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Pruritus is the leading symptom of dermatophytosis. Microsporium canis is one of the predominant dermatophytes causing dermatophytosis. However, the pruritogenic agents and the related molecular mechanisms of the dermatophyte M canis remain poorly understood. In this study, the secretion of the dermatophyte M canis was found to dose-dependently evoke itch in mice. The fungal peptide micasin secreted from M canis was then identified to elicit mouse significant scratching and itching responses. The peptide micasin was further revealed to directly activate mouse dorsal root ganglia neurons to mediate the nonhistaminergic itch. Knockout and antagonistic experiments demonstrated that MRGPRX1/C11/A1 rather than MRGPRX2/b2 activated by micasin contributed to pruritus. The chimeras and single-amino acid variants of MRGPRX1 showed that 3 domains (extracellular loop 3, transmembrane helical domain 3, and transmembrane helical domain 6) and 4 hydrophobic residues (Y99, F237, L240, and W241) of MRGPRX1 played the key role in micasin-triggered MRGPRX1 activation. Our study sheds light on the dermatophytosis-associated pruritus and may provide potential therapeutic targets and strategies against pruritus caused by dermatophytes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fenpropathrin (Fen), a volatile pyrethroid insecticide, is used widely for agricultural applications and has been reported to increase the risk of Parkinson's disease (PD). However, the molecular basis, underlying mechanisms, and pathophysiology of Fen-exposed Parkinsonism remain unknown. Recent studies have revealed epigenetic mechanisms underlying PD-related pathway regulation, including DNA methylation. Epigenetic mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases. After whole-genome bisulfite sequencing (WGBS) of midbrain tissues from a Fen-exposed PD-like mouse model, we performed an association analysis of DNA methylation and gene expression. Then we successfully screened for the DNA methylation differential gene Ambra1, which is closely related to PD. The hypermethylation-low expression Ambra1 gene aggravated DA neuron damage in vitro and in vivo through the Ambra1/Parkin/LC3B-mediated mitophagy pathway. We administered 5-aza-2'-deoxycytidine (5-Aza-dC) to upregulate Ambra1 expression, thereby reducing Ambra1-mediated mitophagy and protecting DA neurons against Fen-induced damage. In conclusion, these findings elucidate the potential function of Ambra1 under the regulation of DNA methylation, suggesting that the inhibition of DNA methylation may alleviate Fen-exposed neuron damage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Animal venom is an important evolutionary innovation in nature. As one of the most representative animal venoms, scorpion venom contains an extremely diverse set of bioactive peptides. Scorpion venom peptides not only are 'poisons' that immobilize, paralyze, kill, or dissolve preys but also become important candidates for drug development and design. Here, the review focuses on the molecular diversity of scorpion venom peptides, their typical structural characteristics, and their multiple therapeutic or pharmaceutical applications in channelopathies, viral infections and cancers. Especially, the group of scorpion toxin TRPTx targeting transient receptor potential (TRP) channels is systematically summarized and worthy of attention because TRP channels play a crucial role in the regulation of homeostasis and the occurrence of diseases in human. We also further establish the potential relationship between the molecular characteristics and functional applications of scorpion venom peptides to provide a research basis for modern drug development and clinical utilization of scorpion venom resources., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tributyltin chloride (TBTCL), a commonly used antiseptic substance, is commonly found in the environment. Human exposure to TBTCL through the consumption of contaminated seafood, fish, or drinking water has aroused concern. It is well-characterized that TBTCL has multiple detrimental effects on the male reproductive system. However, the potential cellular mechanisms are not fully elucidated. Here, we characterized molecular mechanisms of TBTCL-induced cell injury in Leydig cells, a critical supporter for spermatogenesis. We showed that TBTCL induces apoptosis and cell cycle arrest in TM3 mouse Leydig cells. RNA sequencing analyses revealed that endoplasmic reticulum (ER) stress and autophagy were potentially involved in TBTCL-induced cytotoxicity. We further showed that TBTCL causes ER stress and inhibited autophagy flux. Notably, the inhibition of ER stress attenuates not only TBTCL-induces autophagy flux inhibition but also apoptosis and cell cycle arrest. Meanwhile, the activation of autophagy alleviates, and inhibition of autophagy exaggerates TBTCL-induced apoptosis and cell cycle arrest flux. These results suggest that TBTCL-induced ER stress and autophagy flux inhibition contributed to apoptosis and cell cycle arrest in Leydig cells, providing novel understanding into the mechanisms of TBTCL-induced testis toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The application of immune checkpoint inhibitors and FGFR protein tyrosine kinase inhibitors have made a tremendous breakthrough in bladder cancer therapy. However, inadequate drug responses and drug resistance interfere with successful treatment outcomes. For a new drug to enter the market, there is a long development cycle with high costs and low success rates. Repurposing previously Food and Drug Administration (FDA)-approved medications and using novel drug discovery strategies may be an optimal approach. Homoharringtonine (HHT) has been used for hematologic malignancies for over 40 years in China and was approved by the FDA approximately 10 years ago. Many studies have demonstrated that HHT effectively inhibits the development of several types of solid tumors, although the underlying mechanisms of action are unclear. In this study, we investigated the mechanisms underlying HHT activity against bladder cancer growth. We first compared HTT with the drugs currently used clinically for bladder cancer treatment. HHT showed stronger inhibitory activity than cisplatin, carboplatin, and doxorubicin. Our in vitro and in vivo data demonstrated that HHT inhibited proliferation, colony formation, migration, and cell adhesion of bladder cancer cells and induced apoptosis and cell cycle arrest in the nanomolar concentration range. Furthermore, we revealed that HHT treatment could downregulate the MAPK/Erk and PI3k/Akt signaling pathways by inactivating the integrin α5/β1-FAK/Src axis. HHT-induced activity reduced cell-ECM interactions and cell migration, thus suppressing tumor metastasis progression. Altogether, HHT shows enormous potential as an anticancer agent and may be applied as a combination treatment strategy for bladder cancer., Competing Interests: Conflict of interest The authors declare that we have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ligand peptides that have high affinity for ion channels are critical for regulating ion flux across the plasma membrane. These peptides are now being considered as potential drug candidates for many diseases, such as cardiovascular disease and cancers. In this work, we developed Multi-Branch-CNN, a CNN method with multiple input branches for identifying three types of ion channel peptide binders (sodium, potassium, and calcium) from intra- and inter-feature types. As for its real-world applications, prediction models that are able to recognize novel sequences having high or low similarities to training sequences are required. To this end, we tested our models on two test sets: a general test set including sequences spanning different similarity levels to those of the training set, and a novel-test set consisting of only sequences that bear little resemblance to sequences from the training set. Our experiments showed that the Multi-Branch-CNN method performs better than thirteen traditional ML algorithms (TML13), yielding an improvement in accuracy of 3.2%, 1.2%, and 2.3% on the test sets as well as 8.8%, 14.3%, and 14.6% on the novel-test sets for sodium, potassium, and calcium ion channels, respectively. We confirmed the effectiveness of Multi-Branch-CNN by comparing it to the standard CNN method with one input branch (Single-Branch-CNN) and an ensemble method (TML13-Stack). The data sets, script files to reproduce the experiments, and the final predictive models are freely available at https://github.com/jieluyan/Multi-Branch-CNN., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cell division is a tightly-regulated process that involves the contribution of a large number of proteins. Before they are able to undergo mitosis, cells must first synthesize new DNA, effectively and accurately duplicating their genome. This occurs during what is called the S-phase and requires a fine control in order to avoid replication errors. The synthesis of new DNA takes place in the origin, specific locations in the genome where the double strands of DNA are unwound and separated, allowing for the binding of proteins and complexes that will build new strands of the genomic material, using the existing ones as molds, in what is referred to as semi-conservative process. While the overall flow of the DNA synthesis process has been elucidated, its regulation and the exact role of its contributors are not yet entirely understood. It is believed that the Minichromosome Maintenance (MCM) proteins occupy a central role in DNA synthesis. Given their contribution to a central aspect in the conservation of life, further studies have been launched to understand how the MCM proteins may affect or be affected by pathologies involving cell division, such as neoplasia. In this review, we aim to give an overview on the members of the MCM family, what their functions are in a healthy environment and how they are altered in cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Turmeric is commonly used as a medicinal herb and dietary supplement. Its active ingredient, curcumin, has been shown to possess antitumor effects in colorectal cancer patients. However, poor absorption of curcumin in intestine impedes its wide clinical application. Our previous findings showed that the presence of turmerones increased the accumulation of curcumin inside colonic cells. Hence, we hypothesized that curcumin with turmerones or present in turmeric ethanolic extract would augment its anti-tumor activities in tumor-bearing mice. The pharmacokinetics of curcumin in different preparations (containing same amount of curcumin) were studied in mice. The anti-tumor efficacies of curcumin or turmeric extract (with absorbable curcumin) in combination with bevacizumab were further investigated in HT29 colon tumor-bearing mice. Pharmacokinetic results showed that the plasma curcumin level of turmeric extract-fed mice was the highest, suggesting turmeric extract had the best bioavailability of curcumin. Besides, combined turmeric extract plus bevacizumab treatment significantly inhibited the tumor growth. Such inhibitory effects were stronger than those of curcumin plus bevacizumab or bevacizumab alone and were comparable with those of 5-fluorouracil+leucovorin+oxaliplatin (FOLFOX) plus bevacizumab. Notably, there was no observable side effect induced by turmeric extract treatment while significant side effects were found in FOLFOX-treated mice. In conclusion, combination of turmeric extract with bevacizumab possessed potent anti-tumor effects without observable side effects, strongly suggesting the adjuvant use of turmeric extract in colorectal cancer therapy. Our current findings warrant the confirmation regarding the benefits arising from the combined use of bevacizumab and turmeric in colorectal cancer patients in the near future., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The main goal of anti-cancer therapy is to specifically inhibit the malignant activity of cancer cells, while leaving healthy cells unaffected. As such, for every proposed therapy, it is important to keep in mind the therapeutic index - the ratio of the toxic dose over the therapeutic dose. The use of immunotherapy has allowed a means to both specifically block protein-protein interaction and deliver cytotoxic events to a tumor-specific antigen., Review Scope: It is the objective of this review to give an overview on current immunotherapy treatment for cancers using monoclonal antibodies. We demonstrate three exciting targets for immunotherapy, TNF-α Converting Enzyme (TACE), Cathepsin S and Urokinase Plasmogen Activator and go over the advances made with one of the most used monoclonal antibodies in cancer therapy, Rituximab; as well as Herceptin, which is used for breast cancer therapy. Furthermore, we touch on other venues of immunotherapy, such as adaptive cell transfer, the use of nucleic acids and the use of dendritic cells. Finally, we summarize some ongoing studies that spell tentative advancements for anti-cancer immunotherapy., General Significance: Immunotherapy is at the forefront of anti-cancer therapies, allying both a high degree of specificity to general high effectiveness and fewer side-effects.