Protein and Peptide Letters最新文献

Amyloid refers to a specific quaternary structure characterized by fibrillar arrangements of proteins or peptides forming cross β-sheet architectures. Initially associated with diseases like Alzheimer's, amyloid was seen predominantly as pathological. However, recent research has revealed that amyloid also plays functional roles across various biological systems, from bacteria to mammals. The cross β-sheet structure of amyloid enables the transformation of soluble proteins into insoluble fibrils, providing high stability and a robust prion-like copying mechanism. However, recent research has revealed that amyloid also plays functional roles in various biological systems, such as biofilm formation in bacteria, aiding melanin biosynthesis in humans, and supporting the formation of fungal hyphae. Understanding the dual nature of amyloid-a pathological and functional entity-offers insights into disease mechanisms and therapeutic strategies. Recognizing the distinction between pathological and functional amyloids is crucial for advancing diagnostics and treatments. This review highlights the importance of functional amyloids (FAs), particularly in disease detection, underscoring their significant biological roles and potential applications.

Background: Since the Coronavirus Disease (COVID-19) became a pandemic in late 2019, vaccination remains the primary approach to combating the virus. Nevertheless, the emergence of new variants poses challenges to vaccine efficacy. This study aimed to identify targets within the SARS-CoV-2 spike (S) protein to detect T-cell responses to the five variants of concern from SARS-CoV-2: Alpha, Beta, Delta, Gamma, and Omicron.

Methods: Herein, immunoinformatics tools were employed to develop a peptide-based vaccine targeting the spike protein of SARS-CoV-2 and its major variants, including Alpha, Beta, Delta, Gamma, and Omicron. The peptides were screened for antigenicity, toxicity, allergenicity, and physicochemical properties to ensure their safety and efficacy.

Results: The potential T-cell epitopes with high immunogenicity and IFN-γ induction, are essential for a robust immune response by a comprehensive computational analysis. Population coverage analysis revealed significant coverage across diverse geographical regions, with significant efficacy in areas heavily impacted by the pandemic. Molecular docking simulations revealed strong interactions between the selected peptides and major histocompatibility complex class I (MHC-I) molecules, indicating their potential as vaccine candidates.

Conclusion: Our study provides a systematic approach to the rational design of a peptide-based vaccine against COVID-19, providing insights for further experimental validation and development of effective vaccines.

Members of the 14-3-3 protein family are involved in various cellular processes, including migration, angiogenesis, cell cycle, apoptosis, and signal transduction. Nevertheless, the 14-3-3 family possibly plays a fundamental role in the development of diseases and cancer by regulating various biological pathways. MicroRNAs (miRNAs) are mainly transcribed by RNA polymerase II (pol II), with only a few exceptions involving RNA polymerase III (pol III). They can control cell mechanisms through different pathways. miRNAs inhibit or destroy mRNAs by binding to them. They control intracellular mechanisms by binding to molecules such as the 14-3-3ζ protein. miRNAs play a role in regulating this protein, and by inducing or suppressing it, they contribute to either the development or the prevention of the diseases. Therefore, considering the importance of the 14-3-3ζ protein in different pathways within the body, we decided to investigate the relationship between miRNAs and 14-3-3ζ and clarify their interactions, in this review.

Introduction: The etiology of acute Achilles tendon rupture (ATR) remains unclear. This study conducted a comprehensive case-control study of the proteome profile to gain insights into the potential pathogenesis of acute ATR and identify novel biomarkers.

Methods: Serum (iTRAQ) and urine (label-free proteomics) from 15 acute ATR patients and 15 healthy controls were analyzed. Significant differential expression was defined as ≥1.2-fold (serum) or ≥2-fold (urine) change with p < 0.05. Bioinformatics analyses (GO, KEGG, PPI) were performed.

Results: 44 serum and 198 urine proteins were differentially expressed. Enriched pathways included immune response, metabolism, immune response, and redox regulation. protein-protein interaction analysis of the differentially expressed proteins (P < 0.05) highlighted abnormalities in major protein-protein interaction hubs, specifically pyruvate kinase (PKM), peroxiredoxin-1 (PRDX1), phosphoglycerate kinase 1 (PKG1), profilin-1, and apolipoprotein A-IV, observed in the serum and urine samples of acute ATR patients.

Discussion: Metabolic dysregulation may affect tendon structure/strength; redox imbalance could promote degeneration. Immune-related proteins may reflect injury responses. Glycolytic enzymes (PKM, PGK1) suggest disrupted energy metabolism.

Conclusion: Proteomic abnormalities in metabolism, immune, and redox pathways, along with key proteins (PKM, PRDX1, PGK1), may contribute to ATR pathogenesis, offering potential biomarkers warranting further validation.

Proteins and peptides play a crucial role in biological functions and contemporary therapeutic approaches; however, their clinical effectiveness is frequently hindered by swift renal clearance and enzymatic degradation. Peptides possess structured amino acid sequences that facilitate targeted drug delivery and enhance patient adherence. In contrast, proteins demonstrate intricate stability behaviors affected by pH and environmental conditions, requiring careful formulation strategies. Addressing these challenges necessitates a comprehensive understanding of stability and regulatory requirements. Regulatory agencies, including the FDA, EMA, and PMDA, require comprehensive stability testing per guidelines such as ICH Q5C and ICH Q1A(R2). This ensures meticulous management of factors such as temperature control, formulation optimization, and aggregation mitigation. Stability enhancement requires the application of innovative techniques, including protein engineering, lyoprotection, and nanoparticle encapsulation, in conjunction with ongoing quality monitoring. Integrating scientific expertise with regulatory standards enables researchers and pharmaceutical manufacturers to develop safe, effective, and compliant protein and peptide therapeutics for various patient populations.

Background: Cholelithiasis is the most prevalent inflammatory condition of the gallbladder. The regulation of biological processes, including energy homeostasis, and control of body weight are key mechanisms that the leptin and melanocortin pathways play a role in Cholelithiasis is the most prevalent inflammatory condition of the gallbladder. There are various risk factors for the development of gallstone disease, especially weight gain, and obesity is just one of them. This risk factor can be minimized by maintaining appetite and energy balance. Here, leptin and melanocortin pathways are the key mechanisms in maintaining appetite and energy homeostasis.

Objectives: The aim of this study was to investigate the relationship between the levels of LEP, LEPR, TrkB, BDNF, POMC, and MC4R proteins in patients with Cholelithiasis. This study aims to determine the relationship between LEP, LEPR, TrkB, BDNF, POMC, and MC4R protein levels, which play a role in maintaining appetite and energy homeostasis, and cholelithiasis.

Methods: This study examined 44 patients diagnosed with Cholelithiasis and 44 healthy control subjects who had not previously been diagnosed with any form of Cholelithiasis. The levels of leptin (LEP), Leptin Binds To Leptin Receptors (LEPR), Tropomyosin Receptor Kinase B (TrkB), Brain-Derived Neurotrophic Factor (BDNF), Pro-OpioMelanoCortin (POMC), and Melanocortin- 4 Receptors (MC4R) molecules were analyzed using the Enzyme-Linked Immunosorbent Assay (ELISA) method. The results were analyzed using the SPSS Software (Version 22.0) program and GraphPad Prism 8.0.1 software.

Results: The study found a statistically significant decrease (p < 0.05) in MC4R, TrkB, BDNF, and POMC protein levels in Cholelithiasis patients compared to the control group. There was no statistically significant difference in LEP and LEPR concentration values between the two groups (p = 0.247, p = 0.674).

Conclusion: The proteins MC4R, TrkB, BDNF, and POMC, which are involved in the leptin and melanocortin pathways may play a significant role in Cholelithiasis disease. However, more detailed research on the relevant proteins is needed. Nevertheless, this research will guide new studies.

Purpose: This study compares the activity of BRCA-1 mimetics on WTp53 (wild-type p53 protein) and MTp53 (mutated-type p53 protein) proteins, examining the impact of TP53 mutations in breast cancer. p53 activators can be a new insight and synthesis of effective compounds for the treatment of cancer. The project contributes to the growing body of research on p53 activators and provides new insights into the design and synthesis of effective compounds for the treatment of cancer.

Methods: Molecular docking predicted binding affinity values for WTp53 and MTp53. The MMGBSA of top compounds was run to get binding-free energies. The MD simulations were calculated, and six metal coordinates were synthesized. In vitro MTT-assays were performed with WTp53 (MCF-7) and R273H-MTp53 (MDA-MB-468) cell lines, comparing results with known p53 activator PRIMA-1 (p53-reactivation and induction of massive apoptosis-1).

Results: The p53 activators established a three-featured (2RA, 1HBA) pharmacophore. The designed compounds had better Glide gscore compared to p53 activators PRIMA-1, PRIMA-1- MET (methylated PRIMA-1), and Tamoxifen with p53 protein (WTp53, R175H and R273H MTp53). The MM-GBSA results of top compounds showed binding free energies with R175HMTp53 (-22.24 to -75.45 kcal/mol), R273H-MTp53 (-22.8 to -36.36 kcal/mol), and WTp53 (-26.45 to -50.3 kcal/mol) compared to the p53 activator. The MD simulation of TSCO5/3KMD-MT in 100 ns indicated a stable complex when compared to TSCO5/3KMD-WT. The six metal coordinates (TSCO5-Zn, TSCO6-Zn, TSCO6-Sn, TSCO13-Zn, TSCO13-Sn, TSCO9-Sn) were synthesised. Based on in vitro results, IC₅₀ for TSCO5-Zn (WTp53: 0.089 μM, MTp53: 0.074 μM) and TSCO5- Sn (WTp53: 0.092 μM, MTp53: 0.073 μM) have shown significant cytotoxicity.

Conclusion: As compared to PRIMA-1, the designed compound TSCO5 metal coordinates have shown good in silico and in vitro activity on mutated p53 cell lines and are more potent than the p53 activator PRIMA-1.

Endogenous or exogenous DNA damage needs to be repaired, therefore, cells in all the three domains have repair pathways to maintain the integrity of their genetic material. Uracil DNA glycosylases (UDGs), also known as UNGs (uracil-DNA N-glycosylases), are part of the base-excision repair (BER) pathway. These enzymes specifically remove uracil from DNA molecules by cleaving the glycosidic bond between the uracil base and the deoxyribose sugar. UDGs can be broadly classified into six families, and each of them share conserved motifs that are critical for substrate recognition and catalysis. Recently, an unconventional UDG known as UDGX has been identified from the species Mycobacterium smegmatis, which is different from other UDG members in forming an irreversible and extremely stable complex with DNA that is resistant to even harsh denaturants such as SDS, NaOH, and heat. This suicide inactivation mechanism prevents uracil excision and might play a protective role in maintaining genome integrity, as bacterial survival under hypoxic conditions is reduced due to the overexpression of MsmUDGX. Additionally, due to the importance of UDGs, the number of structures has been resolved. Moreover, high-resolution 3D structures of apo MsmUDGX, as well as uracil and DNAbound forms, are available in PDB. This review aims to provide insights into the specific structural- functional aspects of each UDG family member for theragnostic applications.

Background: Increasing evidence proves that long non-coding RNAs (lncRNAs) play a key role in the occurrence and development of colorectal cancer. However, the function and molecular mechanism of LINC01836 in CRC are still unknown.

Methods: The differentially expressed lncRNAs in colorectal cancer were obtained from the RNA sequencing data. The effects of LINC01836 on colorectal cancer cells were tested in in vitro experiments. The mechanism of LINC01836 action was investigated through western blot, RNA immunoprecipitation assay and luciferase reporter assay. Moreover, the xenograft mouse model was conducted to examine the effects of LINC01836 in vivo.

Results: In this study, we showed that LINC01836 was significantly elevated in colorectal cancer tissues and cells. Elevated LINC01836 expression significantly correlated with larger tumor size, positive lymph node metastasis, distant metastasis, advanced tumor-node-metastasis (TNM) stage, and poor prognosis. Furthermore, decreased expression of LINC01836 repressed proliferation, migration, and invasion in vitro and vivo, and high LINC01836 expression displayed the opposite effect. Further analysis revealed that LINC01836 could regulate the expression of SLC17A9 by competing with miR---1226-3p. Furthermore, down-regulation of LINC01836 or increased expression of miR-1226-3p markedly reversed the effects of SLC17A9 overexpression on colorectal cancer cells.

Conclusion: This study showed that LINC01836 regulated the expression of SLC17A9 through sponge miR-1226-3p by acting as a competitive endogenous RNA (ceRNA), promoted the progression of colorectal cancer, and suggested a new prognostic biomarker and potential cancer treatment target for colorectal cancer.

Introduction: Parvovirus B19 (B19V) is a human pathogen, and the minor capsid protein of B19V possesses a unique N terminus called VP1u that plays a crucial role in the life cycle of the virus.

Objectives: The objective of this study was to develop a method for domain segmentation of B19 VP1u using intein technology, particularly its receptor binding domain (RBD) and phospholipase A2 (PLA₂) domain.

Methods: RBD and PLA₂ domains of VP1u were each fused to the DnaE split inteins derived from the Nostoc punctiforme. Each of these precursor proteins was expressed in E. coli. Combining the purified precursors in equal molar ratios resulted in the formation of full-length VP1u. Furthermore, Circular Dichroism (CD) spectroscopy and PLA₂ assays were used to probe the structure and activity of the newly formed protein.

Results: The CD spectrum of the full length VP1u confirmed the secondary structure of protein, while the PLA₂ assay indicated minimal disruption in enzymatic activity.

Conclusion: This method would allow for the selective incorporation of NMR-active isotopes into either of the VP1u domains, which can reduce signal overlap in NMR structural determination studies.