Current protein & peptide science最新文献

Background: Sulfonamides are widely used carbonic anhydrase inhibitors (CAIs) in clinical settings, however, their nonspecific inhibition of multiple carbonic anhydrase isoforms can lead to reduced efficacy and side effects. This study aimed to develop sulfanilamide-diazo derivatives incorporating benzoic acid moieties as novel inhibitors of hCA II activity to reduce side effects and enhance selectivity for different CA isozymes.

Methods: We investigated the interaction between these derivatives and the hCA II isozyme via various spectroscopic and docking methods.

Results: The kinetic data demonstrates that compound 1 (C1) and compound 2 (C2) share a similar inhibitory strength against hCA II, effectively inhibiting its esterase activity through a noncompetitive mechanism with Ki values at low micromolar levels. Fluorescence measurements indicated that the synthesized compounds suppressed the inherent fluorescence of hCA II via a static quenching process, with each compound showing a singular binding site within the enzyme. Thermodynamic evidences highlight the significance of van der Waals interactions and hydrogen bonding in the binding process. The results of molecular docking indicated that both C1 and C2 effectively obstruct the entrance to hCA II's active site, with no significant differences in their binding conformations.

Conclusion: While C1 and C2 exhibit CA inhibitory potency lower than that of sulfonamide compounds, this study offers valuable insights that could pave the way for the development of a promising scaffold for designing new carbonic anhydrase inhibitors.

Introduction: Caleosins are recognized as the key proteins found in Lipid Droplets (LDs) and are crucial for the creation, maintenance, and breakdown of LDs. Nevertheless, our understanding of caleosins remains limited within Theaceae, a prominent botanical family encompassing economically significant tea and oil tea species.

Methods: In this research, we conducted a comprehensive genome-wide exploration and examination of the caleosin family in Theaceae species with sequenced genomes. The gene number of caleosin was similar among Theaceae species. Segmental duplication was the main form of caleosin expansion in Shuchazao (SCZ), Huangdan (HD), Biyun (BY), Tieguanyin (TGY), Longjing (LJ), C. lanceoleosa (Cla) and C. chekiangoleosa (CCH). Synteny analysis revealed one-to-more and more-to-one collinear relationships of caleosin genes among Theaceae species.

Results: Caleosins in Theaceae are categorized into either the H-family or the L-family, each exhibiting distinct motif structures and physicochemical properties. Expression analysis revealed an apparent flower-predominant expression pattern of caleosin genes in Theaceae species. In addition, most paralogous pairs displayed expression divergence.

Conclusion: This research enhanced our understanding of the lineage-specific evolution of caleosin genes in Theaceae, and is valuable for future functional analysis of this gene family in tea and oil-tea species.

The latex of the xerophytic plant Calotropis procera, popularly known as giant milkweed, contains a complex mixture of secondary metabolites and proteins and has attracted the attention of many researchers. Several bioactive laticifer enzymes from C. procera have been studied for their potential applications in the medical, agricultural and food industries. The present work aimed to review the current scientific knowledge on cysteine peptidases from the latex of this plant, highlighting their biochemical properties and possible uses as biotechnological tools. Bibliographic databases (PubMed, Scopus and Web of Science) were searched for scientific works published in the last six decades reporting the purification, biochemical characterization, molecular cloning and potential applications of laticifer cysteine peptidases from C. procera. Since the first works published in the late 1960s on the occurrence of thiol peptidases in this species, five cysteine peptidases (procerain, procerain B, CpCP-1, CpCP-2 and CpCP-3) have been purified and biochemically characterized. The characterized enzymes are members of the subfamily C1A of sulfhydryl proteases, showing the characteristic biochemical and structural features of papain and related proteins. Several biological activities of the purified enzymes have been demonstrated, including the inhibition of phytopathogenic fungi and milk coagulation properties, which may be of practical use. Moreover, pharmacologically active propeptides released from the posttranslational processing of C. procera cysteine peptidase zymogens have been shown to be promising therapeutic agents against cancer cells. Further research is needed to provide a better comprehensive understanding of the mode of action and biosafety of these molecules.

Diet has emerged as a pivotal factor in the current time for diet-induced obesity (DIO). A diet overloaded with fats and carbohydrates and unhealthy dietary habits contribute to the development of DIO through several mechanisms. The prominent ones include the transition of normal gut microbiota to obese microbiota, under-expression of AMPK, and abnormally high levels of adipogenesis. DIO is the root of many diseases. The present review deals with various aspects of DIO and its target proteins that can be specifically used for its treatment. Also, the currently available treatment strategies have been explored. It was found that the expression of five proteins, namely, PPARγ, FTO, CDK4, 14-3-3 ζ protein, and Galectin-1, is upregulated in DIO. They can be used as potential targets for drug-designing studies. Thus, with these targets, the treatment strategy for DIO using natural bioactive compounds can be a safer alternative to medications and bariatric surgeries.

Background: Crotalus Neutralizing Factor (CNF) is a γ-type Phospholipase A₂ (PLA₂) inhibitor present in the blood of Crotalus durissus terrificus snake. Particularly, CNF inhibits the toxic action of Crotoxin (CTX), which is a major neurotoxin found in C. d. terrificus venom. CTX induces also myotoxic action and demonstrates high selectivity for skeletal muscle fibers. Consequently, CTX can diffuse beyond the site of infection, which can potentially evoke rhabdomyolysis. The present study has evaluated the effects of CTX on myoblasts and myotubes of muscle cells C2C12 in vitro and the effect of CNF on CTX-induced damage.

Methods: Cytotoxicity assays were performed by measuring the mitochondrial enzyme dehydrogenase levels. Furthermore, creatine kinase and lactate dehydrogenase levels were used as indicators of muscle damage.

Results: Crotoxin has been found to have cytotoxic effects on C2C12 myoblast cells, while CNF has not shown toxic effects on these cells. Furthermore, the findings have shown CNF (50 μg/mL) to abolish CTX toxicity in myoblasts. The myotubes, differentiated cells, showed no change in mitochondrial respiration when exposed to CNF or CTX, showing greater resistance to the toxic actions of crotoxin.

Conclusion: The data have confirmed the potential of CNF as an anti-myotoxic agent to prevent CTX-damaged myoblasts and increase resistance to the toxic effects of crotoxin on differentiated cells.

Migraine is a neurological disease that, while not inherently causing "chronic headaches," can evolve into a chronic condition over time including major symptoms such as nausea, and light, sound, and allodynia, particularly in cases of frequent episodic migraine or due to factors such as medication overuse or inadequate management. This condition's complex pathophysiology makes treatment difficult. Genetics, trigeminovascular system activation, and cortical spreading depression are involved. Epidemiological research estimates that one in seven persons worldwide are affected, mostly women. Migraine prevalence has increased dramatically in recent decades; however, it varies by demographic and location. This review covers pharmaceutical and non-pharmacological migraine therapy methods and their future. Second-generation triptans have reduced side effects and administration issues, however, Zolmitriptan and Sumatriptan still treat migraines. Monoclonal antibodies that target calcitonin gene-related peptides may prevent migraines; however, their accessibility and safety are problems. Antiepileptics, beta-blockers, and neuromodulation devices are also available. Wearable technology offers customized monitoring and intervention. Precision medicine and gene-based medicines provide hope for tailored migraine treatments, but access, privacy, and informed consent raises ethical concerns. Stakeholder engagement must promote patient autonomy and well-being, responsible implementation, and equal access to novel therapies. A holistic and multidisciplinary approach is needed to manage migraines, taking into consideration present and future therapy developments and new challenges. Research, collaboration, and ethics can improve migraine outcomes and quality of life.

Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide, and despite advances in treatment, there remains a critical need for novel therapeutic approaches. Recently, anti-microbial peptides (AMPs) have gained attention for their potential use in cancer therapy due to their selective cytotoxicity towards cancer cells.

Objective: This study aims to evaluate the anti-cancer potential of two computationally engineered anti-microbial peptides (EAMPs) in SW620, SW480, and HCT116 colon cancer cells and the normal colon epithelial cell line CCD 841, focusing on their effects on cell proliferation, apoptosis, and DNA damage.

Methods: Cell proliferation and survival were measured using the CellTiter-Glo Luminescence and clonogenic assays. DNA damage was assessed through the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Flow cytometry was used to examine cell apoptosis, cell cycle distribution, and mitochondrial membrane potential in SW620 cells.

Results: EAMPs inhibited CRC cell proliferation in a dose-dependent manner, with minimal toxicity observed in normal colon epithelial cells. In SW620 cells, EAMPs induced DNA damage, resulting in cell cycle arrest at the S/G2 phase, apoptosis, and a reduction in mitochondrial membrane potential. The proliferation results were confirmed in SW480 and HCT116 CRC cell lines.

Conclusion: Our findings revealed that EAMPs exhibited significant anti-cancer activity against CRC cells in vitro while sparing normal epithelial cells. These results suggest that EAMPs may offer a potential therapeutic approach for colorectal cancer and warrant further investigation.

Background: Glioblastoma is a common primary malignant intracranial tumor in adults associated with high disability and mortality. Despite the use of traditional surgical methods, postoperative radiotherapy, and targeted therapies, the median survival for glioma patients remains disappointingly brief. As a result, there is an urgent need to explore new targets and develop novel targeted drugs to potentially improve patient survival. Notably, CLIC1 expression is upregulated in tumors and correlated to tumor aggressiveness, metastasis, and poor prognosis. Nonetheless, its potential role in gliomas remains largely unclear.

Objective: This study aimed to investigate the bioinformatics characteristics and clinicopathological features of CLIC1, including WHO classification and OS.

Methods: Immunohistochemistry and western blot analysis were carried out to detect the expression of CLIC1 in glioma tissues. Moreover, CCK8, plate clone formation assay, and EdU proliferation assay were carried out for cell proliferation ability. Transwell and scratch assay were performed for cell invasion and migration. Western blotting was also conducted to verify the relationship between CLIC1 and EMT and ERK1/2 signaling pathway. The effect of the knockdown of CLIC1 on tumor growth capacity was assessed in an intracranial xenograft model.

Results: CLIC1 was found to be associated with poor prognosis in glioma patients, and in vivo experiments demonstrated that CLIC1 promoted GBM cell proliferation, invasion, and migration. In addition, CLIC1 positively regulated ERK1/2 signaling to promote the EMT process in GBM cells. In vitro experiments showed that CLIC1 could affect intracranial tumor progression in mice.

Conclusion: In summary, these findings expand our knowledge of CLIC1, confirming its oncogenic role and laying the groundwork for future development of pharmacological agents targeting this gene.

Objective: The objective of this study was to design and synthesize the ug46 peptide, incorporate its fibrils into composite materials, and evaluate its structural and antimicrobial properties. Another objective was to utilize spectroscopy and molecular simulation, enhanced by Machine Vision methods, to monitor the aggregation process of the ug46 peptide and assess its potential as a scaffold for an antimicrobial peptide.

Methods: The structural analysis of the ug46 peptide reveals its dynamic conformational changes. Initially, the peptide exhibits a disordered structure with minimal α-helix content, but as incubation progresses, it aggregates into fibrils rich in β-sheets. This transformation was validated by CD and ThT assays, which showed decreased molar ellipticity and an increase in ThT fluorescence.

Results: Laser-induced fluorescence and molecular dynamics simulations further revealed the transition from a compact native state to extended "worm-like" filament structures, influenced by peptide concentration and temperature. TEM and AFM confirmed these changes, showing the evolution of protofibrils into mature fibrils with characteristic twists. When incorporated into chitosan- bioglass composites, these fibrils significantly enhanced antimicrobial activity against pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa.

Conclusion: Overall, ug46 peptide fibrils show promise as a multifunctional scaffold with structural and antimicrobial benefits in composite biomaterials.

Introduction: The PICK1 PDZ domain has been identified as a potential drug target for neurological disorders. After many years of effort, a few inhibitors, such as TAT-C5 and mPD5, have been discovered experimentally to bind to the PDZ domain with a relatively high binding affinity. With the rapid growth of computational research, there is an urgent need for more efficient computational methods to design viable ligands that target proteins.

Methods: Recently, a newly developed program called AfDesign (part of ColabDesign) at https:// github.com/sokrypton/ColabDesign), an open-source software built on AlphaFold, has been suggested to be capable of generating ligands that bind to targeted proteins, thus potentially facilitating the ligand development process. To evaluate the performance of this program, we explored its ability to target the PICK1 PDZ domain, given our current understanding of it. We found that the designated length of the ligand and the number of recycles play vital roles in generating ligands with optimal properties.

Results: Utilizing AfDesign with a sequence length of 5 for the ligand produced the highest comparable ligands to that of prior identified ligands. Moreover, these designed ligands displayed significantly lower binding energy compared to manually created sequences.

Conclusion: This work demonstrated that AfDesign can potentially be a powerful tool to facilitate the exploration of the ligand space for the purpose of targeting PDZ domains.