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Cryptococcus neoformans threaten the health, causing cryptococcal meningitis and pneumonia, especially in immunosuppressed patients, which can be fatal. Recently, our research group evaluated and studied the mechanisms of action of four synthetic peptides (SP) against C. neoformans. Here, in silico and in vitro analyses help deepen understanding of peptides' mechanisms of action. The interaction of the peptides with a membrane receptor was analyzed by docking analysis, in addition to ROS overproduction and the modulation of redox metabolism, inhibition of ergosterol biosynthesis, and release of cytochrome c. Out of four, three peptides interacted with membrane receptor PHO36 altering its structure and function and leading to a higher accumulation of O₂- and H2O2. C. neoformans cells treated with SP presented a reduction in the activity of antioxidant enzymes, corroborating ROS accumulation. However, in the presence of the antioxidant ascorbic acid, some peptides could not induce this oxidative stress and have the activity against C. neoformans affected. Curiously, two of these SPs still maintained the activity against C. neoformans and even induced the membrane pore formation as revealed by propidium iodide uptake assay, revealing their mechanism of action is ROS-independent. Additionally, SPs inhibited the biosynthesis of ergosterol, which corroborates the pore formation on the membrane of C. neoformans cells, inhibited the lactate dehydrogenase activity affecting the cell metabolism, and induced the release of Cyt c from the mitochondria inducing death by apoptosis in the cryptococcal cells. Our findings strongly suggest that SPs act by multiple mechanisms, making it difficult for C. neoformans to acquire resistance highlighting the potential of SPs as alternative molecules in treating infections caused by C. neoformans.

Eggplant is a popular vegetable in Asia; however, it has a short storage life and considerable economic losses have resulted from eggplant browning. Calcium has been reported to play a key role in the postharvest storage of plants. Here, we found that exogenous calcium application could delay eggplant fruit browning and maintain higher storage quality. The increased browning index (BI), relative electrolytic leakage (REL), and water loss were suppressed by calcium treatment during storage. Delayed browning with calcium treatment might result from a higher phenolic level and suppressed the activity of polyphenol oxidase (PPO). Less H2O2 and O2 ‐ but more activated reactive oxygen species (ROS) scavenging enzymes accumulated in calcium‐treated fruits than in H2O‐treated fruits. Moreover, the nonenzymatic antioxidant, ascorbic acid (AsA), was accumulated more in calcium‐treated eggplant fruits. Taken together, our data demonstrated that exogenous calcium application delayed eggplant fruit browning by regulating phenol metabolism and enhancing antioxidant systems., 1. Calcium treatment delayed browning of eggplant fruits during storage.2. Calcium treatment maintained ROS scavenging enzyme activities in eggplant fruits during storage.

Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor superfamily, participates in multiple physiological and pathological processes. Extensive studies have revealed the relationship between PPARγ and various tumors. However, the expression and function of PPARγ in bladder cancer seem to be controversial. It has been demonstrated that PPARγ affects the occurrence and progression of bladder cancer by regulating proliferation, apoptosis, metastasis, and reactive oxygen species (ROS) and lipid metabolism, probably through PPARγ-SIRT1 feedback loops, the PI3K-Akt signaling pathway, and the WNT/β-catenin signaling pathway. Considering the frequent relapses after chemotherapy, some researchers have focused on the relationship between PPARγ and chemotherapy sensitivity in bladder cancer. Moreover, the feasibility of PPARγ ligands as potential therapeutic targets for bladder cancer has been uncovered. Taken together, this review summarizes the relevant literature and our findings to explore the complicated role and function of PPARγ in bladder cancer.

Background: Abnormal redox equilibrium is a major contributor to tumor malignancy and treatment resistance. Understanding reactive oxygen species (ROS) metabolism is a key to clarify the tumor redox status. However, we have limited methods to evaluate ROS in tumor tissues and little knowledge on ROS metabolism across human cancers. Methods: The Cancer Genome Atlas multi-omics data across 22 cancer types and the Genomics of Drug Sensitivity in Cancer data were analyzed in this study. Cell viability testing and xenograft model were used to validate the role of ROS modulation in regulating treatment efficacy. Results: ROS indexes reflecting ROS metabolic balance in five dimensions were developed and verified. Based on the ROS indexes, we conducted ROS metabolic landscape across 22 cancer types and found that ROS metabolism played various roles in different cancer types. Tumor samples were classified into eight ROS clusters with distinct clinical and multi-omics features, which was independent of their histological origin. We established a ROS-based drug efficacy evaluation network and experimentally validated the predicted effects, suggesting that modulating ROS metabolism improves treatment sensitivity and expands drug application scopes. Conclusion: Our study proposes a new method in evaluating ROS status and offers comprehensive understanding on ROS metabolic equilibrium in human cancers, which provide practical implications for clinical management.

Neural stem cell (NSC) neuronal differentiation requires a metabolic shift towards oxidative phosphorylation. We now show that a branched-chain amino acids-driven, persistent metabolic shift toward energy metabolism is required for full neuronal maturation. We increased energy metabolism of differentiating neurons derived both from murine NSCs and human induced pluripotent stem cells (iPSCs) by supplementing the cell culture medium with a mixture composed of branched-chain amino acids, essential amino acids, TCA cycle precursors and co-factors. We found that treated differentiating neuronal cells with enhanced energy metabolism increased: i) total dendritic length; ii) the mean number of branches and iii) the number and maturation of the dendritic spines. Furthermore, neuronal spines in treated neurons appeared more stable with stubby and mushroom phenotype and with increased expression of molecules involved in synapse formation. Treated neurons modified their mitochondrial dynamics increasing the mitochondrial fusion and, consistently with the increase of cellular ATP content, they activated cellular mTORC1 dependent p70S6 K1 anabolism. Global transcriptomic analysis further revealed that treated neurons induce Nrf2 mediated gene expression. This was correlated with a functional increase in the Reactive Oxygen Species (ROS) scavenging mechanisms. In conclusion, persistent branched-chain amino acids-driven metabolic shift toward energy metabolism enhanced neuronal differentiation and antioxidant defences. These findings offer new opportunities to pharmacologically modulate NSC neuronal differentiation and to develop effective strategies for treating neurodegenerative diseases.

Graphical abstract, Highlights • H2O2 down-regulated expression of ROS scavenging-related genes in longan pulp. • H2O2 reduced activities of ROS scavenging enzymes (SOD, CAT, APX) in longan pulp. • H2O2 reduced ROS scavenging capacity and raised O2–. generation rate in longan pulp. • H2O2 promoted lipid peroxidation of cell membrane in pulp of harvested longan fruit. • H2O2-reduced ROS scavenging capacity led to H2O2-stimulated pulp breakdown of longans., The influence of hydrogen peroxide (H2O2) on the ROS metabolism and its relationship to pulp breakdown of fresh longan cv. Fuyan during storage was evaluated. Contrasted to control fruit, H2O2-treated samples manifested a higher index of pulp breakdown, an enhanced rate of O2–. generation, and an increased amount of MDA, but lower APX, CAT and SOD activities, reduced expressions of DlAPX, DlCAT and DlSOD, and lower concentrations of total phenolics, flavonoid, AsA, and GSH as well as lower levels of free radicals scavenging capacity. These data revealed that H2O2-induced pulp breakdown of longan was because H2O2 reduced ability of removing ROS but increased ROS generation and accumulation, which promoted peroxidation of cell membrane lipid, and subsequently led to damaging cell membrane structure and breakdown occurrence in pulp of postharvest fresh longan.

The seven in absentia homolog (Siah) family proteins are components of E3 RING zinc finger ubiquitin ligase complexes that catalyze the ubiquitination of proteins. Siah proteins target their substrates for proteasomal degradation. Evidence is growing that Siah proteins are implicated in the progression of various cancer cells and play a critical role in angiogenesis and tumorigenesis, particularly through Ras, p53, estrogen, and hypoxia inducible factor (HIF)-mediated signaling pathways in response to DNA damage or hypoxia.

Phomopsis longanae Chi is a major pathogenic fungus that infects harvested longan fruit. This study aimed to investigate the effects of P. longanae on reactive oxygen species (ROS) metabolism and its relation to the pericarp browning and disease development of harvested longan fruit during storage at 28°C and 90% relative humidity. Results showed that compared to the control longans, P. longanae-inoculated longans displayed higher indexes of pericarp browning and fruit disease, higher O2 -. generation rate, higher accumulation of malondialdehyde (MDA), lower contents of glutathione (GSH) and ascorbic acid (AsA), lower 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging ability and reducing power in pericarp. In addition, P. longanae-infected longans exhibited higher activities of superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) in the first 2 days of storage, and lower activities of SOD, CAT, and APX during storage day 2-5 than those in the control longans. These findings indicated that pericarp browning and disease development of P. longanae-infected longan fruit might be the result of the reducing ROS scavenging ability and the increasing O2 -. generation rate, which might lead to the peroxidation of membrane lipid, the loss of compartmentalization in longan pericarp cells, and subsequently cause polyphenol oxidase (PPO) and peroxidase (POD) to contact with phenolic substrates which result in enzymatic browning of longan pericarp, as well as cause the decrease of disease resistance to P. longanae and stimulate disease development of harvested longan fruit.

Cytoplasmic male sterility is crucial for the utilization of hybrid heterosis and it possibly occurs in parallel with tapetal programmed cell death (PCD) and oxidative metabolism responses. However, little is known about the mechanisms that underlie pollen abortion in wheat. Therefore, we obtained two isonuclear alloplasmic male sterile lines (IAMSLs) with Aegilops kotschyi and Ae. juvenalis cytoplasm. Compared with the maintainer line, cytochemical analyses of the anthers demonstrated that the IAMSLs exhibited anomalous tapetal PCD and organelles, with premature PCD in K87B1-706A and delayed PCD in Ju87B1-706A. We also found that the dynamic trends in reactive oxygen species (ROS) were consistent in these two IAMSLs during anther development and they were potentially associated with the initiation of tapetal PCD. In addition, the activities of ROS-scavenging enzymes increased rapidly, whereas non-enzymatic antioxidants were downregulated together with excess ROS production in IAMSLs. Real-time PCR analysis showed that the expression levels of superoxide dismutase, catalase, and ascorbate peroxidase genes, which encode important antioxidant enzymes, were significantly upregulated during early pollen development. Thus, we inferred that excessive ROS and the abnormal transcript levels of antioxidant enzyme genes disrupted the balance of the antioxidant system and the presence of excess ROS may have been related to aberrant tapetal PCD progression, thereby affecting the development of microspores and ultimately causing male sterility. These relationships between the mechanism of PCD and ROS metabolism provide new insights into the mechanisms responsible for abortive pollen in wheat.

Cytoplasmic male sterility (CMS) plays a crucial role in the utilization of hybrid vigor. Pollen development is often accompanied by oxidative metabolism responses and tapetal programmed cell death (PCD), and deficiency in these processes could lead to male sterility. Aegilops uniaristata cytoplasmic male sterility (Mu-CMS) wheat is a novel male-sterile line in wheat, which possess important potential in hybrid wheat breeding. However, its CMS mechanisms remain poorly understood. In our study, U87B1-706A, with the Aegilops uniaristata cytoplasm, and the maintainer line 706B were used to explore the abortive reason. Compared with 706B, histological analysis and PCD detection of the anther demonstrated that U87B1-706A appeared as delayed tapetal PCD as well as a disorganized organelle phenotype in the early uninucleate stage. Subsequently, a shrunken microspore and disordered exine structure were exhibited in the late uninucleate stage. While the activities of antioxidase increased markedly, the nonenzymatic antioxidant contents declined obviously following overacummulation of reactive oxygen species (ROS) during pollen development in U87B1-706A. Real-time quantitative PCR testified that the transcript levels of the superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) genes, encoding pivotal antioxidant enzymes, were up-regulated in early pollen development. Therefore, we deduce excess ROS as a signal may be related to the increased expression levels of enzyme genes, thereby breaking the antioxidative system balance, resulting in delayed tapetal PCD initiation, which finally led to pollen abortion and male sterility in U87B1-706A. These results provide evidence to further explore the mechanisms of abortive pollen in CMS wheat.

A greenhouse hydroponic experiment was performed using Cd-sensitive (cv. Dong 17) and Cd-tolerant (Weisuobuzhi) barley seedlings to evaluate how different genotypes responded to cadmium (Cd) toxicity in the presence of sodium nitroprusside (SNP), a nitric oxide (NO) donor. Results showed that 5μM Cd increased the accumulation of O2•-, H2O2, and malondialdehyde (MDA) but reduced plant height, chlorophyll content, net photosynthetic rate (P n), and biomass, with a much more severe response in the Cd-sensitive genotype. Antioxidant enzyme activities increased significantly under Cd stress in the roots of the tolerant genotype, whereas in leaves of the sensitive genotype, superoxide dismutase (SOD) and ascorbate peroxide (APX), especially cytosol ascorbate peroxidase (cAPX), decreased after 5-15days Cd exposure. Moreover, Cd induces NO synthesis by stimulating nitrate reductase and nitric oxide synthetase-like enzymes in roots/leaves. A Cd-induced NO transient increase in roots of the Cd-tolerant genotype might partly contribute to its Cd tolerance. Exogenous NO dramatically alleviated Cd toxicity, markedly diminished Cd-induced reactive oxygen species (ROS) and MDA accumulation, ameliorated Cd-induced damage to leaf/root ultrastructure, and increased chlorophyll content and P n. External NO counteracted the pattern of alterations in certain antioxidant enzymes induced by Cd; for example, it significantly elevated the depressed SOD, APX, and catalase (CAT) activities in the Cd-sensitive genotype after 10- and 15-day treatments. Furthermore, NO significantly increased stromal APX and Mn-SOD activities in both genotypes and upregulated Cd-induced decrease in cAPX activity and gene expression of root/leaf cAPX and leaf CAT1 in the Cd-sensitive genotype. These data suggest that under Cd stress, NO, as a potent antioxidant, protects barley seedlings against oxidative damage by directly and indirectly scavenging ROS and helps to maintain stability and integrity of the subcellular structure. A greenhouse hydroponic experiment was performed using Cd-sensitive (cv. Dong 17) and Cd-tolerant (Weisuobuzhi) barley seedlings to evaluate how different genotypes responded to cadmium (Cd) toxicity in the presence of sodium nitroprusside (SNP), a nitric oxide (NO) donor. Results showed that 5 μM Cd increased the accumulation of O2•-, H2O2, and malondialdehyde (MDA) but reduced plant height, chlorophyll content, net photosynthetic rate (P n), and biomass, with a much more severe response in the Cd-sensitive genotype. Antioxidant enzyme activities increased significantly under Cd stress in the roots of the tolerant genotype, whereas in leaves of the sensitive genotype, superoxide dismutase (SOD) and ascorbate peroxide (APX), especially cytosol ascorbate peroxidase (cAPX), decreased after 5-15 days Cd exposure. Moreover, Cd induces NO synthesis by stimulating nitrate reductase and nitric oxide synthetase-like enzymes in roots/leaves. A Cd-induced NO transient increase in roots of the Cd-tolerant genotype might partly contribute to its Cd tolerance. Exogenous NO dramatically alleviated Cd toxicity, markedly diminished Cd-induced reactive oxygen species (ROS) and MDA accumulation, ameliorated Cd-induced damage to leaf/root ultrastructure, and increased chlorophyll content and P n. External NO counteracted the pattern of alterations in certain antioxidant enzymes induced by Cd; for example, it significantly elevated the depressed SOD, APX, and catalase (CAT) activities in the Cd-sensitive genotype after 10- and 15-day treatments. Furthermore, NO significantly increased stromal APX and Mn-SOD activities in both genotypes and upregulated Cd-induced decrease in cAPX activity and gene expression of root/leaf cAPX and leaf CAT1 in the Cd-sensitive genotype. These data suggest that under Cd stress, NO, as a potent antioxidant, protects barley seedlings against oxidative damage by directly and indirectly scavenging ROS and helps to maintain stability and integrity of the subcellular structure.

CMP-Neu5Ac hydroxylase (Cmah) disruption caused several abnormalities and diseases including hearing loss in old age. However, underling molecular mechanisms that give rise to age-related hearing loss (AHL) in Cmah-null mouse are still obscure. In this study, Cmah-null mice showed age-related decline of hearing associated with loss of sensory hair cells, spiral ganglion neurons, and/or stria vascularis degeneration in the cochlea. To identify differential gene expression profiles and pathway associated with AHL, we performed microarray analysis using Illumina MouseRef-8 v2 Expression BeadChip and pathway-focused PCR array in the cochlear tissues of Cmah-null mouse. Pathway and molecular mechanism analysis using differentially expressed genes provided evidences that altered biological pathway due to oxidative damage by low expressed antioxidants and dysregulated reactive oxygen species (ROS) metabolism. Especially, low sirtuin 3 (Sirt3) gene expressions in Cmah-null mice decreased both of downstream regulator (Foxo1 and MnSod) and regulatory transcription factor (Hif1α and Foxo3a) gene expression. Taken together, we suggest that down-regulation of Sirt3 expression leads to oxidative stress and mitochondrial dysfunction by regulation of ROS and that it could alter various signaling pathways in Cmah-null mice with AHL.