Current Protein and Peptide Science - Volume 26, Issue 4, 2025

TLR4 stands at the forefront of innate immune responses, recognizing various pathogen-associated molecular patterns and endogenous ligands, thus serving as a pivotal mediator in the immune system's defense against infections and tissue damage. Beyond its canonical role in infection, emerging evidence highlights TLR4's involvement in numerous non-infectious human diseases, ranging from metabolic disorders to neurodegenerative conditions and cancer. Targeting TLR4 signaling pathways presents a promising therapeutic approach with broad applicability across these diverse pathological states. In metabolic disorders such as obesity and diabetes, dysregulated TLR4 activation contributes to chronic low-grade inflammation and insulin resistance, driving disease progression. In cardiovascular diseases, TLR4 signaling promotes vascular inflammation and atherogenesis, implicating its potential as a therapeutic target to mitigate cardiovascular risk. Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, exhibit aberrant TLR4 activation linked to neuroinflammation and neuronal damage, suggesting TLR4 modulation as a strategy to attenuate neurodegeneration.

Additionally, in cancer, TLR4 signaling within the tumor microenvironment promotes tumor progression, metastasis, and immune evasion, underscoring its relevance as a target for anticancer therapy. Advances in understanding TLR4 signaling cascades and their contributions to disease pathogenesis have spurred the development of various pharmacological agents targeting TLR4. These agents range from small molecule inhibitors to monoclonal antibodies, with some undergoing preclinical and clinical evaluations. Furthermore, strategies involving TLR4 modulation through dietary interventions and microbiota manipulation offer additional avenues for therapeutic exploration. Hence, targeting TLR4 holds significant promise as a therapeutic strategy across a spectrum of human diseases, offering the potential to modulate inflammation, restore immune homeostasis, and impede disease progression.

Alzheimer's disease (AD), the most common kind of dementia worldwide, is characterized by elevated levels of the amyloid-β (Aβ) peptide and hyperphosphorylated tau protein in the neurons. The complexity of AD makes the development of treatments infamously challenging. Apolipoprotein E (APOE) genes’s ɛ4 allele is one of the main genetic risk factors for AD. While the APOE gene's ɛ4 allele considerably increases the chance of developing AD, the ɛ2 allele is protective compared to the prevalent ɛ3 variant. It is fiercely discussed how APOE affects the development and course of disease since it has a variety of activities that influence both neuronal and non-neuronal cells. ApoE4 contributes to the formation of tau tangles, deposition of Aβ, neuroinflammation, and other processes. Four decades of research have provided a significant understanding of the structure of APOE and how this may affect the neuropathology and pathogenesis of AD. APOE is a crucial lipid transporter essential for the growth of the central nervous system (CNS), upkeep, and repair. The mechanisms by which APOE contributes to the pathophysiology of AD are still up for discussion, though. Evidence suggests that APOE affects the brain's clearance and deposition of Aβ. Additionally, APOE has Aβ-independent pathways in AD, which has led to the identification of new functions for APOE, including mitochondrial dysfunction. This study summarizes important studies that describe how APOE4 affects well-known AD pathologies, including tau pathology, Aβ, neuroinflammation, and dysfunction of neural networks. This study also envisions some of the therapeutic approaches being used to target APOE4 in the hopes of preventing or treating AD.

Human paraoxonase 1 (hPON1) is a Ca²⁺-dependent metalloenzyme with multifunctional properties. Due to its diverse activities (arylesterase, phosphotriesterase, and lactonase), it plays a significant role in disease conditions. Researchers across the globe have demonstrated different properties of PON1, like anti-oxidant, anti-inflammatory, anti-atherogenic, anti-diabetic, and OP-neutralization. Due to its pleotropic role in disease conditions like atherosclerosis, diabetes, cardiovascular diseases, neurodegenerative disorders, and OP-poisoning, it can be considered as a potential candidate for the development of therapeutic interventions. Attempts are being made in this direction to identify the exact role of PON1 in these disease conditions. Different approaches like directed evolution, genetic as well as chemical fusion, liposomal delivery of PON1, etc., are being developed and evaluated for their therapeutic effects in different pathological conditions. In this review, we outline the exact role and involvement of different properties of PON1 in the pathophysiology of different diseases and how it can be utilized and developed as a therapeutic intervention in PON1-associated disease conditions.

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.