Apoptosis, an important form of programmed cell death (PCD), is a tightly regulated cellular process to eliminate unwanted or damaged cells. Resistance of apoptosis is a hallmark of cancer cells. ...Inhibitor of apoptosis proteins (IAPs) is a class of key apoptosis regulators that promote cancer cell resistant to apoptosis, particularly in cancer treatment. Disrupting the binding of IAPs with their functional partners therefore is a promising strategy to restore the apoptotic response to proapoptotic stimuli, particularly those introduced by standard cancer therapies. The most successful example is the use of small molecules to mimic the IAP-binding motif of an endogenous IAP antagonist, second mitochondria-derived activator of caspase (SMAC). Here we will review the functions of IAPs, the structural interactions of IAPs with SMAC, four generations of SMAC-mimetic IAP antagonists, and representative antagonists in clinical evaluations, focusing on research articles over the past 15 years. Outlooks and perspectives on the associated challenges are provided as well.
Kava beverages are typically prepared from the root of Piper methysticum. They have been consumed among Pacific Islanders for centuries. Kava extract preparations were once used as herbal drugs to ...treat anxiety in Europe. Kava is also marketed as a dietary supplement in the U.S. and is gaining popularity as a recreational drink in Western countries. Recent studies suggest that kava and its key phytochemicals have anti-inflammatory and anticancer effects, in addition to the well-documented neurological benefits. While its beneficial effects are widely recognized, rare hepatotoxicity had been associated with use of certain kava preparations, but there are no validations nor consistent mechanisms. Major challenges lie in the diversity of kava products and the lack of standardization, which has produced an unmet need for quality initiatives. This review aims to provide the scientific community and consumers, as well as regulatory agencies, with a broad overview on kava use and its related research. We first provide a historical background for its different uses and then discuss the current state of the research, including its chemical composition, possible mechanisms of action, and its therapeutic potential in treating inflammatory and neurological conditions, as well as cancer. We then discuss the challenges associated with kava use and research, focusing on the need for the detailed characterization of kava components and associated risks such as its reported hepatotoxicity. Lastly, given its growing popularity in clinical and recreational use, we emphasize the urgent need for quality control and quality assurance of kava products, pharmacokinetics, absorption, distribution, metabolism, excretion, and foundational pharmacology. These are essential in order to inform research into the molecular targets, cellular mechanisms, and creative use of early stage human clinical trials for designer kava modalities to inform and guide the design and execution of future randomized placebo controlled trials to maximize kava's clinical efficacy and to minimize its risks.
Recently, Mg(OH)2 nanoparticles were reported to be efficient antibacterial agent. In this work, the antibacterial behavior of Mg(OH)2 nanoparticles against Escherichia coli was further investigated. ...Results indicate that the antibacterial mechanism of Mg(OH)2 nanoparticles is different from the existing ones of metal-based compounds. It is found that the Mg2+ increased a lot in the sample culture after the antibacterial test. Mg(OH)2 nanobars of about 2μm length did not show any antibacterial property, and the ultraviolet illumination for certain time can accelerate the antibacterial behavior of Mg(OH)2 nanoplatelets. A novel possible antibacterial mechanism of Mg(OH)2 nanoparticles was consequently proposed. When contacting directly with a bacterial cell, Mg(OH)2 nanoparticles would enter into the cell through endocytosis and accumulate in vivo. Since there is over 70% water inside the cell, the Mg(OH)2 nanoparticles would inevitably dissolve and OH− would be released until an equilibrium is reached (pH of ~10). Therefore, the intracellular high pH would lead to cell death.
•Mg(OH)2 nanobars of about 2μm length could not kill E. coli.•UV illumination for 4h may accelerate the antibacterial behavior of Mg(OH)2.•Mg2+ in the sample culture increased a lot after the antibacterial test.•Nano Mg(OH)2 would enter into cells through endocytosis and release OH−.•The intracellular high pH (pH of ~10) may lead to cell death.
Pogostemon cablin
(patchouli) cultivation is challenged by serious soil sickness, of which autotoxins accumulation is a major cause. p-hydroxybenzoic acid (p-HBA) is one of the main autotoxins of ...patchouli. However, the molecular mechanism underlying the response of patchouli to p-HBA remains unclear. In this study, RNA-sequencing combined with physiological analysis was used to monitor the dynamic transcriptomic and physiological changes in patchouli seedlings 0, 6, 12, 24, 48, and 96 h after p-HBA treatment. p-HBA stress inhibited root biomass accumulation, induced excessive hydrogen peroxide accumulation and lipid peroxidation, and activated most antioxidant enzymes. Compared with that of the control, the osmotic adjustment substance content was elevated with treatment. Subsequently, 15,532, 8,217, 8,946, 2,489, and 5,843 differentially expressed genes (DEGs) at 6, 12, 24, 48, and 96 h after p-HBA treatment, respectively, were identified in patchouli roots. GO functional enrichment analysis showed that the DEGs were enriched mainly in plasma membrane, defense response, response to chitin, DNA-binding transcription factor activity and abscisic acid-activated signaling pathway. The upregulated genes were involved in glycolysis/gluconeogenesis, cysteine and methionine metabolism, starch and sucrose metabolism, biosynthesis of unsaturated fatty acids, and linoleic acid metabolism. Genes associated with MAPK signaling pathway-plant, plant-pathogen interaction, plant hormone signal transduction were downregulated with p-HBA treatment. These pathways are related to root browning and rotting, leading to plant death.
Lung cancer is the leading cause of cancer-related deaths due to its high incidence, late diagnosis, and limited success in clinical treatment. Prevention therefore is critical to help improve lung ...cancer management. Although tobacco control and tobacco cessation are effective strategies for lung cancer prevention, the numbers of current and former smokers in the USA and globally are not expected to decrease significantly in the near future. Chemoprevention and interception are needed to help high-risk individuals reduce their lung cancer risk or delay lung cancer development. This article will review the epidemiological data, pre-clinical animal data, and limited clinical data that support the potential of kava in reducing human lung cancer risk via its holistic polypharmacological effects. To facilitate its future clinical translation, advanced knowledge is needed with respect to its mechanisms of action and the development of mechanism-based non-invasive biomarkers in addition to safety and efficacy in more clinically relevant animal models.
The shuttle effect is one of the most notable challenges in the fundamental research and practical use of lithium-sulfur (Li-S) batteries, especially within high-polarity electrolytes containing ...enriched polysulfides. Herein, we demonstrate a proof-of-concept study showing that the issue can be resolved by constructing a liquid-state/quasi-solid-state (LS/QSS) two-phase interface that is composed of a high-polarity QSS electrolyte and a weak-polarity LS one. The weak-polarity electrolyte shows negligible solubility to polysulfides and good compatibility to Li metal, resulting in the substantially improved cyclic stability of the Li anode for more than 1400 h in Li∣Li symmetrical cells. Moreover, over 300 cycles were achieved in the Li-S battery with the polysulfide-enriched LS/QSS electrolyte. This finding indicates that the LS/QSS electrolyte can effectively suppress the chemical reaction between electrolyte components and lithium metal. The concept of LS/QSS two-phase electrolyte provides a new strategy for the application of high-polarity solvents in energy conversion/storage devices.
For several decades, Black patients have carried a higher burden of laryngeal cancer among all races. Even when accounting for sociodemographics, a disparity remains. Differentially expressed ...microRNAs have been linked to racially disparate clinical outcomes in breast and prostate cancers, yet an association in laryngeal cancer has not been addressed. In this study, we present our computational analysis of differentially expressed miRNAs in Black compared with White laryngeal cancer and further validate microRNA-9-5p (miR-9-5p) as a potential mediator of cancer phenotype and chemoresistance.
Bioinformatic analysis of 111 (92 Whites, 19 Black) laryngeal squamous cell carcinoma (LSCC) specimens from the TCGA revealed miRNAs were significantly differentially expressed in Black compared with White LSCC. We focused on miR-9-5 p which had a significant 4-fold lower expression in Black compared with White LSCC (p<0.05). After transient transfection with either miR-9 mimic or inhibitor in cell lines derived from Black (UM-SCC-12) or White LSCC patients (UM-SCC-10A), cellular migration and cell proliferation was assessed. Alterations in cisplatin sensitivity was evaluated in transient transfected cells
IC50 analysis. qPCR was performed on transfected cells to evaluate miR-9 targets and chemoresistance predictors, ABCC1 and MAP1B.
Northern blot analysis revealed mature miR-9-5p was inherently lower in cell line UM-SCC-12 compared with UM-SCC-10A. UM -SCC-12 had baseline increase in cellular migration (p < 0.01), proliferation (p < 0.0001) and chemosensitivity (p < 0.01) compared to UM-SCC-10A. Increasing miR-9 in UM-SCC-12 cells resulted in decreased cellular migration (p < 0.05), decreased proliferation (p < 0.0001) and increased sensitivity to cisplatin (p < 0.001). Reducing miR-9 in UM-SCC-10A cells resulted in increased cellular migration (p < 0.05), increased proliferation (p < 0.05) and decreased sensitivity to cisplatin (p < 0.01). A significant inverse relationship in ABCC1 and MAP1B gene expression was observed when miR-9 levels were transiently elevated or reduced in either UM-SCC-12 or UM-SCC-10A cell lines, respectively, suggesting modulation by miR-9.
Collectively, these studies introduce differential miRNA expression in LSCC cancer health disparities and propose a role for low miR-9-5p as a mediator in LSCC tumorigenesis and chemoresistance.
Up to 60% of patients with small cell lung cancer (SCLC) continue to smoke, which is associated with worse clinical outcomes. Platinum-based chemotherapies, in combination with topoisomerase ...inhibitors, are first-line therapies for SCLC, with rapid chemoresistance as a major barrier. We provided evidence in this study that nicotine and its major metabolite, cotinine, at physiologically relevant concentrations, reduced the efficacy of platinum-based chemotherapies and facilitated chemoresistance in SCLC cells. Mechanistically, nicotine or cotinine reduced chemotherapy-induced DNA damage by modulating cellular redox processes, with nAChRs as the upstream targets. Surprisingly, cisplatin treatment alone also increased the levels of nAChRs in SCLC cells, which served as a self-defense mechanism against platinum-based therapies. These discoveries were confirmed in long-term in vitro and in vivo studies. Collectively, our results depicted a novel and clinically important mechanism of chemoresistance in SCLC treatment: nicotine exposure significantly compromises the efficacy of platinum-based chemotherapies in SCLC treatment by reducing therapy-induced DNA damage and accelerating chemoresistance acquisition. The results also emphasized the urgent need for tobacco cessation and the control of NRT use for SCLC management.
Polymer‐based quasi‐solid‐state electrolyte (QSE) is an effective means to solve the safety problem of lithium (Li) metal batteries, and stable solid‐electrolyte‐interface (SEI) layers between ...electrolyte and anode/cathode are highly required for their long‐term stability. Herein, it is demonstrated that a silicon‐doped polyether functions as a multifunctional unit, which can induce the formation of stable and robust SEI layers with rich LixSiOy on both the surfaces of cathode and anode. It simultaneously solves the compatibility of electrolyte and electrodes in the quasi‐solid‐state Li‐metal battery. Moreover, the robust polymer skeleton with a cross‐linked network is beneficial to inhibit liquid volatilization and improve battery safety. The assembled Li|QSE|LiFePO4 batteries show a capacity retention rate as high as 97.5% after 400 cycles at 1 C (30 °C), and reach 78.1% after 1000 cycles. Furthermore, there is almost no attenuation of reversible capacity after 100 cycles for the assembled Li|QSE|LiNi0.8Mn0.1Co0.1O2 batteries. The concept of silicon‐doped polymer with a crosslinking structure provides an important strategy for designing solid‐state or quasi‐solid‐state polymer electrolytes for the stable long‐term operation of both anode and cathode.
A silicon‐doped polyether as a multifunctional unit of quasi‐solid‐state electrolyte for Li‐metal batteries is reported, which can form the stable solidelectrolyte‐interface layers with rich LixSiOy on the anode and cathode, as well as improve the battery safety.
Abstract Porous polymer membranes as separator plays important roles in separating cathode and anode, storing electrolytes, and transporting ions in energy storage devices. Here, an effective ...strategy is reported to prepare an electrolyte superwetting membrane, which shows good Li + transport rate and uniformity, as well as electrode‐friendly properties to afford the reduction and oxidation of electrodes. It thereby improves the cycle stability and safety of Li metal batteries. With the arrayed capillaries technique, a thin layer of polyvinylidene fluoride (PVDF) and polyacrylonitrile (PAN) composite is uniformly coated on the surface and pores of polypropylene (PP) membrane with a total thickness of 30 µm. After treating it with n‐butyllithium and LiNO 3 in turn, a chemically inert membrane with efficient and uniform ion transport is prepared, and the cycle stability of Li||Li symmetric cells is up to 1500 h, 4 times higher than that of PP membrane. Moreover, the Li||LiFePO 4 with as‐prepared membranes achieve a higher capacity retention rate of 92% after 190 cycles at a current density of 3.6 mA cm −2 and a capacity of 3.6 mAh cm −2 , and the Li||NCM721 batteries achieve a capacity retention rate of 71% after 600 cycles at a current density of 1.8 mA cm −2 .
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