Current protein & peptide science最新文献

In recent years, novel therapeutic approaches have revolutionized the landscape of medicine, offering promising avenues for the cure of various diseases. The novel approaches explore advancements in gene therapy in pharmaceuticals, immunotherapy, RNA-based therapeutics, cell-based therapies, and targeted tumor therapies. Gene therapy has emerged as a groundbreaking approach, leveraging genetic material to cure or prevent diseases by targeting defective genes. In pharmaceuticals, gene therapy holds immense potential for addressing genetic disorders, offering a personalized approach to medicine. Immunotherapy, on the other hand, harnesses the body's immune system to combat diseases, including tumors, by enhancing immune responses or directly targeting malignant cells. RNA-based therapeutics have gained prominence due to their ability to modulate gene expression, offering targeted and precise interventions for a wide range of diseases. Cell-based therapies involve the transplantation or manipulation of cells to restore or enhance their function, offering innovative solutions for diseases such as neurodegenerative disorders and cardiovascular diseases. Furthermore, targeted tumor therapies have revolutionized tumor cure by specifically targeting molecular alterations driving tumor growth and minimizing damage to healthy cells. Overall, these novel therapeutic approaches represent a paradigm shift in medicine, offering tailored and precise interventions with the potential to significantly improve patient outcomes and quality of life.

Introduction: Secreted Frizzled-Related Protein 2 (SFRP2) is considered to be the most potent modulator of the Wnt signaling. This pathway is involved in the pathogenesis of Polycystic Ovary Syndrome (PCOS). This research aimed to compare the levels of SFRP2 in PCOS [infertile and Recurrent Pregnancy Loss (RPL) patients] with the control group and determine the correlation of SFRP2 with inflammation and insulin resistance.

Methods: This case-control study was conducted on 108 POCS patients (53 infertile patients and 55 women with RPL) and 54 healthy controls. The levels of biochemical factors along with SFRP2, adiponectin, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), free testosterone, and insulin, high-sensitivity C-Reactive Protein (hs-CRP) were measured following the manufacturer's instructions.

Results: Both infertile and RPL groups presented notably higher levels of SFRP2 (49.32 ± 17.72 ng/ml and 55.89 ± 17.36 ng/ml, respectively) compared to the control group (30.21 ± 10.12 ng/ml, P<0.001 for both groups). In PCOS patients, a positive correlation was observed between SFRP2 and body mass index (BMI) (r = 0.42, P < 0.001), insulin (r = 0.19, P = 0.04), fasting blood glucose (FBG) (r = 0.24, P = 0.01), Homeostatic Model Assessment for Insulin Resistance (HOMA- IR) (r = 0.21, P = 0.03), triglyceride (r = 0.25, P = 0.009), and hs-CRP (r = 0.21, P = 0.02). Furthermore, SFRP2 increased the risk of RPL (OR (95% CI) = 1.15 (1.10 -1.20), P < 0.001) and infertility (OR (95% CI) = 1.12 (1.07 -1.17), P < 0.001) in comparison with the controls.

Conclusion: Our findings suggested that SFRP2 may have a potential involvement in the development of PCOS and might be a promising target for diagnosis, but additional research is required to confirm this.

A special kind of posttranslational process known as proteolytic cleavage controls the half-lives and functions of several extracellular and intracellular proteins. The metalloproteinase ADAM10 has attracted attention because it cleaves a growing amount of protein substrates close to the extracellular membrane leaflet. The process known as "ectodomain shedding" controls the turnover of certain transmembrane proteins that are essential for receptor signaling and cell adhesion. It may trigger nuclear transport, intramembrane proteolysis, and cytoplasmic domain signaling. Additional human illnesses linked to ADAM10 include cancer, immune system malfunction, and neurodegeneration. The difficulty in targeting proteases for medicinal reasons stems from the many substrates that these enzymes, particularly ADAM10, have. It is usually necessary to precisely identify the therapeutic beneficial window of use since blocking or accelerating a particular protease activity is linked with undesirable side effects. More knowledge of the regulatory pathways governing ADAM10 expression, subcellular localization, and activity will probably lead to the identification of viable therapeutic targets, enabling more targeted and precise manipulation of the enzyme's proteolytic activity.

Schizophrenia is now diagnosed mostly based on symptoms and physical signs rather than the patient's pathological and physiological markers. While oncologists once felt satisfied when their patients experienced a long remission, today, they are leading research into innovative treatments with molecularly targeted drugs, as well as strategies to enhance diagnostic accuracy and alleviate symptoms as the disease advances. Because biomarkers reflect an organism's physiological, physical, and biochemical state, they are very beneficial and have a wide range of real-- world uses. The identification of blood biomarkers may open up new avenues for studying schizophrenia. MicroRNAs (miRNAs) may serve as diagnostic indicators for schizophrenia as their abnormal expression has recently been linked to the disease's pathophysiology. The precise etiological process of schizophrenia remains largely unknown despite the general agreement that developmental and genetic factors play a critical role in the pathophysiology of the disorder. miRNAs have gained recognition as an essential post-transcriptional regulator in the regulation of gene expression in recent decades. The importance of miRNAs for brain development and neuroplasticity is well established.

Mitochondria are organelles in eukaryotic organisms with an electron transport chain consisting of four complexes (i.e., CI, CII, CIII, and CIV) on the inner membrane, which have functions such as providing energy, electron transport, and generating proton gradients. NADH dehydrogenase type 2 (NDH-2), widely found in bacterial, plant, fungal and protist mitochondria, is a nonproton-pumping single-subunit enzyme bound to the surface of the inner mitochondrial membrane that partially replaces NDH-1. NDH-2 has a crucial role in the energy metabolism of pathogenic microorganisms, and the lack of NDH-2 or its homologs in humans makes NDH-2 an essential target for the development of antimicrobial drugs. There is a wide variety of pathogenic microorganisms that invade the human body and cause diseases; therefore, more and more inhibitors targeting NDH-2 of different pathogenic microorganisms continue to be reported. This paper first reviews the structure and function of NDH-2 and summarizes the classification of compounds targeting NDH-2. Given the relative paucity of inhibition mechanisms for NDH-2, which has greatly hindered the development of targeted drugs, the article concludes with a summary of two possible mechanisms in action: allosteric inhibition and competitive inhibition. This review will provide theoretical support for the subsequent molecular design and modification of drugs targeting the pathogenic microorganism NDH-2.

Background: Osteoarthritis (OA) is a persistent joint condition marked by gradual softening and breakdown of articular cartilage. Current research in OA treatment explores biologics that target proinflammatory cytokines and proteases, as well as promote chondrocyte regeneration and cartilage repair. Human placental tissues, abundant in anti-catabolic factors, can mitigate cartilage degradation by inhibiting protease expression and maintaining cartilage homeostasis in the presence of anabolic factors.

Objective: This investigation examined placental protein interactions with proteases and OA target proteins through protein-protein docking and dynamic studies.

Methods: The NCBI conserved domain database was utilized to predict functional protein domains. Protein sequence motifs were identified using literature, the MEME suite tool, and the My- Hits database. The Expasy-ProtParam online tool was employed to analyze protein physical parameters. ClusPro Advanced Options was used to dock binding site residues of selected placental proteins against specific OA target proteins, while PDBsum and Biovia Discovery Studio were used to visualize and examine molecular interactions. A 100 ns molecular dynamics (MD) study was conducted using DESMOND software.

Results: Protein-protein docking revealed strong interactions of placental proteins with docking scores ranging from -1700 to -2450.3 against proteases and -900 to -1400 against specific target proteins. PDBsum analysis of placental protein-target protein docked complexes revealed residue interactions, hydrogen bonds, and non-bonded contacts. Molecular dynamics simulations further confirmed the stability of these complexes, indicating favorable protein-protein interactions (PPIs). The anti-inflammatory activity of human placental tissue against lipopolysaccharide-induced macrophages was investigated using flow cytometry.

Conclusion: These results provide a foundation for future experimental studies to confirm the predicted interactions and to explore their potential therapeutic applications in OA treatment. Additionally, patients with OA and other arthritic conditions could benefit from the biologics chondroprotective biofactors, which serve as a promising alternative to conventional knee replacement surgery.

Introduction: Ex vivo preconditioning increases the therapeutic potential of mesenchymal stem cells (MSCs) in terms of antioxidant activity, growth factor production, homing, differentiation, and immunomodulation. Therefore, it is considered an effective strategy to be used before transplantation and therapeutic application of MSCs. Histone deacetylase inhibitor (HDACi), valproic acid (VPA), has been reported to induce hepatic differentiation in MSCs. Although individual studies have shown that preconditioning and epigenetic modification enhance the survival and differentiation of MSCs, the combined effects of these therapies have not been fully explored. This study aims to investigate the combined effect of hydrogen peroxide (H₂O₂) preconditioning and HDACi (valproic acid) on the differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) into hepatic-like cells.

Methods: MSCs were first preconditioned with H₂O₂ and then cultured with VPA. The migration and proliferation potential of the treated cells were evaluated using wound healing and colonyforming unit assays. Furthermore, the expression of hepatic genes (FOXA2, CK8, CK18, TAT) and proteins (AFP, ALB, TAT) was evaluated in all treated groups.

Results: The combined therapy group exhibited enhanced cell migration and proliferation, as evidenced by wound healing and colony-forming unit assays. Additionally, the combined treatment group showed higher expression of FOXA2, CK8, and CK18 hepatic genes and TAT protein, suggesting an improved differentiation of stem cells into hepatocytes.

Conclusion: In conclusion, the combination of H₂O₂ and VPA emerges as an important factor in promoting hepatocyte differentiation. However, further studies are required to optimize this protocol for future therapeutics.

Introduction: Clinic infections caused by various microorganisms are a public health concern. The rise of new strains resistant to traditional antibiotics has exacerbated the problem. Thus, the search for new antimicrobial molecules remains highly relevant.

Methods: The current study purified, characterized, and assessed the antimicrobial activity of a papain inhibitor from Terminalia catappa L. seeds.

Results: The inhibitor was purified by heating the crude extract at 80°C for 30 min, followed by ion exchange chromatography on a DEAE cellulose column. The purification index was 9-fold, yielding 2.3%. SDS-PAGE and size exclusion chromatography revealed that the protease inhibitor (TcPI) is a 15.9 kDa monomeric protein. The inhibition kinetics showed that TcPI is a competitive inhibitor specific to papain (Ki = 1.02 x 10^-4 M). TcPI remained active even after heating at 100oC for 120 min and at pH conditions varying from 2.0 to 10.0. Even after 60 min, TcPI was resistant to papain proteolysis. TcPI exhibited antimicrobial activity against Candida parapsilosis and Staphylococcus aureus. Conclusion: Here, we show that TcPI is a highly stable type-1 cystatin with the potential to combat infections caused by C. parapsilosis and S. aureus. Additional investigations into TcPI's structural aspects and mechanism of action, as well as safety assessments, are essential prerequisites for its potential application as a novel therapeutic intervention.

The misfolding and aggregation of amyloid proteins are closely associated with a range of neurodegenerative diseases. Liquid-liquid phase separation (LLPS) can initiate the aggregation of proteins, indicating that LLPS may serve as an alternative pathway for the pathological aggregation of amyloid proteins. The co-occurrence of two or more amyloid pathologies has been observed in extensive pathophysiological studies and is linked to faster disease progression. The co- LLPS (also known as co-condensation) and co-aggregation of different disease-related proteins have been proposed as a potential molecular mechanism for combined neuropathology. Here, we reviewed the current state of knowledge regarding the co-aggregation and co-condensation of various amyloid proteins, including Aβ, tau, α-synuclein, TDP-43, FUS, and hnRNPA/B protein family, C9orf72 dipeptide repeats and prion protein. We briefly introduced the epidemiological correlation among different neurodegenerative diseases and specifically presented recent experimental findings about co-aggregation and co-condensation of two different amyloid proteins. Additionally, we discussed computational studies focusing on the molecular interactions between amyloid proteins to offer mechanistic insights into the co-LLPS and co-aggregation processes. This review provides an overview of the synergistic interactions between different disease-related proteins, which is helpful for understanding the mechanisms of combined neuropathology and developing targeted therapeutic strategies.

Background: Actinomycetes, Gram-positive bacteria, are recognized for producing bioactive metabolites. Lonar Soda Lake, an alkaline ecosystem, hosts diverse actinomycetes with possible anticancer activities.

Aim: To assess the cytotoxic potential of fermentation metabolites from actinomycetes isolated from Lonar Soda Lake against HeLa cancer cells employing in-vitro and in-silico methods.

Objectives: Evaluate the cytotoxicity of fermentation metabolites from Lonar Lake actinomycetes on HeLa cells. Execute molecular docking to forecast metabolite connections with cancer-related proteins.

Materials and methods: The actinomycetes were isolated from the sediment sample of Lonar Lake using a selective medium and recognized by gene sequencing. Cytotoxicity on HeLa cells was assessed using the MTT assay, in consort with oxidative stress and apoptotic markers (GSH, MDA, TNF-α, and caspase 3). Molecular docking and molecular dynamics studies evaluated metabolite binding to cancer-related proteins (Bcl-2, TNF-α, caspase 3).

Results: Fermentation metabolites of three Lonar Lake Sediment isolates (LLSD), LLSD-5, LLSD- 7, and LLSD-9 showing promising cytotoxic activity against HeLa cell lines by MTT assay, also significantly modulate the oxidative stress parameters (GSH, MDA), and cell apoptotic marker (TNF-α, caspase 3). IC₅₀ values were 34.17 μM (LLSD-5), 53.85 μM (LLSD-7), and 69.54 μM (LLSD-9). Furthermore, molecular docking displayed robust binding affinities to cancer-related proteins, uncovering the possible mechanism of action.

Conclusion: The fermentation metabolites actinomycete isolates from Lonar Lake exhibit significant cytotoxic activity against HeLa cancer cell lines. Both in-vitro and in-silico analyses support the potential of these metabolites as anticancer agents.