scholarly journals The Specific Connexin 43–Inhibiting Peptide Gap26 Improved Alveolar Development of Neonatal Rats With Hyperoxia Exposure

2021 ◽  
Vol 12 ◽  
Author(s):  
Cai Qing ◽  
Zhao Xinyi ◽  
Yu Xuefei ◽  
Xue Xindong ◽  
Fu Jianhua
Keyword(s):  
Oxidative Stress ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Stress Signaling ◽  
Ros Production ◽  
Cx43 Expression ◽  
Alveolar Development ◽  
Hyperoxia Exposure

Bronchopulmonary dysplasia (BPD) is a common devastating pulmonary complication in preterm infants. Alveolar maldevelopment is the crucial pathological change of BPD highly associated with oxidative stress–mediated excessive apoptosis. Cellular injury can be propagated and amplified by gap junction (GJ)–mediated intercellular communication. Connexin 43 (Cx43) is the most ubiquitous and critical GJ protein. Gap26 is a specific Cx43 mimic peptide, playing as a Cx43-GJ inhibitor. We hypothesized that Cx43-GJ was involved in alveolar maldevelopment of BPD via amplifying oxidative stress signaling and inducing excessive apoptosis. Neonatal Sprague Dawley rats were kept in either normoxia (21% O2) or hyperoxia (85% O2) continuously from postnatal day (PN) 1 to 14 in the presence or absence of Gap26. Moreover, RLE-6TN cells (type II alveolar epithelial cells of rats) were cultured in vitro under normoxia (21% O2) or hyperoxia (85% O2). RLE-6TN cells were treated by N-acetyl cysteine (NAC) (a kind of reactive oxygen species (ROS) scavenger) or Gap26. Morphological properties of lung tissue are detected. Markers associated with Cx43 expression, ROS production, the activity of the ASK1-JNK/p38 signaling pathway, and apoptotic level are detected in vivo and in vitro, respectively. In vitro, the ability of GJ-mediated intercellular communication was examined by dye-coupling assay. In vitro, our results demonstrated ROS increased Cx43 expression and GJ-mediated intercellular communication and Gap26 treatment decreased ROS production, inhibited ASK1-JNK/p38 signaling, and decreased apoptosis. In vivo, we found that hyperoxia exposure resulted in increased ROS production and Cx43 expression, activated ASK1-JNK/p38 signaling, and induced excessive apoptosis. However, Gap26 treatment reversed these changes, thus improving alveolar development in neonatal rats with hyperoxia exposure. In summary, oxidative stress increased Cx43 expression and Cx43-GJ–mediated intercellular communication. And Cx43-GJ–mediated intercellular communication amplified oxidative stress signaling, inducing excessive apoptosis via the ASK1-JNK/p38 signaling pathway. The specific connexin 43–inhibiting peptide Gap26 was a novel therapeutic strategy to improve the alveolar development of BPD.

scholarly journals Protection of the vascular endothelium in experimental situations

2011 ◽  
Vol 4 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Ružena Sotníková ◽  
Jana Nedelčevová ◽  
Jana Navarová ◽  
Viera Nosáľová ◽  
Katarína Drábiková ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vascular Endothelium ◽  
Vascular Dysfunction ◽  
Antioxidant Properties ◽  
Pharmacological Intervention ◽  
Ros Production ◽  
Nitric Oxide Radical ◽  
Endothelium Dependent Relaxation

Protection of the vascular endothelium in experimental situationsOne of the factors proposed as mediators of vascular dysfunction observed in diabetes is the increased generation of reactive oxygen species (ROS). This provides support for the use of antioxidants as early and appropriate pharmacological intervention in the development of late diabetic complications. In streptozotocin (STZ)-induced diabetes in rats we observed endothelial dysfuction manifested by reduced endothelium-dependent response to acetylcholine of the superior mesenteric artery (SMA) and aorta, as well as by increased endothelaemia. Changes in endothelium-dependent relaxation of SMA were induced by injury of the nitric oxide radical (·NO)-signalling pathway since the endothelium-derived hyperpolarising factor (EDHF)-component of relaxation was not impaired by diabetes. The endothelial dysfunction was accompanied by decreased ·NO bioavailabity as a consequence of reduced activity of eNOS rather than its reduced expression. The results obtained using the chemiluminiscence method (CL) argue for increased oxidative stress and increased ROS production. The enzyme NAD(P)H-oxidase problably participates in ROS production in the later phases of diabetes. Oxidative stress was also connected with decreased levels of reduced glutathione (GSH) in the early phase of diabetes. After 10 weeks of diabetes, adaptational mechanisms probably took place because GSH levels were not changed compared to controls. Antioxidant properties of SMe1EC2 foundin vitrowere partly confirmedin vivo.Administration of SMe1EC2 protected endothelial function. It significantly decreased endothelaemia of diabetic rats and improved endothelium-dependent relaxation of arteries, slightly decreased ROS-production and increased bioavailability of ·NO in the aorta. Further studies with higher doses of SMe1EC2 may clarify the mechanism of its endothelium-protective effectin vivo.

scholarly journals The Protective Roles of Estrogen Receptor β in Renal Calcium Oxalate Crystal Formation via Reducing the Liver Oxalate Biosynthesis and Renal Oxidative Stress-Mediated Cell Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Wei Zhu ◽  
Zhijian Zhao ◽  
Fu-Ju Chou ◽  
Li Zuo ◽  
Tongzu Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Estrogen Receptor ◽  
Nadph Oxidase ◽  
Calcium Oxalate ◽  
Cell Lines ◽  
Ros Production ◽  
Crystal Deposition ◽  
Caox Crystal

Females develop kidney stones less frequently than males do. However, it is unclear if this gender difference is related to altered estrogen/estrogen receptor (ER) signaling. Here, we found that ER beta (ERβ) signals could suppress hepatic oxalate biosynthesis via transcriptional upregulation of the glyoxylate aminotransferase (AGT1) expression. Results from multiple in vitro renal cell lines also found that ERβ could function via suppressing the oxalate-induced injury through increasing the reactive oxygen species (ROS) production that led to a decrease of the renal calcium oxalate (CaOx) crystal deposition. Mechanism study results showed that ERβ suppressed oxalate-induced oxidative stress via transcriptional suppression of the NADPH oxidase subunit 2 (NOX2) through direct binding to the estrogen response elements (EREs) on the NOX2 5′ promoter. We further applied two in vivo mouse models with glyoxylate-induced renal CaOx crystal deposition and one rat model with 5% hydroxyl-L-proline-induced renal CaOx crystal deposition. Our data demonstrated that mice lacking ERβ (ERβKO) as well as mice or rats treated with ERβ antagonist PHTPP had increased renal CaOx crystal deposition with increased urinary oxalate excretion and renal ROS production. Importantly, targeting ERβ-regulated NOX2 with the NADPH oxidase inhibitor, apocynin, can suppress the renal CaOx crystal deposition in the in vivo mouse model. Together, results from multiple in vitro cell lines and in vivo mouse/rat models all demonstrate that ERβ may protect against renal CaOx crystal deposition via inhibiting the hepatic oxalate biosynthesis and oxidative stress-induced renal injury.

scholarly journals Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Hailong Yu ◽  
Xiang Cao ◽  
Wei Li ◽  
Pinyi Liu ◽  
Yuanyuan Zhao ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Connexin 43 ◽  
Nuclear Translocation ◽  
Neurological Deficits ◽  
Proximity Ligation Assay ◽  
Neuroprotective Effects ◽  
Cx43 Expression ◽  
Anti Inflammatory

Abstract Background In the central nervous system (CNS), connexin 43 (Cx43) is mainly expressed in astrocytes and regulates astrocytic network homeostasis. Similar to Cx43 overexpression, abnormal excessive opening of Cx43 hemichannels (Cx43Hcs) on reactive astrocytes aggravates the inflammatory response and cell death in CNS pathologies. However, the role of excessive Cx43Hc opening in intracerebral hemorrhage (ICH) injury is not clear. Methods Hemin stimulation in primary cells and collagenase IV injection in C57BL/6J (B6) mice were used as ICH models in vitro and in vivo. After ICH injury, the Cx43 mimetic peptide Gap19 was used for treatment. Ethidium bromide (EtBr) uptake assays were used to measure the opening of Cx43Hcs. Western blotting and immunofluorescence were used to measure protein expression. qRT-PCR and ELISA were used to determine the levels of cytokines. Coimmunoprecipitation (Co-IP) and the Duolink in situ proximity ligation assay (PLA) were applied to measure the association between proteins. Results In this study, Cx43 expression upregulation and excessive Cx43Hc opening was observed in mice after ICH injury. Delayed treatment with Gap19 significantly alleviated hematoma volume and neurological deficits after ICH injury. In addition, Gap19 decreased inflammatory cytokine levels in the tissue surrounding the hematoma and decreased reactive astrogliosis after ICH injury in vitro and in vivo. Intriguingly, Cx43 transcriptional activity and expression in astrocytes were significantly increased after hemin stimulation in culture. However, Gap19 treatment downregulated astrocytic Cx43 expression through the ubiquitin-proteasome pathway without affecting Cx43 transcription. Additionally, our data showed that Gap19 increased Yes-associated protein (YAP) nuclear translocation. This subsequently upregulated SOCS1 and SOCS3 expression and then inhibited the TLR4-NFκB and JAK2-STAT3 pathways in hemin-stimulated astrocytes. Finally, the YAP inhibitor, verteporfin (VP), reversed the anti-inflammatory effect of Gap19 in vitro and almost completely blocked its protective effects in vivo after ICH injury. Conclusions This study provides new insight into potential treatment strategies for ICH injury involving astroglial Cx43 and Cx43Hcs. Suppression of abnormal astroglial Cx43 expression and Cx43Hc opening by Gap19 has anti-inflammatory and neuroprotective effects after ICH injury.

ROS dependence of cyclooxygenase-2 induction in rats subjected to unilateral ureteral obstruction

2014 ◽  
Vol 306 (2) ◽  
pp. F259-F270 ◽  
Author(s):  
Martin Østergaard ◽  
Michael Christensen ◽  
Line Nilsson ◽  
Inge Carlsen ◽  
Jørgen Frøkiær ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ureteral Obstruction ◽  
Oxidase Inhibitor ◽  
Unilateral Ureteral Obstruction ◽  
Tubular Damage ◽  
Ros Production ◽  
Cox 2 ◽  
And Oxidative Stress

Oxidative stress resulting from unilateral ureteral obstruction (UUO) may be aggravated by increased production of ROS. Previous studies have demonstrated increased cyclooxygenase (COX)-2 expression in renal medullary interstitial cells (RMICs) in response to UUO. We investigated, both in vivo and in vitro, the role of ROS in the induction of COX-2 in rats subjected to UUO and in RMICs exposed to oxidative and mechanical stress. Rats subjected to 3-day UUO were treated with two mechanistically distinct antioxidants, the NADPH oxidase inhibitor diphenyleneiodonium (DPI) and the complex I inhibitor rotenone (ROT), to interfere with ROS production. We found that UUO-mediated induction of COX-2 in the inner medulla was attenuated by both antioxidants. In addition, DPI and ROT reduced tubular damage and oxidative stress after UUO. Moreover, mechanical stretch induced COX-2 and oxidative stress in RMICs. Likewise, RMICs exposed to H2O2 as an inducer of oxidative stress showed increased COX-2 expression and activity, both of which were reduced by DPI and ROT. Similarly, ROS production, which was increased after exposure of RMICs to H2O2, was also reduced by DPI and ROT. Furthermore, oxidative stress-induced phosphorylation of ERK1/2 and p38 was blocked by both antioxidants, and inhibition of ERK1/2 and p38 attenuated the induction of COX-2 in RMICs. Notably, COX-2 inhibitors further exacerbated the oxidative stress level in H2O2-exposed RMICs. We conclude that oxidative stress as a consequence of UUO stimulates COX-2 expression through the activation of multiple MAPKs and that the induction of COX-2 may exert a cytoprotective function in RMICs.

scholarly journals Dextromethorphan Reduces Oxidative Stress and Inhibits Uremic Artery Calcification

2021 ◽  
Vol 22 (22) ◽  
pp. 12277
Author(s):  
En-Shao Liu ◽  
Nai-Ching Chen ◽  
Tzu-Ming Jao ◽  
Chien-Liang Chen
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Vascular Calcification ◽  
Wistar Rats ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Oxidase Inhibitor ◽  
In Vivo Studies ◽  
Ros Production

Medial vascular calcification has emerged as a key factor contributing to cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs) with osteogenic transdifferentiation play a role in vascular calcification. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors reduce reactive oxygen species (ROS) production and calcified-medium–induced calcification of VSMCs. This study investigates the effects of dextromethorphan (DXM), an NADPH oxidase inhibitor, on vascular calcification. We used in vitro and in vivo studies to evaluate the effect of DXM on artery changes in the presence of hyperphosphatemia. The anti-vascular calcification effect of DXM was tested in adenine-fed Wistar rats. High-phosphate medium induced ROS production and calcification of VSMCs. DXM significantly attenuated the increase in ROS production, the decrease in ATP, and mitochondria membrane potential during the calcified-medium–induced VSMC calcification process (p < 0.05). The protective effect of DXM in calcified-medium–induced VSMC calcification was not further increased by NADPH oxidase inhibitors, indicating that NADPH oxidase mediates the effect of DXM. Furthermore, DXM decreased aortic calcification in Wistar rats with CKD. Our results suggest that treatment with DXM can attenuate vascular oxidative stress and ameliorate vascular calcification.

scholarly journals Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction

2020 ◽  
Vol 31 (10) ◽  
pp. 2312-2325
Author(s):  
Wei Cao ◽  
Liling Wu ◽  
Xiaodong Zhang ◽  
Jing Zhou ◽  
Jian Wang ◽  
...  
Keyword(s):  
Gap Junction ◽  
Vascular Resistance ◽  
Connexin 43 ◽  
Structural Changes ◽  
Ex Vivo ◽  
Resistance Arteries ◽  
Cx43 Expression ◽  
Neurovascular Transmission

BackgroundHypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)–dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown.MethodsA mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance.ResultsBy 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice.Conclusions5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.

scholarly journals Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Dongdong Yuan ◽  
Xiaoyun Li ◽  
Chenfang Luo ◽  
Xianlong Li ◽  
Nan Cheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Transplantation ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Organ Protection ◽  
Cx43 Expression

Abstract Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague–Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.

scholarly journals Propofol Mediated Protection of the Brain From Ischemia/Reperfusion Injury Through the Regulation of Microglial Connexin 43

2021 ◽  
Vol 9 ◽  
Author(s):  
Tingting Zhang ◽  
Yanyan Wang ◽  
Qin Xia ◽  
Zhiyi Tu ◽  
Jiajun Sun ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neuronal Population ◽  
Neuronal Morphology ◽  
Microglial Cells ◽  
Cx43 Expression ◽  
The Brain

Cerebral ischemia/reperfusion (I/R) injury is a serious condition that leads to increased apoptosis of microglial and neurons in the brain. In this study, we identified that Cx43 expression level is significantly increased in the microglial cells during I/R injury. Using an in vitro model (hypoxia/reoxygenation-H/R injury), we observed that H/R injury leads to an increase in activation of microglial cells and increase in levels of pro-inflammatory markers such as IL-1β, IL-6, and TNF-α. Additionally, we could also observe significant increase in phosphorylation of Cx43 and Cav3.2 levels. To assess the role of H/R injured microglial cells on neuronal population, we cultured the neurons with conditioned media (MCS) from H/R injured microglial cells. Interestingly, we observed that microglial H/R injury significantly decreased Map2 expression and affected neuronal morphology. Further, we aimed to assess the effects of propofol on cerebral H/R injury, and observed that 40 μM propofol significantly decreased Cx43, Cx43 phosphorylation, and CaV3.2 levels. Additionally, propofol decreased apoptosis and increased Map2 expression levels in H/R injured neurons. Using silencing experiments, we confirmed that siCx43 could significantly improve the propofol’s rescue after H/R injury in both microglia and neurons. We further developed an in vivo MCAO (middle cerebral artery occlusion) rat model to understand the effect of propofol in I/R injury. Interestingly, propofol treatment and downregulation of Cx43 significantly decreased the infract volume and apoptosis in these MCAO rats. Thus, this study clearly establishes that propofol protects the brain against I/R injury through the downregulation of Cx43 in microglial cells.

Anti-fatigue Effects of Ginseng Antler Yam Tang Modulation of Oxidative Stress Signaling in a Mice Model

2020 ◽  
Author(s):  
Lei Miao ◽  
Rongrong Zhang ◽  
Shuai Shao ◽  
Hongyin Zhang ◽  
Fengqin Xiao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
High Performance ◽  
Antioxidant Activities ◽  
Chemical Components ◽  
Stress Signaling ◽  
Mice Model ◽  
Biochemical Index

Abstract Background: Ginseng Antler Yam Tang (GAYT), believe to invigorate “Qi” (vital energy), nourish “Blood” (body circulation) and engender “liquid” (body fluid), is a traditional Chinese medicine formula derived from the traditional prescription and Chinese traditional medicine partner theory. Methods: In this study, we aimed to evaluate the anti-fatigue effects of GAYT and its mechanisms are related to oxidative stress signaling using GAYT composition, in vitro and in vivo antioxidant, and biochemical index detection. Chemical components analysis of GAYT was performed by high performance liquid chromatography (HPLC) and ultraviolet spectrophotometry (UV). Results: The results show that the GAYT is rich in protein, total flavonoids, total polysaccharide and saponin. The mice model was treatment by GAYT (0.9, 1.8 and 3.6g/kg) for 4 weeks. GAYT treatment enhanced antioxidant activities. GAYT significantly enhances the exercise performance in weight-loaded swimming, rotating rod, and forced running test. Biochemical index levels showed that these effects were closely correlated with inhibiting the depletion of glycogen, blood lactic acid (LD) and adenosine triphosphate (ATP) stores, regulating oxidative stress-related parameters (superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and malonaldehyde (MDA)) in serum and liver of mice. Moreover, the results show that the effects of GAYT may be related with its regulation on the activations of AMP-activated protein kinase and protein kinase B in liver of mice.Conclusions: GAYT can induce recovery from fatigue in mice via the activation of the AMPK and AKT/mTOR pathways. Provide a theoretical basis for the study of GAYT's anti-fatigue effect

scholarly journals Novel Anticancer Platinum(IV) Complexes with Adamantylamine: Their Efficiency and Innovative Chemotherapy Strategies Modifying Lipid Metabolism

2008 ◽  
Vol 2008 ◽  
pp. 1-15 ◽  
Author(s):  
Alois Kozubík ◽  
Alena Vaculová ◽  
Karel Souček ◽  
Jan Vondráček ◽  
Jaroslav Turánek ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Metabolism ◽  
Platinum Complexes ◽  
The Other ◽  
Stress Signaling ◽  
Cell Death Pathway ◽  
Cellular Lipids ◽  
In Vivo Effects

The impressive impact of cisplatin on cancer on one side and severe side effects, as well as the development of drug resistance during treatment on the other side, were the factors motivating scientists to design and synthesize new more potent analogues lacking disadvantages of cisplatin. Platinum(IV) complexes represent one of the perspective groups of platinum-based drugs. In this review, we summarize recent findings on both in vitro and in vivo effects of platinum(IV) complexes with adamantylamine. Based on a literary overview of the mechanisms of activity of platinum-based cytostatics, we discuss opportunities for modulating the effects of novel platinum complexes through interactions with apoptotic signaling pathways and with cellular lipids, including modulations of the mitochondrial cell death pathway, oxidative stress, signaling of death ligands, lipid metabolism/signaling, or intercellular communication. These approaches might significantly enhance the efficacy of both novel and established platinum-based cytostatics.

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