Promising Drug For Prevention Research Articles

Emodin attenuates cardiomyocyte pyroptosis in doxorubicin-induced cardiotoxicity by directly binding to GSDMD

BackgroundDoxorubicin (Dox), which is an anticancer drug, has significant cardiac toxicity and side effects. Pyroptosis occurs during Dox-induced cardiotoxicity (DIC), and drug inhibition of this process is one therapeutic approach for treating DIC. Previous studies have indicated that emodin can reduce pyroptosis. However, the role of emodin in DIC and its molecular targets remain unknown. Hypothesis/PurposeWe aimed to clarify the protective role of emodin in mitigating DIC, as well as the mechanisms underlying this effect. MethodsThe model of DIC was established via the intraperitoneal administration of Dox at a dosage of 5 mg/kg per week for a span of 4 weeks. Emodin at two different doses (10 and 20 mg/kg) or a vehicle was intragastrically administered to the mice once per day throughout the Dox treatment period. Cardiac function, myocardial injury markers, pathological morphology of the heart, level of pyroptosis and mitochondrial function were assessed. Protein microarray, biolayer interferometry and pull-down assays were used to confirm the target of emodin. Moreover, GSDMD-overexpressing plasmids were transfected into GSDMD−/− mice and HL-1 cells to further verify whether emodin suppressed GSDMD activation. ResultsEmodin therapy markedly enhanced cardiac function and reduced cardiomyocyte pyroptosis in mice induced by Dox. Mechanistically, emodin binds to GSDMD and inhibits the activation of GSDMD by targeting the Trp415 and Leu290 residues. Moreover, emodin was able to mitigate Dox-induced cardiac dysfunction and myocardial injury in GSDMD−/− mice overexpressing GSDMD, as shown by increased EF and FS, decreased serum levels of CK-MB, LDH and IL-1β and mitigated cell death and cell morphological disorder. Additionally, emodin treatment significantly reduced GSDMD-N expression and plasma membrane disruption in HL-1 cells overexpressing GSDMD induced by Dox. In addition, emodin reduced mitochondrial damage by alleviating Dox-induced GSDMD perforation in the mitochondrial membrane. ConclusionEmodin has the potential to attenuate DIC by directly binding to GSDMD to inhibit pyroptosis. Emodin may become a promising drug for prevention and treatment of DIC.

Protective effect of metformin on a rat model of lipopolysaccharide‐induced preeclampsia

Recent in vitro and clinical studies have found that metformin (MET) may play a preventive or therapeutic role in preeclampsia (PE) and may be a candidate drug for the prevention and/or treatment of PE. In this study, we used lipopolysaccharide (LPS) to induce a PE-like rat model and investigated the intervention effect of MET from the perspectives of clinical manifestations, placental morphology, serum marker for placental injury, systemic inflammatory response and oxidative/nitrative stress, and placental nuclear factor-κB (NF-κB) signaling. The results showed that MET improved LPS-induced hypertension, proteinuria, fetal growth restriction (FGR) and stillbirth, alleviated placental injury and decreased maternal serum marker alpha-fetoprotein (MS-AFP) level; MET suppressed LPS-induced TNF-α and IL-6 productions, reduced oxidative/nitrative stress as evidenced by increased superoxide dismutase (SOD) activity, decreased inducible nitric oxide synthase (iNOS) activity, and decreased levels of malondialdehyde (MDA) and nitric oxide (NO); MET inhibited LPS-induced NF-κB activation in placentas. Based on these findings, it can be concluded that MET is beneficial to the PE-like rat model by protecting placentas from injury, suppressing systemic inflammatory response and oxidative/nitrative stress, and inhibiting placental NF-κB signaling pathway. MET is a promising drug for prevention and/or treatment of PE.

Abstract 2010: SKI-G-801, an AXL kinase inhibitor, blocks metastasis and induces anti-tumor immune responses in various syngeneic cancer models

Abstract Introduction: Aberrant AXL expression plays a critical role in cancer cell migration, metastasis and drug resistance. Researchers have revealed that AXL signaling is also over expressed on cells associated with tumor microenvironment. These findings highlight AXL as an attractive drug candidate for targeting tumor evasion and metastasis. Here we present SKI-G-801, a small molecule inhibitor that targets phosphorylation of AXL (IC50 = 20 nM) and its downstream signals. Methods: Inhibitory effects of SKI-G-801 on cancer viability (MTT and colony formation assay), invasion and migration (trans-well invasion assay) were examined in AXL high-expressing lung cancer cells in vitro. LLC2 lung and 4T1 breast cancer bearing mouse models were established. in addition, C57BL/6 mice were injected intravenously with B16F10 melanoma cells to establish lung metastasis model. Mice were administrated with 30 mg/kg of SKI-G-801 orally before (metastasis model) or after (syngeneic model) tumor injection. To elucidate the involvement of AXL inhibitor on tumor microenvironment, the population of T cells and myeloid cells was analyzed by flow cytometry from the LLC2 tumor. Results: Treatment of SKI-G-801 showed strong inhibition of cancer migration and invasion, when its direct killing effect on cancer cells was modest. These results were reproduced in vivo test that pretreatment of SKI-G-801 significantly reduced metastatic burden in B16F10 model (p < 0.05). LLC2 and 4T1 tumors were decreased in SKI-G-801 treatment group (p < 0.05), but not in anthemic nude mice. CD3+CD8+ T cell population and memory Tc cells were increased in SKI- G-801 treatment group (p < 0.05). Especially, granzyme B+ Tc and gp70+ tumor specific Tc were increased (p < 0.05). SKI-G-801 increase the helper T cell population; CD3+CD4+ (p < 0.05), and CD44+ memory Th cells (p < 0.01). Conclusion: SKI-G-801 demonstrates great potential in anti-cancer activity though immune responses. The anti-cancer effects lead to a reversal of the metastatic phenotype in animal model. Our results suggest that SKI-G-801 is a promising drug for prevention against metastatic cancer. Citation Format: Chun-Feng Xin, Sung Eun Kim, Kyoung-Ho Pyo, Ha Ni Jo, Jae Seok Cho, Jae Hwan Kim, Wongeun Lee, Hee Kyu Lee, Jung-Ho Kim, Ho-Juhn Song, Jong Sung Koh, Byoung Chul Cho. SKI-G-801, an AXL kinase inhibitor, blocks metastasis and induces anti-tumor immune responses in various syngeneic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2010.

Tubeimoside-1 inhibits the proliferation and metastasis by promoting miR-126-5p expression in non-small cell lung cancer cells.

Tubeimoside-1 (TBMS1) possesses broad anticancer activities, including the cytostatic and anti-angiogenesis effects in lung cancer. However, the effect of TBMS1 on the metastasis of non-small cell lung cancer (NSCLC) cells and the potential underlying mechanism remain unclear. In the present study, a cell counting kit-8 assay revealed that TBMS1 suppressed the proliferation of NCI-H1299 cells significantly, particularly following 48 h of treatment. Further studies showed that TBMS1 notably enhanced the apoptosis, and inhibited the migration and invasion of NCI-H1299 cells upon treatment for 48 h. A total of 14 NSCLC tissues and 14 normal adjacent tissues were collected, reverse transcription-quantitative polymerase chain reaction revealed decreased expression of microRNA (miR)-126-5p in NSCLC tissues compared with adjacent NSCLC tissues, which was reversed following TBMS1 administration in NCI-H1299 cells. The overexpression of miR-126-5p induced by TBMS1 was demonstrated to target and downregulate vascular endothelial growth factor (VEGF)-A. Simultaneously, the expression of VEGF-R2 was reduced notably, along with a significant declined in the phosphorylation levels of dual specificity mitogen-activated protein kinase kinase 1 and extracellular signal-regulated kinase (ERK)1/2. Overall, the aforementioned results indicated that TBMS1 inhibited the proliferation and metastasis, and promoted the apoptosis of NCI-H1299 cells, which may be mediated by overexpressing miR-126-5p, which inactivates the VEGF-A/VEGFR2/ERK signaling pathway. Therefore, TBMS1 may be a promising drug for prevention and treatment of NSCLC.

Curcumin alleviates glucocorticoid-induced osteoporosis by protecting osteoblasts from apoptosis in vivo and in vitro.

Curcumin, an active component of the rhizomes of Curcumin longa L., possesses broad anti-inflammation and anti-cancer properties. Curcumin was previously reported to be capable of protecting ovariectomized rats against osteoporosis. However, the effect of curcumin on glucocorticoid-induced osteoporosis (GIO) is not yet clear. The present study investigated the effects of curcumin on dexamethasone (Dex)-induced osteoporosis in vivo and Dex-induced osteoblast apoptosis in vivo and in vitro. The GIO rat model was induced by subcutaneous injection of Dex for 60 days and verified to be successful as evidenced by the significantly decreased bone mineral density (BMD) determined using dual X-ray absorptiometry. Subsequently, curcumin administration (100 mg/kg) for 60 days obviously increased BMD and bone-alkaline phosphatase, decreased carboxy-terminal collagen cross links, enhanced bone mechanical strength, and improved trabecular microstructure, thereby alleviating Dex-induced osteoporosis. Mechanically, curcumin remarkably reversed Dex-induced femoral osteoblast apoptosis in vivo. In cultured primary osteoblasts, pretreatment with curcumin concentration-dependently decreased the number of Dex-induced apoptotic osteoblasts by down-regulating the ratio of Bax/Bcl-2 as well as the levels of cleaved caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Moreover, curcumin pretreatment activated extracellular signal regulated kinase (ERK) signalling in Dex-induced osteoblasts by up-regulating the expression level of p-ERK1/2. Taken together, our study demonstrated that curcumin could ameliorate GIO by protecting osteoblasts from apoptosis, which was possibly related to the activation of the ERK pathway. The results suggest that curcumin may be a promising drug for prevention and treatment of GIO.

Effects of artemisinin in broiler chickens following chronic oral intake.

Artemisinin has been used for centuries to treat malaria, intestinal tract helminthosis, diarrhea, and used as an antipyretic and sedative agent, but the usage in veterinary medicine is a new field. Recently, it has been used successfully to control experimental poultry coccidiosis. The present study aimed to determine the effects of different doses of artemisinin in broiler chickens with chronic usage. Sixty birds divided into one control and four treatment groups that fed rations mixed with artemisinin at doses of 17, 34, 68, and 136 ppm for 36 days. During the experiment, birds showed no clinical signs except anemia. In microscopic examinations, heart, lung, and spleen had no lesion, but liver, kidney, and brain showed various lesions. Degenerative lesions like intracytoplasmic eosinophilic inclusions were seen in both kidney and liver but fatty change was seen only in liver. There was no relationship between severity of the liver lesions and drug dosage. Central chromatolysis, scattered neuronal necrosis, and mild spongy changes were observed in five regions of the brain that were chosen for sectioning (motor cortex, cerebellar nuclei, midbrain nuclei, and hindbrain nuclei at two separate levels). Severity of lesions in brain was dose-dependent, and cerebral cortex was the most vulnerable area. Haematologic tests showed lower values for hematocrit and red blood cell count dose-dependently. In conclusion, artemisinin is a promising drug for prevention and control of coccidiosis in broiler chickens and its side effects are not too much serious especially at therapeutic doses.

Protective action of tetramethylpyrazine phosphate against dilated cardiomyopathy in cTnTR141W transgenic mice

Dilated cardiomyopathy (DCM) is the most common cause of heart failure, and pharmacological intervention is not currently available. Here we investigate the effect of tetramethylpyrazine phosphate (TMPP) on the progression of DCM in the cTnT(R141W) transgenic mouse model. The cTnT(R141W) transgenic mice aged 2 months were divided into model group and TMPP group, whereas age-matched nontransgenic mice were used as wild-type control. TMPP 45 mg.kg(-1).d(-1) was administered for 7 months. Following assessment of cardiac function by echocardiography, cardiac tissues were prepared for histology and electron microscopy. Levels of molecular markers for cardiomyocyte hypertrophy and fibrosis were detected by RT-PCR. Expression of structural proteins of the sarcomere and intercalated disc was determined by Western blot. TMPP significantly prevented cardiac dilatation and dysfunction with the development of DCM, and decreased mortality by 54%. TMPP decreased HW/BW ratios and expression of hypertrophic markers BNP and ACTA1, as well as reduced interstitial collagen deposition and expression of profibrotic markers Col1a1 and Col3a1. TMPP attenuated ultrastructural disruption caused by cTnT(R141W) expression and decreased expression of structural proteins myotilin and E-cadherin which were up-regulated in the cTnT(R141W) heart. Moreover, TMPP reduced the mRNA expression of Calm1 and Camk2b in the cTnT(R141W) heart. Our results suggest that TMPP could be a promising drug for prevention and treatment of DCM.

Simvastatin prevents cardiac hypertrophy in vitro and in vivo via JAK/STAT pathway

Simvastatin (SIM), a HMG-CoA reductase inhibitor, has therapeutic effects that are not limited to cholesterol reduction. In this study, we investigated the change in the cell surface area and protein content of cultured rat cardiomyocytes on exposure to cardiotrophin-1 (CT-1), a cytokine involved in the growth and survival of cardiac cells, plus SIM, and thus confirmed that SIM ameliorated cardiomyocyte hypertrophy induced by CT-1. We also showed that SIM attenuated cardiac hypertrophy in rats with pressure overload due to abdominal aortic constriction by measuring such parameters as systolic blood pressure, ratio of heart weight to body weight and ratio of left ventricular weight to body weight in rats as well as cross-sectional area of cardiomyocytes. Western blot analysis indicated that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway was involved in the mechanisms underlying the in vitro and in vivo inhibitory effects of SIM on cardiac hypertrophy. Moreover, the effect of SIM amelioration on CT-1-induced cultured cardiomyocyte hypertrophy might be related to the change in angiotensinogen (AGT) mRNA expression, as evidenced by RT-PCR analysis, and the subsequent alteration in angiotensin II (Ang II) levels. The results of our study provide further evidence that SIM, like other HMG-CoA reductase inhibitors, is a promising drug for prevention and treatment of cardiac hypertrophy.

Stronger growth-inhibitory effect of interferon (IFN)-β compared to IFN-α is mediated by IFN signaling pathway in hepatocellular carcinoma cells

Interferon (IFN) is a promising drug for prevention and treatment of hepatocellular carcinoma (HCC) in combination with chemotherapeutic agents. We previously reported that the spectra of antiproliferative activity and synergistic effect of IFN-beta when combined with anticancer drugs are more potent than those of IFN-alpha in HCC cells. However, the mechanism of the diverse antitumor effects of the IFNs is not understood yet. We studied the expression of IFN alpha receptor 2 (IFNAR2), STATs, and IFN-alpha, IFN-beta's growth-inhibitory effect, signal transduction and binding to IFNAR2 on three HCC cell lines and a tumor xenografted mouse model (12 animals/group). From the results, IFN-beta showed a significantly stronger growth-inhibitory effect than IFN-alpha on the HuH7 cell line (expressing low IFNAR2), however it was similarly high on PLC/PRF/5 and weak on HLE. In the nude mouse tumor xenograft model, IFN-beta injection significantly suppressed tumor volume relative to vehicle injection, while IFN-alpha showed weaker growth-inhibition. IFN signal transduction (phosphorylated-STAT1, 3) induced by IFN-beta was higher than that by IFN-alpha in HuH7 and tumor xenografts. Pretreatment of hepatoma cells with anti-IFNAR2 antibody blocked the IFN signaling, more for IFN-alpha. IFN-alpha's antiproliferative effect was reduced by the antibody in lower concentrations compared to that of IFN-beta. Taken together, the HCC cells that express low IFNAR2 and are resistant to IFN-alpha were sensitive to the growth-inhibitory effect of IFN-beta, which might be mediated by stronger IFN signal transduction and distinct binding to IFNAR compared to IFN-alpha.

Nifedipine, A Promising Drug for Prevention of Heart Changes During Weightlessness

NASA plans to have a space station operating in 1994 and is considering a 30 month Mars flight. These plans call for exposure to microgravity for longer periods of time than space travelers have endured to date. Vascular deconditioning is known to occur during space flight and during simulated weightlessness. The degree of deconditioning for these extended flights and the amount of possible reversibility is unknown. If a sudden demanding burden should be placed on the astronaut after prolonged deconditioning, there could be serious consequences. Exercise has been tried with limited success. What is needed is a counter measure to deconditioning. Calcium channel blockers are known to protect the heart during the recovery phase after heart attacks by regulating the calcium influx, thus protecting the cell and mitochondria from calcium overload. Sudden demands also increase blood flow, mimicking the post attack reperfusion, and could be serious for a deconditioned heart. We have found nifedipine, a calcium channel blocker, to be a promising drug for prevention of structural changes during simulated weightlessness.