Age-related obesity significantly increases the risk of chronic diseases such as type 2 diabetes, cardiovascular diseases, hypertension, and certain cancers. The insulin–leptin axis is crucial in understanding metabolic disturbances associated with age-related obesity. Rho GTPase Cdc42 is a member of the Rho family of GTPases that participates in many cellular processes including, but not limited to, regulation of actin cytoskeleton, vesicle trafficking, cell polarity, morphology, proliferation, motility, and migration. Cdc42 functions as an integral part of regulating insulin secretion and aging. Some novel roles for Cdc42 have also been recently identified in maintaining glucose metabolism, where Cdc42 is involved in controlling blood glucose levels in metabolically active tissues, including skeletal muscle, adipose tissue, pancreas, etc., which puts this protein in line with other critical regulators of glucose metabolism. Importantly, Cdc42 plays a vital role in cellular processes associated with the insulin and leptin signaling pathways, which are integral elements involved in obesity development if misregulated. Additionally, a change in Cdc42 activity may affect senescence, thus contributing to disorders associated with aging. This review explores the complex relationships among age-associated obesity, the insulin–leptin axis, and the Cdc42 signaling pathway. This article sheds light on the vast molecular web that supports metabolic dysregulation in aging people. In addition, it also discusses the potential therapeutic implications of the Cdc42 pathway to mitigate obesity since some new data suggest that inhibition of Cdc42 using antidiabetic drugs or antioxidants may promote weight loss in overweight or obese patients.

Background/Objectives: An inhibitor of small Rho GTPase Cdc42, CASIN, has been shown to reduce cancer cell proliferation, migration, and invasion, yet it has several limitations, including rapid drug elimination and low bioavailability, which prevents its systemic administration. In this study, we designed and characterized a nanoparticle-based delivery system for CASIN encapsulated within poly(lactide-co-glycolide)-block-poly(ethylene glycol)-carboxylic acid endcap nanoparticles (PLGA-PEG-COOH NPs) for targeted inhibition of Cdc42 activity in colon cancer. Methods: We applied DLS, TEM, and UV–vis spectroscopy methods to characterize the size, polydispersity index, zeta potential, encapsulation efficiency, loading capacity, and in vitro drug release of the synthesized nanoparticles. The CCK-8 cell viability test was used to study colorectal cancer cell growth in vitro. Results: We showed that CASIN-PLGA-PEG-COOH NPs were smooth, spherical, and had a particle size of 86 ± 1 nm, with an encapsulation efficiency of 66 ± 5% and a drug-loading capacity of 5 ± 1%. CASIN was gradually released from NPs, reaching its peak after 24 h, and could effectively inhibit the proliferation of HT-29 (IC50 = 19.55 µM), SW620 (IC50 = 9.33 µM), and HCT116 (IC50 = 10.45 µM) cells in concentrations ranging between 0.025–0.375 mg/mL. CASIN-PLGA-PEG-COOH NPs demonstrated low hemolytic activity with a hemolytic ratio of less than 1% for all tested concentrations. Conclusion: CASIN-PLGA-PEG-COOH NPs have high encapsulation efficiency, sustained drug release, good hemocompatibility, and antitumor activity in vitro. Our results suggest that PLGA-PEG-COOH nanoparticles loaded with CASIN show potential as a targeted treatment for colorectal cancer and could be recommended for further in vivo evaluation.

Introduction. Colorectal cancer remains one of the most lethal malignant tumours, and the deterioration in prognosis is largely due to the development of metastases. Cdc42, a small Rho GTPase, regulates the actin cytoskeleton, cellular polarity, and invasively metastatic phenotype, making it an attractive cancer therapy target. The low molecular weight Cdc42 inhibitor CASIN has antitumor activity, but its use is limited by unfavourable physico-chemical properties. We previously developed PLGA-PEG nanoparticles loaded with CASIN, demonstrating hemocompatibility and antiproliferative effect in vitro. Here, for the first time, we investigated their effect on migration and invasion of colorectal cancer cells. Objective. To evaluate the effect of PLGA-PEG nanoparticles loaded with the Cdc42 inhibitor CASIN on migration and invasion of human colorectal cancer cell lines in vitro. Methods. PLGA-PEG nanoparticles loaded with CASIN were prepared by single-stage nanoprecipitation. The HCT116, SW620, and HT 29 cell lines were studied. Migration was assessed by scratch assay (wound gap closure dynamics) and invasion by Transwell assay with matrigel-coated membranes. Cells were incubated with PLGA-PEG-CASIN at IC50 concentrations; untreated cells served as controls. Results. PLGA-PEG-CASIN at concentrations close to IC50 significantly suppressed migration and invasion in all three colorectal cancer lines. In scratch assay, nanoparticle treatment slowed down the closure of the wound defect: in HT 29, the gap area after 24 and 72 hours was 91% and 86% versus 85% and 60% in the control; in SW620, 88% and 82% versus 72% and 52%; in HCT116, 90% and 85% versus 81% and 64%, respectively. In the Transwell assay, invasive activity decreased approximately 3.6-fold in HT-29, 5.3-fold in SW620, and 4.3-fold in HCT116 compared with controls. Conclusions. PLGA-PEG nanoparticles loaded with the Cdc42 inhibitor CASIN effectively reduce migration and invasion of colorectal cancer cells in vitro, supporting their potential as a candidate for preclinical development of targeted therapy for metastatic colorectal cancer. Keywords: colorectal cancer, targeted therapy, Cdc42, PLGA-PEG nanoparticles.

Background. Aging represents a complex biological process characterized by the progressive accumulation of molecular and cellular alterations that ultimately lead to a decline in tissue functional capacity and the development of age-associated diseases. The concept of the hallmarks of aging provides a systematic framework for analyzing the mechanisms underlying biological aging. In recent years, accumulating evidence has highlighted the important role of the small GTPase Cdc42 in the regulation of aging-related processes at multiple levels of cellular organization. This review presents an analysis of current studies addressing the impact of Cdc42 on all three categories of aging hallmarks—primary, antagonistic, and integrative. The mechanisms through which Cdc42 contributes to genomic instability, epigenetic alterations, cellular senescence, oxidative stress, and impaired intercellular communication, including SASP-dependent processes, are discussed. Particular attention is given to the role of Cdc42 in the regulation of cytoskeletal dynamics, mitochondrial function, and the DNA damage response. The potential of pharmacological inhibition of Cdc42 is also considered as a promising approach for correcting age-associated cellular dysfunctions and developing geroprotective strategies. This review underscores the central role of Cdc42 in the biology of aging and provides a foundation for future studies aimed at slowing age-related physiological processes and promoting functional longevity. Keywords: Cdc42, aging, cellular senescence, hallmarks of aging, mesenchymal stem cells, genomic instability, oxidative stress, SASP, epigenetic alterations, geroprotection.

Tumor hypoxia is a hallmark of solid tumors that promotes aggressiveness and resistance to therapy. Within hypoxic tumors, hypoxia-inducible factor (HIF)-dependent transcriptional programs drive metabolic reprogramming, lactate accumulation, extracellular acidosis, angiogenesis, immune suppression, and invasive phenotypes. Translation of these adaptations into increased tumor cell motility and invasion requires coordinated remodeling of the cytoskeleton and cell polarity machinery. Cdc42, a Rho-family small GTPase regulating actin dynamics, cell polarity, and migration, may therefore link hypoxic signaling to invasive tumor behavior. Here, we review current evidence on the regulation and function of Cdc42 in hypoxic solid tumors and its therapeutic implications. Available studies indicate that hypoxia can induce rapid and potentially reversible Cdc42 activation in selected cancer models. In some experimental systems, interference with Cdc42-associated signaling attenuates hypoxia-induced HIF-1α and VEGF responses, suggesting a role in pro-angiogenic adaptation. However, effects of hypoxia on Cdc42 expression, localization, and activation vary by tumor type, oxygen concentration, exposure duration, and microenvironmental context. Cdc42 therefore remains an emerging rather than validated therapeutic target. Future studies should employ physiologically relevant in vivo models of chronic and cycling hypoxia, directly measure Cdc42-GTP, and more accurately distinguish tumor-cell-intrinsic effects from those occurring in stromal components of the tumor microenvironment.