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Phenotypic mutants are valuable resources for elucidating the function of genes responsible for their expression. This study examined mutant rice strains expressing three traits: spotted leaf 6 (spl6), lax panicle (lax), and liguleless (lg). In the mutant, the spl6 phenotype was a genetically programmed lesion-mimicking mutation (LMM) that displayed spontaneously scattered spots across the leaf surface. In the lg trait, the plant lacked a collar region, and there were no auricles and ligules at the junction of the leaf blade and leaf sheath. The lax panicle trait manifested as sparely arranged spikelets resulting from the terminal spikelet with no lateral spikelets, which caused a drastic reduction of the total seed number in the mutant. All three mutant genes were genetically recessive and had nuclear gene regulation. The dihybrid segregation of the lg gene was classified independently according to the Mendelian 9:3:3:1 dihybrid segregation ratio in the F2 generation, suggesting that the lg gene is not linked to the same chromosome as the lax and spl6 genes. On the other hand, spl6 and lax were not assorted independently, indicating that they are closely linked on chromosome 1 in rice. Additional linkage analysis from the recombination of spl6 and lax genes reconfirmed that the two genes were ~9.4 cM away from each other. The individual single-gene mutant plant from one plant with a three-gene mutation (spl6, lax, and lg) was isolated and characterized, which will be a crucial resource for the gene cloning and molecular characterization of these genes. [ABSTRACT FROM AUTHOR]

[Display omitted] Regulated protein degradation plays a crucial role in maintaining proteostasis along with protein refolding and compartmentalisation which collectively control biological functions. The N-end rule pathway is a major ubiquitin-dependent protein degradation system. The short-lived protein substrates containing destabilizing amino acid residues (N-degrons) are recognized by E3 ubiquitin ligases containing UBR box domains (N-recognin) for degradation. The dysregulated pathway fails to maintain the metabolic stability of the substrate proteins which leads to diseases. The mammalian substrates of this pathway are involved in many hallmarks of cancer such as resisting cell death, evading growth suppression, chromosomal instability, angiogenesis, and deregulation of cellular metabolism. Besides, mutations in E3 N-recognin have been detected in human cancers. In this review, we discuss the mammalian N-end rule pathway components, functions, and mechanism of degradation of substrates, and their implications in cancer pathogenesis. We also discuss the impact of pharmacological and genetic inhibition of this pathway component on cancer cells and chemoresistance. We further highlight how this pathway can be manipulated for selective protein degradation; for instance, using PROTAC technique. The challenges and future perspectives to utilize this pathway as a drug target for cancer therapy are also discussed. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) uses a photosensitizer (PS) and visible light to induce cancer cell death. Pyroptosis is a new type of programmed cell death that is associated with the gasdermin protein family. However, the precise mechanism of pyroptosis in PDT-induced suppression of esophageal cancer remains unknown. We demonstrate that PDT can induce gasdermin E (GSDME)-mediated pyroptosis, which is characterized by the formation of pyroptotic blebs in esophageal squamous cell carcinoma (ESCC), which burst and release intracellular contents and pro-inflammatory mediators. Mechanistically, PDT may inhibit pyruvate kinase M2 (PKM2) and consequently, activate caspase-8 and caspase-3, which ultimately releases N-GSDME and triggers pyroptosis in ESCC. Moreover, PDT decreased the efficiency of pyroptosis in the presence of a glycolytic inhibitor. Overall, our results show that PDT induces pyroptosis in ESCC by targeting the PKM2/caspase-8/caspase-3/GSDME axis. This is the first in-depth study of the specific mechanism underlying PKM2-mediated pyroptosis under PDT in ESCC, and potentially has great implications for the clinical application of PDT in ESCC. • PDT can induce pyroptosis in human esophageal carcinoma cells. • PDT can induce pyroptosis by targeting PKM2/caspase-8/caspase-3/GSDME pathway. • 2-Deoxy-d-glucose has potential for PDT-induced pyroptosis treatment. [ABSTRACT FROM AUTHOR]

Organic and synthetic chemistry plays a crucial role in drug discovery fields. Moreover, chemical modifications of available molecules to enhance their efficacy, selectivity and safety have been considered as an attractive approach for the development of new bioactive agents. Indoles, a versatile group of natural heterocyclic compounds, have been widely used in pharmaceutical industry due to their broad spectrum of activities including antimicrobial, antitumoral and anti-inflammatory among others. Herein, we report the amoebicidal activity of different indole analogs on Acanthamoeba castellanii Neff. Among the 40 tested derivatives, eight molecules were able to inhibit this protistan parasite. The structure-activity relationship (SAR) analysis of their anti- Acanthamoeba activity would suggest that a carboxylation of C-3 position and the incorporation of halogen as chlorine/fluorine would enhance their biological profile, presumably by increasing their lipophilicity and therefore their ability to cross the cell membrane. Fluorescence image base system was used to investigate the effect of indole 6o c-6 on the cytoskeleton network and various programmed cell death features. We were able to highlight that the methyl 6-chloro-1H-indole-3-carboxylate could induce program cell death by the mitochondrial dysfunction., Competing Interests: The authors declare no conflict of interest.

With the advent of checkpoint blockade therapies, immunotherapy is now a critical modality for the treatment of some cancers. While some patients respond well to checkpoint blockade, many do not, necessitating the need for other forms of therapy. Vaccination against malignancy has been a long sought goal of science. For cancers holding a microbial etiology, vaccination has been highly effective in reducing the incidence of disease. However, vaccination against established malignancy has been largely disappointing. In this review, we discuss efforts to develop diverse vaccine modalities in the treatment of cancer with a particular focus on melanoma. Recent work has suggested that vaccines targeting patient-specific tumor mutations may be more relevant than those targeting unmutated proteins. Nonetheless, tumor cells utilize many strategies to evade host immunity. It is likely that the full potential of cancer vaccination will only be realized when vaccines are combined with other therapies targeting tumor immunoevasive mechanisms. By modulating inhibitory molecules, regulatory immune cells, and the metabolic resources and demands of T cells, scientists and clinicians can ensure vaccine-stimulated T cells are fully functional within the immunosuppressive tumor microevironment.

With the advent of checkpoint blockade therapies, immunotherapy is now a critical modality for the treatment of some cancers. While some patients respond well to checkpoint blockade, many do not, necessitating the need for other forms of therapy. Vaccination against malignancy has been a long sought goal of science. For cancers holding a microbial etiology, vaccination has been highly effective in reducing the incidence of disease. However, vaccination against established malignancy has been largely disappointing. In this review, we discuss efforts to develop diverse vaccine modalities in the treatment of cancer with a particular focus on melanoma. Recent work has suggested that vaccines targeting patient-specific tumor mutations may be more relevant than those targeting unmutated proteins. Nonetheless, tumor cells utilize many strategies to evade host immunity. It is likely that the full potential of cancer vaccination will only be realized when vaccines are combined with other therapies targeting tumor immunoevasive mechanisms. By modulating inhibitory molecules, regulatory immune cells, and the metabolic resources and demands of T cells, scientists and clinicians can ensure vaccine-stimulated T cells are fully functional within the immunosuppressive tumor microevironment. [ABSTRACT FROM AUTHOR]

Hepatic malignancies are one of the leading causes of cancer death globally. Considering the limited efficacy of current standard treatments in management of patients with advanced liver cancers, there has been a growing interest in identifying novel therapies. Despite achieving promising results in initial clinical trials, the therapeutic benefit of immunotherapy is limited due to strong immune-tolerogenic characteristics of liver tumors. Therapeutic regimens that impede tumor immunosuppressive mechanisms or elaborate tumor-specific immunity may improve clinical outcomes of patients with liver malignancies. Programmed cell death 1 (PD-1), an inhibitory checkpoint molecule, and its ligands (PD-L1 and -L2) are the main mediators of immunosuppression within the tumor microenvironment. The expression level of PD-1/PD-L1 may act as a biomarker to predict disease progression, as well as long-term survival. Furthermore, early trials have demonstrated the efficacy and safety of targeting PD-1/PD-L1 as an emerging field in the management of patients with advanced hepatocellular carcinoma. We herein review the role of PD-1/PD-L1 in the pathogenesis of liver malignancies, as well as its potential diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Apoptosis plays a causative role in acute lung injury in part due to epithelial cell loss. We recently reported that zinc protects the lung epithelium during inflammatory stress whereas depletion of intracellular zinc enhances extrinsic apoptosis. In this investigation, we evaluated the relationship between zinc, caspase-3, and cell-to-cell contact via proteins that form the adherens junction complex. Cell adhesion proteins are directly responsible for formation of the mechanical barrier of the lung epithelium. We hypothesized that exposure to inflammatory cytokines, in conjunction with zinc deprivation, would induce caspase-3, leading to degradation of junction proteins, loss of cell-to-cell contact, and compromised barrier function. Primary human upper airway and type I/IT alveolar epithelial cultures were obtained from multiple donors and exposed to inflammatory stimuli that provoke extrinsic apoptosis in addition to depletion of intracellular zinc. We observed that zinc deprivation combined with tumor necrosis factor-α, interferon-γ, and Fas receptor ligation accelerates caspase-3 activation, proteolysis of E-cadherin and β-catenin, and cellular apoptosis, leading to increased paracellular leak across monolayers of both upper airway and alveolar lung epithelial cultures. Zinc supplementation inhibited apoptosis and paracellular leak, whereas caspase inhibition was less effective. We conclude that zinc is a vital factor in the lung epithelium that protects against death receptor-mediated apoptosis and barrier dysfunction. Furthermore, our findings suggest that although caspase-3 inhibition reduces lung epithelial apoptosis it does not prevent mechanical dysfunction. These findings facilitate future studies aimed at developing therapeutic strategies to prevent acute lung injury. [ABSTRACT FROM AUTHOR]

Summary Programmed cell death (PCD) plays critical roles in plant immunity but must be regulated to prevent excessive damage. The E3 ubiquitin ligase SPL11 negatively regulates PCD and immunity in plants. We show that S PL11 cell- d eath s uppressor 2 (SDS2), an S-domain receptor-like kinase, positively regulates PCD and immunity in rice by engaging and regulating SPL11 and related kinases controlling defense responses. An sds2 mutant shows reduced immune responses and enhanced susceptibility to the blast fungus Magnaporthe oryzae . Conversely, SDS2 over-expression induces constitutive PCD accompanied by elevated immune responses and enhanced resistance to M. oryzae . SDS2 interacts with and phosphorylates SPL11, which in turn ubiquitinates SDS2, leading to its degradation. In addition, SDS2 interacts with related receptor-like cytoplasmic kinases, OsRLCK118/176, that positively regulate immunity by phosphorylating the NADPH oxidase OsRbohB to stimulate ROS production. Thus, a plasma membrane-resident protein complex consisting of SDS2, SPL11, and OsRLCK118/176 controls PCD and immunity in rice. [ABSTRACT FROM AUTHOR]