Search Results (3,657)

Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects the elderly population. It is characterized by cognitive impairment and dementia due to abnormal levels of amyloid beta peptide (Aβ) and axonal Tau protein in the brain. However, the complex underlying mechanisms affecting this disease are not yet known, and there is a lack of standardized biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, AD-affected brain tissue was analyzed using the GSE138260 dataset, identifying 612 differentially expressed genes (DEGs). Functional analysis revealed 388 upregulated DEGs associated with sensory perception and 224 downregulated DEGs linked to the regulation and modulation of synaptic processes. Protein–protein interaction network analysis identified 20 hub genes. Furthermore, miRNA target gene networks revealed 1767 miRNAs linked to hub genes, among which hsa-mir-106a-5p, hsa-mir-17-5p, hsa-mir-26a-5p, hsa-mir-27a-3p and hsa-mir-34a-5p were the most relevant. This study presents novel biomarkers and therapeutic targets for AD by analyzing the information obtained with a comprehensive literature review, providing new potential targets to study their role in AD. Full article

Oral diseases, both acute and chronic, of infectious or non-infectious etiology, represent some of the most serious medical problems in dentistry. Data from the literature increasingly indicate that changes in the oral microbiome, and therefore, the overgrowing of pathological microflora, lead to a variety of oral-localized medical conditions such as caries, gingivitis, and periodontitis. In recent years, compelling research has been devoted to the use of natural antimicrobial peptides as therapeutic agents in the possible treatment of oral diseases. This review focuses on the potential of ceragenins (CSAs), which are lipid analogs of natural antimicrobial peptides, as molecules for the development of new methods for the prevention and treatment of oral diseases. Studies to date indicate that ceragenins, with their spectrum of multidirectional biological activities, including antimicrobial, tissue regeneration-stimulating, anti-inflammatory, and immunomodulatory properties, are strong candidates for further development of oral formulations. However, many of the beneficial properties of ceragenins require confirmation in experimental conditions reproducing the oral environment to fully determine their application potential. Their transition to practical use also requires more advanced testing of these molecules in clinical trials, which have only been conducted in limited numbers to date. Full article

The venoms of Theraphosidae spiders have evolved into diverse natural pharmacopeias through selective pressures. Cryptococcus neoformans is a global health threat that frequently causes life-threatening meningitis and fungemia, particularly in immunocompromised patients. In this study, we identify a novel anti-C. neoformans peptide, QS18 (QCFKVCFRKRCFTKCSRS), from the venom gland of China’s native spider species Chilobrachys liboensis by utilizing bioinformatic tools. QS18 shares over 50% sequence similarity with tachyplesin peptides, previously identified only in horseshoe crab hemocytes, expanding the known repertoire of the tachyplesin family to terrestrial arachnids. The oxidative folding of QS18 notably enhances its antifungal activity and stability, resulting in a minimum inhibitory concentration of 1.4 µM. The antimicrobial mechanism of QS18 involves cell membrane disruption. QS18 exhibits less than 5% hemolysis in human erythrocytes, indicating microbial selectivity and a favorable safety profile for therapeutic use. Furthermore, mouse model studies highlight QS18’s ability as an antifungal agent with notable anti-inflammatory activity. Our study demonstrates QS18 as both a promising template for spider venom peptide research and a novel candidate for the development of peptide antifungals. Full article

Therapeutic nucleic acids (TNAs) including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) have emerged as promising treatment strategies for a wide variety of diseases, offering the potential to modulate gene expression with a high degree of specificity. These small, synthetic nucleic acid-like molecules provide unique advantages over traditional pharmacological agents, including the ability to target previously “undruggable” genes. Despite this promise, several biological barriers severely limit their clinical efficacy. Upon administration, TNAs primarily enter cells through endocytosis, becoming trapped inside membrane-bound vesicles known as endosomes. Studies estimate that only 1–2% of TNAs successfully escape endosomal compartments to reach the cytosol, and in some cases the nucleus, where they bind target mRNA and exert their therapeutic effect. Endosomal entrapment and inefficient nuclear localization are therefore critical bottlenecks in the therapeutic application of TNAs. This review explores the current understanding of TNA endosomal escape and nuclear transport along with strategies aimed at overcoming these challenges, including the use of endosomal escape agents, peptide-TNA conjugates, non-viral delivery vehicles, and nuclear localization signals. By improving both endosomal escape and nuclear localization, significant advances in TNA-based therapeutics can be realized, ultimately expanding their clinical utility. Full article

The epidermal growth factor receptor (EGFR) is frequently overexpressed in a variety of human epithelial tumors, and its aberrant activation plays a pivotal role in promoting tumor growth, invasion, and metastasis. The clinically approved passive EGFR-related therapies have numerous limitations. Seven EGFR-ECD epitope peptides (EG1-7) were selected through bioinformatics epitope prediction tools including NetMHCpan-4.1, NetMHCIIpan-3.2, and IEDB Consensus (v2.18 and v2.22) and fused to the translocation domain of diphtheria toxin (DTT). The A549 tumor model was successfully established in a murine mouse model. The vaccine was formulated by combining the adjuvants Alum and CpG and subsequently assessed for its immunogenicity and anti-tumor efficacy. DTT-EG (3;5;6;7) vaccines elicited specific humoral and cellular immune responses and effectively suppressed tumor growth in both prophylactic and therapeutic mouse tumor models. The selected epitopes EG3 (HGAVRFSNNPALCNV145-159), EG5 (KDSLSINATNIKHFK346-360), EG6 (VKEITGFLLIQAWPE398-412), and EG7 (LCYANTINWKKLFGT469-483) were incorporated into vaccines for active immunization, representing a promising strategy for the treatment of tumors with overexpressed epidermal growth factor receptor (EGFR). The vaccine design and fusion method employed in this study demonstrate a viable approach toward the development of cancer vaccines. Full article

Background/Objectives: Neoantigens have attracted attention as ideal therapeutic targets for anti-tumour immunotherapy because the T cells that respond to neoantigens are not affected by central immune tolerance. Recent findings have revealed that the activation of CD4-positive T cells plays a central role in antitumor immunity, and thus targeting human leukocyte antigen (HLA) class II-restricted neoantigens, which are targets of CD4-positive T cells, is of significance. However, there are very few detailed reports of neoantigen vaccine therapies that use an HLA class II-restricted long peptide. In the present study, we retrospectively analysed the ability of HLA class II-restricted neoantigen-pulsed dendritic cell vaccines to induce immune response in five breast cancer patients. Methods: We performed whole exome and RNA sequencing of breast cancer tissues and neoantigen prediction using an in silico pipeline. We then administered dendritic cells pulsed with synthesized an HLA class II-restricted long peptide containing an epitope with high affinity to HLA class I in the lymph node. Results: ELISPOT analysis confirmed that a T-cell response specific for the HLA class II-restricted neoantigen was induced in all cases. TCR repertoire analysis of peripheral blood mononuclear cells before and after treatment in three patients showed increases of specific T-cell clones in two of the three patients. Importantly, no recurrence was observed in all patients. Conclusions: Our analysis demonstrated the immunological efficacy of the HLA class II-restricted neoantigen peptide dendritic cell vaccine against breast cancer and provides useful information for the development of neoantigen vaccine therapy for breast cancer. Full article

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. Methods: This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation. The database, obtained from the Coconut website, was filtered according to a set of physicochemical descriptors, then was shape screened against the crystal ligand conformation. This filtered database consisting of 26,325 compounds was used for virtual screening against the GLP-1 allosteric site. Results: The results identified ten best hits with the XP score ranging from −9.6 to −7.6 and MM-GBSA scores ranging from −50.8 to −32.4 and another 58 hits from docked pose filter and a second round of XP docking and MM-GBSA calculation followed by molecular dynamics. The analysis of results identified hits from various natural products (NPs) classes, to whom attributed antidiabetic and anti-obesity effects have been previously reported. The results also pointed to β-lactam antibiotics that may be evaluated in drug repurposing studies for off-target effects. The calculated ADMET properties for those hits revealed suitable profiles for further development in terms of bioavailability and toxicity. Conclusions: The current study identified several NPs as potential GLP-1 positive allosteric modulators and revealed common structural scaffolds including peptidomimetics, lactams, coumarins, and sulfonamides with peptidomimetics being the most prominent especially in indole and coumarin cores. Full article

Adropin, a secreted peptide hormone identified in 2008, plays a significant role in regulating energy homeostasis, glucose metabolism, and lipid metabolism. Its expression is linked to dietary macronutrient intake and is influenced by metabolic syndrome, obesity, diabetes, and cardiovascular diseases. Emerging evidence suggests that adropin might be a biomarker for various conditions, including metabolic syndrome, coronary artery disease, and hypertensive disorders complicating pregnancy. In cerebrovascular diseases, adropin demonstrates protective effects by reducing blood–brain barrier permeability, brain edema, and infarct size while improving cognitive and sensorimotor functions in ischemic stroke models. The protective effects of adropin extend to preventing endothelial damage, promoting angiogenesis, and mitigating inflammation, making it a promising therapeutic target for cardiovascular and neurodegenerative diseases. This review provides a comprehensive overview of adropin’s multifaceted roles in physiological and pathological conditions, as well as our recent work demonstrating adropin’s role in subarachnoid hemorrhage-mediated neural injury and delayed cerebral infarction. Full article

Recombinant antibodies and, more recently, T cell receptor (TCR)-engineered T cell therapies represent two immunological strategies that have come to the forefront of clinical interest for targeting intracellular neoantigens in benign and malignant diseases. T cell-based therapies targeting neoantigens use T cells expressing a recombinant complete TCR (TCR-T cell), a chimeric antigen receptor (CAR) with the variable domains of a neoepitope-reactive TCR as a binding domain (TCR-CAR-T cell) or a TCR-like antibody as a binding domain (TCR-like CAR-T cell). Furthermore, the synthetic T cell receptor and antigen receptor (STAR) and heterodimeric TCR-like CAR (T-CAR) are designed as a double-chain TCRαβ-based receptor with variable regions of immunoglobulin heavy and light chains (VH and VL) fused to TCR-Cα and TCR-Cβ, respectively, resulting in TCR signaling. In contrast to the use of recombinant T cells, anti-neopeptide MHC (pMHC) antibodies and intrabodies neutralizing intracellular neoantigens can be more easily applied to cancer patients. However, different limitations should be considered, such as the loss of neoantigens, the modification of antigen peptide presentation, tumor heterogenicity, and the immunosuppressive activity of the tumor environment. The simultaneous application of immune checkpoint blocking antibodies and of CRISPR/Cas9-based genome editing tools to engineer different recombinant T cells with enhanced therapeutic functions could make T cell therapies more efficient and could pave the way for its routine clinical application. Full article

Psoriasis is a chronic inflammatory skin disorder characterized by abnormal immune responses and keratinocyte hyperproliferation. Limonin, a bioactive compound found in citrus fruits, has anti-inflammatory properties in various models; however, its effects on psoriasis are not fully understood. We investigated the therapeutic potential of limonin in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced psoriasis mouse model. Mice were treated with TPA to induce psoriasis-like skin lesions, followed by intraperitoneal administration of limonin (200 or 400 μg/mouse) for six days. The results showed that limonin improved psoriasis-related symptoms in a psoriasis-like mouse model by suppressing the mRNA expression of pro-inflammatory cytokines and inflammation-related antimicrobial peptides and regulating the expansion of myeloid cells and T cells. Specifically, limonin reduced glucose uptake and oxidative phosphorylation to shift the metabolic program in the inflamed skin cells of psoriasis-like mice. Limonin activates AMPK and proteins related to mTOR inhibition, thereby suppressing the mTOR signaling pathway. It also inhibits mitochondrial mass and mitochondrial ROS production, thereby preventing the development of dysfunctional mitochondria in inflamed skin cells. Overall, limonin modulates key immune responses and metabolic pathways related to inflammation and mitochondrial health in psoriasis. Therefore, it is a promising natural candidate for the treatment of psoriasis and various inflammatory skin diseases. Full article

Nicotinamide mononucleotide (NMN) possesses a variety of physiological functions and has therapeutic effects on cardio-cerebral diseases, senile degenerative diseases, neurodegenerative diseases, delayed aging, etc. However, its ability to cross the blood–brain barrier (BBB) and the mechanism of its transport have not been reported. In this study, we used the immortalized hCMEC/D3 cell line to construct an in vitro monolayer cell BBB model, evaluated its ability to cross the blood–brain barrier, and explored the mechanism by carrying out transport and efflux experiments on NMN. The ability of NMN to cross the BBB was investigated by preparing NMN-loaded liposomes conjugated with ANG peptide and RVG peptide. The results showed that the transmembrane transport ability of NMN was moderate, and the transport mechanism was passive transport relying on the concentration difference. The trans-BBB ability of ANG peptide coupled with NMN could be highly significantly improved. Full article

Background: 5-Fluorouracil (5-FU) is a common chemotherapeutic medication used to treat cancer. However, the intestinal tract may sustain oxidative damage as a result. Objectives: The purpose of this study was to clarify the underlying molecular mechanisms and examine the preventive benefits of cereal-based fermented drinks (CFBs) against intestinal injury in mice caused by 5-FU. Methods: The mice were injected intraperitoneally with 5-FU to induce intestinal mucosal and treated with CFB. The factors for intestinal barrier integrity, oxidative stress and inflammation were measured. Results: The findings demonstrated that CFBs had high levels of polyphenol, flavonoids, and peptides and had in vitro high free radical scavenging capacity. Furthermore, CFBs effectively ameliorated 5-FU-induced intestinal epithelium damage, characterized by increasing intestinal tight junctions and reducing apoptosis in intestinal cells. These protective effects may attribute to the increased activity of antioxidant-related enzymes (SOD, CAT, and GSH) as well as decreased amounts of inflammatory and oxidative damage markers (IL-1β, TNF-α, and MDA) in the intestinal tract. Conclusions: Overall, these results show that CFBs can mitigate intestinal damage caused by 5-FU by reducing oxidative stress, suggesting the potential utility of CFBs for therapeutic treatment against intestinal mucositis. Full article

Background/Objectives: Inflammation serves as a vital response to diverse harmful stimuli like infections, toxins, or tissue injuries, aiding in the elimination of pathogens and tissue repair. However, persistent inflammation can lead to chronic diseases. Peptide therapeutics have gained attention for their specificity in targeting cells, yet their development remains costly and time-consuming. Therefore, small molecules, with their stability, low immunogenicity, and oral bioavailability, have become a focal point for predicting anti-inflammatory small molecules (AISMs). Methods: In this study, we introduce a computational method called AISMPred, designed to classify AISMs and non-AISMs. To develop this approach, we constructed a dataset comprising 1750 AISMs and non-AISMs, each annotated with ${\mathrm{I}\mathrm{C}}_{50}$ values sourced from the PubChem BioAssay database. We computed two distinct types of molecular descriptors using PaDEL and Mordred tools. Subsequently, these descriptors were concatenated to form a hybrid feature set. The SVC-L1 regularization method was implemented for the optimum feature selection to develop robust Machine learning (ML) models. Five different conventional ML classifiers were employed, such as RF, ET, KNN, LR, and Ensemble methods. Results: A total of 15 ML models were developed using 2D, FP, and Hybrid feature sets, with the ET model with hybrid features achieving the highest accuracy of 92% and an AUC of 0.97 on the independent test dataset. Conclusions: This study provides an effective method for screening AISMs, potentially impacting drug discovery and design. Full article

Peptide Lv is a small endogenous secretory peptide with ~40 amino acids and is highly conserved among certain several species. While it was first discovered that it augments L-type voltage-gated calcium channels (LTCCs) in neurons, thus it was named peptide “Lv”, it can bind to vascular endothelial growth factor receptor 2 (VEGFR2) and has VEGF-like activities, including eliciting vasodilation and promoting angiogenesis. Not only does peptide Lv augment LTCCs in neurons and cardiomyocytes, but it also promotes the expression of intermediate-conductance K_Ca channels (K_Ca3.1) in vascular endothelial cells. Peptide Lv is upregulated in the retinas of patients with early proliferative diabetic retinopathy, a disease involving pathological angiogenesis. This review will provide an overview of peptide Lv, its known bioactivities in vitro and in vivo, and its clinical relevance, with a focus on its role in angiogenesis. As there is more about peptide Lv to be explored, this article serves as a foundation for possible future developments of peptide Lv-related therapeutics to treat or prevent diseases. Full article

Background: Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed as a treatment for renal anemia. However, their therapeutic impact on patients with concomitant heart failure remains uncertain. We investigated the impact of HIF-PH inhibitors on improving renal anemia and associated clinical outcomes in patients with heart failure. Methods: Patients with both heart failure and renal anemia who received HIF-PH inhibitors were retrospectively analyzed over a six-month follow-up period. Hemoglobin levels and other clinical parameters were compared between the six-month pre-treatment period without HIF-PH inhibitors and the six-month treatment period with HIF-PH inhibitors. Results: A total of 69 patients (median age 82 years, 27 male) were included. Baseline hemoglobin was 9.2 (8.8, 10.3) g/dL, baseline plasma B-type natriuretic peptide level was 264 (156, 372) pg/mL, and baseline estimated glomerular filtration rate was 29.1 (19.0, 35.1) mL/min/1.73 m². Hemoglobin levels declined during the pre-treatment period from 10.5 (9.4, 11.5) g/dL to 9.2 (8.8, 10.3) g/dL (p < 0.001) but subsequently increased to 10.9 (10.1, 12.0) g/dL following six months of HIF-PH inhibitor treatment (p < 0.001). This increase in hemoglobin was accompanied by a reduction in plasma BNP levels, improved renal function, and reduced systemic inflammation (p < 0.05 for all). Conclusions: HIF-PH inhibitors demonstrated efficacy in this cohort of patients with heart failure, with associated improvements in heart failure severity, renal function, and systemic inflammation. Full article