Current Protein and Peptide Science - Volume 24, Issue 8, 2023

Hyperphosphatemia is independently linked with vascular calcification, cardiovascular disease, bone-mineral disease, progression of renal insufficiency, and all-cause mortality in chronic kidney disease (CKD) and end-stage renal disease (ESRD). The emerging importance of fibroblast growth factor-23 (FGF-23) and its co-factor Klotho play very important roles as phosphaturic hormones; however, phosphate levels rise due to a loss of renal Klotho production and the phosphaturic effects of the FGF-23/Klotho axis. Hyperphosphatemia is also associated with calciphylaxis, acceleration of renal tubulointerstitial disease, renal osteodystrophy, and uremic cardiomyopathy. This review incorporates ultrastructural remodeling of the thoracic aorta to provide a different perspective on vascular calcification. Nine-week-old male heterozygous (mRen2) 27 (Ren2) rat models of hypertension, insulin resistance, vascular oxidative stress and albuminuria are utilized to demonstrate aortic remodeling associated with vascular calcification. Nine-week-old male Zucker obese (fa/fa) rat models are utilized to better understand nephrolith formation. Phosphate homeostasis, toxicity, multiple metabolic and uremic toxicities, renal osteodystrophy, and vascular calcification are also discussed. Additionally, the role of the endothelium, vascular smooth muscle cells, inflammatory monocytes/macrophages and mast cells, pericytes, oxidative stress, hydrogen sulfide, and extraosseous calcification in the kidney are discussed as they relate to CKD, ESRD and calciphylaxis.

Antimicrobial peptides (AMPs) are widely sourced and have a variety of biological activities such as broad-spectrum antibacterial, antiviral, and anticancer. Since AMPs are less likely to cause drug resistance, they are expected to be an alternative to antibiotics. Compared with natural extraction and chemical synthesis methods, producing AMPs using genetic engineering is a hot research topic for the large-scale production of AMPs. This paper outlines the sources of AMPs, focuses on different expression systems, and reviews the current status of AMPs applications in animal husbandry, food preservation and medicine, and agriculture to provide a theoretical basis and support for using genetic engineering to express AMPs.

New Delhi Metallo-β-lactamase is an enzyme produced by gram-negative bacteria which has become one of the global concerns for physicians to treating the infection. These Metallo- β-lactamase are capable of catalyzing the hydrolysis of almost all β-lactam antibiotics, endangering infection treatment. Substitution of single or multiple amino acids results in new NDM variants. Forty NDM variants have been identified in different bacterial strains across the globe. In this review, we focused on the structural insight of all NDM variants including the type of amino acid residues and their position of substitution, country of origin, and type of bacteria carrying these resistant markers. We also discussed the carbapenemase activity and stability of enzymes that helps to design potent inhibitors to combat drug-resistant infections.

Aims: To reveal the prognostic role of unfolded protein response (UPR) -related genes in hepatocellular carcinoma (HCC). Background: Hepatocellular carcinoma is a genetically heterogeneous tumor, and the prediction of its prognosis remains a challenge. Studies elucidating the molecular mechanisms of UPR have rapidly increased. However, the UPR molecular subtype characteristics of the related genes in HCC progression have yet to be thoroughly studied. Objective: Conducting a comprehensive assessment of the prognostic signature of genes related to the UPR in patients with HCC can advance our understanding of the cellular processes contributing to the progression of HCC and offer innovative strategies in precise therapy. Methods: Based on the gene expression profiles associated with UPR in HCC, we explored the molecular subtypes mediated by UPR-related genes and constructed a UPR-related genes signature that could precisely predict the prognosis for HCC. Results: Using microarray data of HCC patients, differentially expressed UPR-related genes (DEGs) were discovered in malignancies and normal tissues. The HCC was classified into two molecular subtypes by the NMF algorithm based on DEGs modification of the UPR. Moreover, we developed a UPR-related model for predicting HCC patients' prognosis. The robustness of the UPR- related model was confirmed in external validation. Moreover, we analyzed immune responses in different risk groups. Analysis of immune functions revealed that Treg, Macrophages, aDCs, and MHC class-I were significantly up-regulated in high-risk HCC. At the same time, cytolytic activity and type I and II INF response were higher in a low-risk subgroup. Conclusion: This study identified two UPR molecular subtypes of HCC and developed a ten-gene HCC prognostic signature model (EXTL3, PPP2R5B, ZBTB17, CCT3, CCT4, CCT5, GRPEL2, HSP90AA1, PDRG1, and STC2), which can robustly forecast the progression of HCC.

Background: The oral cancer microenvironment plays an important role in the development and progression of the disease which depicts the heterogeneous nature of diseases. Several cellular and non-cellular factors, including dipeptides, have been reported to drive tumor progression and metastasis. Among various secreted molecules in the tumor microenvironment, prolylhydroxyproline (Pro-Hyp) is a collagen-degraded product with specific relevance to fibrosis and oral cancer. However, the detection of Pro-Hyp in the nails of oral cancer patients is a potential biomarker, and our understanding of the biological relevance of Pro-Hyp is highly limited. Methods: Here, the authors have attempted to use a novel and in-house vertical tube gel electrophoresis (VTGE) protocol to evaluate the level of Pro-Hyp in the nails of oral cancer patients and healthy subjects. Furthermore, we employed molecular docking and molecular dynamics (MD) simulations to predict the biological function of Pro-Hyp. ADME profiles such as the druglikeness and leadlikeness of Pro-Hyp and a known PLC-β2 activator, m-3M3FBS, were evaluated by the SWISS-ADME server. Results: We report that among various key metabolites, Pro-Hyp, a dipeptide, is reduced in the nails of oral cancer patients. Molecular docking and MD simulations helped to suggest the potential role of Pro-Hyp as an activator of Phospholipase C-β2 (PLC-β2). Pro-Hyp displayed good binding affinity (-7.6 kcal/mol) with specific interactions by a conventional hydrogen bond with key residues, such as HIS311, HIS312, VAL641, and GLU743. MD simulations showed that the activator binding residues and stability of complexes are similar to the well-known activator m-3M3FBS of PLC-β2. ADME profiles such as the druglikeness and leadlikeness of Pro-Hyp were found to be highly comparable and even better than those of m-3M3FBS. Conclusion: This study is one of the first reports on Pro-Hyp as a metabolite biomarker in the nails of oral cancer patients. Furthermore, the implications of Pro-Hyp are proposed to activate PLC-β2 as a pro-tumor signaling cascade. In the future, diagnostic and therapeutic approaches may be explored as biomarkers and mimetic of Pro-Hyp.