intracellular Ca2+ ([Ca2+]i) transient. The results show that GA reduced the ST segment elevation, decreased the heart rate, prevented ISO-induced QT-interval shortening, improved heart morphology, and decreased the activity of CK and LDH. GA blocked ICa-L in a dose-dependent manner. The concentration for 50% of the maximal effect (EC50) of GA was 145.54 µg/mL, and the maximal inhibition was 47.43 ± 0.75% at 1000 µg/mL. However, GA did not affect the dynamical properties of the Ca2+ channel. GA reversibly reduced the amplitude of cell contraction in a dose-dependent manner and slowed down its deflection and recovery, as well as the [Ca2+]i transient. The data demonstrate that GA inhibits L-type Ca2+ channels, decreases the [Ca2+]i transient, and shows a negative cardiac inotropic effect in the ventricular myocardial cells of adult rats. It also protects the myocardia from ischemia injury induced by ISO.