Increased generation of reactive oxygen species (ROS) has been implicated in the pathogenesis of a variety of diseases such as cardiovascular diseases and cancer. NADPH oxidase (Nox), a ...multicomponent enzyme, has been identified as one of the key sources of ROS. Nox4, one of the seven members of Nox family (Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2), has been extensively investigated in recent years. Its unique structures result in the constitutive generation of hydrogen peroxide (H
2
O
2
) as the main product. As a key oxygen sensor, Nox4-derived H
2
O
2
plays diverse roles in cell proliferation, migration and death. Increased expression of Nox4 in cancer has been observed, which participates in metastasis, angiogenesis and apoptosis. Expression of Nox4 in endothelial cells actively mediated endothelial activation, dysfunction and injury, which contributes to the development of atherosclerosis, hypertension, cardiac hypertrophy and among others. This article explores the experimental studies related to the gene, structure, physiological function and pathological significance of Nox4. As Nox4 might serve as a potential target for the therapy of cardiovascular diseases and cancer, the Nox4 inhibitor is also discussed in this article.
Salvia miltiorrhiza Bunge (Danshen in Chinese) is a classical Huoxue Huayu (a traditional Chinese medical term means promoting blood circulation and removing blood stasis) herb with 1000 years of ...clinical application. It mainly contains two groups of ingredients: the hydrophilic phenolic acids and the lipophilic tanshinones. Both groups have demonstrated multiple bioactivities, such as antioxidative stress, antiplatelet aggregation, anti‐inflammation, among others. Recent data have demonstrated that its lipophilic compounds, especially the tanshinones, show potent anticancer activities both in vitro and in vivo. The anticancer effects of the hydrophilic phenolic acids have also been reported. Furthermore, tanshinones provide structural skeletons for chemical modifications, allowing for a series of derivatives of interests. This review provides a systematic summary of the anticancer profile and the underlying mechanisms of the bioactive compounds isolated from Danshen with special emphasis on tanshinones, aiming to bring new insights for further research and development of this ancient herb.
Neurodegenerative diseases (NDD) are typically associated with neuron loss in nervous system areas. Interventions with related death mechanisms may ameliorate NDD progression. Oxidative stress plays ...an important role in NDD cell death routines. However, tert-butylhydroperoxide (t-BHP), a widely used oxidative stress stimulus, induces neural cell death through a mechanism that remains elusive. In our study, the ferroptosis marker events occurred after co-treatment with 100 μM t-BHP for 1 h, all of which were reversed in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine, implying the occurrence of ferroptosis. Moreover, mitochondrial dysfunction accompanied by a decreased in membrane potential and ATP production, increased mitochondrial ROS generation. Furthermore, this mitochondrial dysfunction could be reversed by Fer-1. In addition, JNK1/2 and ERK1/2 were activated upstream of the ferroptosis and mitochondrial dysfunction. In summary, these data suggest that ferroptosis, coupled with mitochondrial dysfunction, was involved in t-BHP-induced PC12 death. JNK1/2 and ERK1/2 played important roles in t-BHP-induced cell death. Overall, this study might provide clues to the oxidative stress-based strategies for cell protection in NDD.
Chemotherapy is the standard internal medical treatment for cancer. However, the resistance of cancer cells to nearly all kinds of chemotherapeutic drugs and targeted drugs has become prevalent, and ...approximately 80–90% of deaths in cancer patients are directly or indirectly attributed to drug resistance. The progress of new drug research and development has also been impeded by the occurrence of drug resistance, which has emerged as a considerable challenge in cancer therapy. Fortunately, natural products with diverse chemical structures and pharmacological effects serve as effective substances against drug resistance. Since the discovery of a series of drug‐resistant proteins, drug‐efflux inhibition has been applied as the primary strategy to overcome drug resistance by maintaining the intracellular concentrations of chemotherapeutic drugs. Nonapoptotic cell death is considered an alternative strategy because most cases of drug resistance result in evasion and insensitivity to apoptosis. In this concise review, we summarize two strategies using natural products against drug resistance.
Psoralea corylifolia Linn. (P. corylifolia) is an important medicinal plant with thousands of years of clinical application. It has been widely used in many traditional Chinese medicine formulas for ...the treatment of various diseases such as leucoderma and other skin diseases, cardiovascular diseases, nephritis, osteoporosis, and cancer. Phytochemical studies indicated that coumarins, flavonoids, and meroterpenes are the main components of P. corylifolia, and most of these components are present in the seeds or fruits. The extracts and active components of P. corylifolia demonstrated multiple biological activities, including estrogenic, antitumor, anti-oxidant, antimicrobial, antidepressant, anti-inflammatory, osteoblastic, and hepatoprotective activities. This paper systematically summarized literatures on the chemical constituents and biological activities of P. corylifolia, which provided useful information for the further research and development toward this potent medicinal plant.
As an anthracycline antibiotic, doxorubicin (DOX) is one of the most potent and widely used chemotherapeutic agents for various types of solid tumors. Unfortunately, clinical application of this drug ...results in severe side effects of cardiotoxicity.
We aim to review the research focused on elimination or reduction of DOX cardiotoxicity without affecting its anticancer efficacy by natural products.
This study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect. The literature mainly focusing on natural products and herb extracts with therapeutic efficacies against experimental models both in vitro and in vivo was identified.
Current evidence revealed that multiple molecules and signaling pathways, such as oxidative stress, iron metabolism, and inflammation, are associated with DOX-induced cardiotoxicity. Based on these knowledge, various strategies were proposed, and thousands of compounds were screened. A number of natural products and herb extracts demonstrated potency in limiting DOX cardiotoxicity toward cultured cells and experimental animal models.
Though a panel of natural products and herb extracts demonstrate protective effects on DOX-induced cardiotoxicity in cells and animal models, their therapeutic potentials for clinical needs further investigation.
•The small-molecule inhibitors targeting CD47/SIRPα axis, a promising phagocytosis checkpoint in cancer therapy, are reviewed for the first time.•In addition to targeting the interaction of ...CD47/SIRPα, compounds regulating CD47 at transcriptional, translational and posttranslational levels are summarized.•Challenges followed by the corresponding strategies are proposed for further development of small-molecule inhibitors targeting CD47/SIRPα axis.
Immunotherapy has become an indispensable part of cancer treatment. A pivotal phagocytosis checkpoint, named cluster of differentiation 47 (CD47), which functions as ‘don’t eat me’ signal to protect cells from phagocytosis upon interaction with signal regulatory protein alpha (SIRPα) on macrophages, has recently attracted much attention. Numerous antibodies targeting the CD47/SIRPα axis have shown encouraging efficacy in clinical trials. Meanwhile, studies on small-molecule inhibitors that interfere with CD47/SIRPα interaction or regulate CD47 expression are also in full swing. In this review, we summarize the small-molecule inhibitors interrupting the binding of CD47/SIRPα and regulating CD47 at the transcriptional, translational, and post-translational modification (PTM) levels. We provide perspectives and strategies for targeting the CD47/SIRPα phagocytosis checkpoint.
Our previous studies have revealed that the protective effect of an enriched environment (EE) may be linked with astrocyte proliferation and angiogenesis. However, the relationship between astrocytes ...and angiogenesis under EE conditions still requires further study. The current research examined the neuroprotective effects of EE on angiogenesis in an astrocytic interleukin-17A (IL-17A)-dependent manner following cerebral ischemia/reperfusion (I/R) injury.
A rat model of ischemic stroke based on middle cerebral artery occlusion (MCAO) for 120 min followed by reperfusion was established, after which rats were housed in either EE or standard conditions. A set of behavior tests were conducted, including the modified neurological severity scores (mNSS) and the rotarod test. The infarct volume was evaluated by means of 2,3,5-Triphenyl tetrazolium chloride (TTC) staining. To evaluate the levels of angiogenesis, the protein levels of CD34 were examined by means of immunofluorescence and western blotting, while the protein and mRNA levels of IL-17A, vascular endothelial growth factor (VEGF), and the angiogenesis-associated factors interleukin-6 (IL-6), JAK2, and STAT3 were detected by western blotting and real-time quantitative PCR (RT-qPCR).
We found that EE promoted functional recovery, reduced infarct volume, and enhanced angiogenesis compared to rats in standard conditions. IL-17A expression in astrocytes was also increased in EE rats. EE treatment increased the levels of microvascular density (MVD) and promoted the expression of CD34, VEGF, IL-6, JAK2, and STAT3 in the penumbra, while the intracerebroventricular injection of the IL-17A-neutralizing antibody in EE rats attenuated EE-mediated functional recovery and angiogenesis.
Our findings revealed a possible neuroprotective mechanism of astrocytic IL-17A in EE-mediated angiogenesis and functional recovery after I/R injury, which might provide the theoretical basis for EE in clinical practise for stroke patients and open up new ideas for the research on the neural repair mechanism mediated by IL-17A in the recovery phase of stroke.
Napabucasin (also known as BBI608) is a natural naphthoquinone originally identified as a cancer cell stemness inhibitor. Accumulated in vitro and in vivo evidence demonstrated that napabucasin ...showed significant anticancer effects in various types of cancers. Napabucasin inhibits cancer cell proliferation, induces apoptosis and cell cycle arrest, and suppresses metastasis and relapse. Such anticancer activities of napabucasin mainly rely on the inhibition of cancer stemness by targeting signal transducer and activator of transcription 3 (STAT3) and its related gene inhibition. However, several novel molecular targets for napabucasin, such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and thioredoxin reductase 1 (TrxR1), have been reported. Napabucasin represents a promising anticancer lead for multiple cancers. In this mini review, the anticancer potential and the molecular mechanism of napabucasin will be briefly highlighted.
In this paper, the power density capability of AlGaN/GaN high-electron mobility transistors (HEMTs) made on Si, SiC, and diamond substrates were compared with devices on Si and SiC with integrated ...microchannel cooling. A device temperature limit of 200 °C was used to define the power density. The numerical model accounts for heat transfer from channel of the AlGaN/GaN HEMTs to the heat sink, fluid flow rates, pressure drop, and pumping power required for liquid cooling. The diamond substrate was shown to be superior in reducing the junction temperatures in conventional passive cooling methods employing high thermal conductivity substrates. However, singlephase liquid cooling with microchannels integrated into a SiC substrate showed that it is possible to operate the devices at power densities higher than that on 200-μm-thick diamond substrates, considering a maximum operational temperature of 200 °C. Microchannels integrated into the Si substrate also showed a slight increase in the power density compared with passively cooled devices on SiC. Overall, this methodology shows a promising alternative to expensive high thermal conductivity substrates for cooling AlGaN/GaN HEMTs.
PDF
