Current Drug Targets - Online First

Cancer is a significant human health concern due to its increasing mortality rate and profound impact on public health and healthcare systems. The cytotoxic, antiproliferative, immunosuppressive, and apoptogenic properties of scorpion venom proteins and peptides have been observed in various cancer cell lines. Therefore, the purpose of this study was to investigate the potential use of proteins derived from scorpion venom in cancer treatment. In this study, the effects of different scorpion venoms on transmembrane channels, the inhibition of angiogenesis, the inhibition of invasion and metastasis, the inhibition of proliferation, and the induction of apoptosis were investigated, as were their clinical applications in the treatment of hepatocellular carcinoma and breast, cervical, prostate, colorectal, and melanoma cancers. The results showed that various scorpion venoms can suppress cell growth, stimulate apoptosis, reduce tumor size, and enhance the immune response, thereby serving as alternative drugs for treating various types of cancers and their metastasis. This review suggests a positive association between scorpion venom (SV) proteins and the treatment of these cancers. Future research should focus on understanding the underlying mechanisms, identifying biomarkers to predict response, and exploring potential combination therapies to increase the efficacy of scorpion venom proteins in cancer treatment.

Double homeobox A pseudogene 9 (DUXAP9), also known as long intergenic non-coding RNA 1296 (LINC01296) and lymph node metastasis-associated transcript 1 (LNMAT1), is an emerging lncRNA encoded by a pseudogene. It has been reported to be upregulated in various tumor types and functions as an oncogenic factor. The high expression of DUXAP9 is closely related to clinical pathological features and poor prognosis in 16 types of malignant tumors. DUXAP9 is transcriptionally activated by YY-1 and Twist1 and functions as a guide or scaffold for biomolecular complexes and chromatin modifiers, or as a "decoy" for miRNAs, mRNAs, and proteins, thereby regulating gene expression. Moreover, the PI3K/AKT, NF-κB, MAPK/ERK, and Wnt/β- catenin signaling pathways are variously activated or inhibited by DUXAP9, subsequently influencing the biological behaviors of tumor cells, including proliferation, apoptosis, cell cycle arrest, migration, invasion, epithelial-mesenchymal transition (EMT), and drug resistance. This review summarizes recent research on DUXAP9 in oncology, offering insights into its expression characteristics, biological functions, molecular mechanisms, and clinical significance for cancer diagnosis, treatment, and prognosis.

Sepsis is a lethal clinical condition representing severe inflammation and immune suppression to pathogen or infection, leading to tissue damage or organ dysfunction. Hyper-inflammation and immune suppression cause a fatal, escalated Blood-Brain Barrier permeability, being a secondary response towards infection resulting in sepsis-associated brain dysfunction. These changes in the BBB lead to the brain’s susceptibility to increased morbidity and mortality. An important mechanism of sepsis-associated brain dysfunction includes excessive activation of microglial cells, altered brain endothelial barrier function, and BBB dysfunction. Lipopoly- saccharide, a bacterial cell wall component (endotoxin), by forming a complex through membrane-bound CD receptors on macrophages, monocytes, and neutrophils, begins synthesizing anti-inflammatory agents for defense of the host, including nitric oxide, cytokines, chemokines, interleukins, and the complement system. Unrestrained endotoxemia and pro-inflammatory cytokines result in microglial as well as brain endothelial cell stimulation, downregulation of tight junctions, along with intense recruitment of leucocytes. Subsequent neuroinflammation, together with BBB dysfunction, aggravates brain pathology as well as worsens sepsis-associated brain dysfunction. The clinical demonstration includes mild (confusion and delirium) along with severe (cognitive impairment, coma, as well as sequel death). Different clinical neurophysiological evaluation parameters can be used for the quantification and important issues of the disorder, including SOFA, imaging methods, and the use of biomarkers associated with brain dysfunction. The present review addresses the mechanism, clinical examination, the long-term cognitive effects, and current treatment modalities for sepsis-associated brain dysfunction.

Depression is a debilitating psychiatric disorder characterized by loss of interest, anhedonia, and social isolation, which is projected to become the leading cause of disability worldwide by 2030. Despite the greater economic and social burden imposed by depression, the precise pathophysiology underlying the development of depression remains elusive. Betaine (N, N, N-trimethylglycine), an amino acid derivative, is widely distributed in various animals and plants and has been shown to have numerous beneficial effects, including antioxidant activities, anti-inflammatory functions, regulation of energy metabolism, and reduction of endoplasmic reticulum stress. It has been used to treat Alcohol-Associated Liver Disease (AALD), type 2 diabetes, cancer, obesity, and Alzheimer's Disease (AD). Interestingly, accumulating evidence has shown that betaine exerts a significant role in alleviating depressive-like behavior in patients and animals resulting from chronic stress. Although the antidepressant effects of betaine have not been compared with traditional antidepressants with insufficient verification, based on the neurobiological mechanisms of depression, it may be a potential alternative medicine for the treatment of depression. This is the first review aiming to provide a comprehensive overview of the remarkable effects of betaine in the pathophysiology of depression. These pieces of evidence are of great importance for deepening our understanding of the antidepressant mechanism of betaine, so as to develop betaine supplements for the supplementary treatment of depression.

B-cell lymphoma-2 (BCL-2) plays a key role in regulating apoptosis. Venetoclax (VEN), a BCL-2 inhibitor, has been approved for the treatment of a variety of hematologic malignancies. VEN is primarily metabolized by CYP3A, and a variety of factors (such as CYP3A inhibitors, as well as food and hepatic functions) have been reported to significantly influence the metabolic process. There is significant interindividual variability in VEN plasma concentrations, and studies have shown that its exposure levels are correlated with efficacy, although the relationship with adverse effects remains controversial. The value of applying of therapeutic drug monitoring (TDM) in individualized VEN therapy has been confirmed by some studies, but the optimal therapeutic window for different malignancies is still unclear. This review summarizes the pharmacokinetic characteristics, along with the factors influencing VEN pharmacokinetics, drug-drug interactions, and advancements in TDM research on VEN, aiming to provide a theoretical basis for TDM-guided individualized therapy.

Matrix metalloproteinase-9, also known as MMP-9, gelatinase B, or 92 kDa type IV collagenase, is an enzyme that belongs to the matrix metalloproteinase (MMP) family. It is involved in the remodeling of the extracellular matrix in various physiological and pathological processes. MMPs are expressed in low, tightly regulated concentrations; their overexpression or dysregulation can lead to diseases, including cancer. MMP-9 is increasingly recognized as a significant drug target in cancer therapy due to its involvement in tumorigenesis, including processes like cell migration, angiogenesis, and pro-apoptotic and anti-apoptotic activities. Despite MMP-9's significance as a cancer target, developing effective inhibitors remains challenging due to MMP structural similarities. Utilizing MMP-9 as a cancer biomarker could advance cancer diagnosis, prognosis, disease monitoring, recurrence prediction, and other procedures. Biosensors are emerging as pivotal tools in cancer diagnosis and treatment, leveraging their ability to detect specific biomarkers associated with various cancers. Recent advancements have led to the development of both cleavage-based and non-cleavage-based biosensors that enable rapid and sensitive analysis at clinically relevant concentrations of biomarkers while allowing specificity and low detection limits, enhancing point-of-care diagnostics. The cleavage-based biosensors leverage the enzymatic activity of MMP-9, utilizing substrates that are specifically cleaved by MMP-9, while the non-cleavage-based biosensors employ affinity methods, such as antibodies and aptamers for detection. The present review aims to evaluate the role of MMP-9 as a significant biomarker in cancer and its detection through innovative biosensor technologies, while exploring its involvement in various cancer-related processes. This review discusses the significance of MMP-9 in cancer progression, highlighting clinical trials that assess MMP-9 inhibitors as potential therapeutic agents to halt metastatic spread. Furthermore, MMP-9 is detected via biosensors, and insights into the translational potential of MMP-9 both as a biomarker for early cancer detection and a viable target for therapeutic intervention are provided, ultimately contributing to improved patient outcomes in oncology.

In the past several years, human life expectancy has increased dramatically, and the global aging process is accelerating at an unprecedented rate. Impaired organ functions and systemic inflammation increase the risk of aging-related diseases. It seriously affects the quality of life in older adults and places a heavy burden on the global economy and public health. Inflammation is the cornerstone of many age-related diseases, and among various inflammatory mediators, Prostaglandin E2 (PGE2) has emerged as a key player. For example, PGE2 could participate in the progression of Alzheimer's disease (AD) by modulating neuroinflammation. Plasma PGE2 is regarded as a potential and specific diagnostic biomarker, and higher initial PGE2 levels are positively correlated with longer survival in AD. PGE2 also mediates bone and muscle metabolism to affect age-related musculoskeletal diseases, including sarcopenia, osteoporosis, and osteoarthritis. It activates the EP4 receptor on sensory nerves to inhibit sympathetic nerve activity and modulate bone formation. Moreover, the PGE2/EP4 axis positively regulates muscle mass and strength. In diabetes, increased Cox-2 and m-PGES2 promote PGE2 production. The activated PGE2/EP3 axis exacerbates the progression of type 2 diabetes (T2D) by impairing glucose metabolism and accelerating β-cell senescence. Therefore, the role of PGE2 in age-related diseases deserves greater attention. Its involvement is driven by the dysregulation of its biosynthesis, metabolism, and receptor-mediated signaling. Regulating the concentration of PGE2 or modulating receptor activity represents a promising therapeutic strategy for managing age-related diseases.

Delayed diagnosis and limited treatment options make ovarian cancer difficult to treat. This paper examines the growing role of Carbon Dots (CDs) in ovarian cancer diagnosis and treatment. Photoluminescence and biocompatibility make CDs ideal for biomedical use. We emphasize their ability to improve fluorescence and molecular imaging in imaging and diagnostics. We also demonstrate the efficacy of carbon dots in targeted drug delivery systems in overcoming drug resistance and improving therapeutic outcomes. Photodynamic and photothermal therapies are used to show that CDs can treat hypoxic ovarian cancer tumours. We also discuss CD safety issues and constraints, emphasising the need for thorough assessments and fine-tuning. Future research focuses on personalised medicine and CD integration with other therapies. This text concludes by discussing CDs' clinical use and the challenges of production and regulatory approval. CDs can improve ovarian cancer diagnosis and treatment, improving patient outcomes and survival.